Newborn Surgery

Newborn Surgery To Veena, Abir, Anita and Niki for their love and patience Newborn Surgery Second Edition Edited b...

Author: Prem Puri

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Newborn Surgery

To Veena, Abir, Anita and Niki for their love and patience

Newborn Surgery Second Edition

Edited by

Prem Puri MS FRCS FRCS (Ed) FACS Newman Clinical Research Professor, University College Dublin Consultant Paediatric Surgeon, Our Lady’s Hospital for Sick Children and National Children’s Hospital, Dublin, Ireland Director of Research, Children’s Research Centre, Our Lady’s Hospital for Sick Children, Dublin, Ireland

A member of the Hodder Headline Group LONDON

First published in Great Britain in 1996 by Butterworth-Heinemann Ltd This edition published in 2003 by Arnold, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Distributed in the United States of America by Oxford University Press Inc. 198 Madison Avenue, New York, NY 10016 Oxford is a registered trademark of Oxford University Press © 2003 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1T 4LP Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side effects recognized. For these reasons the reader is strongly urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 0 340 76144 X (hb) 2 3 4 5 6 7 8 9 10 Publisher: Joanna Koster Development Editor: Michael Lax Production Editor: James Rabson Production Controller: Bryan Eccleshall Cover Design: Stewart Larking Typeset in Great Britain by Phoenix Photosetting, Chatham, Kent Printed and bound in Great Britain by CPI Bath

Contents

Preface Contributors PART 1

xi xiii

GENERAL

1

1

Embryology of malformations Dietrich Kluth, Wolfgang Lambrecht and Christoph Bührer

3

2

Prenatal diagnosis of surgical diseases Tippi C. MacKenzie and N. Scott Adzick

15

3

Fetal and birth trauma Prem Puri

27

4

Transport of the surgical neonate Prem Puri and Diane De Caluwé

39

5

Preoperative assessment Prem Puri and Diane De Caluwé

45

6

Anesthesia Declan Warde

59

7

Postoperative management Desmond Bohn

71

8

Fluid and electrolyte balance in the newborn Winifred A. Gorman

89

9

Nutrition Agostino Pierro

103

10

Vascular access in the newborn Juda Z. Jona

121

11

Radiology in the newborn Noel S. Blake

131

12

Immune system of the newborn Denis J. Reen

139

13

Hematological problems in the neonate Owen P. Smith

147

14

Genetics in neonatal surgical practice Andrew Green

157

15

Ethical considerations in newborn surgery Jacqueline J. Glover and Donna A. Caniano

173

16

Minimally invasive neonatal surgery Ashley Vernon, Timothy Kane and Keith E. Georgeson

183

vi Contents 17

Fetal surgery Jyoji Yoshizawa, Lourenço Sbragia and Michael R. Harrison

189

PART 2

HEAD AND NECK

199

18

Choanal atresia in the newborn Francesco Cozzi and Denis A. Cozzi

201

19

Pierre Robin sequence Evelyn H. Dykes

207

20

Macroglossia George G. Youngson

215

21

Tracheostomy in infants Thom E. Lobe

219

22

Miscellaneous conditions of the neck and oral cavity Anies Mahomed

227

PART 3

CHEST

237

23

Congenital thoracic deformities Robert C. Shamberger

239

24

Mediastinal masses in the newborn Steven J. Shochat

247

25

Subglottic stenosis Felix Schier

253

26

Tracheomalacia I. Vinograd and R. M. Filler

259

27

Vascular rings Ehud Deviri and Morris J. Levy

267

28

Pulmonary air leaks Prem Puri

277

29

Chylothorax and other pleural effusions in neonates Richard G. Azizkhan

283

30

Congenital malformations of the lung Horace P. Lo and Keith T. Oldham

295

31

Congenital diaphragmatic hernia Tina Granholm, Craig T. Albanese and Michael R. Harrison

309

32

Extracorporeal membrane oxygenation for neonatal respiratory failure Eugene S. Kim and Charles J. H. Stolar

317

33

Bronchoscopy in the newborn John D. Russell

329

PART 4

ESOPHAGUS

335

34

Esophageal atresia and tracheo-esophageal ﬁstula Paul D. Losty and Colin T. Baillie

337

35

Congenital esophageal stenosis Shintaro Amae, Masaki Nio, Yutaka Hayashi and Ryoji Ohi

353

Contents vii 36

Esophageal duplication cysts Leela Kapila, H. W. Holliday

359

37

Esophageal perforation in the newborn Hirikati S. Nagaraj

365

38

Gastro-esophageal reﬂux Victor E. Boston

369

PART 5

GASTROINTESTINAL

381

39

Pyloric atresia and prepyloric antral diaphragm Vincenzo Jasonni

383

40

Hypertrophic pyloric stenosis Prem Puri and Ganapathy Lakshmanadass

389

41

Gastric volvulus Mark D. Stringer

399

42

Gastric perforation Robert K. Minkes

405

43

Gastrostomy Michael W. L. Gauderer

411

44

Duodenal obstruction Yechiel Sweed

423

45

Malrotation Lewis Spitz

435

46

Persistent hyperinsulinemic hypoglycemia of infancy Lewis Spitz

441

47

Jejuno-ileal atresia and stenosis Heinz Rode and A. J. W. Millar

445

48

Colonic and rectal atresias Tomas Wester

457

49

Meconium ileus Edward Kiely

465

50

Meconium peritonitis Jose Boix-Ochoa and J. Lloret

471

51

Duplications of the alimentary tract Prem Puri

479

52

Mesenteric and omental cysts Daniel L. Mollitt

489

53

Neonatal ascites Prem Puri

497

54

Necrotizing enterocolitis Ann M. Kosloske

501

55

Hirschsprung’s disease Prem Puri

513

56

Anorectal anomalies Alberto Peña

535

57

Congenital segmental dilatation of the intestine Hiroo Takehara and Hiroki Ishibashi

553

viii Contents 58

Intussusception Spencer W. Beasley

557

59

Inguinal hernia Juan A. Tovar

561

60

Short bowel syndrome and surgical techniques for the baby with short intestines Michael E. Höllwarth

569

PART 6

LIVER AND BILIARY TRACT

577

61

Biliary atresia Ken Kimura

579

62

Congenital biliary dilatation (choledochal cyst) Takeshi Miyano and Atsuyuki Yamataka

589

63

Hepatic cysts and abscesses David A. Partrick and Frederick M. Karrer

597

PART 7

ANTERIOR ABDOMINAL WALL DEFECTS

603

64

Omphalocele and gastroschisis Steven W. Bruch and Jacob C. Langer

605

65

Omphalomesenteric duct remnants David A. Lloyd

615

66

Bladder exstrophy: considerations and management of the newborn patient Fernando A. Ferrer and John P. Gearhart

619

67

Cloacal exstrophy Jonathan I. Groner and Moritz M. Ziegler

629

68

Prune belly syndrome Prem Puri and Hideshi Miyakita

637

69

Conjoined twins Harry Applebaum

643

PART 8

TUMORS

649

70

Epidemiology and genetic associations of neonatal tumors Sam W. Moore and Jack Plaschkes

651

71

Hemangiomas and vascular malformations Prem Puri and Laszlo Nemeth

663

72

Congenital nevi Bruce S. Bauer and Julia Corcoran

675

73

Lymphatic malformations (cystic hygroma) Jacob C. Langer and Vito Forte

687

74

Cervical teratomas Michael W. L. Gauderer

697

75

Sacrococcygeal teratoma Kevin C. Pringle

703

76

Nasal tumors Alfred Lamesch and Peter Lamesch

715

Contents ix 77

Neuroblastoma Raymond J. Fitzgerald

721

78

Soft-tissue sarcoma David A. Lloyd

733

79

Hepatic tumors Yoshiaki Tsuchida and Norio Suzuki

739

80

Congenital mesoblastic nephroma and Wilms’ tumor Robert Carachi

747

81

Neonatal ovarian tumors Jean Gaudin

751

PART 9

SPINA BIFIDA AND HYDROCHEPHALUS

759

82

Spina biﬁda and encephalocele Prem Puri and Rajendra Surana

761

83

Hydrocephalus Raymond J. Fitzgerald

775

PART 10 GENITOURINARY

785

84

Imaging of the renal tract in the neonate Isky Gordon

787

85

Management of antenatally detected hydronephrosis Jack S. Elder

793

86

Multicystic dysplastic kidney David F. M. Thomas and Azad S. Najmaldin

809

87

Upper urinary tract obstructions Prem Puri and Boris Chertin

817

88

Duplication anomalies Prem Puri and Hideshi Miyakita

831

89

Vesico-ureteric reﬂux Prem Puri

837

90

Ureteroceles in the newborn Peter Frey, Mario Mendoza-Sagaon and Blaise J. Meyrat

845

91

Congenital posterior urethral obstruction Reisuke Imaji, Daniel Moon and Paddy A. Dewan

855

92

Neuropathic bladder Paddy A. Dewan, Paul D. Anderson and Gunnar Aksnes

867

93

Hydrometrocolpos Devendra Gupta

875

94

Intersex Ronald J. Sharp

883

95

Male genital anomalies John M. Hutson

903

96

Neonatal testicular torsion David M. Burge

909

x Contents PART 11 LONG-TERM OUTCOMES IN NEWBORN SURGERY

913

97

Long-term outcomes in newborn surgery Mark D. Stringer

915

Index

925

Preface to the Second Edition

The 2nd edition of Newborn Surgery has been extensively revised. Many new chapters have been added to take account of the recent developments in the care of the newborn with congenital malformations. This edition which comprises 97 chapters by 121 contributors from all ﬁve continents of the world, provides an authoritative, comprehensive and complete account of the various surgical conditions in the newborn. Each chapter is written by the current leading expert(s) in their respective ﬁelds. Newborn Surgery in the 21st century demands of its practitioners detailed knowledge and understanding of the complexities of congenital anomalies as well as the highest standards of operative techniques. In this textbook great emphasis continues to be placed on providing a comprehensive description of operative techniques of each individual congenital condition in the newborn.

The book is intended for trainees in paediatric surgery, established paediatric surgeons, general surgeons with an interest in paediatric surgery as well as neonatologists and paediatricians seeking more detailed information on newborn surgical conditions. I wish to thank most sincerely all the contributors for the outstanding work they have done for the production of this innovative textbook. I also wish to express my gratitude to Mrs Karen Alfred and Ms Ann Brennan for their secretarial help and to the staff of Arnold for their help during the preparation and publication of this book. I am thankful to the Children’s Medical & Research Foundation, Our Lady’s Hospital for Sick Children, Dublin for their support. Prem Puri 2003

Preface to the First Edition

During the last three decades, newborn surgery has developed from an obscure subspeciality to an essential component of every major academic paediatric surgical department throughout both the developed and the developing world. Major advances in perinatal diagnosis, imaging, neonatal resuscitation, intensive care and operative techniques have radically altered the management of newborns with congenital malformations. Embryological studies have provided new valuable insights into the development of malformations, while improvements in prenatal diagnosis are having a signiﬁcant impact on approaches to management. Monitoring techniques for the sick neonate pre- and postoperatively have become more sophisticated and there is now greater emphasis on physiological aspects of the surgical newborn as well as their nutritional and immune status. This book provides a comprehensive compendium of all these aspects as a prelude to an extensive description of surgical conditions in the newborn. Modern-day newborn surgery demands detailed knowledge of the complexities of newborn problems. Research developments, laboratory diagnosis, imaging and innovative

surgical techniques are all part of the challenge facing surgeons dealing with congenital conditions in the newborn. In this book, a comprehensive description of operative techniques of each individual condition is presented. Each contributor was selected to provide an authoritative, comprehensive and complete account of their respective topics. The book, comprising 90 chapters, is intended primarily for trainees in paediatric surgery, established paediatric surgeons, general surgeons with an interest in paediatric surgery and neonatologists. I am most grateful to all contributors for their willingness to contribute chapters at considerable cost of time and effort. I am indebted to Mr Maurice De Cogan for artwork, Mr Dave Cullen for photography and Ms Ann Brennan and Ms Deirdre O’Driscoll for skilful secretarial help. I am thankful to the Children’s Research Centre, Our Lady’s Hospital for Sick Children, for their support. Finally, I wish to thank the editorial staff, particularly Ms Susan Devlin, of Butterworth-Heinemann for their help during the preparation and publication of this book. Prem Puri

Contributors

N. Scott Adzick MD Professor of Surgery Surgeon-in-Chief Department of Surgery The Center for Fetal Diagnosis and Treatment Children’s Hospital of Philadelphia Philadelphia, USA Gunnar Aksnes MD PhD Consultant Paediatric Surgeon Department of Paediatric Surgery Ulleval University Hospital Oslo, Norway Craig T. Albanese MD Professor of Surgery Chief, Division of Pediatric Surgery Stanford University Medical Center Palo Alto California, USA

Colin T. Baillie MBChB DCH ChM FRCS(Paeds) Consultant Paediatric Surgeon Royal Liverpool Children’s Hospital (Alder Hey) Liverpool, UK Bruce S. Bauer MD FACS FAAP Professor & Head Division of Pediatric Plastic Surgery Children’s Memorial Hospital Division of Plastic Surgery McGraw Medical School of Northwestern University Chicago Illinois, USA Spencer W. Beasley MBChB (Otago) MS (Melb) FRACS Professor of Paediatric Surgery Paediatric Surgeon and Urologist Department of Paediatric Surgery Christchurch Hospital Christchurch, New Zealand

Shintaro Amae MD Lecturer Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan

Noel S. Blake FRCR FFRRCSI Consultant Radiologist Our Lady’s Hospital for Sick Children Dublin, Ireland

Paul D. Anderson MBBS Urology Research Fellow Urology Unit Royal Children’s Hospital Melbourne, Australia

Desmond Bohn MB FRCPC MRCP(UK) FFARCS Associate Chief Department of Critical Care Medicine The Hospital for Sick Children Toronto, Canada

Harry Applebaum MD Head, Division of Pediatric Surgery Department of Surgery Kaiser Permanente Medical Center Los Angeles California, USA Richard G. Azizkhan MD Surgeon-in-Chief Lester Martin Chair of Pediatric Surgery Cincinnati Children’s Hospital Professor of Surgery and Pediatrics University of Cincinnati School of Medicine Cincinnati Ohio, USA

Jose Boix-Ochoa MD Chairman of Pediatric Surgery Professor of Pediatric Surgery Autonomous University of Barcelona Hospital Materno-Infantil Vall d’Hebron Barcelona, Spain Victor E. Boston MD FRCS(Ed) FRCSI FRCS (Eng) Consultant Paediatric Surgeon Royal Belfast Hospital for Sick Children Honorary Senior Lecturer Department of Surgery Queen’s University Belfast, UK

xiv Contributors LCDR Steven W. Bruch MC USNR Staff Pediatric Surgeon Naval Medical Center Portsmouth, USA Christoph Bührer MD Consultant Paediatrician Department of Neonatology Campus-Virchow-Klinikum Medical Faculty Charite Humboldt University Berlin, Germany

Ehud Deviri MD MSurg Consultant Cardiothoracic Surgeon Department of Cardiothoracic Surgery Hadassah University Hospital Hebrew University Jerusalem, Israel Paddy A. Dewan PhD MD MS MmedSc FRCS FRACS Paediatric Urologist Royal Children’s Hospital Melbourne, Australia

David Burge FRCS FRCPCH Consultant Paediatric Surgeon Wessex Regional Centre for Paediatric Surgery Southampton, UK

Evelyn H. Dykes MBChB FRCS (Paeds) Senior Lecturer in Paediatric Surgery Kings College London, UK

Diane De Caluwé MD Consultant Paediatric Surgeon Department of Paediatric Surgery Chelsea and Westminster Hospital London, UK

Jack S. Elder MD Director Division of Pediatric Urology Rainbow Babies & Children’s Hospital Professor of Urology & Pediatrics Case Western Reserve University School of Medicine Cleveland Ohio, USA

Donna A. Caniano MD Surgeon-in-Chief Department of Pediatric Surgery Children’s Hospital Ohio, USA Robert Carachi MD FRCS Head of Department Department of Surgical Paediatrics Royal Hospital for Sick Children Glasgow, UK Boris Chertin MD Consultant Pediatric Urologist Department of Urology Shane Zedek Medical Center Jerusalem, Israel Julia Corcoran MD FACS FAAP Attending Surgeon Division of Pediatric Plastic Surgery Children’s Memorial Hospital Division of Plastic Surgery McGraw Medical School of Northwestern University Chicago Illinois, USA

Fernando A. Ferrer MD Assistant Professor of Pediatric Urology Connecticut Childrens’ Hospital Hartford Connecticut, USA R. M. Filler MD FRCS(C) Professor and Surgeon-in-Chief Hospital of Sick Children Professor of Pediatrics University of Toronto Ontario, Canada Raymond J. Fitzgerald MA MB FRCSI FRCS FRACS (Paed Surg) FRCS (Ed) Ad. hom

Associate Professor in Paediatric Surgery Trinity College Consultant Paediatric Surgeon Children’s Hospital and Our Lady’s Hospital for Sick Children Dublin, Ireland

Denis A. Cozzi MD Consultant Pediatric Surgeon Department of Pediatric Surgery University of Rome Rome, Italy

Vito Forte MD FRCSC Paediatric Otolaryngologist Hospital for Sick Children Associate Professor of Otolaryngology University of Toronto Toronto, Canada

Francesco Cozzi MD Associate Professor and Head of Pediatric Surgery Department of Pediatric Surgery University of Rome Rome, Italy

Peter Frey MD BSc PD FMH Consultant Pediatric Surgeon Department of Pediatric Surgery Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland

Contributors xv Michael W. L. Gauderer MD FACS, FAAP Professor of Surgery University of South Carolina School of Medicine Chief, Department of Pediatric Surgery Children’s Hospital Greenville Hospital System Greenville South Carolina, USA Jean Gaudin MD Paediatric Surgeon Department of Paediatric Surgery Hôpital St Louis La Rochelle, France John P. Gearhart MD Professor & Director Division of Pediatric Urology James Buchanan Brady Urological Institute Johns Hopkins Hospital Baltimore Maryland, USA Keith E. Georgeson MD Professor and Director Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA Jacqueline J. Glover PhD Associate Professor Center for Health Ethics and Law West Virginia University College of Medicine and Children’s Hospital Morgantown West Virginia, USA

Andrew Green MB, PhD, FRCPI, FFPath(RCPI) Director National Centre for Medical Genetics Our Lady’s Hospital for Sick Children Dublin, Ireland Jonathan I. Groner MD Assistant Professor Department of Surgery Children’s Hospital Columbus Ohio State University Columbus Ohio, USA Devendra Gupta MS MCH Professor of Paediatric Surgery All India Institute of Medical Sciences New Delhi, India Michael R. Harrison MD Professor of Surgery Pediatrics and Obstetrics Gynecology and Reproductive Sciences Director, Fetal Treatment Center Chief, Division of Pediatric Surgery University of California` San Francisco California, USA Yutaka Hayashi MD Professor Division of Pediatric Oncology Tohoku University School of Medicine Sendai, Japan Howard W. Holliday FRCS Consultant Paediatric Surgeon Derbyshire Children’s Hospital Derbyshire, UK

Isky Gordon FRCR Consultant Radiologist Great Ormond Street Hospital for Children Honorary Senior Lecturer Institute for Child Health London, UK

Michael E. Höllwarth MD Professor & Head Department of Paediatric Surgery University of Graz Medical School Graz, Austria

Winifred A. Gorman BSc FRCPI FAAP Consultant Paediatrician Department of Neonatology National Maternity Hospital Dublin, Ireland

John M. Hutson BS MD(Monash), MD(Melb) FRACS Professor & Director Russell Howard Department of General Surgery Royal Children’s Hospital F Douglas Stephens Surgical Research Laboratory Murdoch Children’s Research Institute Melbourne, Australia

Tina Granholm MD PhD Associate Professor Department of Pediatric Surgery Astrid Lindgren Children’s Hospital Director of Postgraduate Studies Department of Woman and Child Health Karolinska Hospital Karolinska Institute Stockholm, Sweden

Reisuke Imaji MD PhD Clinical Research Fellow Urology Unit Royal Children’s Hospital Department of Paediatrics University of Melbourne Murdoch Children’s Research Institute Melbourne, Australia

xvi Contributors Hiroki Ishibashi MD Pediatric Surgeon Department of Digestive and Pediatric Surgery University of Tokushima Tokushima, Japan Vincenzo Jasonni MD Professor and Director School of Pediatric Surgery Istituto Scientiﬁco ‘G Gaslini’ University of Genoa Genoa, Italy Juda Z. Jona MD FACS FAAP(S) Chief Division of Pediatric Surgery Evanston Northwestern Healthcare Evanston Illinois, USA Timothy Kane MD Chief Clinical Fellow Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA Leela Kapila OBE FRCS Consultant Paediatric Surgeon Department of Paediatric Surgery Queen’s Medical Centre Nottingham, UK Frederick M. Karrer MD Associate Professor of Surgery & Pediatrics & Head Division of Pediatric Surgery University of Colorado Health Sciences Center Surgical Director Pediatric Liver Transplantation Department of Pediatric Surgery The Children’s Hospital Denver Colorado, USA Edward Kiely FRCSI FRCS FRCPCH Consultant Paediatric Surgeon Hospital for Sick Children Great Ormond Street London, UK Eugene S. Kim MD Chief Resident Division of Pediatric Surgery College of Physicians and Surgeons Columbia University Children’s Hospital of New York New York Presbyterian Hospital New York, USA

Ken Kimura MD Professor of Surgery and Pediatrics Department of Surgery University of Iowa Hospitals & Clinics Iowa City Iowa, USA Dietrich Kluth MD PhD Paediatric Surgeon Department of Paediatric Surgery University Hospital Hamburg Hamburg, Germany Ann M. Kosloske MD MPH Professor of Surgery and Pediatrics Texas Technical University Health Science Center Lubbock Texas, USA Ganapathy Lakshmanadass MS MChFRCS Senior Registrar in Paediatric Surgery Department of Paediatric Surgery National Children’s Hospital Dublin, Ireland Wolfgang Lambrecht MD Surgeon-in-Chief Department of Paediatric Surgery Eppendorf University Hospital Hamburg, Germany Alfred Lamesch MD FACS Emeritus Professor Université Libre de Bruxelles Surgeon-in-Chief Emeritus Department of Paediatric Surgery Luxembourg Hospital Center Honorary Member of the Académie Royale de Médecine Belgium Peter Lamesch MD FACS Professor of Surgery Department of Abdominal, Transplant & Vascular Surgery University of Leipzig Leipzig, Germany Jacob C. Langer MD FRCSC Chief, Paediatric General Surgery Hospital for Sick Children Toronto, Canada Morris J. Levy MD Professor of Surgery Department of Thoracic and Cardiovascular Surgery Sackler School of Medicine Tel Aviv University Tel Aviv, Israel David A. Lloyd MChir FRCS FCS(SA) Professor of Paediatric Surgery Institute of Child Health Royal Liverpool Children’s Hospital (Alder Hey) Liverpool, UK

Contributors xvii J. Lloret MD Pediatric Surgeon Neonatal and Oncological Unit Hospital Materno-Infantil Vall d’Hebron Barcelona, Spain Horace P. Lo MD Senior Resident Department of Surgery Medical College of Wisconsin Milwaukee Wisconsin, USA Thom E. Lobe MD Chairman, Section of Pediatric Surgery University of Tennessee Memphis Tennessee, USA Paul D. Losty MD FRCSI FRCS(Eng) FRCS(Ed) FRCS(Paed) Reader & Honorary Consultant Paediatric Surgeon Department of Paediatric Surgery Royal Liverpool Children’s Hospital (Alder Hey) and The University of Liverpool Liverpool, UK Tippi C. MacKenzie MD Fetal Surgery Research Fellow The Center for Fetal Diagnosis and Treatment Children’s Hospital of Philadelphia Philadelphia, USA Anies Mahomed MBBCH FCS(SA) FRCS(Glas.Ed) FRCS(Paeds) Consultant Paediatric Surgeon Department of Paediatric Surgery Royal Aberdeen Children’s Hospital Aberdeen, UK Mario Mendoza-Sagaon MD Senior Registrar Department of Pediatric Surgery CHUV Lausanne, Switzerland Blaise J. Meyrat MD Consultant Paediatric Urologist and Surgeon Department of Pediatric Surgery CHUV Lausanne, Switzerland A. J. W. Millar FRCS (Eng) (Edin) FRACS DCH Associate Professor Department of Paediatric Surgery University of Cape Town Senior Surgeon Red Cross War Memorial Children’s Hospital Cape Town, South Africa

Robert K. Minkes MD PhD Associate Professor of Surgery Chief, Section of Pediatric Surgery Louisiana State University Heath Sciences Center Children’s Hospital of New Orleans Louisiana, USA Hideshi Miyakita MD Consultant Paediatric Urologist Tokai University School of Medicine Kanagawa, Japan Takeshi Miyano MD, PhD, FAAP(Hon), FACS, FAPSA(Hon) Director of Juntendo University Hospital Professor and Head Department of Pediatric Surgery Juntendo University Scholl of Medicine Tokyo, Japan Daniel L. Mollitt MD Professor and Chief Division of Pediatric Surgery University of Florida Health Scince Center Jacksonville Florida, USA Daniel Moon MB, BS Urology Research Fellow Kids Urology Research Unit Royal Children’s Hospital Melbourne, Australia Sam W. Moore MBChB FRCS MD Professor & Head Department of Paediatric Surgery Faculty of Medicine University of Stellenbosch Tygerberg, South Africa Hirikati S. Nagaraj MD Associate Professor of Surgery Kosair Children’s Hospital University of Louisville Chief, General and Thoracic Surgery Kentucky, USA Azad S. Najmaldin MB ChB MS FRCSEd FRCS Consultant Paediatric Surgeon & Urologist St James’s University Hospital Leeds, UK Laszlo Nemeth MD Consultant Paediatric Surgeon University of Szeged Szeged, Hungary Masaki Nio MD Associate Professor of Pediatric Surgery Senior Lecturer Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan

xviii Contributors Ryoji Ohi MD Professor and Chief Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan Keith T. Oldham MD Professor and Chief Division of Pediatric Surgery Vice Chairman Department of Surgery Medical College of Wisconsin Milwaukee Wisconsin, USA David A. Partrick MD Assistant Professor in Surgery and Pediatrics University of Colorado Health Sciences Center Director of Surgical Endoscopy The Children’s Hospital Denver Colorado, USA Alberto Peña MD FACS FAAP Professor & Chief Division of Pediatric Surgery Albert Einstein College of Medicine Schneider Children’s Hospital New Hyde Park New York, USA Agostino Pierro MD FRCS FAAP Professor of Paediatric Surgery Institute of Child Health and Great Ormond Street Hospital London, UK Jack Plaschkes MD FRCS Department of Paediatric Surgery Faculty of Medicine University of Stellenbosch Tygerberg, South Africa Kevin C. Pringle MB ChB FRACS Professor of Paediatric Surgery & Head Department of Obstetrics & Gynaecology Wellington School of Medicine and Health Sciences University of Otago Wellington, New Zealand Prem Puri MS FRCS FRCS(Ed) FACS Newman Clinical Research Professor University College, Dublin Consultant Paediatric Surgeon, Our Lady’s Hospital for Sick Children and National Children’s Hospital, Dublin Director of Research, Children’s Research Centre, Dublin, Ireland

Denis Reen MSc PhD Adjunct Professor in Medicine, University College, Dublin Professor, The Children’s Research Centre Our Lady’s Hospital for Sick Children Dublin, Ireland Heinz Rode Mmed(Chir) FCS(SA) FRCSEd Charles F M Saint Professor of Paediatric Surgery Department of Paediatric Surgery Red Cross Children’s Hospital Rondebosch, South Africa John D. Russell FRCSI, FRCS(ORL) Consultant Paediatric Otolaryngologist Our Lady’s Hospital for Sick Children Dublin, Ireland Lourenço Sbragia MD PhD Postdoctoral Research Scholar Fetal Treatment Center Division of Pediatric Surgery University of California San Francisco, USA Robert C. Shamberger MD Professor of Surgery Harvard Medical School Chief of Surgery (Interim) Department of Paediatric Surgery Childrens Hospital Boston Massachusetts, USA Ronald J. Sharp MD Director of Surgery Children’s Mercy Hospital Kansas City Missouri, USA Felix Schier MD Head of Department Department of Paediatric Surgery University Medical Centre Jena, Germany Steven J. Shochat MD Surgeon-in-Chief & Chairman Department of Surgery St Jude Children’s Research Hospital Memphis Tennessee, USA Owen P. Smith MA MB BA Mod (Biochem), FRCPCH FRCPI, FRCPLon, FRCPEdin, FRCPGlasg, FRCPath

Consultant Paediatric Haematologist Our Lady’s Hospital for Sick Children, and St James’s Hospital, Dublin Senior Lecturer in Haematology, Trinity College Dublin, Ireland

Contributors xix Lewis Spitz MB ChB PhD MD(Hon), FRCS(Edin), FRCS(Eng), FAAP(Hon), FRCPCH

Nufﬁeld Professor of Paediatric Surgery Institute of Child Health University College London and Great Ormond Street Hospital London, UK Charles J. H. Stolar MD Professor of Surgery and Pediatrics Division of Pediatric Surgery College of Physicians and Surgeons Columbia University Director of Pediatric Surgery Children’s Hospital of New York New York Presbyterian Hospital New York, USA

Juan A. Tovar MD Professor of Surgery Department of Surgery Hospital Infantil ‘La Paz’ Madrid, Spain Yoshiaki Tsuchida MD PhD FACS Director Department of Surgery Gunma Children’s Medical Center Gunma, Japan Ashley Vernon MD Research Fellow Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA

Mark D. Stringer BSc MS FRCS FRCS(Paed) FRCP FRCPCH Consultant Paediatric Surgeon Children’s Liver & GI Unit St James’s University Hospital Leeds, UK

I. Vinograd MD Head Department of Pediatric Surgery DANA Children’s Hospital Tel-Aviv, Israel

Rajendra Surana MS FRCS(Paed) Consultant Paediatric Surgeon Welsh Centre for Paediatric Surgery University Hospital of Wales Cardiff, UK

Declan Warde MB BCH FFARCSI Consultant Anaesthetist Department of Anesthesia The Children’s Hospital Dublin, Ireland

Norio Suzuki MD Chief of Surgery Department of Surgery Gunma Children’s Medical Center Gunma, Japan Yechiel Sweed MD Senior Lecturer in Surgery Rappaport School of Medicine The Technion Haifa Head Pediatric Surgery Western Galilee Hospital Nahariya, Israel Hiroo Takehara MD Associate Professor and Chief of Pediatric Surgeons Department of Digestive and Pediatric Surgery University of Tokushima Tokushima, Japan David F.M. Thomas FRCP FRCS Consultant Paediatric Urologist Reader in Paediatric Surgery Leeds Teaching Hospitals University of Leeds Leeds, UK

Tomas Wester MD PhD Consultant Paediatric Surgeon Department of Paediatric Surgery University Children’s Hospital Uppsala, Sweden Atsuyuki Yamataka MD Associate Professor of Pediatric Surgery Department of Pediatric Surgery Juntendo University School of Medicine Tokyo, Japan Jyoji Yoshizawa MD PhD Assistant Professor of Surgery Fetal Treatment Center University of California San Francisco, USA George G. Youngson PhD FRCS Honorary Professor of Paediatric Surgery Department of Paediatric Surgery Royal Aberdeen Children’s Hospital Aberdeen, UK Moritz M. Ziegler MD Robert E Gross Professor of Surgery Harvard Medical School Surgeon-in-Chief Children’s Hospital Boston Maryland, USA

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1 General

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1 Embryology of malformations DIETRICH KLUTH, WOLFGANG LAMBRECHT AND CHRISTOPH BÜHRER

INTRODUCTION

DEFINITION OF THE TERM ‘MALFORMATION’

Approximately 3% of human newborns present with congenital malformations.1 Without surgical intervention, one-third of these infants would die since their malformations are not compatible with sustained life outside the uterus.1,2 In ﬁgures, this means that in a country such as Germany, nearly 6000 children are born every year with a life-threatening malformation. Due to the development of prenatal diagnostic procedures, advanced surgical techniques, and intensive postoperative care, most infants with otherwise fatal malformations can be rescued by an operation in the neonatal period. However, morbidity remains high in some of these children2 with the necessity of repeated operations and hospitalizations despite a successful primary operation. This may also be the fate of many children with non-life-threatening malformations such as hypospadias or cleft palate. Mortality is still high in newborns with certain malformations such as congenital diaphragmatic hernias or severe combined defects. As a consequence, congenital malformations today are the main cause of death in the neonatal period. In the USA, 21% of neonatal mortality can be related to congenital malformations.3 These ﬁgures probably do not reﬂect a real increase of the actual incidence of congenital malformation. The observed mortality shift might rather be due to improved intensive care medicine in today’s western world countries where neonates (even those with birth defects) have a better chance of survival. On the other hand, this statistical shift indicates that knowledge about congenital malformations lags behind the progress clinical research has made in the surrounding ﬁelds. Efforts are needed to close the gap and learn more about baby killer No. 1. Identiﬁcation of teratogens will help to reduce the incidence of malformations when exposure can be avoided, and pathogenetic studies might aid in designing therapeutic measures. Both treatment and prevention critically depend on basic embryological research.

After birth neonates can present with a broad spectrum of deviations from normal morphology. This extends from minor variations of normal morphology without any clinical signiﬁcance to maximal organ defects with extreme functional deﬁcits of the malformed organs or of the whole organism. The degree of functional disorder is decisive when dealing with the question of whether a variation of normal morphology has to be viewed as a dangerous malformation requiring surgical correction. This means that functional disturbance is essential when using the term ‘malformation’. Inborn deviations can be detrimental, neutral, or even beneﬁcial, otherwise evolutionary progress could not take place. An example of a beneﬁcial deviation is the longevity syndrome of people with abnormally low serum cholesterol levels. Abnormalities with little or no functional disturbance might still require surgical correction when patients are in danger of social stigmatization. Coronal or glandular hypospadias might serve as an example for this condition.

ETIOLOGY OF CONGENITAL MALFORMATIONS In most cases, the etiology of congenital malformations remains unclear. Possible etiological factors are listed in Table 1.1. In about 20% of cases genetic factors (gene mutation and chromosomal disorders) can be identiﬁed.1,2,4 In 10% an environmental origin can be demonstrated.1,2 In 70% the factors responsible remain obscure. Table 1.1 Etiology of congenital malformations Genetic disorders Environmental factors Unknown etiology

20% 10% 70%

4 Embryology of malformations

Environmental factors A large number of agents are known which might interfere with the normal development of organ systems during embryogenesis.1,4 The underlying mechanisms of this interference is poorly understood in most cases. Characteristically, during organogenesis, different organs of the embryo show distinct periods of greatest sensitivity to the action of the teratogen. These phases of greatest sensitivity are called the ‘teratogenetic period of determination’.5 The typical patterns of some syndromes can be explained by an overlap of these phases during embryological development. In 1983, Shepard2 published a catalog of suspected teratogenic agents. Over 900 agents are known to produce congenital anomalies in experimental animals. In 30 evidence for teratogenic action in humans could be demonstrated. Teratogenic agents can be divided into four groups (Table 1.2). The teratogenic potential of virus infections,1 especially rubella and herpes, and that of radiation1 has been clearly established. Maternal metabolic defects and lack of essential nutritives can be teratogenic. After a vitamin A-free diet6 and riboﬂavin-free diet7 various congenital malformations were observed in rats and mice. Among these were diaphragmatic hernias, isolated esophageal atresias, and isolated tracheo-esophageal ﬁstulas. Similarly, inappropriate administration of hormones can be associated with intrauterine dysplasias.8 Industrial and pharmaceutical chemicals such as tetrachlor-diphenyl-dioxin (TCDD) or thalidomide have inﬂicted tragedies by their teratogenic action. When thalidomide was prescribed to women in the early 1960s as a ‘safe’ sleeping medication, numerous children were born with dysmelic deformities.4,9,10 In addition, atresias of the esophagus, the duodenum, and the anus were observed in some children.9 The data collected suggest that teratogenic agents do not cause new patterns of malformations but rather mimic sporadic birth defects. This had posed problems in identifying thalidomide as the responsible agent. It appears likely that among those 70% congenital malformations with unclear etiology a considerable percentage might be precipitated by as yet unidentiﬁed environmental factors. In a rat model, the herbicide nitrofen (2.4-dichloro-phenyl-p-nitrophenyl Table 1.2 Teratogenic agents in congenital malformations Physical agents

Radiation, heat, mechanical factors

Infectious agents

Viruses, treponemes, parasites

Chemical, drug, environmental agents

Thalidomide, nitrofen, hormones, vitamin deﬁciencies

Maternal, genetic factors

Chromosomal disorders, multifactorial inheritance

After Nadler.1

ether) has been shown to induce congenital diaphragmatic hernias, cardiac abnormalities and hydronephrosis.11–15 In 1978, Thompson et al. described the teratogenicity of the anti-cancer drug adriamycin in rats and rabbits.16 More recently, Diez-Pardo et al.17 redescribed this model with emphasis to its potentials as a model for foregut anomalies. Today, the adriamycin model is generally described as a model for the VACTERL-association (V=vertebral, A=anorectal, C=cardiac, T=tracheal, E=esophageal, R=renal, L=limb).18,19 Thus, classic malformations such as atresias of the esophagus and the intestinal tract, intestinal duplications and others can be mimicked by teratogens in animal models.

Genetic factors Approximately 20% of congenital malformations are of genetic origin. Most surgically correctable malformations are associated with chromosomal disorders, e.g. trisomy 21,13, or 18, or are of multifactorial inheritance20 with a small risk of recurrence. The assumption of multifactorial inheritance results from the fact that with nearly all major anomalies familiar occurrences had been observed.1 In animals inheritance has also been found for some malformations.21–24

EMBRYOLOGY OF MALFORMATIONS Disturbances of normal embryological processes will result in malformations of organs. This was ﬁrst shown by Spemann25 in 1901 by experimentally producing supernumary organs in the triton embryo after establishing close contact between excised parts of triton eggs and other parts of the same egg. Spemann and Mangold5 coined the term ‘induction’ to describe this observation. They found that certain parts of the embryo obviously were able to control embryonic development of other parts. These controlling parts were called ‘organizers’.5 The process of inﬂuence itself was called ‘induction’. It was believed by many scientists in the ﬁeld that ‘induction’ could serve as the overall principle of hierarchical control of embryonic development. Ensuing investigations, however, made modiﬁcations necessary, which ﬁnally resulted in a very complex model of organizers and inductors. The nature of inductive substances remained obscure and attempts to isolate inductive substances, meanwhile called ‘morphogenes’, were unsuccessful.26 Interestingly, not only live cells could induce development in certain experiments but also dead and denaturated material.5 A process essential for the formation of early embryonic organs is the invagination of epithelial sheets. This invagination is preceded by a thickening of the

Embryology of malformations 5

epithelial sheet,27 a process known as placode formation. The thickening itself is caused by elongation of individual cells of the placode. This process can be studied in detail in epithelial morphogenesis.28 The same sequence of developmental events has been observed in the formation of the neural plate, in the formation of the otic and lens placode and in the development of most epitheliomesenchymal organs including lung, thyroid gland and pancreas. From these observations it can be concluded that most epithelial cells behave uniformly in the early phase of embryonic development. Today it is generally accepted, that early embryonic organs are especially sensitive for alterations. Therefore researchers are more and more interested to understand the formation of early embryonic organs. In 1985 ETTERSOHN.29 stated that most invaginations are the results of mechanical forces that are local in origin. He focussed on three possible mechanisms which might lead to placode formation and subsequent invagination: 1 Change of cell shape by cell adhesion 2 Microﬁlament-mediated change of cell shape 3 Cell growth and division. In the following part, we will discuss some aspects of these mechanisms. A teratological method used to determine the function of cell adhesion molecules in vivo during embryogenesis has been reported recently.30 Mouse hybridoma cells producing monoclonal antibodies against the avian integrin complex were grafted into 2- or 3-day-old chick embryos. Depending on the site of engraftment, local muscle agenesis was observed. This is an example that the immunologic immaturity of the embryo can be exploited to study the contribution of cell attachment molecules to organ development in a functional fashion. A number of monoclonal antibodies directed against cell attachment molecules of various species have become available over the last 8 years, and the structure of the binding molecules has been elucidated biochemically and by cDNA cloning. Functionally, adhesion molecules may be grouped into three families: Cell adhesion molecules (CAMs), which mediate speciﬁc and mostly transient cell recognition of other cells, substrate adhesion molecules (SAMs), necessary for attachment to extracellular matrix proteins, and cell-junctional molecules (CJMs), found in tight and gap junctions. Whereas CJMs apparently play an important role for metabolic signalling within established tissues, CAMs and SAMs are necessary for the formation of histologically distinct structures and directed migration of single cells. Among CAMs and SAMs, at least three families have been identiﬁed biochemically: integrins,31 members of the immunoglobulin superfamiliy, and LEC-CAMS.32 Integrins are heterodimeric molecules consisting of a larger β chain, which is associated with a smaller α chain in a calcium-dependent way. Usually, one given β chain might be found in

association with various chains but promiscuity of α chains has been described recently. Functionally, members of the integrin family present as SAMs (adhesion to vitronectin, collagen, ﬁbronectin, complement components, or other intercellular matrix proteins) or CAMs (direct adhesion to other cells via corresponding cell surface target molecules). For example, cells bearing the integrin LFA-1 on their cell surface bind to cells expressing ICAM-1 or ICAM-2, both of which are members of the immunoglobulin superfamily.33,34 Other members of the immunoglobulin superfamily which are known to be important during morphogenesis include L-CAM35 (liver cell adhesion molecule) and N-CAM36,37 (neural cell adhesion molecule). Both show homophilic aggregation, that is, N-CAM serves as a target structure for N-CAM, and L-CAM serves as a target structure for L-CAM, but there is no cross-reactivity. In developing feather placodes in avian embryos, L-CAM and N-CAM are mutually exclusive expressed on epidermal or mesodermal cells, respectively. When the placodes are incubated with antibodies to L-CAM, primarily only epidermal cell-to-cell contact is disturbed.38 However, the structure of the surrounding mesoderm is altered subsequently, suggesting an inductive signal loop between epidermal and mesodermal cells. A third group of adhesion molecules has been termed LEC-CAMs to indicate that their extracellular part consists of a lectin domain, an epidermal growth factor-like domain, and a complement regulatory protein repeat domain. The lectin domain is presumed to contain the active center; binding mediated by the murine homolog to the leukocyte adhesion molecule 1 (LAM-1)39 can be blocked by mannose-6-phosphate or its polymers.40 Lectindependent organ formation should be accessible experimentally by administration of the respective carbohydrates but few if any data have been reported so far. Cell shape is mainly maintained by microtubules forming the cellular cytoskeleton. In addition, contractile elements exist such as actin, which are essential for cell movement, the so-called microﬁlaments. These structures are thought to be essential for the process of placode formation and invagination.41 Microﬁlamentmediated change of cell shape is based on the idea that actin ﬁlaments could alter the shape of cells by contraction. Most of these ﬁlaments are found at the apex of epithelial cells. Contraction of these ﬁlaments in each individual cell of a cell layer would result in an increasing infolding of the whole cell layer,41,42 ﬁnally resulting in invagination. It is a disadvantage of this model, however, that there is no apparent reason why apical constriction should be proceeded by cell elongation.29 Cell proliferation is probably an essential factor in the morphogenesis of epithelio-mesenchymal organs.22 During morphogenesis of these organs repeated invagination can be observed, which might be dependent upon cell proliferation.43 The way in which epithelial cell growth and proliferation is controlled in the embryo is

6 Embryology of malformations

not clear. However, it is believed that the surrounding mesenchyme might regulate the timing and location of invagination of the epithelial layer. Goldin and Opperman44 proposed that epidermal growth factor (EGF) might be excreted by mesenchymal cells, which would stimulate epithelial cell proliferation and repeated invagination. When agarose pellets impregnated with EGF were cultured alongside 5-day embryonic chick tracheal epithelium, supernumerary buds were induced to form at those sites. EGF and the related peptide transforming growth factor-α (TGFα) have been shown to lead to precocious eyelid opening when injected into newborn mice.45 Thus, complex changes of late-stage organ development can be induced by physiological stimuli in the laboratory. Interestingly, EGF is a mitogen for many epithelial cells in vitro without affecting most mesenchymal cells. A large variety of cells have been demonstrated to display the receptor for EGF/TGF α on their cell surface, which is encoded by the cellular protooncogene c-erbB. Structural alterations of this receptor are known to result in uncontrolled proliferation and ultimately malignant transformation. When secreted locally, EGF might provide physically associated cells with appropriate on- and off-signals required for the formation of complex organs. Other polypeptides, such as platelet-derived growth factor (PDGF) or transforming growth factor-β (TGFβ) appear to function in an antagonistic way in that they stimulate rather the proliferation of mesenchymal cells.46,47 In deﬁned experimental situations, TGFβ has been shown to be a mitogen for osteoblasts while being a potent inhibitor of the proliferation of epithelial and endothelial cells at the same time. Embryonic ﬁbroblasts, however, are also inhibited by TGFβ.48 TGFβ is a powerful chemotactic agent for ﬁbroblasts and enhances the production of both collagen and ﬁbronectin by these cells. There is, however, little data available concerning the involvement of these factors during normal and pathologic development of the embryo. Future investigations using such powerful approaches as in situ hybridization with cloned genes, preparation of transgenic animals, and direct administration of the recombinant proteins to various parts of the embryo might shed some light on signalling pathways mediated by soluble cytokines. The surrounding mesenchyme might limit the epithelial bud to expand49 forcing the epithelial sheet to fold in characteristic patterns. If a growing cell layer is restricted from lateral expansion, ‘mitotic pressure’ by dividing cells will result in elongation of cells and then invagination of the ‘crowded’ cell sheet. This does not necessarily imply that cells divide more rapidly in the region of invagination than in the surrounding areas. The main effect is caused by restriction of lateral expansion.50,51 In the early anlage of the thymus, cell proliferation counts are actually lower in the thymus anlage than in the surrounding epithelium.52 Steding50 and Jacob51 have shown experimentally that restriction

of lateral expansion might be responsible for thickening and subsequent invagination of epithelial sheets. In their experiments, restriction of lateral expansion was caused by a tiny silver ring placed on the epithelium of chick embryos.

EXAMPLES OF PATHOLOGICAL EMBRYOLOGY The focus of our research has been the embryology of foregut, anorectal and diaphragmatic malformations. We studied the normal development of all embryonic organs involved by scanning electron microscopy (SEM).53–59 In addition, we employed two rodent animal models to study malformations of the anorectum and the diaphragm. Pathogenetic concepts concerning these malformations were controversial in the past due to lack of detailed data.

EMBRYOLOGY OF FOREGUT MALFORMATIONS The differentiation of the primitive foregut into the ventral trachea and dorsal esophagus is thought to be the result of a process of septation.60 It is guessed that lateral ridges appear in the lateral walls of the foregut, which fuse in midline in a caudo-cranial direction thus forming the tracheo-esophageal septum. This theory of septation has been described in detail by Rosenthal and Smith.61–62 However, others63–64 were not able to verify the importance of the tracheo-esophageal septum for the differentiation of the foregut. They instead proposed individually that the respiratory tract develops simply by further growth of the lung bud in a caudal direction. Using scanning electron microscopy (SEM), we studied the development of the foregut in chick embryos.53,54 In this study, we were unable to demonstrate the formation of a tracheo-esophageal septum (Fig. 1.1). A sequence of SEM photographs of staged chick embryos suggests that differentiation of the primitive foregut is best explained by a process of ‘reduction of size’ of a foregut region called ‘tracheo-esophageal space’ (Fig. 1.2). This reduction is caused by a system of folds that develops in the primitive foregut. They approach each other but do not fuse (Fig. 1.2). Based on these observations, the development of the malformation can be explained by disorders either of the formation of the folds or of their developmental movements: 1 Atresia of the esophagus with ﬁstula (Fig. 1.3a): • The dorsal fold of the foregut bends too far ventrally. As a result the descent of the larynx is blocked. Therefore the tracheo-esophageal space remains partly undivided and lies in a ventral position. Due to this ventral position it differentiates into trachea.

Development of the diaphragm 7

Figure 1.3 Sketch of formal pathogenesis of typical foregut malformations (see text for details): (a) atresia of esophagus with ﬁstula; (b) atresia of trachea with ﬁstula; (c) laryngotracheo-esophageal cleft. Arrows indicate sites of possible deformation of the developing foregut

Figure 1.1 SEM photograph of the inner layer of foregut epithelium in a chick embryo (approx. 3.5 days old). View from cranial. Between trachea (tr) on bottom and esophagus (es) on top, the tip of the tracheo-esophageal fold (tef) is recognizable. Lateral ridges or signs of fusion are not found 45,46

2 Atresia of the trachea with ﬁstula (Fig. 1.3b): • The foregut is deformed on its ventral side. The developmental movements of the folds are disturbed and the tracheo-esophageal space is dislocated in a dorsal direction. Therefore it differentiates into esophagus. 3 Laryngo-tracheo-esophageal clefts (Fig. 1.3c): • Faulty growth of the folds results in the persistence of the primitive tracheo-esophageal space. Recently it has been shown that esophageal atresias and tracheo-esophageal ﬁstulas can be induced by maternal application of adriamycin into the peritoneal cavity of pregnant rats.16,17 The dosage may vary between 1.5 mg to 2.0 mg/kg depending on the number of days it will be given. In most reports the most promising dosage is 1.75 mg/kg given on days 6–9 of pregnancy. The adriamycin model has been intensively studied over the last couple of years, resulting in more than 30 reports between 1997 and 2001.65 It could be demonstrated that in this model not only foregut malformations but also atypical patterns of malformation can be observed which are usually summarized under the term ‘VATER’ or ‘VACTERL’ association.18,19 Therefore, this model is not only promising for the studies of foregut anomalies but also for anomalies of the hind- and mid-gut.

DEVELOPMENT OF THE DIAPHRAGM Figure 1.2 Summarizing sketch of foregut development. The tracheo-esophageal space (tes) is reduced in size by developmental movements of folds (indicated by arrows) (es, esophagus; la, anlage of larynx; br, bronchus; tr, trachea). Short arrow marks tip of tracheo-esophageal fold (tef) (compare Figure 1.1)

In the past, several theories were proposed to explain the appearance of postero-lateral diaphragmatic defects: 1 Defects caused by improper development of the pleuro-peritoneal membrane66,67

8 Embryology of malformations

2 Failure of muscularization of the lumbocostal trigone and pleuro-peritoneal canal, resulting in a ‘weak’ part of the diaphragm66,68 3 Pushing of intestine through postero-lateral part (foramen of Bochdalek) of the diaphragm69 4 Premature return of the intestines into the abdominal cavity with the canal still open66,68 5 Abnormal persistence of lung in the pleuroperitoneal canal, preventing proper closure of the canal70 6 Abnormal development of the early lung and posthepatic mesenchyme, causing non-closure of pleuro-peritoneal canals.15 Of these theories, failure of the pleuro-peritoneal membrane to meet the transverse septum is the most popular hypothesis to explain diaphragmatic herniation. However, using SEM techniques,55 we could not demonstrate the importance of the pleuro-peritoneal membrane for the closure of the so-called pleuro-peritoneal canals (Fig. 1.4). As stated earlier, most authors assume that delayed or inhibited closure of the diaphragm will result in a diaphragmatic defect that is wide enough to allow herniation of gut into the fetal thoracic cavity. However, this assumption is not the result of appropriate embryological observations but rather the result of interpretations of anatomical/pathological ﬁndings. In a series of normal staged embryos we measured the width of the pleuro-peritoneal openings and the transverse diameter of gut loops.54 On the basis of these measurements we

Figure 1.4 SEM photograph of right pleural sac in a rat embryo (approx. 16.5 days old). View from cranial. The socalled pleuro-peritoneal canal (PPC) is nearly closed. Small arrows point at the margin of PPC. In the depth of the abdomen the right adrenals (ad) are seen. Large arrows point at margins of the so-called pleuro-peritoneal membrane. Its contribution to the closure of the canal is minimal47 (es, esophagus)

estimated that a single embryonic gut loop requires at least an opening of 450 μ size to herniate into the fetal pleural cavity. However, in none of our embryos the observed pleuro-peritoneal openings were of appropriate dimensions. This means that delayed or inhibited closure of the pleuro-peritoneal canal cannot result in a diaphragmatic defect of sufﬁcient size. Herniation of gut through these openings is therefore impossible. Thus the proposed theory about the pathogenetic mechanisms of congenital diaphragmatic hernia (CDH) development lacks any embryological evidence. Furthermore the proposed timing of this process is highly questionable.57 Recently, an animal model for diaphragmatic hernia has been developed11–15 using nitrofen as noxious substance. In these experiments CDHs were produced in a reasonably high percentage of newborns.12,13 Most diaphragmatic hernias were associated with lung hypoplasias. Using electron microscopy, our group56–59 used this model to give a detailed description of the development of the diaphragmatic defect. Our results are as follows:

Timing of diaphragmatic defect appearance Iritani15 was the ﬁrst to notice that nitrofen-induced diaphragmatic hernias in mice are not caused by an improper closure of the pleuro-peritoneal openings but rather the result of a defective development of the socalled post-hepatic mesenchymal plate (PHMP). In our study in rats, clear evidence of disturbed development of the diaphragmatic anlage was seen on day 13 (left side) and day 14 (right side, Fig. 1.5).56,59 In all embryos

Figure 1.5 Cranial view of the pleural sacs in a rat embryo after exposition to nitrofen on day 11 of pregnancy. The embryo is approx. 15 days old. Note the big defect of the right diaphragmatic primordium. Small black arrows point at margins of the defect, which leaves parts of the liver (li) uncoated. On the left, the diaphragmatic anlage is normal. Note the low position of the cranial border of the pleuro-peritoneal opening on this side (white arrows). (ad, adrenals; di, anlage of diaphragm)

Development of the cloaca 9

affected, the PHMP was too short. This age group is equivalent to 4–5-week-old human embryos.56

Location of diaphragmatic defect In our SEM study, the observed defects were localized in the PHMP (Fig. 1.5). We identiﬁed two distinct types of defects: (1) large ‘dorsal’ defects and (2) small ‘central’ defects.56 Large defects extended into the region of the pleuro-peritoneal openings. In these cases, the closure of the pleuro-peritoneal openings was usually impaired by the massive ingrowth of liver (Figs 1.6 & 1.7). If the defects were small, they were consistently isolated from the pleuro-peritoneal openings closing normally at the 16th or 17th day of gestation. Thus, in our embryos with CDH, the region of the diaphragmatic defect was a distinct entity and was separated from that part of the diaphragm where the pleuro-peritoneal ‘canals’ are localized. We conclude therefore that the pleuro-peritoneal openings are not the precursors of the diaphragmatic defect.

Why lungs are hypoplastic Soon after the onset of the defect in the 14-day-old embryo, liver grows through the diaphragmatic defect into the thoracic cavity (Fig. 1.6). This indicates that from this time on the available thoracic space is reduced for the lung and further lung growth hampered. In the following stages, up to two-thirds of the thoracic cavity can be occupied by liver (Fig. 1.7). Herniated gut was found in our embryos and fetuses only in late stages of development (21 days and newborns). In all of these, the lungs were already hypoplastic, when the bowel entered the thoracic cavity.53

Figure 1.6 Liver (li) protrudes through diaphragmatic defect. Arrows point to the margin of the defect (di, diaphragmatic anlage). Rat embryo (approx. 16 days old), nitrofen exposition on day 11 of pregnancy

Figure 1.7 SEM photograph of a right pleural sac in a rat embryo after nitrofen exposure on day 11 of pregnancy. The embryo is approximately 15.5 days old. Note the big defect of the right dorsal diaphragm (large arrows). The closure of the pleuro-peritoneal canal (PPC) is impaired by the ingrowths of liver (small arrows). Li1 = liver growing through PPC. Li1 + Li2 = liver growing through the defect of the diaphragm

Based on these observations, we conclude that the early ingrowth of the liver through the diaphragmatic defect is the crucial step in the pathogenesis of lung hypoplasia in CDH. This indicates that growth impairment is not the result of lung compression in the fetus but rather the result of growth competition in the embryo: the liver that grows faster than the lung reduces the aviable thoracic space. If the remaining space is too small, pulmonary hypoplasia will result.

DEVELOPMENT OF THE CLOACA In the literature several theories have been put forward to explain the differentiation of the cloaca into the dorsal anorectum and the ventral sinus urogenitalis. To many authors this differentiation is caused by a septum which develops cranially then caudally and thus divides the cloaca in a frontal plane. Disorders in this process of differentiation are thought to be the cause of cloacal anomalies such as persistent cloaca and anorectal malformations. However, there is no agreement on the mechanisms of the septational process. While some authors71,72 believe that the descent of a single fold separates the urogenital part from the rectal part by ingrowth of mesenchyme from cranial, others73 think that lateral ridges appear in the lumen of the cloaca, which progressively fuse along the midline and thus form the septum. In a recent paper74 the process of septation had been questioned altogether. Using SEM techniques, our group studied cloacal development in rat and sd-mice embryos. The sd-mouse

10 Embryology of malformations

is a spontaneous mutation of the house mouse characterized by having a short tail (Fig. 1.8). Homozygous or heterozygous offspring of these mice show skeletal, urogenital and anorectal malformations.18 Therefore these animals are ideal in the study of the development of anorectal malformations.

Figure 1.8 Characteristic short tail (arrow) of sd-mouse embryo (approx. 13 days old) (ll, left lower limb; ge, genital tuberculum, abnormal)

Figure 1.9 Malformed cloaca of sd-mouse embryo (approx. 11 days old). The surrounding mesenchyme is removed by microdissection. View on the basal layer of the cloacal entoderm. The cloaca has lost its contact to the ectoderm of the genitals (white arrow). The dorsal part of the cloaca is missing (black arrow). Tailgut (tg) and hindgut (hg) are hypoplastic. This malformed cloaca developed because the anlage of the cloacal membrane was too short in early embryogenesis (see text for details) (cc, rest of cloaca; u, urachus, rudimentary)

Normal cloacal embryology (rat) As in the foregut of chick embryos, signs of median fusion of lateral cloacal parts could not be demonstrated during normal cloacal development in the rat. However, in contradiction to vdPUTTE,74 the current authors think that downgrowth of the urorectal fold takes place, although it is probably not responsible for the formation of cloacal malformations.

Abnormal cloacal embryology (sd-mouse) Cloacal malformations are caused by improper development of the early anlage of the cloacal membrane as demonstrated in sd-mice embryos.75,76 Our studies of abnormal cloacal development in sdmice had the following results: 1 The basis of the pathogenesis of anorectal malformations is too short a cloacal membrane 2 The anlage of the cloacal membrane is too short and results in a maldeveloped anlage of the cloaca, which is undeveloped in its dorsal part (Fig. 1.9) 3 The caudal movement of the urorectal fold is impaired by the malformed cloaca. Thus the hindgut remains in abnormal contact with the cloaca. This opening is true ectopic and will develop into the recto-urogenital ﬁstula (Fig. 1.10).

Figure 1.10 Malformed cloaca of sd-mouse, embryo (approx. 13 days old). Urachus (u) and rectum (re) nearly normal (cl, ventral part of cloaca with short cloacal membrane). The dorsal part of the cloaca is missing (long white arrows). Short white arrow points to the region of the future ﬁstula

HYPOSPADIAS Many investigators77–80 believe that the urethra develops by fusion of the paired urethral folds following the disintegration of the urogenital membrane. Impairment of this process is thought to result in the different forms

References 11

of hypospadia80 However, in our study of normal cloacal development,81 we were puzzled by the fact that disintegration of the urogenital part of the cloacal membrane could not be observed in rat embryos (Fig. 1.11). This ﬁnding caused us to call in question the generally assumed concepts of hypospadia formation. Instead we found that: 1 The urethra is always present as a hollow organ during embryogenesis of rats and that it is always in contact with the tip of the genitals, and that 2 An initially double urethral anlage exists. The differentiation in female and male urethra starts in rats of 18.5 days old. On the other hand, we found no evidence for: • The disintegration of the urogenital cloacal membrane, and • A fusion of lateral portions within the perineum. In our opinion, more than one embryological mechanism is at play in the formation of the hypospadias complex. The moderate degrees, such as the penile and glandular forms, represent a developmental arrest of the genitalia (Fig. 1.12). They take their origin from a situation comparable to the 20-day-old embryo. Consequently the penis, not the urethra is the primary organ of the malformation. Perineal and scrotal hypospadias are different from the type discussed previously. Pronounced signs of feminization in these forms suggest that we are dealing with a female-type urethra. Origin of this malformation complex is an undifferentiated stage as may be seen in the 18.5-day-old rat embryo.

Figure 1.12 Genitals of a normal male rat embryo (approx. 20 days old) (gl, glans; pf, preputial fold; sc, scrotum). Arrow points to the raphe up to this stage; disintegration of the urogenital part of the cloacal membrane was not seen. Note similarity with clinical picture of hypospadia!

CONCLUSION Despite the long history of experimental embryology, we know very little about etiology and pathogenesis of congenital malformations. For decades, hypotheses were abundant while few data existed to support them. The tremendous progress of neighboring biological sciences is now providing powerful tools for researchers in the ﬁeld, such as recombinant DNA and hybridoma technology. Future investigations will monitor closely how genes are switched on and off during embryogenesis and determine the relation of spatial and temporal disturbances to ensuing malformations. Target structures of chemical or viral teratogens within the embryonic cells await identiﬁcation. Finally, improved understanding of growth coordination in utero will extend to related areas such as wound healing and proliferation of cancer cells.

REFERENCES

Figure 1.11 Genitals of a normal female rat embryo (approx. 18.5 days old) (gl, glans). Arrow points to future opening of the female urethra. No signs of disintegration of the cloacal membrane

1. Nadler HL. Teratology. In: Welch KJ, Randolph JG, Ravitch MM, O’Neill JA, Rowe MJ. Pediatric Surgery. 4th edn (eds), Year Book Medical Publishers: Chicago: Year Book Medical Publishers 1986: 11–13. 2. Shepard TH. Catalogue of Teratogenic Agents. 4th edn. Baltimore: Johns Hopkins Press, 1983. 3. United States National Center for Health Statistics. Monthly Vital Statistics Report, Vol. 31. No. 5. Birth, marriages, divorces, and deaths for May 1982. Hyattsville, MD: Public Health Service, 1982:1–10. 4. McCredie J, Loewenthal J. Pathogenesis of congenital malformations. Am J Surg 1978; 135:293–7. 5. Spemann, Mangold, cited by Starck D. Stuttgart: Embryologie, Thieme, 1975: 135–63.

12 Embryology of malformations 6. Warkany J, Roth CB, Wilson JG. Multiple congenital malformations: a consideration of etiological factors. Pediatrics 1948; 1:462–71. 7. Kalter H. Congenital malformations induced by riboﬂavin deﬁciency in strains of inbred mice. Pediatrics 1959; 23:222–30. 8. Kalter H. The inheritance of susceptibility to the teratogenic action of cortisone in mice. Genetics 1954; 39:185. 9. Lenz W. Fragen aus der Praxis. Wochenschr.:Dtsch Med, 1961; 86:25–55. 10. Ministry of Health Reports on Public Health and Medical Subjects No. 112. Deformities caused by thalidomide. London: HMSO, 1964. 11. Ambrose AM, Larson PS, Borcelleca JF et al. Toxicological studies on 2,4-dichlorophenyl-P-nitrophenyl ether. Toxicol Appl Pharmacol 1971; 19:263–75. 12. Tenbrinck R, Tibboel D, Gaillard JLJ et al. Experimentally induced congenital diaphragmatic hernia in rats. J Pediatr Surg 1990; 25:426–9. 13. Kluth D, Kangha R, Reich P et al. Nitrofen-induced diaphragmatic hernia in rats – an animal model. J Pediatr Surg 1990; 25:850–4. 14. Costlow RD, Manson JM. The heart and diaphragm: target organs in the neonatal death induced by nitrofen (2,4dichloro-phenyl-P-nitrophenyl ether). Toxicology 1981; 20:209–27. 15. Iritani L. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol 1984; 169:133–9. 16. Thompson DJ, Molello JA, Strebing RJ, Dyke IL. Teratogenicy of adriamycin and daunomycin in the rat and rabbit. Teratology 1978; 17:151–8. 17. Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent experimental model of esophageal atresia and tracheoesophageal ﬁstula: preliminary report. J Pediatr Surg 1996; 31:498–502. 18. Beasley SW, Diez-Pardo J, Qi BQ, Tovar JA, Xia HM. The contribution of the adriamycin-induced rat model of the VATER association to our understanding of congenital abnormalities and their embryogenesis. Pediatr Surg Int 2000; 16:465–72. 19. Orford JE, Cass DT. Dose response relationship between adriamycin and birth defects in a rat model of VATER association. J Pediatr Surg 1999; 34:392–8. 20. Rosenbaum KN. Genetics and dysmorphology. In: Welch KJ, Randolph MM, Ravitch MM, O’Neill JA, Rowe MJ, editors. Pediatric Surgery, 4th edn. Chicago: Year Book Medical Publishers, 1986: 3–11. 21. van der Putte SCJ, Neeteson FA. The pathogenesis of hereditary congenital malformations in the pig. Acta Morphol Neerl Scand 1984; 22:17–40. 22. Kluth D, Lambrecht W, Reich P et al. SD mice – an animal model for complex anorectal malformations. Eur J Pediatr Surg 1991; 1:183–8. 23. Lambrecht W, Lierse W. The internal sphincter in anorectal malformations: morphologic investigations in neonatal pigs. J Pediatr Surg 1987; 22:1160–8.

24. Dunn LC, Gluecksohn-Schoenheimer S, Bryson V. A new mutation in the mouse affecting spinal column and urogenital system. J Hered 1940; 31:343–8. 25. Spemann H. Entwicklungsphysiologische Studien am Tritonei. ROIIX Arch Entw Mech 1901; 12:224–64. 26. Murray JD, Maini PK. A new approach to the generation of pattern and form in embryology. Sri Progr Oxf 1986; 70:539–53. 27. Gudernatsch JF. Concerning the mechanisms and direction of embryonic folding. Anat Rec 1913; 7:411–31. 28. Oster G, Alberich P. Evolution and bifurcation of developmental programmes. Evolution 1982; 36:444–59. 29. Ettersohn CA. Mechanisms of epithelial invagination. Q Rev Biol 1985; 60:289–307. 30. Jaffredo T, Horwitz AF, Buck CA et al. Myoblast migration speciﬁcally inhibited in the chick embryo by grafted CSAT hybridoma cells secreting an anti-integrin antibody. Development 1988; 103:431–46. 31. Ruoslahti E, Pierschbacher MD. 7 New perspectives in cell adhesions: RDG and integrins. Science 198; 238:491–7. 32. Stoolman LM. Adhesion molecules controlling lymphocyte migration. Cell 1989; 56:907–10. 33. Simmons D, Makgoba MW, Seed B. ICAM, an adhesion ligand for LFA-1, is homologous to the neural cell adhesion molecule NCAM. Nature 1988; 331:624–7. 34. Staunton DE, Dustin L, Springer TA. Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature 1989; 339:61–4. 35. Gallin WJ, Sorkin C, Edelman GM et al. Structure of the gene for the liver cell adhesion molecule, L-CAM. Proc Natl Acad Sci USA 1987; 84:2808–12. 36. Edelman GM. Morphoregulatory molecules. Biochemistry 1988; 27:3533–43. 37. Rutishauser U, Acheson A, Hall AK et al. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 1988; 240:53–7. 38. Edelman GM. Topobiology. Sci Amer 1989; May: 44–52. 39. Tedder TF, Isaacs CM, Ernst TJ et al. Isolation and chromosomal localisation of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. J Exp Med 1989; 170:123–33. 40. Yednock TA, Rosen D. Lymphocyte homing. Adv Immunol 1989; 44:313–78. 41. Spooner BS. Microﬁlaments, microtubules, and extracellular materials in morphogenesis. BioScience 1975; 25:440–51. 42. Baker PC, Schroeder TE. Cytoplasmatic ﬁlaments and morphogenetic movement in the amphibian neural tube. Devl Biol 1967; 15:432–50. 43. Alescio T, DiMichele M. Relationship of epithelial growth to mitotic rate in mouse embryonic lung developing in vitro. Embryol Exp Morphol 1968; 19:227–37. 44. Goldin GV, Opperman LA. Induction of super-numerary tracheal buds and the stimulation of DNA synthesis in the embryonic chick lung and trachea by epidermal growth factor. J Embryol Exp Morphol 1980; 60:235–43.

References 13 45. Smith JM, Sporn MB, Roberts AB et al. Human transforming growth factor-alpha causes precocious eyelid opening in newborn mice. Nature 1985; 315:515–16. 46. Sporn MB, Roberts AB, Wakeﬁeld LM et al. Transforming growth factor-beta: biological function and chemical structure. Science 1986; 233:532–34. 47. Sporn MB, Roberts AB, Wakeﬁeld LM et al. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 1987; 105:1039–45. 48. Anzano MA, Roberts AB, Sporn MB. Anchor-ageindependent growth of primary rat embryo cells is induced by platelet-derived growth factor and inhibited by type-beta transforming growth factor. J Cell Physiol 1986; 126:312–18. 49. Nogawa H. Determination of the curvature of epithelial cell mass by mesenchyme in branching morphogenesis of mouse salivary gland. J Embryol Exp Morphol 1983; 73:221–32. 50. Steding G. Ursachen der embryonalen Epithelverdickung. Acta Anat 1967; 68:37–67. 51. Jacob HJ. Experimente zur Entstehung entodermaler Organanlagen. Untersuchungen an explantierten Hühnerembryonen. Anat Anzeiger 1971; 128:271–8. 52. Smuts MS, Hilfer SR, Searls RL. Patterns of cellular proliferation during thyroid organogenesis. J Embryol Exp Morphol 1978; 48:269–86. 53. Kluth D, Steding G, Seidl W. The embryology of foregut malformations. J Pediatr Surg 1987; 22:389–93. 54. Kluth D, Habenicht R. The embryology of usual and unusual types of oesophageal atresia. Pediatr Surg Int 1987; 1:223–7. 55. Kluth D, Petersen C, Zimmermann HJ et al. The embryology of congenital diaphragmatic hernia. In: Puri P, editor. Congenital Diaphragmatic Hernia: Modern Problems in Pediatrics, Vol. 24, Basel: Karger, 1989: 7–21. 56. Kluth D, Tenbrinck R, v. Ekesparre M et al. The natural history of congenital diaphragmatic hernia in pulmonary hypoplasia in the embryo. J Pediatr Surg 1993; 28:456–63. 57. Kluth D, Tander B, v. Ekesparre M et al. Congenital diaphragmatic hernia: the impact of embryological studies. Pediatr Surg Int 1995; 10:16–22. 58. Kluth D, Losty PD, Schnitzer JJ, Lambrecht W, Donahoe PK. Toward understanding the developmental anatomy of congenital diaphragmatic hernia. Clin Perinatol 1996; 23:655–69. 59. Kluth D, Keijzer R, Hertl M, Tibboel D. Embryology of congenital diaphragmatic hernia. Semin Pediatr Surg 1996; 5:224–33. 60. His W. Zur Bildungsgeschichte der Lungen beim menschlichen Embryo. Arch Anat Entwickl Gesch 1887; 89–106. 61. Rosenthal AH. Congenital atresia of the esophagus with tracheo esophageal ﬁstula: report of eight cases. Arch Pathol 1931; 12:756–72.

62. Smith EL. The early development of the trachea and the esophagus in relation to atresia of the esophagus and tracheo-oesophageal ﬁstula. Contrib Embyol Carneg Inst 1957; 36:41–57. 63. Zaw Tun HA. The tracheo-esophageal septum – fact or fantasy? Acta Anat 1982; 114:1–21. 64. O’Rahilly R, Muller F. Chevalier Jackson Lecture. Respiratory and alimentary relations in staged human embryos. New embyrological data and congenital anomalies. Ann Otol Rhinol Laryngol 1984; 93:421–9. 65. Medline recherché: http://www.ncbi.nlm.nih.gov/PubMed/. 66. Gray SW, Skandalakis JE. Embryology for Surgeons. Philadelphia: Saunders, 1972: 359–85. 67. Grosser 0, Ortmann R. Grundriß der Entwicklungsgeschichte des Menschen. 7th edn. Berlin: Springer, 1970: 124–7. 68. Holder RM, Ashcraft KW. Congenital diaphragmatic hernia. In: Ravitch MM, Welch KJ, Benson CD, Aberdeen E, Randolph JG, editors. Pediatric Surgery. 3rd edn. Vol. 1. (eds), Chicago: Year Book Medical Publishers, 1979: 432–45. 69. Bremer JL. The diaphragm and diaphragmatic hernia. Arch Pathol 1943; 36:539–49. 70. Gattone VH II, Morse DE. A scanning electron microscopic study on the pathogenesis of the posterolateral diaphragmatic hernia. J Submicrosc Cytol 1982; 14:483–90. 71. Tourneux F. Sur le premiers developpements du cloaque du tubercle genitale et de l’anus chez l’embryon moutons, avec quelques remarques concernant le developpement des glandes prostatiques. J Anat Physiol 1888; 24:503–17. 72. DeVries P, Friedland GW. The staged sequential development of the anus and rectum in human embryos and fetuses. J Pediatr Surg 1974; 9:755–69. 73. Retterer E. Sur l’origin et de l’evolution de la region anogénitale des mammiferes. J Anat Physiol 1890; 26:126–216. 74. vd Putte SCJ. Normal and abnormal development of the anorectum. J Pediatr Surg 1986; 21:434–40. 75. Kluth D, Hillen M, Lambrecht W. The principles of normal and abnormal hindgut development. J Pediatr Surg 1995; 30:1143–7. 76. Kluth D, Lambrecht W. Current concepts in the embryology of anorectal malformations. Semin Pediatr Surg 1997; 6:180–6. 77. Felix W. Die Entwicklung der Harn-und Geschlechtsorgane. In: Keibel F, Mall FP, editors. Handbuch der Entwicklungsgeschichte des Menschen. Vol. 2. Leipzig: Hirzel, 1911: 92–5. 78. Spaulding MH. The development of the external genitalia in the human embryo. Contrib Embryol Carneg 1921; 13:67–88. 79. Glenister TW. A correlation of the normal and abnormal development of the penile urethra and of the intraabdominal wall. J Urol 1958; 30:117–26.

14 Embryology of malformations 80. Gray SW, Skandalakis JE. Embryology for Surgeons. Philadelphia: Saunders, 1972: 595–631.

81. Kluth D, Lambrecht W, Reich P. Pathogenesis hypospadias – more questions than answers. J Pediatr Surg 1988; 23:1095–1101.

2 Prenatal diagnosis of surgical diseases TIPPI C. MACKENZIE AND N. SCOTT ADZICK

Box 2.2 Defects that may require cesarian delivery

INTRODUCTION Prenatal diagnosis has undergone an explosion of growth in the past decade. The primary impetus for this rapid expansion has come from the widespread use of prenatal ultrasonography. Most correctable malformations that can be diagnosed in utero are best managed by appropriate medical and surgical therapy after maternal transport and planned delivery at term. Prenatal diagnosis may inﬂuence the timing (Box 2.1) or mode (Box 2.2) of delivery, and in some cases may lead to elective termination of the pregnancy. In rare cases, various forms of in utero therapy may be possible (Table 2.1). Prenatal diagnosis has deﬁned a ‘hidden mortality’ for some lesions such as congenital diaphragmatic hernia, bilateral hydronephrosis, sacrococcygeal teratoma, and cystic hygroma. These lesions, when ﬁrst evaluated and treated postnatally demonstrate a favorable selection bias. The most severely affected fetuses often die in utero or immediately after birth, before an accurate diagnosis has been made. Consequently, such a condition detected

Myelomeningocele Gastroschisis Large sacrococcygeal teratoma Giant neck masses (EXIT procedure)

prenatally may have a worse prognosis than the same condition diagnosed after delivery.1 The perinatal management of the patients involves many different medical disciplines, including obstetricians, sonographers, neonatologists, geneticists, pediatric surgeons, and pediatricians. It is essential that the affected family be managed using a team approach, and that information and experience be exchanged freely. In this chapter we will discuss the prenatal diagnosis of neonatal surgical lesions. First, a brief summary of the diagnostic methods currently available will be given. Then a review of prenatal diagnosis by organ system will be presented.

DIAGNOSTIC METHODS Box 2.1 Defects that may lead to induced preterm delivery Obstructive hydronephrosis Gastroschisis or ruptured omphalocele Intestinal ischemia and necrosis secondary to volvulus, meconium ileus, etc. Sacrococcygeal teratoma with hydrops

Ultrasound Ultrasound testing has become a routine part of the prenatal evaluation of almost all pregnancies. It is especially important to perform ultrasound for pregnancies with maternal risk factors (e.g. age over 35 years, diabetes,

Table 2.1 Diseases amenable to fetal surgical intervention in selected cases Malformation

Effect on development

In utero treatment

Congenital diaphragmatic hernia CCAM or BPS

Pulmonary hypoplasia, respiratory failure Pulmonary hypoplasia, hydrops

Sacrococcygeal teratoma Urethral obstruction Myelomeningocele

Massive arteriovenous shunting, placentomegaly, hydrops Hydronephrosis, lung hypoplasia Damage to spinal cord, paralysis

Tracheal occlusion Thoracoamniotic shunting, lobectomy Excision Vesicoamniotic shunting Closure of defect

16 Prenatal diagnosis of surgical diseases

previous child with anatomic or chromosomal abnormality) and if there is an elevation in maternal serum alphafetoprotein (MSAFP). Most defects can be reliably diagnosed in the late ﬁrst or early second trimester by a skilled sonographer. More recently, nuchal translucency measurements have emerged as an independent marker of chromosomal abnormalities, with a sensitivity of about 60%.2 This abnormality may be detected on transvaginal ultrasound at 10–15 weeks’ gestation, thus providing an early test for high-risk pregnancies. Nuchal cord thickening may also be a marker for congenital heart disease3 and may be a valuable initial screen to detect high-risk fetuses for referral for fetal echocardiography. It is important to remember that sonography is operator dependent; the scope and reliability of the information obtained is directly proportional to the skill and experience of the sonographer.

Magnetic resonance imaging Until recently, the long acquisition times required for magnetic resonance imaging (MRI) were not conducive to fetal imaging because fetal movements resulted in poor quality images. Obtaining adequate images with the traditional spin-echo techniques required fetal sedation or paralysis.4 With the development of ultrafast scanning techniques, the artifacts caused by fetal motion have almost been eliminated.5 This technique is now an important part of prenatal evaluation of fetuses referred to our institution and has greatly enhanced our ability to diagnose and treat fetal malformations.

Amniocentesis The ﬁrst report of the culture and karyotyping of fetal cells from amniocentesis was by Steele and Berg in 1966.6 Since then, it has become the gold standard for detecting fetal chromosomal abnormalities by karyotyping. It is usually performed at 15–16 weeks’ gestation and involves a very low risk of fetal injury or loss. Attempts at early amniocentesis (at 11–12 weeks’ gestation) have been complicated by a higher pregnancy loss, increased risk of iatrogenic fetal deformities and increased postamniocentesis leakage rate.7 For this reason, the most reliable method for ﬁrst trimester diagnosis remains chorionic villus sampling.

Chorionic villus sampling Chorionic villus sampling (CVS) may be performed at 10–14 weeks’ gestation and involves the biopsy of the chorion frondosum, the precursor for the placenta. Either a transcervical or transabdominal approach may be used, both under ultrasound guidance. The cells obtained may be subjected to a variety of tests including

karyotype, genetic probes, or enzyme analysis. Due to the high mitotic rate of the chorionic villus cells, results for karyotyping may be obtained in less than 24 hours. Disadvantages include diagnostic errors due to maternal decidual contamination or genetic mosaicism of the trophoblastic layer of the placenta. When preformed by experienced operators, the pregnancy loss rate is equivalent to that of second trimester amniocentesis.8

BIOCHEMICAL MARKERS Maternal blood and amniotic ﬂuid can be screened for the presence of various biochemical markers that indicate fetal disease. About two-thirds of women in the USA currently undergo screening for Down syndrome and other chromosomal abnormalities with the ‘triple test,’ which includes measuring serum alphafetoprotein with human chorionic gonadotropin and unconjugated estriol.9 This screening is performed in the early second trimester, and the detection rate for Down syndrome is 69%, with a 5% false-positive test.10 A positive result on the serum screening test indicates a need for chromosome analysis by amniocentesis.

Percutaneous umbilical blood sampling Obtaining umbilical venous blood can also be used to determine the karyotype and diagnose various metabolic and hematological disorders. The percutaneous umbilical blood sampling (PUBS) procedure is performed at around 18 weeks’ gestation under ultrasound guidance. Karyotype results may be obtained within 24–48 hours. In various large series, the mortality from the procedure has been reported to be 1–2%, with increasing mortality rates with long procedure times and multiple punctures.11–13

Fetal cells in the maternal circulation Since the advent of ﬂuorescence-activated cell sorting (FACS), there has been growing interest and progress in detecting circulating fetal cells in maternal blood for diagnostic purposes.14 The cell type most successfully used in this endeavor is the fetal nucleated red blood cell, since these are abundant in the ﬁrst trimester fetal circulation. These cells may be separated from maternal nucleated red blood cells by staining for CD71 or fetal and embryonic hemoglobins.15 Genetic analysis may then be performed using polymerase chain reaction (PCR) or ﬂuorescence in situ hybridization (FISH) for chromosome-speciﬁc probes. Although the test currently has a low sensitivity (40–50%),15 the falsepositive rate is negligible, which is an advantage over the 5% false-positive rate of the conventional triple screen.

Prenatal diagnosis of speciﬁc surgical lesions 17

PRENATAL DIAGNOSIS OF SPECIFIC SURGICAL LESIONS Neck masses Fetal airway obstruction could be a result of extrinsic compression of the airway by lesions such as cervical teratoma or cystic hygroma, or intrinsic defects in the airway such as congenital high airway obstruction syndrome. Although large congenital neck masses causing airway obstruction previously carried an enormous perinatal mortality16 the advent of the ex utero intrapartum treatment (EXIT) procedure17,18 has improved their outcome by providing a means of controlling the airway during delivery and converting an airway emergency into an elective procedure (Fig. 2.1). Cystic hygroma diagnosed in utero is a severe diffuse lymphatic abnormality which is frequently associated with hydrops, polyhydramnios, and other abnormalities.19 Chromosomal abnormalities are very common (62% overall), the most common being Turner’s syndrome.20 There are two groups of prenatally diagnosed cervical lymphangiomas: those diagnosed in the second trimester (usually in the posterior triangle of the neck, have a high incidence of associated abnormalities, and carry a very poor prognosis),21 and those diagnosed later in gestation (most often isolated lesions and generally do not lead to hydrops). Hydrops is an ominous ﬁnding in fetuses with cystic hygroma,16 as is the presence of aneuploidy and septations in the mass.22 However, fetuses with normal karyotype, non-septated masses, and no evidence of hydrops may have a good prognosis.23 Therefore, it is important to monitor the fetus for development of hydrops by serial evaluations.

Teratomas are asymmetrical lesions which are frequently unilateral, with well-deﬁned margins. They may also be multiloculated, irregular masses with solid and cystic components. Most teratomas contain calciﬁcations. MRI is a very useful adjunct to ultrasound in evaluating giant neck masses. We have used it successfully for showing the relationship of the mass to the airway in preparation for an EXIT procedure.24 T1-weighted images may help differentiate teratomas from lymphangiomas.25 The EXIT procedure, originally designed for removal of tracheal clips,17 has proven to be life-saving for many fetuses with giant neck masses.18 This procedure involves performing a maternal hysterotomy and obtaining control of the fetal airway while the fetus remains on placental support. In order to prevent uterine contractions during the procedure, the mother is given inhalational anesthetic and tocolytics, warm saline is infused through a level I device, and only the head and shoulders of the fetus are delivered. After attaching a pulse oximeter to the fetal hand to monitor heart rate and oxygen saturation, direct laryngoscopy and, if possible, endotracheal intubation is performed. If the airway cannot be secured in this way, a rigid bronchoscope is inserted to determine the anatomy. If secure airway establishment is still unsuccessful, a tracheostomy can be performed. After securing the airway, surfactant is administered for premature fetuses, the cord is clamped, and the infant is taken to an adjacent operating room for resuscitation and possible immediate resection of the mass. In our review of the EXIT procedure,19 ten fetuses underwent the procedure and eight survived. In six patients, endotracheal intubation was accomplished, three patients needed a tracheostomy, and one patient expired due to parental refusal for a tracheostomy. One patient expired in the postnatal period due to pulmonary hypoplasia.

Sacrococcygeal teratoma Sacrococcygeal teratoma (SCT) is the most common newborn tumor, occurring in one out of 35 000 to 40 000 births.26 The American Academy of Pediatrics, Surgical Section classiﬁcation27 deﬁnes four types of SCT with differing prognoses: 1 Type 1 tumors are external, with at most a small presacral component, and carry the best prognosis. 2 Type 2 tumors are predominantly external with a large intrapelvic portion. 3 Type 3 lesions are predominantly intrapelvic with abdominal extension with only a minor external component. 4 Type 4 lesions are entirely intrapelvic and abdominal. Figure 2.1 EXIT procedure for giant neck mass

The latter have the worst prognosis since they are difﬁcult to diagnose, sometimes less amenable to surgical

18 Prenatal diagnosis of surgical diseases

We reported the ﬁrst successful case of SCT resection in a fetus of 26 weeks’ gestation with a large SCT and accompanying polyhydramnios, mild placentomegaly, and maternal tachycardia and proteinuria.35 Fetal resection of the mass reversed the pathophysiology and prevented the development of hydrops. The algorithm we currently recommend is to follow the fetus by serial ultrasounds for the development of signs of high output cardiac failure.36 If placentomegaly and hydrops are seen after pulmonary maturation, the fetus should be delivered by emergency cesarian section. If the fetus is too young for immediate delivery after development of hydrops, open fetal surgery may be considered. The role of radiofrequency ablation for minimally invasive fetal treatment is currently being tested in the laboratory.37

Congenital chest lesions CONGENITAL CYSTIC ADENOMATOID MALFORMATION AND BRONCHOPULMONARY SEQUESTRATION

Figure 2.2 MRI of large sacrococcygeal teratoma

resection, and frequently malignant at the time of diagnosis because of the delay in diagnosis. Overall, prenatally diagnosed SCT has a worse prognosis than those tumors diagnosed at time of birth. On prenatal ultrasound, SCT appears as a mixed solid and cystic lesion arising from the sacral lesion. The tumor frequently contains calciﬁcations. Since there is acoustic shadowing by the fetal pelvic bones, it is not always possible to determine the most cephalad portion of the tumor by ultrasound. Ultrafast fetal MRI is superior,28 since it can determine the intrapelvic dimensions of the tumor as well as the presence of hemorrhage (Fig. 2.2). Those fetuses with mainly solid and highly vascular SCT have a higher risk of developing hydrops.29,30 We have demonstrated by Doppler ultrasound that in severe cases, the tumor behaves as a large arteriovenous ﬁstula with markedly increased distal aortic blood ﬂow and shunting of blood away from the placenta to the tumor. High output cardiac failure may occur as a result of the hemodynamic effects of the large blood ﬂow to the tumor31,32 and anemia from hemorrhage into the tumor may compound this problem. In severe cases, the mother with placentomegaly develops ‘mirror syndrome,’ a severe pre-eclamptic state with vomiting, hypertension, proteinuria, and edema. This phenomenon may be mediated by the release of vasoactive compounds from the edematous placenta. The development of hydrops is a grave sign, with almost 100% mortality without fetal intervention.33,34

Congenital cystic adenomatoid malformation (CCAM) represents a spectrum of disease characterized by cystic lesions of the lung.38 Macrocystic lesions are larger than 5 mm in diameter and may be solitary cysts that grow to several centimeters in size (Fig. 2.3). Microcystic disease has multiple cystic lesions less than 5 mm in diameter. Prenatal ultrasound can generally distinguish individual cysts in macrocystic disease while microcystic lesions usually have the appearance of an echogenic, solid lung mass.39 Bronchopulmonary sequestration (BPS) is an aberrant lung mass which is non-functional and usually has a systemic blood supply. It may be difﬁcult to distinguish microcystic CCAM from BPS on ultrasound. Indeed, there is growing evidence that the two lesions may be related embryologically, with several reported cases of hybrid lesions which have CCAM-like architecture and a systemic blood supply.40,41 Some of these

Figure 2.3 Ultrasound image of large CCAM following the placement of a thoracoamniotic shunt. L = lung

Prenatal diagnosis of speciﬁc surgical lesions 19

lesions may decrease in size or disappear altogether during fetal life42 but postnatal evaluation is still warranted to detect residual disease for resection.43 MRI is useful in delineating normal lung from abnormal.44 In CCAM, the number and size of cysts contribute to the signal intensity on T2 weighted images.5 MRI can also deﬁne BPS from surrounding lung due to its high signal intensity and homogeneous appearance.44 To date, ultrasound has been more accurate in demonstrating systemic feeding vessels. MRI may also be helpful in making the correct diagnosis in cases where ultrasound is ambiguous. In a recent series of 18 lung lesions which were viewed with both ultrasound and MRI, multiple chest abnormalities were misdiagnosed as CCAM on ultrasound, including congenital diaphragmatic hernia (CDH), tracheal atresia, pulmonary agenesis, neurenteric cyst, bronchial stenosis, and BPS.44 MRI helped form the correct diagnosis in these cases and was thus crucial for perinatal management. Polyhydramnios is a frequent accompanying ﬁnding in fetuses with large chest masses. This is likely due to esophageal compression caused by the large thoracic mass, decreasing the fetal ability to swallow amniotic ﬂuid.45 The most important prognostic indicator in fetuses with CCAM is the development of hydrops. Hydrops is secondary to obstruction of the vena cava or cardiac compression from extreme mediastinal shift.46 In our recent series,45 all 25 fetuses with managed hydrops died expectantly. The volume of the CCAM compared to the head circumference (CCAM volume ratio, (CVR)) may also have prognostic indications: fetuses with a CVR greater than1.2 are more likely to develop hydrops.47 In utero surgical decompression may reverse hydrops and allow sufﬁcient lung growth to permit survival in severe cases. We recently reviewed the outcome in 175 prenatally diagnosed lung lesions.45 In the CCAM category (134 fetuses) 13 fetuses with hydrops underwent fetal lobectomy, with resolution of hydrops and survival to birth in eight out of 13 (62%) cases. There were ﬁve intraoperative or postoperative deaths. In addition, six fetuses with large cystic masses underwent thoracoamniotic shunting and ﬁve survived. Overall, in our experience, 17 out of 25 fetuses with hydrops who underwent fetal therapy (open surgery or shunting) survived, indicating that this is a feasible option in highly selected cases. In the BPS group, there were 41 total lesions of which 28 regressed or disappeared completely. Three fetuses developed hydrops secondary to tension hydrothorax from ﬂuid or lymph secretion by the mass. These fetuses underwent fetal thoracentesis or thoracoamniotic shunt placement and survived to delivery, after which the masses were resected. One fetus with hydrops who was managed expectantly died after birth despite postnatal resection and extracorporeal membrane oxygenation (ECMO). We have learned from these and other cases that fetuses with large chest masses without hydrops can be managed expectantly with planned

delivery and postnatal resection, whereas those earlier than 32 weeks’ gestation with the development of hydrops may beneﬁt from prenatal intervention.

Congenital diaphragmatic hernia Herniation of abdominal viscera into the chest in utero occurs most commonly due to failure of the pleuroperitoneal folds to fuse normally. The left side is affected ﬁve times more commonly than the right. The ultrasonographic diagnostic criteria include herniated abdominal viscera, abnormal upper abdominal anatomy, mediastinal shift away from the side of herniation and polyhydramnios. The extent of pulmonary hypoplasia is proportional to the timing of herniation, the size of the diaphragmatic defect, and the amount of viscera herniated. Despite earlier impressions that CDH was infrequently associated with other serious congenital lung lesions, recent reports state that other major anomalies occur in 10–50% of cases, including a high proportion of chromosomal abnormalities and cardiac anomalies. Distinguishing CDH from other congenital chest conditions and gastrointestinal lesions can be difﬁcult. The presence of abdominal contents intrathoracically on a transverse sonographic scan at the level of a fourchamber view of the heart is required for diagnosis. In the case of a right-sided defect, the presence of liver and especially gall bladder in the chest makes the diagnosis more clear cut. MRI is superior in deﬁning the position of the liver in CDH (above or below the diaphragm), which carries important prognostic signiﬁcance (Fig. 2.4).48,49 MRI is also better at determining the exact diagnosis, when ultrasound may mistake CDH for congenital lung masses. The best predictor of outcome in CDH has been the right lung to head circumference ratio (LHR), deﬁned as right lung area (measured at the level of the transverse four-chamber cardiac view) divided by head circumference. (Fig. 2.5)50 In a recent prospective study, fetuses with LHR <1 did not survive; those with LHR >1.4 all survived, and those with LHR 1–1.4 had a 38% survival rate.51 The position of the liver is also important, with lower survival rates and more need for ECMO in patients with liver herniation.52 The current strategy for in utero treatment of CDH involves tracheal occlusion with a tracheal clip or a balloon. The basis for this approach is the recognition that fetal tracheal occlusion leads to compensatory lung growth due to a decrease in lung liquid egress, as conﬁrmed in lamb models of CDH.53 The fetal clip may be applied via open fetal surgery or fetoscopically.54 Given the embryology of lung growth, occlusion earlier in gestation, prior to the pseudoglandular stage of lung development, may lead to more reliable lung growth. The outcome in fetuses after tracheal occlusion has been

20 Prenatal diagnosis of surgical diseases

Gastrointestinal lesions ESOPHAGEAL AND BOWEL ATRESIAS

Figure 2.4 MRI of a CDH showing liver (L) and stomach (S) in the chest

Esophageal atresia is typically diagnosed on prenatal ultrasound by the presence of a small or absent stomach bubble and polyhydramnios, but no ultrasound ﬁnding is absolutely predictive. Stringer et al.58 found in a recent series examining the accuracy of these two factors in diagnosing esophageal atresia, that there were many fetuses with these ﬁndings who were born normal (positive predictive value 56%), and many cases in which the diagnosis was missed by antenatal ultrasound (sensitivity 42%). Esophageal atresia is associated with anatomic and chromosomal abnormalities in 63% of cases,59 most notably trisomy 18 and vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal ﬁstula, renal agenesis, and limb defects (VACTERL). Duodenal atresia has a characteristic ‘double bubble’ appearance on prenatal ultrasound, resulting from dilatation of the stomach and proximal duodenum. Although the incidence of associated malformations is high (classically with Down syndrome and endocardial cushion defects), prenatally diagnosed duodenal atresia does not select for a group with a worse prognosis, as is the case with esophageal atresia. Survival rates of 94–100% have been reported.60 There are many bowel abnormalities which may be noted on prenatal ultrasound (dilated bowel, ascites, cystic masses, hyperperistalsis, and polyhydramnios); however, none is absolutely predictive of postnatal outcome. Patients with obstruction frequently have ﬁndings of increased bowel diameter (especially in the third trimester), hyperperistalsis, or polyhydramnios, but ultrasound is much less sensitive in diagnosing large bowel anomalies than those in small bowel.61 Since the large bowel is mostly a reservoir, with no physiologic function in utero, defects in this region such as anal atresia or Hirschsprung’s disease are very difﬁcult to detect, although a low MSAFP level may be a marker for anal atresia.62 Bowel dilatations may be associated with cystic ﬁbrosis, therefore all such fetuses should undergo postnatal evaluation for this disease.61

Abdominal wall defects Figure 2.5 Ultrasound of CDH at the level of the transverse four-chamber view of the heart (H) showing measurements used for LHR calculation on the right lung (L)

favorable in both the lamb model55 and in the patients after in utero clip procedures.56,57 Our current algorithm for in utero treatment of CDH is for fetuses with isolated CDH, diagnosed before 26 weeks’ gestation, who have liver herniation with LHR <0.9.

Omphalocele is thought to be secondary to failure of the abdominal viscera to return to the abdomen in the 10th week of gestation.63 It characteristically has a viable sac composed of amnion and peritoneum containing herniated abdominal contents. The defect is in the midline, usually near the insertion point of the umbilical cord. Ultrasound may demonstrate the internal viscera and sometimes the liver within the sac. Ascites may also be present. Since chromosomal and structural abnormalities are very common in omphalocele (cardiac and renal anomalies, chromosomal anomalies including

Prenatal diagnosis of renal anomalies 21

Beckwith–Wiedemann syndromes and Pentology of Cantrell), fetuses with this defect should be screened by karyotype in addition to detailed sonographic review and echocardiogram.64 Gastroschisis is more often an isolated lesion with a right para-umbilical defect.64 There is no membrane covering the exposed bowel. On ultrasound, the bowel appears to be free-ﬂoating and the loops may appear to be thickened due to peel formation from exposure to amniotic ﬂuid (Fig. 2.6). Dilated loops of bowel may be seen from obstruction secondary to protrusion from a small defect. Gastroschisis is sometimes complicated by intestinal atresias or obstruction, leading to polyhydramnios and preterm labor. The pathophysiology of bowel damage is due to amniotic ﬂuid exposure and bowel constriction, the latter leading to ischemia and venous obstruction.65,66 Predicting outcome in fetuses with gastroschisis based on prenatal ultrasound ﬁndings remains a challenge. There is some evidence that maximum small bowel diameter may be predictive,67,68 consistent with the observation that patients who have a poorer outcome frequently have bowel atresias.68 Although bowel ischemia may be a contributing factor in the prenatal damage, Doppler velocimetry measurements of superior mesenteric artery are not predictive of outcome.69 The perinatal management and mode of delivery are also controversial: although there are conﬂicting views as to vaginal vs cesarian section delivery, a recent series failed to detect a difference in outcome based on mode of delivery, site of delivery, diagnostic methods, or prenatal Maternal Fetal Medicine (MFM) consult.70 Currently, we advocate serial ultrasound measurements to monitor for development of bowel obstruction and offer an immediate repair strategy after planned cesarian section.

PRENATAL DIAGNOSIS OF RENAL ANOMALIES Of all fetal abnormalities diagnosed on prenatal ultrasound, 20% involve the genitourinary tract.71 The ultrasound ﬁndings of hydronephrosis (HN) include a dilated renal pelvis and calyces, with or without dilatation of the bladder and ureter, depending on the cause of hydronephrosis (Fig. 2.7). The differential diagnosis of prenatal hydronephrosis includes ureteropelvic junction (UPJ) obstruction, multicystic kidney, primary obstructive megaureter, ureterocele, ectopic ureter, and posterior urethral valves.71 Severe, bilateral hydronephrosis leads to oligohydramnios with a fetus small for gestational age. Because of the lack of amniotic ﬂuid, ultrasound diagnosis may be difﬁcult and MRI may help to deﬁne the cause of hydronephrosis.5

Figure 2.7 Ultrasound of hydronephrosis showing enlarged bladder (BL), compressed renal parenchyma (K), and dilated renal pelvices (P)

Upper urinary tract obstruction

Figure 2.6 Ultrasound of fetus with gastroschisis with crossmarks showing the abdominal wall defect and arrow indicating extra-abdominal bowel

The most common cause of prenatal HN is UPJ obstruction. The prognosis of prenatally diagnosed HN is excellent, if there is unilateral disease72 and if the renal pelvic diameter is < 10 mm.73 In a recent series by Kitagawa et al., 80% were normal at 3 years and 17% were normal at birth, suggesting spontaneous resolution of the problem.74 Only 17% needed surgical intervention. Prenatally diagnosed HN requires follow up with ultrasound at birth and at 1 month. If there is any evidence of abnormality, a voiding cystourethrogram, and diuretic renal scintigram should be performed.75

22 Prenatal diagnosis of surgical diseases

Lower urinary tract obstruction The most common cause of lower urinary tract obstruction (LUTO) is posterior urethral valves. This occurs in male fetuses (in female fetuses, it is usually part of a cloacal anomaly). The most important factor in the morbidity and mortality from fetal urethral obstruction is pulmonary hypoplasia secondary to oligohydramnios.76 For patients with posterior urethral valves, prenatal diagnosis deﬁnes a subgroup of patients with very poor prognosis, with 64% incidence of renal failure and transient pulmonary failure, compared to 33% in the postnatally diagnosed group.77 Serial fetal urine analysis may provide prognostic information in this group of fetuses. Drainage of the bladder three times at 48–72hour intervals with measurement of sodium, chloride, osmolality, calcium, β-2 microglobulin, and total protein should be performed to determine renal function. A decrease in the electrolytes, proteins, and tonicity correlate with a favorable outcome.78 The rationale for prenatal intervention originates from sheep models of the disease, in which bladder outlet obstruction in fetal lambs reproduced the pulmonary hypoplasia and renal dysplasia seen in patients with bilateral obstructive uropathy.79 Correction of the obstruction led to normal lung growth.80 Fetal intervention in prenatal obstructive uropathy is only warranted in male fetuses with oligohydramnios, bladder distention, and bilateral hydronephrosis (with no other abnormalities), who have improving urine proﬁles with serial bladder drainage.81 These fetuses may be considered for vesicoamniotic shunting or fetal cystoscopy with cystoscopic ablation of posterior urethral valves.82 Although shunting has been fraught with technical problems, the beneﬁt in survival following prenatal shunting in carefully selected populations of fetuses has been reported, with 43% of patients having reached normal renal function 2 years after birth.83 Short-term outcomes are variable in different reports,72 underlining the need for careful patient selection.

Arnold–Chiari malformation, characterized by the caudal displacement of the vermis and cerebellum with midbrain herniation through the foramen magnum. Ultrasound conﬁrmation can be made as early as 18 weeks, which allows localization of the defect as well as assessment of limb function, the presence of clubbing or of the Arnold–Chiari malformation (Fig. 2.8). Analysis of the potential beneﬁts of fetal repair of MMC has been accomplished in a sheep model of the defect.87 This model replicates the deﬁcits seen in children with spina biﬁda such as ﬂaccid paraplegia, incontinence, and absent hindlimb somatosensory potentials, indicating that prolonged exposure to amniotic ﬂuid and the intrauterine environment may contribute to the damage seen in MMC. Early experiments showed that in utero repair of the defect using a latissimus dorsi ﬂap prevented the neurological damage in sheep,88 thus providing a compelling reason for in utero repair, the ﬁrst non-lethal disease to be considered for this treatment. Although experimental evidence dictates that the defect be repaired as soon as possible to allow time for neuronal regeneration, preterm labor remains a ratelimiting step in the progress of fetal surgery. The goals of fetal repair are to prevent the chemical and mechanical trauma to the exposed spinal cord, to resolve the hindbrain herniation frequently seen with this defect, to decrease the need for postnatal ventriculoperitoneal shunt, and to allow time for possible neural regeneration after repair. We reported the ﬁrst open repair of fetal MMC which led to improved neurological outcome.89 A 23-week-old fetus with a T11–S1 defect repaired at 23 weeks and delivered at 30 weeks (secondary to preterm labor) showed that the neurological function was intact to the L4 level on the right and L5 level on the left, with resolution of the Arnold–Chiari malformation. We and

Myelomeningocele Myelomeningocele (MMC) is a neural tube defect characterized by the protrusion of the spinal cord and meninges through open vertebral arches. It is the most common form of spina biﬁda, which affects one in 2000 births per year. Maternal serum testing identiﬁes 75–80% of pregnancies with MMC by 16 weeks’ gestation.84 If an increase in serum AFP is noted, amniocentesis is performed to assess amniotic ﬂuid AFP and acetylcholinesterase to conﬁrm the diagnosis.85 The ultrasound characteristics include the ‘lemon’ and ‘banana’ signs, which are a scalloping of the frontal bone and abnormal anterior curvature of the cerebellar hemispheres, respectively.86 Most fetuses have an associated

Figure 2.8 Ultrasound of fetus with MMC showing the sac (cross-marks) over the spinal defect (arrow)

References 23

others have since conﬁrmed the resolution of the hindbrain herniation in nine subsequent fetuses with MMC following open repair.90,91 Since some of the morbidity and mortality of an MMC occurs as a result of the associated Arnold–Chiari malformation, this ﬁnding is signiﬁcant. Our current algorithm for considering fetuses for repair is an age of less than 25 weeks, presence of Arnold–Chiari malformation (Fig. 2.9), good leg movement, absence of clubbed feet, and absence of other anomalies. If fetal repair is not performed, fetuses with MMC should be delivered by planned cesarian section to avoid trauma to the cord during the birth process.92,93

Figure 2.9 MRI of fetus with MMC showing hindbrain herniation (arrow)

CONCLUSION Prenatal ultrasound has led to a rapid increase in the number of pediatric surgical conditions diagnosed in utero. Prenatal detection and serial sonographic study of fetuses with anatomic lesions now makes it possible to deﬁne the natural history of these abnormalities, determine the pathophysiologic causes that affect outcome, and formulate management based on prognosis. Since many congenital anomalies are associated with others, it is important to perform a careful ultrasound evaluation and karyotype analysis when one abnormality is discovered. Careful evaluation of patients followed pre- and postnatally, as well as studies of congenital defects in animal models, has deﬁned select populations of fetuses who may beneﬁt from prenatal intervention. In most cases, these are fetuses who would not be expected to survive the prenatal period given the natural history of their disease. Further progress in prenatal diagnosis and

monitoring as well as continued re-evaluation of outcomes will doubtless tune our current algorithms regarding the management of these congenital anomalies. Pediatric surgeons have a unique opportunity to continue to shape this exciting ﬁeld in this new millennium.

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88.

89.

90.

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92.

93.

myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep (see comments). J Pediatr Surg 1995; 30:1028-32; discussion 1032–3. Meuli M, Meuli-Simmen C, Hutchins GM et al. In utero surgery rescues neurological function at birth in sheep with spina biﬁda. Nat Med 1995; 1:342–7. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina biﬁda (letter) (see comments). Lancet 1998; 352:1675–6. Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele (see comments). Jama 1999; 282:1826–31. Bruner JP, Tulipan N, Paschall RL et al. Fetal surgery for myelomeningocele and the incidence of shuntdependent hydrocephalus (see comments). Jama 1999; 282:1819–25. Luthy DA. Maternal markers and complications of pregnancy (editorial; comment). N Engl J Med 1999; 341:2085–7. Scheller JM, Nelson KB. Does cesarean delivery prevent cerebral palsy or other neurologic problems of childhood? (see comments). Obstet Gynecol 1994; 83:624–30.

3 Fetal and birth trauma PREM PURI

FETAL TRAUMA About 40 years ago,1,2 it was estimated that 6–8% of pregnant women were affected by accidental injury. This number is likely to be greater now because there are more women in the workforce. When a pregnant woman presents with a major trauma, two lives are at risk. The survival of the fetus depends primarily on maternal survival,3 but occasionally the extent of maternal injury does not correlate with the degree of fetal injury.4 Treatment priorities for traumatic pregnant women remain the same as in patients who are not pregnant, although resuscitation and stabilization should be modiﬁed to account for the anatomical and physiological changes of the pregnancy.5,6 The ﬁrst consideration in the management of maternal trauma in an accident is to ensure the survival of the mother, as is recommended by the Advanced Trauma Life Support Program.6 Assessment of the fetus forms part of the secondary survey of the mother, and should be performed in conjunction with an obstetrician, because beyond 26–28 weeks’ gestational age the fetus is potentially viable if urgent delivery is required.6 Assessment of the fetus includes: the date of the last menstrual period, measuring the fundal height, examination for uterine contractions and tenderness, fetal movements and fetal heart rate. An important part is the vaginal examination for amniotic ﬂuid or blood. Fetal distress can occur at any time and without warning. The fetus should be continually monitored to ensure early recognition of fetal distress by using the ultrasonic Doppler cardioscope. Signs of fetal distress include: bradycardia (< 110 b.p.m.), inadequate accelerations in fetal heart rate in response to uterine contraction, and late decelerations in fetal heart rate in response to uterine relaxation. In blunt maternal–fetal trauma, placental injury is the leading cause of death with maternal survival.7,8 Occasionally, minor maternal trauma may disrupt the

placenta ‘lifeline’ by shearing the relatively rigid placenta from the more elastic uterine wall, thereby leading to fetal distress and subsequent fetal death.4 The clinical signs of placental abruption include: vaginal bleeding, uterine irritability, abdominal tenderness, increasing fundal height, maternal hypovolemic shock and fetal distress. Although the common classical presentation of placental abruption involves vaginal bleeding and abdominal pain, some cases of traumatic abruption occur without these symptoms and fetal distress may not develop for several hours. The fetus should be considered salvageable in the face of severe or even mortal maternal injury, and more than 150 cases of successful post-mortem cesarian section delivery and numerous deliveries of normal neonates just before maternal death have been described.7,9 Fetal injuries after trauma may be treatable, but only if they are recognized. Penetrating trauma by gunshot or stab wounds, although rare,4 are usually obvious, and thus appropriate surgical intervention has to be undertaken (Fig. 3.1a,b). Although most cases of penetrating fetal trauma are fatal to the fetus, some cases of fetal salvage have been reported.10,11 In contrast, surgically treatable fetal injury may go unrecognized after blunt maternal trauma, while these injuries are much more frequent. Thus, one can recognize that after 28 weeks’ gestation, cesarian section for fetal salvage is indicated in the presence of placental abruption with fetal distress, treatable life-threatening fetal injury, or if there is obvious impending or recent maternal death. A pediatric surgeon should participate in the evaluation and management of both the pregnant patient and the neonate delivered after maternal trauma, together with the obstetrician and neonatologist. Pregnant women should be hospitalized after trauma for appropriate evaluation and fetal monitoring, in the hope of decreasing traumarelated fetal deaths. In recent years, it is expected that every pediatric surgeon must be familiar with the treatment of pediatric trauma. The treatment of the traumatic pregnant woman and the fetus must be part of this skill, especially if the fetus is to be considered a patient.

28 Fetal and birth trauma

fetal organs or masses. Nevertheless, birth injuries still occur and represent an important problem for the clinician; the incidence of birth trauma is reported to be two to eight per 1000 live births.14,15 Birth injury is usually associated with unusual compressive or traction forces in association with abnormal presentation of the fetus. Factors that predispose birth injury include primiparity, cephalopelvic disproportion, dystocia, prematurity, prolonged labor, macrosomia, abnormal presentation, forceps application, version and extraction.12,14,15 The newborn at greatest risk for birth injury is the one in breech presentation.

Types of birth trauma HEAD INJURIES

(a)

(b) Figure 3.1 (a) X-ray of a neonate born to a mother who sustained accidental gunshot wounds to her abdomen. Note metallic pellet in the right thigh. (b) Clinical photograph of the same infant showing entry wound in the right thigh

Caput succedaneum Caput succedaneum is a diffuse edematous, occasionally hemorrhagic swelling of the scalp, superﬁcial to the periosteum occurring secondary to compression of the presenting part during prolonged labor. Usually, caput succedaneum requires no treatment and the swelling disappears spontaneously in a week or so. Rarely, hemorrhage into soft tissue may cause anemia that requires blood transfusion or may lead to hyperbilirubinemia or both.16 Cephalhematoma Cephalhematoma is a subperiosteal collection of blood most often found in the parietal region and sharply delineated by the surrounding suture lines (Fig. 3.2). In 10–25% of cephalhematomas there is an underlying skull fracture which is usually of linear type and clinically unimportant.17 The precise mechanism of production of cephalhematoma is not well established. Repeated buffeting of the fetal skull against the maternal pelvis during a prolonged labor and mechanical trauma caused by the use of forceps and vacuum extractor in

BIRTH TRAUMA Birth injuries are deﬁned as injuries associated with mechanical forces producing hemorrhage, edema, tissue disruption, or alteration of organ function occurring during the intrapartum period.12 With the improvement in obstetric techniques, increased frequency of cesarian section in potentially difﬁcult deliveries, decreased use of difﬁcult forceps and utilization of fetal heart rate and determination of acid–base status to monitor the fetus during labor, the incidence of birth injuries has decreased in recent years.13 Furthermore, recent advances in the use of prenatal ultrasonography have allowed early identiﬁcation of the risk factors for possible birth trauma, including fetal size and position and enlarged

Figure 3.2 Large cephalhematoma

Birth trauma 29

delivery have been implicated as important factors. Cephalhematomas have been reported to originate in utero, antipartum. Petrikovsky et al. found seven cases of cephalhematomas identiﬁed prenatally on 16 292 fetuses during comprehensive ultrasound examinations. Premature rupture of the membranes was seen and was suggested as an associated factor.18 Most cephalhematomas resolve spontaneously within a few weeks. Aspiration of the hematoma is contraindicated because of the risk of introducing infection. Only in the rare case of superinfection of the cephalhematoma is aspiration, drainage and antibiotic therapy indicated.15 Occasionally, serious complications such as anemia, jaundice, abscess, septicemia, meningitis, osteomyelitis, disseminated intravascular coagulation, shock with acute hemorrhage and depressed skull fractures have been reported in association with cephalhematomas.19–22 Management involves careful observation for these complications. Skull fractures Most of the skull fractures are linear, occurring in association with cephalhematomas and usually involving the parietal bones (Fig. 3.3a). No speciﬁc treatment is required for linear fractures, but skull X-rays should be repeated when the infant reaches 2–4 months of age to rule out ‘growing fracture of the skull’ associated with a leptomeningeal cyst (Fig. 3.3b). A leptomeningeal cyst can occur rarely if the trauma causing the linear fracture tears the underlying dura, thereby permitting herniation of the meninges and brain. This requires surgical intervention to avoid progressive brain damage.20,23 Depressed skull fractures are most often caused by pressure of the fetal head against the maternal pelvis or in association with forceps delivery in all cases of depressed fractures (Fig. 3.4). Several non-surgical techniques for elevation of depressed skull fracture in the newborn have been described, including suction with a breast pump or vacuum extractor,24–26 and by digital manipulation. Indications for surgical elevation of depressed skull fracture include:27 1 Radiographic evidence of bone fragments within the brain 2 Neurological deﬁcit 3 Signs of increased intracranial pressure 4 Failure to elevate the fracture by closed manipulation. Intracranial hemorrhage Intracranial hemorrhage following birth trauma may occur in the subarachnoid space, the subdural space or within the brain. Subarachnoid hemorrhage is the most common form of birth-related traumatic intracranial hemorrhage in the newborn.17 Blood in the subarachnoid space can be documented by lumbar puncture and the diagnosis conﬁrmed by computerized tomography (CT) scan.28 In

(a)

(b) Figure 3.3 (a) Linear fracture of left parietal bone at birth. (b) Three years later the patient presented with a pulsatile swelling in the left parietal region. X-ray shows an extensive bone defect due to leptomeningeal cyst

the vast majority of cases, traumatic subarachnoid hemorrhage is benign and does not require any treatment. Occasionally it may result in a communicating hydrocephalus. Subdural hemorrhage is caused by rupture of the cerebral veins bridging the subdural space, occurring as a result of excessive moulding of the baby’s head during labor or delivery. Most subdural hematomas are infratentorial and bilateral, but occasionally they have been described in the posterior fossa. Principal factors that predispose to the occurrence of subdural hematoma include large-size infants,17 breech delivery29 and forceps extraction in primiparous women.30 Clinical features of neonatal subdural hemorrhage may include pallor, vomiting, irritability, seizures, unequal pupils, drowsi-

30 Fetal and birth trauma

fontanelle. In most cases, subdural collections can be treated successfully with repeated taps. Rarely, membrane stripping or subdural space shunting may be required to deal with persistent subdural collections. Intracerebral hemorrhage Traumatic intracerebral hemorrhage is the least common of intracranial hemorrhage in the newborn.17 The clinical features are those of increased intracranial pressure. The diagnosis can be made with cerebral ultrasonography, CT scan or MRI, and regression or complications can be monitored with serial studies.32

SPINAL CORD INJURIES

Figure 3.4 Depressed fracture or right parietal bone following forceps delivery

ness, hypotonia, high-pitched cry, tense fontanelle and retinal hemorrhages. The diagnosis is conﬁrmed by a subdural tap, CT scan (Fig. 3.5) or magnetic resonance imaging (MRI).32 Ultrasonography is unlikely to be as accurate as a CT scan in diagnosing peripheral lesions in subarachnoid or subdural space.33 The treatment consists of repeated tapping of the subdural space using a 20gauge needle at the lateral margin of the anterior

Figure 3.5 CT brain scan without intravenous contrast medium in a newborn, showing blood in the subarachnoid space (large white arrow) and blood in the ﬂoor of 4th ventricle (small white arrow)

The incidence of birth injury to the spinal cord is difﬁcult to determine because most neonatal postmortem examinations do not include complete examination of the spinal cord.34 The leading cause of neonatal spinal cord injury is delivery of the fetus with marked hyperextension of the neck in a breech presentation. Approximately 75% of reported spinal cord injuries occurred in infants delivered vaginally in breech presentation.35 Other predisposing factors are prematurity, shoulder dystocia, intrauterine hypoxia and precipitous delivery.36 The application of compressive forceps to the fetal spine during fundal pressure to relieve shoulder dystocia has been reported to result in lower thoracic spinal cord injury in the newborn.37 The site of spinal cord injury following breech delivery is usually in the lower cervical and upper thoracic region, while injury following vertex presentation is usually located in the upper or midcervical level.17 The injury is usually caused by stretching of the cord and not by compression. The most common mechanism responsible for spinal cord injury is the use of excessive longitudinal traction on the trunk while the head is still engaged in the pelvis.26 The spinal cord is relatively inelastic compared with the vertebral fracture or dislocation, or both, and cord transection. The clinical manifestations of spinal cord injury may ﬁt into one of the following four recognized groups, depending on the severity of the damage incurred:19,38 1 Babies who are stillborn or die immediately after birth due to a high cervical or brainstem lesion 2 Neonates who die shortly after birth due to respiratory depression and complications and who generally have upper and midcervical lesions 3 Long-term survivors who have ﬂaccid paralysis in the neonatal period and proceed to develop spasticity and hyper-reﬂexia in the ensuing months 4 Those with minimal neurological signs or spasticity who are often classiﬁed as having cerebral palsy.39 The symptoms in these patients result from partial spinal cord injury or cerebral hypoxia. When spinal cord injury is suspected, deﬁnition of the underlying pathology can be difﬁcult using standard diagnostic

Birth trauma 31

procedures, including plain X-ray and CT, with or without myelography MRI, with its excellent deﬁnition and low risk of complication, is the best diagnostic tool available to evaluate clinically suspected spinal cord pathology.40,41 Spinal ultrasound is a good imaging method for guiding diagnosis of traumatic spinal cord lesions.42 Treatment of spinal cord injuries is supportive and includes physiotherapy, braces, and urological, orthopaedic and psychological care. Surgery has little to offer to patients with these types of injuries. Great emphasis should be placed on prevention of spinal cord injury in the newborn.

PERIPHERAL NERVE INJURIES Injury to the peripheral nerves in the newborn is usually caused by excessive traction or direct compression of nerves during delivery. The nerves most commonly involved are the brachial plexus, facial nerve and phrenic nerve. Brachial plexus injury With the improvement in obstetric techniques the incidence of birth-related brachial plexus injuries has decreased considerably in recent years. The incidence varies from 0.15–2.6 per 1000 live births.14,17,43–45 The injury is usually caused by traction and stretching of the plexus. All lesions occur in the plexus above the level of the clavicle and range from simple neuropraxia, classiﬁed by Sunderland46 as grade I, to full neurotemesis when associated with root avulsion, classiﬁed as grade V. Risk factors for brachial plexus injury include a prolonged and difﬁcult labor, breech presentation, large-size baby, and hypotonic, forceps delivery, vacuum extraction, shoulder dystocia and/or asphyxiated infant.47,48 Brachial plexus injury has been divided into three main types depending on the site of the injury: 1 Erb’s palsy, which results from injury of the ﬁfth and sixth cervical nerve roots, is by far the most common type of injury. The affected arm hangs limply adducted and internally rotated at the shoulder, and extended and pronated at the elbow with ﬂexed wrist in the typical ‘waiter’s tip’ posture (Fig. 3.6). The Moro, biceps and redial reﬂexes are absent on the affected side. The grasp reﬂex is intact. These clinical ﬁndings are the result of paralysis of the deltoid, supraspinatus, infraspinatus, brachioradialis and supinator brevis muscles. 2 Klumpke’s paralysis results from injury of the eighth cervical and ﬁrst thoracic nerve roots and is extremely rare as an isolated entity. The intrinsic muscles of the hand and ﬂexors of the wrist and ﬁngers are affected. The grasp reﬂex is absent Injury involving the cervical sympathetic ﬁbres of the ﬁrst thoracic root may result in ipsilateral Horner syndrome.

Figure 3.6 Erb’s palsy. Characteristic deformity of right arm

3 Injury to the entire brachial plexus results in a ﬂaccid arm with absence of sweating, sensation and deep tendon reﬂexes. The differential diagnosis includes: fracture of the clavicle or humerus, traumatic epiphysiolysis of the proximal epiphysis of the humerus, and shoulder dislocation.48 These injuries can of course occur in addition to the plexus paralysis.49 Another associated injury is a phrenic nerve palsy.44 A radiograph of the shoulder, upper arm and clavicle should be taken. A chest X-ray should be obtained because of the possibility of an associated phrenic nerve palsy. Electromyography, although of limited value, may be useful in determining the extent and site of injury and evaluating the prognosis.48, 50 Most neonates with brachial plexus injury make a complete or partial recovery on conservative treatment.17,44 The main principle of management is to maintain the range of ‘motion’ in the affected joints. Treatment should be delayed for a period of 3–4 weeks after the trauma, in which immobilization of the hand and stretched nerve ﬁbers will allow a spontaneous cure. During the ﬁrst 4 weeks, the arm has to be adducted to the thorax. Abduction and external rotation position of the shoulder must be prevented due to considerable tension on the brachial plexus in that position. In the other joints, careful passive physiotherapy should be carried out. Thereafter, a gentle range of motion exercises to shoulder, elbow, wrist and small joints of the hand may have to be started. The prognosis of brachial plexus paralysis is better in the Erb’s patient than in the patient with the Klumpke variety and in both of these groups is better than in total paralysis. In the majority of Erb’s palsy cases, a partial or

32 Fetal and birth trauma

complete recovery can be achieved.51 Surgical exploration and repair of brachial plexus birth injuries are recommended only when there is no recovery of the biceps by 3 months of age. An electromyography and myelogram with CT scanning are performed preoperatively.48 Advances in microsurgical techniques and reconstruction of the injured plexus by grafting from the dural nerve can signiﬁcantly improve the functional result.48,52,53 Facial nerve injury Facial palsy secondary to birth trauma is usually unilateral and most commonly follows compression of the peripheral portion of the nerve, either near its emergence from the stylomastoid foramen or where the nerve transverses the ramus of the mandible. The mechanism of injury is usually either direct trauma from forceps or compression of the side of the face and nerve against the sacral promontory. The affected infant has absent or decreased forehead wrinkling, a persistently open eye, a decreased nasolabial fold and ﬂattening of the corner of the mouth on the affected side (Fig. 3.7). Treatment is conservative, since spontaneous recovery occurs within 1 month in most cases of birth-related facial palsy.15,47 Initial treatment should be directed at protecting the corneal epithelium from drying with the use of methylcellulose drops instilled every 4 hours. Rarely, there is need for surgical intervention and neurolysis or a nerve cable transplant for the injured or degenerative facial nerve, after conﬁrming the diagnosis by electromyographic and electroneurographic tests.54

Phrenic nerve injury Diaphragmatic paralysis in the neonate results from stretching or avulsion of the fourth and ﬁfth cervical roots, which form the phrenic nerve. The most common cause of phrenic nerve injury is a difﬁcult breech delivery. The majority of injuries are unilateral. Bilateral diaphragmatic paralysis is rare.55 Approximately 75% of cases of birth-related phrenic nerve injury have an associated brachial plexus injury.56,57 The clinical features of diaphragmatic paralysis are non-speciﬁc and include respiratory distress with tachypnea, cyanosis and recurrent atelectasis or pneumonia. Chest X-ray demonstrates an elevated hemidiaphragm about two intercostal spaces higher than the adjacent diaphragm (Fig. 3.8a). Diagnosis is conﬁrmed on ﬂuoroscopy, which shows an immobile diaphragm or an abnormal elevation of the diaphragm during inspiration constituting paradoxical movement.58 Real-time ultrasonography can also be employed to diagnose phrenic nerve paralysis and can be performed in the intensive care unit in very young babies (Fig. 3.8b). Most infants with diaphragmatic paralysis make a complete recovery after treatment with oxygen, chest physiotherapy and antibiotics (Fig. 3.8c). A few patients who have severe or increasing respiratory distress may be managed by continuous positive airway pressure (CPAP). Surgery may be required if there is persistent paralysis after 2 weeks of mechanical ventilation or 3 months of medical treatment. The procedures employed include plication of the diaphragm17 or incision and replacement of the diaphragm.59

INTRA-ABDOMINAL INJURIES Birth trauma involving intra-abdominal organs is relatively uncommon. The organs most commonly involved are the liver, spleen, adrenal and kidney.

Figure 3.7 Left facial nerve palsy following difﬁcult forceps. Note obliteration of left nasolabial fold with typical deformity of mouth and wide-open left eye

Liver The liver is the most commonly injured abdominal organ during the birth process. Factors that predispose to liver trauma include breech presentation, infants with hepatomegaly, large infants, prematurity and coagulation disorders.15 The mechanism of birth-related liver injury is thought to be either: (1) thoracic compression and pulling of the hepatic ligaments with consequent tearing of the liver parenchyma, or (2) direct pressure on the liver leading to subcapsular hemorrhage or rupture.15 Hepatic trauma more commonly results in subcapsular hemorrhage than actual rupture of the liver. The infant with subcapsular hemorrhage usually appears to be normal for the ﬁrst 3 days of life, when the capsule ruptures and there is extravasation of blood into the peritoneal cavity. This is followed by sudden circulatory collapse, abdominal distension and a rapid drop in the hematocrit value. If the processus vaginalis is patent, blood may be seen in the scrotum, suggesting hemoperitoneum. In

Birth trauma 33

(a)

(c) Figure 3.8 Phrenic nerve paralysis. (a) Chest radiography shows elevated right diaphragm. (b) Transverse real-time sonogram showing blurring in the region of left diaphragm due to respiratory movement. Right diaphragm did not move and is sharply outlined along the liver. (c) Chest X-ray 3 months later shows normal right diaphragm after conservative treatment

immediate laparotomy, with evacuation of the hematoma and repair of any laceration by sutures or by ﬁbrin glue.60

(b)

patients with primary rupture of the liver, major intraperitoneal bleeding occurs immediately, resulting in severe shock and abdominal distension. Abdominal radiographs are not usually very helpful, but may show uniform opacity of the abdomen, indicating free intraperitoneal ﬂuid. Abdominal ultrasonography may conﬁrm the diagnosis and is also useful in differentiating a solid liver tumor from an unruptured subcapsular hemorrhage. A CT scan is recommended, only if the patient is hemodynamically stable (Fig. 3.9a–d). Abdominal paracentesis is the procedure of choice for rapid diagnosis of hemoperitoneum. Immediate management consists of blood transfusion to restore the blood volume and recognition and correction of any coagulation disorder. This is followed by an

Spleen Rupture of the spleen in the newborn occurs much less often than does rupture of the liver. The predisposing factors and mechanism of injury are quite similar to those of rupture of the liver. Although splenomegaly increases the risk, the vast majority of splenic injuries occur in spleen of normal size.20 The presenting features are cardiovascular collapse and abdominal distension. Abdominal radiographs may indicate free ﬂuid in the peritoneal cavity. Abdominal paracentesis will conﬁrm hemoperitoneum. Management consists of adequate blood transfusion followed by exploratory laparotomy. In the past, management of splenic rupture has been splenectomy. In recent years, repair of the spleen has been advocated because of the risk of subsequent serious infections following splenectomy.61 Since there is a critical mass of spleen which prevents overwhelming post-splenectomy infection (OPSI),62,63 every surgeon should do the utmost to preserve as much of the injured spleen as possible. Fibrin glue, splenorrhaphy or partial splenectomy are the

34 Fetal and birth trauma

(a)

(b)

(c)

(d)

Figure 3.9 Newborn who developed a distended abdomen post-delivery. (a,b) Sonographic scan at 36 h shows echo-poor material due to fresh hemorrhage (white arrow) between the anterior aspect of the right kidney (K) and the inferior aspect of the right lobe of liver (L). (c) Scan through left lobe of liver demonstrating an area of increased echogenicity in keeping with hemorrhage at site of laceration (curved arrows). (d) Laceration in left lobe conﬁrmed on CT scan (black arrow)

preferred surgical procedures.15,64–66 This conservative surgical approach is advocated not only because of the OPSI, but also because of the absence of regeneration of the injured spleen after partial splenectomy, which has been proven in animals.67

Adrenal Neonatal adrenal hemorrhage occurs most commonly following a prolonged and difﬁcult labor, culminating

in a traumatic delivery. Other contributing factors include asphyxia, prematurity, placental hemorrhage, hemorrhagic disease of the newborn, septicemia, renal vein thrombosis, increased vascularity, and congenital syphilis.68–73 The right adrenal is involved in over 70% of cases, with bilateral involvement in 5–10%.74,75 The presenting features vary with the degree of bleeding. The classical adrenal hemorrhage usually presents between birth and the fourth day of life as an abdominal mass with fever and jaundice or anemia.73 The differential

Birth trauma 35

diagnosis may include adrenal cyst, neuroblastoma and Wilms tumour. Diagnosis of neonatal adrenal hemorrhage may be conﬁrmed with a combination of ultrasound and i.v. pyelogram. Sonography would reveal a suprarenal mass that initially is echogenic, and subsequent changes to a cyst-like structure probably indicating fragmentation of the clot (Fig. 3.10a,b). An i.v. pyelogram should demonstrate downward displacement of the kidney on the affected side. An early total body opaciﬁcation ﬁlm may show a lucent region above the kidney. A ‘rim’ suprarenal calciﬁcation may be seen on abdominal radiographs 2–4 weeks after hemorrhage.68,76 In patients with retroperitoneal hemorrhage, treatment consists of blood transfusion, close observation and follow-up ultrasound studies. In infants with massive intra-peritoneal hemorrhage, surgical intervention con-

sists of abdominal paracentesis, laparotomy, evacuation of hematoma, ligation of bleeders or adrenalectomy if indicated. It must be remembered that the underlying pathology may be a neuroblastoma,77,78 and a biopsy should always be taken. Infrequently, a suspicion of an adrenal abscess ensues. In such a situation, a drainage procedure must be performed either percutaneously with ultrasound guidance or by operative exploration. Kidney Birth-related trauma is rare. Rupture of the kidney in the newborn is usually associated with an underlying congenital anomaly.79 The presenting signs are hematuria and renal mass. An i.v. pyelogram may show absence of excretion or leakage of contrast through the renal parenchyma into the perirenal space. Renal ultrasonography may demonstrate renal rupture (Fig. 3.11) or ascites. Treatment consists of conservative management if possible. Only in cases of severe bleeding or a total rupture of parenchyma or pelvis is a laparotomy indicated, with the correction of underlying congenital anomaly whenever it is necessary.

(a) (a)

(b)

(b)

Figure 3.10 (a) Right suprarenal echo-poor mass representing a right adrenal hemorrhage (between cursors) in an infant who suffered birth asphyxia. (b) Scan performed 1 month later, showing that hemorrhage has almost cleared. Small residual echo-poor area persists (white arrow)

Figure 3.11 (a) Longitudinal sonogram showing an echolucent area in upper pole of right kidney consistent with an intracapsular rupture. Both ureters were hydronephrotic with dilated bladder on sonography. (b) Voiding cystogram in the same patient conﬁrmed posterior urethral valves

36 Fetal and birth trauma

BONY INJURIES Fractures due to birth trauma almost always involve the clavicle, humerus or femur. Epiphyseal separations usually involve upper an lower humeral and upper femoral epiphyses. Dislocations caused by birth trauma are rare. Fracture of the clavicle Fracture of the clavicle is the most common fracture in the newborn, usually occurring during a difﬁcult delivery associated with large infants, breech presentation and shoulder dystocia.80 Most fractures are of the greenstick type, occurring in the middle third of the clavicle, but occasionally the fracture is complete (Fig. 3.12). Undisplaced fractures require no treatment. Fractures with marked displacement should be immobilized with a ﬁgure-of-eight bandage. Recovery is usually excellent.

Epiphyseal separations The epiphyseal separation or fracture occurs through the hypertrophied layer of cartilage cells in the epiphysis. The most common cause is a difﬁcult breech delivery.81 A fracture through the proximal epiphyseal plate of the humerus is the most common epiphyseal cartilage injury. Fractures entirely conﬁned to the epiphyseal cartilage cannot be demonstrated radiologically. However, in many cases the fracture extends through a part of the metaphysis, separating a tiny bony fragment. This fragment is attached to the epiphysis and if no displacement of the epiphysis has occurred, the fragment may be the only radiographic evidence of fracture. An increased distance of the metaphysis from the joint compared with the opposite side can also indicate fracture through the epiphyseal plate. After 1–2 weeks, callus becomes visible, conﬁrming the nature of the injury. Diagnosis at the initial stage has to be made primarily on clinical ﬁndings of pain on passive motion, swelling and impaired movement around the joint. Recent reports suggest that epiphyseal separation can be studied by sonography and without the common use of arthrography.81,82 Treatment of a fracture of the proximal epiphysis of the humerus consists of immobilization of the arm by the side with a sling in 90° ﬂexion. Epiphysiolysis of the proximal femur is sometimes confused with congenital dislocation of the hip and septic arthritis, and can occur not only after normal delivery but also after delivery by cesarian section.83 Treatment for a fracture of the proximal epiphysis of the femur is by traction and spica cast for 2 months.

TRAUMA TO THE GENITALIA Figure 3.12 Fracture of right clavicle. Typical fracture of middle third of clavicle following forceps delivery

Fracture of the humerus Fractures of the humerus usually occur in the middle third of the shaft and are either transverse or spiral. They are usually greenstick fractures, but occasionally complete fracture with overriding of fragments may occur. The most common mechanisms responsible for fracture are believed to be traction on the extended arm in the breech presentations and axillary traction to disengage an impacted shoulder in vertex presentations. Treatment consists of strapping the arm to the chest. Complete healing of the fracture fragments usually occurs by 3 weeks. Fracture of the femur Femoral shaft fractures usually occur in the middle third and are transverse. The injury usually follows a breech delivery. X-ray invariably shows overriding of the fracture fragments. Treatment consists of Bryant’s traction for 3–4 weeks. The prognosis in femoral fractures is usually excellent.

The breech delivery is the common cause of tissue injuries involving the external genitalia. Edema, ecchymoses and hematomas of the scrotum or the labia majora can occur. No treatment is needed. Spontaneous resolution of edema occurs within 24–48 hours and of discoloration within 4–5 days. If the tunica vaginalis is injured and blood ﬁlls its cavity, a hematocele is formed. The differential diagnosis should include neonatal torsion and patent processus vaginalis.84 An iatrogenic injury to the scrotum with resultant castration during breech extraction has been reported.85

REFERENCES 1. Peckman CH, King RW. A study of intercurrent conditions observed during pregnancy. Am J Obstet Gynecol 1963; 87:609–24. 2. Patterson RM. Trauma in pregnancy. Clin Obstet Gynecol 1984; 27:32–8. 3. Hoff WS, ‘Amelio LF, Tinkoff GH et al. Maternal predictors of fetal demise in trauma during pregnancy. Surg Gynecol Obstet 1991; 172:175–80.

Referernces 37 4. Farmer DL, Adzick NS, Crombleholme WR et al. Fetal trauma: relation to maternal injury. J Pediatr Surg 1990; 25:711–14. 5. Nash P. Trauma in pregnancy Br Med J 1990; 301:974–6. 6. Committee on Trauma. Trauma in pregnancy. Advanced Trauma Life Support Program (ATLS), Instructor Manual Committee on Trauma, American College of Surgeons, 1998. 7. Ciuil ID, Talucci RC, Schwab CW. Abdominal trauma. J Trauma 1988; 28:708–10. 8. Kettel LM, Branch DW, Scott JR. Occult placental abruption after maternal trauma. Obstet Gynec 1988; 71:449–53. 9. Arthur RK. Postmortem ceserean section. Am Obstet Gynecol 1978; 132:175–9. 10. Buchsbaum HJ, Staples PP. Self inﬂicted gun shot wound to the pregnant uterus: report of two cases.Obstet Gynecol 1985; 65:32S–35S. 11. Zikovic S, Milosevic V, Stanivukovic V. Prenatal gunshot perforation of the colon. J Pediatr Surg 1976; 11:591–2. 12. Curran JS. Birth associated injury. Clin Perinatol 1981; 111–29. 13. Levine MG, Holroye J, Woods JR et al. Birth trauma: incidence and predisposing factors. Obstet Gynecol 1984; 63:792–5. 14. Berle P. Incidence of birth injuries to newborn infants in relation to birth weight. An analysis of the Hessan Perinatal Study. Geburtsch Frauenheilk 1995; 55:23–7. 15. Schullinger JM. Birth trauma. Pediatr Clin North Am 1993; 40:1351–8. 16. Murphy WJ. Birth trauma. In: Cloherty JP, Stark AR, editors. Manual of Neonatal Care. 2nd edn. Boston: Little, Brown, 1985: 251–5. 17. Painter MJ, Bergmen I. Obstectrical trauma to the neonatal central and peripheral nervous system. Semin Perinat 1982; 6:89–104. 18. Petrikovsky BM, Schneider E, Smith-Levitin M, Gross B. Cephalhematoma and caput succedaneum: do they always occur in labor. Am J Obstet Gynecol 1998; 179:906–8. 19. Zelson C, Lee SJ, Pearl, M. The incidence of skull fractures underlying cephalhaematomas in newborn infants. J Pediatr 1974; 85:371–3. 20. Gresham EL. Birth trauma. Pediatr Clin Am 1975; 22:317–28. 21. Curran JS. Birth associate injury. Clin Perinatol 1981; 8:111–29. 22. Raffensperger JG. Trauma in neonate. In: Swenson’s Pedriatic Surgery. 5th edn. Norwalk, CN: Appleton and Lange, 1990: 339–42. 23. Kingsley D, Till K, Hoare R. Growing fractures of the skull. J Neurol Neurosurg Psychiatry 1978; 41:312–18. 24. Schrager GO. Elevation of depressed skull fractures with a breast pump. J Pedriatr 1970; 77:300–1. 25. Saunders BS, Lazoritz S, McArtor RD et al. Depressed skull fracture in the neonate. J Neurosurg 1979; 50:512–14. 26. Tan KL. Elevation of congenital depressed fracture of the

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skull by the vacuum extractor. Acta Periatr Scand 1974; 63:562–4. Loeser JD, Kilburn HL, Jolley T. Management of depressed fracture in the newborn. J Neurosurg 1976; 44:62–4. Kuban K. Intracranial hemorrhage. In: Cloherty JP, Stark AR, editors. Manual of Neonatal Care. 2nd edn. Boston: Little, Brown, 1985: 303–14. Abroms IF, Bresnan MJ, Zucherman JE et al. Cervical cord injuries secondary to hyperextension of the head in breech presentations. Obstet Gynecol 1973; 41:369–78. O’Driscoll K, Meagher , Macdonald D et al. Traumatic intracranial haemorrhage in ﬁrstborn infants and delivery with obstetric forceps. Br J Obstet Gynec 1981; 88:577–81. Hanigan WC, Morgan AM, Stahlberg LK et al. Tentorial hemorrhage associated with vacuum extraction. Pedriatrics 1990; 85:534–9. Barnes PD. Neuroimaging and the timing of fetal and neonatal brain injury. J Perinatol 2001; 21:44–60. Johnson ML, Rumack CM, Mannes EJ et al. Detection of neonatal intracranial hemorrhage utilising real time and static ultrasound. J Clin Ultrasound 1981; 9:427–33. Bucher HU, Boltshauser E, Friderich J et al. Birth injury to the spinal cord. Helv Paediat Acta 1979; 34:517–27. Byers RK. Spinal cord injuries at birth. Ev Med Chil Neurol 1975; 17:103–10. De Sousa SW, Davis JA. Spinal cord damage in a newborn infant. Arch Dis Child 1974; 49:70–71. Hankins GD. Lower thoracic spinal cord injury – a severe complication of shoulder dystocia. Am J Perinatol 1998; 15:443–4. Koch BM, Eng GM. Neonatal spinal cord injury. Arch Phys Med Rehabil 1979; 60:378–81. Nelson KB, Ellenberg JH. Obstetric complications as risk factors for cerebral palsy or seizure disorders. J Am Med Assoc 1984; 251:1843–8. Lanska MJ, Roessmann U, Wiznitzer M. Magnetic resonance imaging in cervical cor lesions in the newborn infant. Pediatr Radiol 1990; 24:245–7. Mills JF, Dargaville PA, Colerman LT, Rosenfeld JV, Ekert PG. Upper cervical spinal cord injury in neonates: the use of magnetic resonance imaging. J Pediatr 2001; 138:105–8. Filippigh P, Clapuyt P, Debauche C et al. Sonographic evaluation of traumatic spinal cord lesions in the newborn infant. Pedriatr Radiol 1994; 24:245–7. Jahnke AH Jr, Bovill DF, McCaroll HR Jr et al. Persistant brachial plexus birth palsies. J Pediatr Orthorp 1991; 11:533–7. Hardy AE. Birth injuries of the brachial plexus: incidence and prognosis. J Bone Joint Surg 1981; 63B:98–101. Gilbert WM, Nesbitt TS, Danielson B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol 1999; 93:536–40. Sunderland S. Nerves and Nerve Injuries. Edinburgh: Churchill Livingstone, 1978: 133. Eng GM. Neuromuscular diseases. In: Avery GB, editor. Neonatalogy. 2nd edn. Philadelphia: JB Lippincott, 1980: 987–92.

38 Fetal and birth trauma 48. Hunt D. Surgical management of brachial plexus birth injuries. Ev Me Child Neurol 1998; 30:824–8. 49. Gordon M, Rich H, Deutschberger J et al. The immediate and long term outcome of obstetric trauma. Brachial plexus paralysis. Am J Obstet Gynecol 1973; 117:51–6. 50. Kwast O. Electrophysiological assessment of maturation of regenerating motor nerve ﬁbres in infants with brachial plexus palsy. Dev Med Child Neurol 1989; 31:56–65. 51. Donn SM, Faix RG. Long term prognosis for the infant with severe birth trauma. Clin Perinat 1983; 10:507–20. 52. Laurent JP, Lee RT. Birth related upper brachial plexus injuries in infants: operative and nonoperative approaches. J Child Neurol 1944; 9:111–17. 53. Piatt JH Jr. Neurosurgical management of birth injuries of the brachial plexus. Neurosurg Clin N Am 1991; 2:175–85. 54. Kornblut AD. Facial nerve injuries in children. Ear Nose Throat 1977; 56:369–76. 55. Zajkowski EJ, Kravath RE. Bilateral diaphragmatic paralysis in the newborn infant: treatment with nasal continuous positive airway pressure. Chest 1979; 75:392–4. 56. Greene W, L’Heureux P, Hunt CE. Paralysis of the diaphragm. Am J Dis Child 1975; 129:1402–1405. 57. Weisman L, Woodall J, Merenstein, G. Constant negative pressure in the treatment of diaphragmatic paralysis secondary to birth injury. Birth Def 1976; 12:297–302. 58. Rugtveit J, Ek J. Isolated birth injury of the phrenic nerve. Ev Med Child Neurol 1989; 31:119. 59. Bowen TE, Zajtchuk R, Albus RA. Diaphragmatic paralysis managed by diaphramatic replacement. Ann Thoracic Surg 1982; 33:184–8. 60. Blocker SH, Ternberg JL. Traumatic liver laceration in the newborn: repair with ﬁbrin glue. J Pedriatr Surg 1986; 21:369–71. 61. Balfranz JR, Nesbit ME, Jarvis C et al. Overwhelming sepsis following splenectomy for trauma. J Pediatr 1976; 88:458–60. 62. Van Wyck DB, Witte MH, Witte CL et al. Critical splenic mass for survival from experimental pneumococcemia. J Surg Res 1980; 28:14–17. 63. Coil JA Jr, Ickerman JD, Horner SR et al. Pulmonary infection in splenectomized mice: protection by splenic remnant. J Surg Res 1980; 28:18–22. 64. Chryss C, Aaron WS. Successful treatment for rupture of normal spleen in newborn. Am J Dis Child 1980; 134:18–19. 65. Matsuyama S, Suzuki N, Nagamachi Y. Rupture of the spleen in the newborn: treatment without splenectomy. J Ped Surg 1976; 11:115–16. 66. Bickler S, Ramachandran V, Gittes GK, Alonso M, Snyder CL. Nonoperative management of newborn splenic injury: a case report. J Ped Surg 2000; 35:500–1.

67. Bar-Maor JA, Sweed Y, Shoshany G. Does the spleen regenerate after partial splenectomy in the dog? J Pediatr Surg 1988; 23:128–9. 68. Mittelstaedt CA, Volberg FM, Merten DF et al. The sonographic diagnosis of neonatal adrenal hemorrhage. Radiology 1979; 131:453–7. 69. Eklof O, Grotte G, Jorulf H et al. Perinatal haemorrhagic necrosis of the adrenal gland. A clinical and radiological evaluation of 24 consecutive cases. Pediatr Radiol 1975; 4:31–6. 70. Khuri FJ, Alton DJ, Hardy BE et al. Adrenal haemorrhage in neonates: report of 5 cases and review of the literature. J Urol 1980; 124:684–7. 71. Pery M, Kaftori JK, Bar-Maor JA. Sonography for diagnosis and follow-up of neonatal adrenal haemorrhage. J Clin Ultrasound 1981; 9:397–401. 72. Lebowitz JM, Belman AB. Simultaneous idiopathic adrenal haemorrhage and renal vein thrombosis in the newborn. J Urol 1983; 129:574–6. 73. Cheves H, Bledsoe F, Rhea WG et al. Adrenal hemorrhage with incomplete rotation of the colon leading to early duodenal obstruction: case report and review of the literature. J Pediatr Surg 1989; 24:300–2. 74. Gross M, Kottmeier PK, Waterhouse K. Diagnosis and treatment of neonatal adrenal hemorrhage. J Pediatr Surg 1967; 2:308–12. 75. Pond GD, Haber K. Echography: a new approach to diagnosis of adrenal hemorrhage. J Can Ass Radiol 1976; 27:40–4. 76. Brill PW, Krasna IH, Aaron H. An early rim sign in neonatal adrenal hemorrhage. Am J Roentgenol 1976; 127:289–91. 77. Murhty TVM, Irving IM, Lister J. Massive adrenal hemorrhage in neonatal neuroblastoma. J Pediatr Surg 1978; 13:31–4. 78. Croitoru P, Sinsky AB, Laberge JM.Cystic neuroblastoma. J Pediatr Surg 1992; 27:1320–1321. 79. Cromie WJ. Genitourinary injuries in the neonate. Perinatal Care Clin Pediatr 1979; 18:292–5. 80. Hsu TY, Hung FC, Lu YJ et al. Neonatal clavicular fracture: Clinical analysis of incidence, predisposing factors, diagnosis and outcome. Amer J Perinatal 2002; 19:17–21. 81. Zeiger M, Dorr U, Schulz RD. Sonography of slipped humeral epiphysis due to birth injury. Pediatr Radiol 1987; 17:425–6. 82. Broker FH, Burbach T. Ultrasonic diagnosis of separation of the proximal humeral epiphysis in the new-born. J Bone Joint Surg 1990; 72A:187–91. 83. Prevot J, Lascombes P, Blanquart D. Geburtstraumatische epiphysenlosung des proximalen femurs 4 falle. Z Kinerchir 1989; 44:289–92. 84. Finan BF, Redman JF. Neonatal genital trauma. Urology 1985; 25:532–3. 85. Samuel G. Castration at birth. Br Med J 1988; 297:1313–14.

4 Transport of the surgical neonate PREM PURI AND DIANE DE CALUWÉ

INTRODUCTION The successful outcome of an operation performed on a newborn with congenital anomalies depends not only on the skill of the pediatric surgeon, but also on that of a large team consisting of a pediatrician, anesthetist, radiologist, pathologist, biochemist, nurses, and others necessary for dealing satisfactorily with the newborn subjected to surgery. Advances in neonatal intensive care (NIC) dictate that effective and efﬁcient treatment of the sickest neonates can only be available by concentrating resources such as equipment and skilled staff in a few specialist pediatric centers which have responsibilities to a particular region.1,2 Neonates with congenital malformations will therefore have to be transported safely to these centers, sometimes over considerable distances.

PRENATAL TRANSFER It has been stated before that prenatal transport of term fetuses with antenatally diagnosed surgical abnormalities does not improve the outcome if the quality of care before and during transport is good.3 The distance involved does not inﬂuence the outcome. However, several other studies support the in utero transportation of the high-risk fetus, particularly the very-low-birth-weight (VLBW) babies and those with life-threatening neonatal surgical problems.4,5,6,7 Hypothermia remains a main problem in these babies and it adversely affects neonatal outcome.8 Poor post-transfer temperature seems to be an independent predictor of death.8,9 Therefore, whenever possible, threatening preterm delivery before 28 weeks’ gestation should be converted to in utero transport.8

PRE-TRANSFER MANAGEMENT Transferring a newborn without proper stabilization is

associated with increased morbidity and mortality. The golden rule still is that no neonate should be transported unless his or her condition has been sufﬁciently stabilized to survive the expected duration of the journey.7 Careful attention to pre-transfer management will provide a higher margin of safety during the journey, when access to the patient is restricted and it may be difﬁcult to provide adequate treatment should problems arise.3 All babies must be properly resuscitated before the journey is undertaken.7 Thermoregulation requires critical attention. Hypothermia causes an increase in the neonate’s metabolic rate with a subsequent increase in glucose and oxygen use ensuing acidosis and if not reversed development of persistent pulmonary hypertension of the neonate.6 This can all be avoided by warming the baby to a core temperature of at least 35°C and using a pre-warmed transport incubator in a pre-warmed ambulance, with the thermal environment adjusted so to maintain correct rectal temperature.10 It should be ensured that the airway is clear and that the baby is well oxygenated, and that ventilation can be maintained during transport. If any risk for deterioration of spontaneous breathing is present, the child should be intubated before departure.3 Every neonate requiring transport must have an adequately sized functioning nasogastric tube to prevent vomiting and aspiration. It should be taped securely in position and kept on open drainage or attached to a low-pressure suction pump which should be aspirated every 10–20 minutes to prevent occlusion.3 Two reliable and secure routes of venous access should be in place. Many surgical newborns have abnormal losses of water, electrolytes and proteins, which must be replaced to prevent hypovolemia and shock. Intravenous ﬂuids must be initiated immediately and sometimes initiation of inotropic vasopressors such as dopamine or dobutamine may be warranted.3,4,6 Glucose homeostasis must also be maintained and close monitoring of glucose blood levels should be performed regularly and corrected if necessary.6 Furthermore, a number of essential data should be transferred with the infant. A summary of the clinical

40 Transport of the surgical neonate

history and any X-ray ﬁlms taken should accompany the patient. All laboratory reports should be included, and the time noted when tests were carried out. It should be clearly documented whether vitamin K was given. Prophylactic broad-spectrum antibiotics should be started if there is a risk of infection. A sample of maternal blood should be sent to facilitate crossmatching. A parental consent for operation, signed by the mother if the parents are not married, should be sent together with a contactable phone number to be able to explain to the parents the surgical condition of their child and the operative procedure.

TRANSPORT TEAM Local and individual circumstances will determine whether the referring or specialist center will send a transport team. The composition of the team may also vary from institution to institution. The team should ideally consist of a pediatrician and a trained neonatal nurse familiar with and able to anticipate potential problems associated with speciﬁc lesions.6,8 They should be familiar with all equipment and its function and should be experienced in stabilizing an infant in suboptimal conditions. Careful delineation of responsibility is important. Some institutions have formed a nursing transport team trained and experienced in the transfer of sick neonates. They guide the doctors and operate the equipment.9

the alveolar membranes becomes more difﬁcult. To maintain the same level of oxygenation, a higher percentage of oxygen may be required. Moreover, the barometric pressure will also decrease with increasing altitude, the volume of gas will increase and any air trapped in a body cavity will expand. This could have a dramatic effect on pulmonary function.6 It is very important to have well-functioning medical and nursing equipment.8 Monitoring is essential during transfer because clinical assessment can be limited due to suboptimal lighting, noise, vibration and lack of space. Invasive and non-invasive measures of arterial pressure, pulse oxymetry, electrocardiograph (ECG), core temperature measurement and pressure transducers for central venous and intracranial pressure readouts must be present. All monitors and syringe pumps should be battery operated.4 A range of airway and ventilatory equipment including self-inﬂating resuscitation bags, masks, airways, laryngoscope handles and blades, uncuffed neonatal endotracheal tubes of various size, humidiﬁers, portable suction apparatus and oxygen supplies must be available in case airway problems should occur. Additionally, an appropriately stocked box including i.v. supplies including intraosseous needles, chest tubes and umbilical catheter kits with sterile equipment and emergency drugs should be present.6 After each transport, a record documenting equipment used should be ﬁlled in and the equipment unit checked and restocked. The equipment kit should be controlled weekly by the neonatal transport nurse on duty and servicing of the transport incubator and the monitoring equipment should be carried out.8

TRANSPORT VEHICLES TRANSPORT INCUBATORS Selection of a transport vehicle is dependent on the distance travelled, geography, weather conditions, the nature of the infant’s problem and the need for speed.1 A variety of conveyances are in popular use, including ground ambulances, helicopters and ﬁxed-wing aircraft. Ambulance transport is generally preferable to that by helicopter but is rather slow. Air transport has several disadvantages. A major disadvantage is that separate ground transport must be arranged at both ends to move the baby between the airport and the hospital. The noise and vibrations and poor lighting makes in-ﬂight monitoring of the infant difﬁcult in a rotary-wing aircraft (helicopter).6,7,11 This problem is not experienced to such a signiﬁcant degree in a ﬁxed-wing aircraft’. The transport incubator should be securely strapped in case of turbulence of the plane. The infant in the incubator should be well ﬁxed with a lockable piece of cloth. Moreover, the space in a plane is limited and can cause difﬁculties in manipulating the airway.6,7 The negative effects of altitude on the neonate’s body can be detrimental.11 With increasing altitude, the partial pressure of oxygen decreases, therefore diffusion of oxygen across

The currently available portable incubator (Fig. 4.1) is designed and equipped for transporting sick newborns.12

Figure 4.1 A portable incubator

Special considerations 41

It is a central piece of equipment that has to provide warmth, visibility and access. It should be able to run on batteries and be capable of providing heat for an extended period of time in various ambient temperature extremes. It should be equipped with a cardiorespiratory monitor, pulse oxymeter, infusion pump, oxygen analyzer, oxygen and air cylinders, double Plexiglas walls and shock-absorbing wheels.6

TRANSPORT PROCEDURE The perfect transfer does not exist yet. It involves early and effective communication between the referring and specialist center, stabilization of the baby pre-transfer and provision of special needs and care during transport.3 All too often, transport is hastily arranged and conducted in a vacuum of communication, resulting in preventable catastrophes such as vomiting and aspiration, hypothermia, hypovolemia and airway obstruction.5 Ideally, transfer is arranged at as senior a level as possible, i.e. a telephone conversation between a specialist pediatric registrar or consultant pediatrician in the referring center and specialist surgical registrar or consultant pediatric surgeon in the receiving center.13 A standardized transfer-form booklet was introduced by the current authors in their institution. A form is ﬁlled in during the initial conversation with the referring center. It contains all the necessary medical and practical details regarding actual transfer and speciﬁc management of the surgical problem of the newborn. By increasing awareness of potential problems, referring hospitals will be less inclined to neglect precise instructions concerning speciﬁc surgical conditions.

RECEIVING CENTER Continuation of care is essential to improving neonatal outcome. On arrival at the tertiary center, a brief report of prenatal, labor, and delivery history should be given by the transport nurse to the newborn intensive care nurse, together with details of the newborn’s resuscitation and any problems experienced during transfer.6 The accompanying pediatrician should review the baby and all documents together with the accepting surgeon and anesthetist, if necessary. The parents should be introduced to all staff who will be involved in the care of their baby. Every procedure should be explained in a clear and comprehensive language to avoid confusion and parental fear. The consent form should be updated if necessary. Blood tests and radiological examinations can be ordered subsequently.

SPECIAL CONSIDERATIONS Gastroschisis The baby with gastroschisis is at a higher risk for hypothermia, excessive ﬂuid loss and shock, infection, intestinal strangulation, necrosis and obstruction due to the small size of the paraumbilical defect and to the lack of a covering peritoneal/amniotic membrane. Treatment starts immediately after delivery in order to prevent water and heat loss (Table 4.1). Heat loss is a frequent problem and hypothermia can result. Therefore radiant heating should be available in the room and the baby should be kept in a warmed incubator with the incubator’s temperature monitored frequently. Intubation and ventilation is carried out if required. Immediate resuscitation with adequate i.v. ﬂuids (120 ml/kg/24 hours) to overcome substantial water, electrolyte and protein losses is started. Pulse rate and mean arterial pressure is observed and blood is taken and glucose level measured. At the same time, vitamin K is given and broad-spectrum antibiotics (ampicillin, gentamicin and metronidazole) are commenced to reduce contamination of the exposed intestinal loops. A nasogastric tube is passed for intestinal decompression and prevention of pulmonary aspiration. A urinary catheter is passed to decompress the bladder and to monitor urinary output. The bowel is localized in the center of the abdomen, and clingﬁlm is used to encircle the exposed intestine and is wrapped around the infant. A dry sterile gauze dressing is draped around the clingﬁlm to support and protect the highly mobile bowel additionally and to prevent mesenteric injury or venous congestion. Table 4.1 Stabilization of a newborn with anterior abdominal wall defect prior to transfer to a referral center Warm environment Evaluate respiratory status Nasogastric tube Gastroschisis: wrap clingﬁlm around defect Omphalocele: wrap dry gauze around sac I.v. ﬂuids, correct deﬁcits Antibiotics Vitamin K

Omphalocele The initial objectives for the neonatologist are to assess and treat respiratory distress, to protect the sac from rupture and infection, and to minimize heat loss.14,15 A nasogastric tube is passed immediately to decompress the stomach and bowel. The sac should be stabilized in the middle of the abdomen to prevent kinking of the vessels and covered with a sterile, dry, non-adherent dressing to prevent trauma and heat loss. I.v. ﬂuids, broad-spectrum antibiotics and vitamin K should be started.

42 Transport of the surgical neonate

Pierre Robin syndrome Babies with Pierre Robin syndrome carry a high risk of tongue swallowing and asphyxiation. The baby should be nursed prone with an oropharyngeal airway.5

Choanal atresia Neonates with choanal atresia suffer from intermittent hypoxia. The baby should be nursed with an appropriately sized oral airway with the end or teeth cut off to keep the mouth open.3

Myelomeningocele The infant with myelomeningocele should be nursed prone in order to prevent trauma and pressure on the spinal area. A warm sterile, saline-soaked dressing is placed over the lesion and clingﬁlm wrapped around the baby to prevent drying and dehiscence. If the sac is ruptured and cerebrospinal ﬂuid (CSF) is leaking, or if the myelomeningocele is open, it should be covered with Betadine-soaked gauze and broad-spectrum antibiotics started. Care must be taken to prevent fecal contamination in sacral lesions.6 Careful observation and documentation of neurological function is essential before, during and after transport including evaluation of the sensorimotor level and assessment of the degree of hydrocephalus.6,14

Bladder extrophy At birth, the umbilical cord should be ligated close to the abdominal wall and the umbilical clamp removed to prevent mechanical damage to the bladder mucosa and excoriation of the bladder surface.4,16,17 Trauma and damage to the exposed bladder mucosa and plate should be avoided by covering the defect with clingﬁlm wrapped around the baby to prevent the mucosa from sticking to clothing or diapers. This will allow urine to escape while establishing a barrier between the environment and the fragile bladder mucosa. Old urine, mucus and any detritus should be washed from the surface of the bladder with sterile saline warmed to body temperature at each diaper change and a clean layer of clingﬁlm applied, also during transfer.16,17 Prophylactic antibiotics should be started immediately.

Cloacal extrophy The same measurements to protect the omphalocele sac as discussed under omphalocele are applicable.

Esophageal atresia with tracheo-esophageal ﬁstula Once the diagnosis of esophageal atresia is suspected, the baby should be transferred to a tertiary referral center for further investigation and surgery. Some babies will require endotracheal intubation and ventilation. These infants are particularly at risk because mechanical ventilation is relatively ineffective due to the presence of a ﬁstula. Therefore, the tip of the endotracheal tube should be placed proximal to the carina but distal to the ﬁstula. Urgent transfer and ligation of the ﬁstula are essential. Generally, the infant should be handled with care and crying avoided to reduce the risk of aspiration and abdominal distension and thereby, respiratory distress.4 Moreover, the baby should be well oxygenated at all times and kept in a warm environment. Regurgitation of gastric contents through the ﬁstula during transport can be prevented by keeping the head of the baby in a slightly elevated position or nursing the baby prone or in a right lateral position and thereby decreasing the work of breathing and improving oxygenation.4,18 The blind upper esophageal pouch should be kept empty. A Replogue sump catheter should be placed in the pouch and connected to low-intermittent or lowcontinuous suction in order to prevent accumulation of saliva. The perforations along the side of the catheter are located only near the tip and therefore minimize the possibility of suctioning oxygenated air away from the larynx.19 However, these double lumen esophageal tubes have a tendency to become blocked with mucus and therefore should be irrigated at frequent intervals during transport. I.v. ﬂuids should be started to provide maintenance and supplemental ﬂuids and electrolytes to compensate esophageal secretion losses. Infection should be prevented and any existing pneumonitis treated by broad-spectrum antibiotics. Vitamin K should be administered prior to transfer.

Congenital diaphragmatic hernia The initial objective for the neonatologist and anesthetist is to stabilize the critically ill neonate before transport to the referral center (Table 4.2). A nasogastric tube should be passed immediately on diagnosis to decompress the Table 4.2 Stabilization of a neonate with congenital diaphragmatic hernia prior to transport Maintain warm environment Nasogastric tube Intubation and ventilation I.v. ﬂuids Arterial blood gases Antibiotics Vitamin K

References 43

gastrointestinal tract and to prevent further compression of the lung. Endotracheal intubation should be performed promptly in a baby with respiratory difﬁculty or poor gas exchange. Full sedation and paralysis will reduce the risk of barotrauma. Mask ventilation should be avoided because it will distend the stomach and further compromise the respiratory status. Hyperventilation, using low pressures and high oxygen content, correction of acidosis and prevention of thermal and metabolic stress are recommended to prevent pulmonary hypertension.6 I.v. ﬂuids, fresh-frozen plasma (FFP) and dopamine, if necessary, should be started to maintain adequate peripheral perfusion. Prophylactic antibiotics should be started and vitamin K administered. Venous access through the umbilicus is useful for obtaining mixed venous blood gas specimens and monitoring central venous pressures if passed across the liver into the right atrium. Arterial access with an umbilical artery catheter will allow monitoring of systemic blood pressure and blood gas measurements at the postductal level. The baby will also need a right radial arterial line to measure preductal blood gasses. This can be inserted on arrival at the referral center. Acute deterioration of the infant’s condition can occur during transfer due to a pneumothorax. Equipment for intercostal drainage must be available since it can be a life-saving maneuver.84,6,18 There has been tremendous growth in the use of extracorporeal life support for neonatal cardiopulmonary failure in the last decade. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage procedure with an 80% survival rate in high-risk neonates with congenital diaphragmatic hernia who fail to respond to mechanical ventilation and meet entry criteria. The number of centers providing ECMO is still limited, so special services are needed to transport critically ill neonates to these centers. These special transport teams should be familiar with the pathophysiology of cardiac and respiratory failure and be equipped to continue the monitoring and treatment started at the referral center, to maintain that level of care during transport, and to treat complications of the disease or therapy itself.20,21 Now, transportable ECMO systems exist that can effectively stabilize and transport high-risk neonates to an ECMOcompetent center.22

Intestinal obstruction Intestinal obstruction can occur as a result of a number of conditions, e.g. malrotation, duplication of the alimentary tract, intestinal atresias, NEC, Hirschsprung’s disease, meconium ileus and anorectal anomalies. The principles of care are the same irrespective of the level or cause of the obstruction.4 The main objectives are to decompress the bowel and prevent aspiration, accurately estimate and correct ﬂuid losses and minimize heat loss. A nasogastric tube should be passed and suction carried

out every 15–30 minutes and left on free drainage between aspirations prior to and during transport. I.v. ﬂuids should be started to correct acid–base and volume deﬁcits and review and adjust these on a 6–8 hourly basis according to the needs of the infant.3 Broad-spectrum antibiotics should be started prophylactically.

Necrotizing enterocolitis Neonates with NEC usually are transferred only if surgery is required in case of perforation of gangrenous bowel resulting in pneumoperitoneum or progressive clinical deterioration with evidence of peritonitis.3. Usually they are critically ill with sepsis and shock. Preferably the transfer is done while the infant’s condition is as stable as possible. Resuscitation with crystalloids, colloids or blood to correct acidosis is started prior to departure. Ventilation with intermittent positive pressure and inotropic support is often required.4. A sump nasogastric tube on continuous suction is passed and suctioned regularly prior and during transport. Broad-spectrum antibiotics are started.

CONCLUSION The approach to the care of the high-risk newborn has changed dramatically in the past 20 years. The newborn with a serious congenital malformation requires assessment and stabilization by experienced staff prior to and during transport to the regional center. Several studies have demonstrated that stabilization of the high-risk newborn before transport is associated with a reduction in perinatal morbidity and mortality.

REFERENCES 1. Darlow BD, Cull AB, Knight DB. Transportation of very low birth weight infants in 1986. N Z Med J 1989; 102:275–7. 2. Ferrera A, Schwartz M, Page H et al. Effectiveness of neonatal transport in New York City in neonates less than 2500 grams – a population study. J Commun Hlth 1988; 13:3–18. 3. Lloyd DA. Transfer of the surgical newborn infant. Semin Neonatol 1996; 1:241–8. 4. McHugh PJ, Stringer MD. Transport of sick infants and children. In: Atwell JD, editor. Pediatric Surgery. New York: Arnold, 1998: 73–9. 5. Harris BA, Wirtschafter DD, Huddleston JF et al. In Utero Versus Neonatal Transportation of High-Risk Pernates: A Comparison. Obstet Gynecol 1981; 57:496–9. 6. Paxton JM. Transport of the surgical neonate. J Perinatal Nurs 1990; 3:43–9.

44 Transport of the surgical neonate 7. Pieper CH, Smith J, Kirsten GF et al. The transport of neonates to an intensive care unit. SAMJ 1994; 84:801–3. 8. Holt J, Fagerli I. Air transport of the sick newborn infant: audit from a sparsely populated county in Norway. Acta Pediatr 1999; 88:66–71. 9. Leslie AJ, Stephenson TJ. Audit of neonatal intensive car transport – closing the loop. Acta Pediatr 1997; 896:1253–6. 10. Morse TS. Transportation of the sick and injured children. In: Gans SL, editor. Surgical Pediatrics. New York: Grune and Stratton, 1980: 27–41. 11. Miller C. The physiological effects of air transport on the neonate. Neonatal Network 1994; 13:7–10. 12. Donn SM, Faix RG, Gates MR. Neonatal transport. Curr Probl Pediatr 1985; 15:1–65. 13. Driver CP, Robinson C, De Caluwé, et al. The Quality of Inter-Hospital Transfer of the Surgical Neonate. Today’s Emerg 2000; 6:102–5. 14. Chance GW. Thermal environment in transport. In: Sinclair JC, editor. Temperature Regulation and Energy Metabolism in the Newborn. New York: Grune and Stratton, 1978: 227–39. 15. Caplan MS, MacGregor SN. Perinatal management of

16.

17.

18. 19. 20.

21.

22.

congenital diaphragmatic hernia and anterior abdominal wall defects. Clin Perinatol 1989; 16:917–38. Gearhart JP, Ben-Chaim J. Extrophy and Epispadias. In: King LR, editor. Urologic Surgery in Infants and Children. Pennsylvania: WB Saunders Company, 1998: 106–13. Gearhart JP. The Bladder Ectrophy-Epispadias-Cloacal Extrophy Complex. In: Gearhart JP, Rink RC, Mouriquand PDE, editors. Pediatric Urology. Pennsylvania: WB Saunders Company, 2001: 511–46. Spitz L, Wallis M, Graves HF. Transport of the surgical neonate. Arch Dis Child 1984; 59:284–8. O’Neill JA, Rowe MI, Grosfeld JL et al. Pediatric Surgery. Mosby – Year Book, St. Louis, 1998. Day SE, Chapman RA. Transport of the critically ill patients in need of extracorporal life support. Crit Care Clin 1992; 8:581–96. Kinsella JP, Schmidt JM, Abman SH. Inhaled nitric oxide treatment for stabilization and emergency treatment of critically ill newborns and infants. J Pediatr 1995; 95:773–6. Cornish JD, Carter JM, Gerstmann DR et al. Extracorporeal membrane oxygenation as a means of stabilizing and transporting high risk neonates. Asaio Trans 1991; 37:564–8.

5 Preoperative assessment PREM PURI AND DIANE DE CALUWÉ

INTRODUCTION Many congenital defects that are of interest to the pediatric surgeon can now be detected before birth, thus the preoperative assessment of the newborn with congenital anomaly starts in utero. When serious malformations incompatible with postnatal life are diagnosed early enough, the family may have the option of terminating the pregnancy. Therefore it is important for every pediatric surgeon who is familiar with the management of the congenital anomalies after birth to be involved in management decisions and family counselling before birth.1 The main goal of prenatal diagnosis is to improve the prenatal care by maternal transport to an appropriate center and delivering the baby in the timing and mode that are appropriate for the speciﬁc fetal malformation. Although prenatal intervention for certain congenital anomalies has been reported recently,2,3 almost all congenital malformations can be successfully managed after birth. During the past 2 decades there have been signiﬁcant advances in modes and techniques for prenatal diagnosis. These modes include: amniocentesis, amniography, fetoscopy, fetal sampling and ultrasonography. The latter, enabling direct imaging of fetal anatomy, is a non-invasive technique, safe for both the fetus and the mother.4 However, it is important to remember that sonography is operator dependent and the reliability of the information obtained is directly proportional to the skill and experience of the sonographer. For example, it is important to distinguish duodenal from jejunal obstruction in a fetus with polyhydramnios, because duodenal obstruction is associated with Down syndrome and requires further genetic evaluation while jejunal obstruction does not. The real-time sonography may yield important information on fetal malformation, fetal movement and fetal vital functions such as breathing movements and heart rate variability. Serial sonographic evaluations are particularly useful in following the progression or regression of any fetal disease. All this important infor-

mation is an integral part of the preoperative assessment of a newborn with any kind of congenital malformation (Figs 5.1 & 5.2). Neonates born with congenital malformations are usually in urgent need of surgery and, in addition to their surgical problem, may suffer from a multitude of medical problems. Furthermore they are at a period when signiﬁcant physiological and maturational changes of transition from fetal to extrauterine life are occurring. The surgical and anesthetic intervention at this time may affect this transition by interfering with normal homeostatic controls of circulation, ventilation, temperature, ﬂuid, and metabolic balance. To facilitate a smooth preoperative course, close cooperation among the neonatologist, pediatric surgeon and pediatric anesthesiologist is necessary. All neonates undergoing surgery must be carefully assessed preoperatively, giving particular attention to the following:

Figure 5.1 Transvaginal ultrasonogram showing a 15-week-old fetus with omphalocele (arrow). Bowel loops protrude through the abdominal wall defect

46 Preoperative assessment

Figure 5.2 Transvaginal ultrasonogram showing 16-week-old fetus with diaphragmatic hernia. The dilated stomach (arrow) appears in the left hemithorax adjacent to the heart

• • • • • • • • •

History and physical examination Maintenance of body temperature Respiratory function Cardiovascular status Metabolic status Coagulation abnormalities Laboratory investigations Vascular access Fluid and electrolytes, and metabolic responses.

HISTORY AND PHYSICAL EXAMINATION The history of a newborn starts months before delivery, as many of the congenital malformations (e.g. Bochdalek hernia, omphalocele, gastroschisis, sacrococcygeal teratoma and others) nowadays are known to the pediatric surgeon prenatally. Not only are the anatomical and structural anomalies important, but even more so are metabolic abnormalities or chromosomal aberrations, which must be diagnosed prenatally or immediately after birth. Anticipation of a problem in the delivery room is often based on prenatal diagnosis. For example, identiﬁcation of a trisomy 21 in the fetus will increase the neonatologist’s awareness in evaluating the infant for those abnormalities closely associated with this chromosomal defect, e.g. evaluation for duodenal atresia and congenital heart disease. Conversely, prenatal identiﬁcation of speciﬁc fetal anomalies should signal the pediatrician to evaluate the infant for a chromosomal abnormality. The most important recent advance in prenatal detection of anatomical problems has been the develop-

ment of fetal ultrasonography (see Chapter 2), and in experienced hands this mode of imaging can be used to detect a wide range of fetal problems, ranging from relatively minor abnormalities to major structural defects. However, this anatomical prenatal diagnosis is only one of the tools that aid in planning care management. An accurate and well-documented family history may increase the suspicion that an infant is at risk for an anatomical defect linked to an inherited disorder. In other cases, only the evidence of polyhydramnios should signiﬁcantly increase suspicion of congenital anomalies. Most problems are best managed expectantly by natural labor and vaginal delivery at term. Certain malformations, however, such as conjoined twins, giant omphalocele, sacrococcygeal teratoma or large cystic hygroma, often require cesarian section for delivery.5 After birth, the assessment of the degree of prematurity, which is an integral part of the physical examination, and the speciﬁc type of congenital anomaly must be identiﬁed and recorded because of the profound anesthetic and postoperative implications that are involved.6,7 The normal full-term infant has a gestational age of 37 weeks or more, and a body weight greater than 2500 g. Infants born with a birth weight of less than 2500 g are deﬁned as being of low birth weight (LBW). Babies may be of LBW because they have been born too early (preterm – earlier than 37 weeks’ gestational age), or because of intrauterine abnormalities affecting growth (growth retardation). ‘Small-for-gestational-age’ (SGA) infants are those whose birth weight is less then the 10th percentile for their age. Infants may, of course, be both growth retarded and born preterm. The principle features of prematurity are: • • • • • •

A head circumference below the 50th percentile A thin, semi-transparent skin Soft, malleable ears Absence of breast tissue Absence of plantar creases Undescended testicles with ﬂat scrotum and, in females, relatively enlarged labia minora.

The physiological and clinical characteristics of these babies are: • • • • • •

Apneic spells Bradycardia Hypothermia Sepsis Hyaline membrane disease Blindness and lung injury due to use of high levels of oxygen • Patent ductus arteriosus. In the SGA infant, although the body weight is low, the body length and head circumference approach that of an infant of normal weight for age. These babies are older and more mature. Their clinical and physiological characteristics are:

Respiratory function 47

• • • • •

Higher metabolic rate Hypoglycemia Thermal instability Polycythemia Increased risk of meconium aspiration syndrome.

In relation to these differences, three important observations have been reported: 1 LBW infants have a mortality 10 times that of fullsized infants. 2 More than 75% of overall perinatal mortality is related to clinical problems of LBW infants. 3 The rate of anatomical malformation in LBW infants is higher then for infants at term.8

MAINTENANCE OF BODY TEMPERATURE The mean and range of temperature for newborns are lower than previously described and most temperatures ≤ 36.3°C are, in fact, within the normal range.9 Newborn infants, particularly premature infants, have a poor thermal stability because of a higher surface area/weight ratio, a thin layer of insulating subcutaneous fat and a high thermoneutral temperature zone. The newborn readily loses heat by conduction, convection, radiation and evaporation, with the major mechanism being radiation. Shivering thermogenesis is absent in the neonate, and the heat-producing mechanism is limited to non-shivering thermogenesis through the metabolizing of brown fat.10 Cold stress in these neonates leads to an increase in metabolic rate and oxygen consumption, and calories are consumed to maintain body temperature. If prolonged, this leads to depletion of the limited energy reserve and predisposes to hypothermia and increased mortality. Hypothermia can also suggest infection and should trigger diagnostic evaluation and antibiotic treatment if required.9 Illness in the newborn, particularly when associated with prematurity, further compounds the problems in the maintenance of body temperature.11 The classic example for such an illness is the newborn with omphalocele or gastroschisis.12 In their group of 23 neonates with gastroschisis, Muraji et al.12 found that hypothermia (31–35.4°C), which was found in seven patients upon arrival at the hospital, was the most serious preoperative problem. To minimize heat losses, it is desirable that most sick neonates be nursed in incubators within a controlled temperature. These incubators are efﬁcient for maintaining the baby’s temperature, but do not allow adequate access to the sick baby for active resuscitation and observation. Overhead radiant heaters, servocontrolled by a temperature probe on the baby’s skin, are preferred and effective in maintaining the baby’s temperature; they also provide visual and electronic monitoring and access for nursing

and medical procedures. Hyperthermia should be avoided, because it is associated with perinatal respiratory depression.13 The environmental temperature must be maintained near the appropriate thermoneutral zone for each individual patient because the increase in oxygen consumption is proportional to the gradient between the skin and the environmental temperature.14 This is 34–35°C for LBW infants up to 12 days of age and 31–32°C at 6 weeks of age. Infants weighing 2000–3000 g have a thermoneutral zone of 31–34°C at birth and 29–31°C at 12 days. In an incubator, either the ambient temperature of the incubator can be monitored and maintained at thermoneutrality, or a servosystem can be used. The latter regulates the incubator temperature according to the patient’s skin temperature, which is monitored by means of a skin probe on the infant. The normal skin temperature for a full-term infant is 36.2°C, but because of many benign factors such as excessive bundling, ambient temperature may affect body temperature. Diurnal and seasonal variations in body temperature have also been described.9 Thus the control of the thermal environment of the newborn and especially the ill baby with congenital malformations is of the utmost importance to the outcome.

RESPIRATORY FUNCTION Assessment of respiratory function is essential in all neonates undergoing surgery. The main clinical features of respiratory distress are restlessness, tachypnea, grunting, nasal ﬂaring, sternal recession, retractions and cyanosis. These symptoms are occasionally present in the delivery room due to anatomical abnormalities involving the airway and lungs and require the most urgent therapy.15 Table 5.1 lists a few common conditions that may be present with respiratory distress at birth. These conditions include: diaphragmatic hernia (Bochalek), lobar emphysema, pneumothorax, esophageal atresia with or without tracheo-esophageal ﬁstula, congenital airway obstruction, congenital cystic adenomatoid malformation of the lung, meconium aspiration syndrome and aspiration pneumonia. It is important to recognize that more than one condition may be present in the same patient. If there is any clinical suspicion or sign of respiratory insufﬁciency, a chest X-ray should be obtained immediately after the resuscitation to determine the cause of respiratory distress. All babies with respiratory distress should have a radio-opaque nasogastric tube passed and a radiograph taken that includes the chest and abdomen in order to localize the esophagus, stomach, and bowel gas, and to avoid misdiagnosis, for example, a diaphragmatic hernia which can be mistaken for a cystic adenomatoid malformation of the lung.16

Condition

Prenatal and perinatal associations

Clinical features

Chest radiographic ﬁndings*

Initial therapy

Respiratory distress syndrome (RDS)

Prematurity, lung immaturity, asphyxia, maternal diabetes, male sex

Increasing respiratory distress after birth, tachypnea, grunting, rib retractions or nasal ﬂaring

Diffuse reticulogranular pattern, air bronchograms

Oxygen, assisted ventilation

RDS, meconium aspiration, endotracheal Acute onset of sternal recession, resuscitation, diaphragmatic hernia, tachypnea, cyanosis, shift in apex assisted ventilation beat position

Intrapleural air, mediastinal shift; varying degrees of lung collapse which is always symmetrical toward the hilum

Oxygen, needle aspiration, chest drain; additional tubes may be needed when large leaks from the lung tissue are present

Polyhydramnios

Sudden respiratory distress usually soon after birth, dyspnea, cyanosis, scaphoid abdomen, shift in heart sounds, decreased breaths sounds in one hemithorax (usually left)

Bowel pattern in one hemithorax, Nasogastric decompression; mediastinal shift with compression intubation and ventilation of the contralateral lung. Abdominal bowel gas is sparse or absent

Occasionally associated with congenital malformations of the heart and great vessels

Rapidly progressive respiratory distress with dyspnea and cyanosis. Absent or diminished breath sounds over the affected side and displacement of the mediastinum

Hyperinﬂation of the affected side – usually left upper (increased translucency). Mediastinum may be shifted.

Thoracotomy and lobectomy required. During induction of anesthesia, the ventilatory pressures must be kept as low as possible until the chest is open

Congenital cystic adenomatoid malformation (CCAM)

Fetal hydrops, polyhydramnios, Severe respiratory distress as above, pulmonary hypoplasia, mediastinal shift, often within hours of birth type II – associated anomalies including prune belly syndrome and pectus excavatum. 25% of infants are stillborn

Homogeneous mass or multicystic lesion on chest X-ray, mediastinal shift. The normal location of the stomach is of help in differentiating CCAM and diaphragmatic hernia

Thoracotomy and lobectomy

Esophageal atresia with tracheo-esophageal ﬁstula

Polyhydramnios, associated malformations (VACTERL), excessive nasopharyngeal saliva

Mild respiratory distress. Early chest auscultation is normal. The abdomen may show progressive distension. (In the common case of atresia and ﬁstula)

Wide, air-ﬁlled pouch in the neck or upper mediastinum. Aspiration pneumonia may be noted, usually in the right upper lobe. Radio-opaque nasogastric tube will be seen to stop and coiled in the blind pouch. The abdomen frequently shows hyperaeration of the intestines

Position of the infant with head elevated 45° or prone position. Place Replogle tube in the blind proximal pouch and connect it to continuous suction. Antibiotics. Evaluate associated congenital malformations

None

Cyanosis at rest, pink when crying; inability to pass catheter through nares; noisy upper airway

None

Placement of oral airway

Air leak syndromes Pneumothorax

Diaphragmatic hernia (Bochdalek)

Lung abnormalities Lobar emphysema

Airway abnormalities Choanal atresia and supralaryngeal lesions

* Combined chest and abdominal ﬁlm is recommended in every newborn baby presenting with respiratory distress. An opaque nasogastric tube in the stomach has an important role both in diagnosis and treatment.

48 Preoperative assessment

Table 5.1 Approach to respiratory distress post-delivery

Cardiovascular status 49

Blood gas studies are essential in the diagnosis and management of respiratory distress. Arterial PO2 and PCO2 indicate the state of oxygenation and ventilation, respectively. In the newborn, repeated arterial blood samples may be obtained either by catheterization of an umbilical artery or by cannulation of radial, brachial or posterior tibial arteries. An important alternative is noninvasive monitoring techniques with transcutaneous PO2 monitors or pulse oximeters.17 Monitoring of arterial pH is also essential in patients with respiratory distress. Acidosis in the neonate produces pulmonary arterial vasoconstriction and myocardial depression. Respiratory alkalosis causes decreased cardiac output, decreased cerebral blood ﬂow, diminished oxyhemoglobin dissociation and increased airway resistance with diminished pulmonary compliance.18 Respiratory failure is the leading cause of death in the neonate. High-frequency ventilation,19 use of surfactant, use of inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) have been shown to improve survival dramatically in selected neonates.20,21 ECMO provides long-term cardiopulmonary support for patients with reversible pulmonary and/or cardiac insufﬁciency. It is well accepted as a standard of treatment for neonatal respiratory failure refractory to conventional techniques of pulmonary support. 21 Typically, patients considered for ECMO are 34 gestational weeks or older or weigh more than 2000 g, have no major cardiac lesions, intracranial hemorrhages less than grade 2, no signiﬁcant coagulopathies and have had mechanical ventilation for fewer than 10–14 days. It is limited to those infants who have a 20% or less chance of survival if treated with only conventional therapies.21,22 The National ECMO Registry in Ann Arbor, MI, USA collected reports from all 46 ECMO centers, summarizing their collective experience with 1489 newborns with an overall survival rate of 81.8%.23 Of this group of neonates, 139 newborns were born with congenital diaphragmatic hernia and underwent ECMO, two-thirds of whom survived. Failure of ventilatory treatment to reverse hypoxemia, acute clinical deterioration after a ‘honeymoon period’ and an alveolar-arterial oxygen gradient > 600 mmHg for 12 hours were the principle criteria that justiﬁed ECMO in these babies. Premature infants were at highest risk and intracranial bleeding was the most common cause of death in these anticoagulated newborns. It is important to emphasize that emergency surgery for congenital diaphragmatic hernia is not necessary and that repair should be done only when the patient has been stabilized using conventional ventilation, high-frequency ventilation, or ECMO if necessary.22,24 ECMO is an accepted form of therapy in the treatment of neonates with otherwise lethal persistent pulmonary hypertension related to meconium aspiration and sepsis.22,25 This mode of therapy has been tried successfully in neonates with congenital cystic lesions of the lung who developed severe pulmonary hypertension

following lobectomy and other life-threatening respiratory problems.22,26 However, the long-term effects on its survivors are unknown. At present, the reported morbidity still ranges between 13% and 33%. The developmental outcome is normal in most patients. 21,27,28 Severe developmental delay has been found in only 2–8% of neonatal patients who undergo ECMO therapy. Only one randomized trial of conventional therapy vs ECMO in 185 full-term infants has been published recently. Of the infants included in the trial, 68% who were randomized to ECMO therapy survived compared to 41% in the conventionally treated group.22 The Extracorporal Life Support Organisation (ELSO), started in 1989, maintains an international database for all ECMO patients and centers. Due to the institution of new therapies and differing management styles for treatment of respiratory failure, there has been a marked decrease in neonatal patients treated with ECMO over time.21 Surfactant replacement is commonly used in the clinical management of neonates with respiratory distress syndrome (RDS). It may also be effective in other forms of lung disease, such as meconium aspiration syndrome (MAS), neonatal pneumonia, the ‘adult’ form of acute respiratory distress syndrome (ARDS), and congenital diaphragmatic hernia (CDH). It ensues that alveolar stability is promoted, atelectasis is reduced, edema formation is decreased, and the overall work of respiration is minimized.29 iNO is available for treatment of persistent pulmonary hypertension of the neonate (PPHN). It decreases pulmonary vascular resistance leading to diminished extrapulmonary shunt and has a microselective effect which improves ventilation/perfusion matching. Clinical trials indicate that the need for ECMO in term newborns with PPHN is diminished by iNO.30,31 In newborns with severe lung disease, HFOV is frequently used to optimize lung inﬂation and minimize lung injury. The combination of HFOV and iNO is reported to cause the greatest improvement in oxygenation in some newborns with severe PPHN complicated by diffuse parenchymal lung disease and underinﬂation.30 In summary, the type of respiratory care in particular neonates will always depend upon clinical and radiological ﬁndings supported by blood gas estimations.

CARDIOVASCULAR STATUS At birth, the circulation undergoes a rapid transition from fetal to neonatal pattern. The ductus arteriosus normally closes functionally within a few hours after birth, while anatomical closure occurs 2–3 weeks later.32 Prior to birth the pulmonary arterioles are relatively muscular and constricted. With the ﬁrst breath, total

50 Preoperative assessment

pulmonary resistance falls rapidly because of the unkinking of the vessels with expansion of the lungs and also because of the vasodilatory effect of inspired oxygen. However, during the ﬁrst few weeks of life, the muscular pulmonary arterioles retain a signiﬁcant capacity for constriction, and any constricting inﬂuences such as hypoxia may result in rapid return of pulmonary hypertension.33 The management of neonates with congenital malformation is frequently complicated by the presence of congenital heart disease. At this time of life, recognition of heart disease is particularly difﬁcult. There may be no murmur audible on ﬁrst examination, but a loud murmur can be audible a few hours, days or a week later.34 A newborn undergoing surgery should have a full cardiovascular examination and a chest X-ray. The presence of cyanosis, respiratory distress, cardiac murmurs, abnormal peripheral pulses or congestive heart failure should be recorded. If there is suspicion of a cardiac anomaly, the baby should be examined by a pediatric cardiologist. In recent years the use of the noninvasive technique of echocardiography allows accurate anatomical diagnosis of cardiac anomalies, in many cases prenatally.35,36

METABOLIC STATUS Acid–base balance The buffer system, renal function and respiratory function are the three major mechanisms responsible for the maintenance of normal acid–base balance in body ﬂuids. Most newborn infants can adapt competently to the physiological stresses of extrauterine life and have a normal acid–base balance. However clinical conditions such as RDS, sepsis, congenital renal disorders and gastrointestinal disorders may result in gross acid–base disturbances in the newborn. Four basic disturbances of acid–base physiology are metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. In a newborn undergoing surgery, identiﬁcation of the type of disorder, whether metabolic or respiratory, simple or mixed, is of great practical importance to permit the most suitable choice of therapy, and for it to be initiated in a timely fashion.37 The acid–base state should be determined by arterial blood gases and pH estimation, and must be corrected by appropriate metabolic or respiratory measures prior to operation.

Hypoglycemia The mechanisms of glucose homeostasis are not well developed in the early postnatal period; this predisposes the neonate, especially the premature neonate, to the risk of both hypoglycemia and hyperglycemia. Prenatally, the

glucose requirements of the fetus are obtained almost entirely from the mother, with very little derived from fetal gluconeogenesis. Following delivery, the limited liver glycogen stores are rapidly depleted and the blood glucose level then depends on the infant’s capacity for gluconeogenesis, the adequacy of substitute stores and energy requirements.38 Table 5.2 identiﬁes infants who are at risk for developing hypoglycemia according to three mechanisms: (1) those with limited glycogen stores, (2) hyperinsulinism, and (3) diminished glucose production. Infants at high risk of developing hypoglycemia include LBW infants (especially SGA infants), infants of toxemic or diabetic mothers and infants requiring surgery who are unable to take oral nutrition and who have the additional metabolic stresses of their disease and the surgical procedure. Hypoglycemia is usually deﬁned as a serum glucose level < 1.6 mmol/L (30 mg%) in the full-term neonate and < 1.1mmol/L (20 mg%) in the LBW infant during the ﬁrst 3 days of life. After 72 hours, serum glucose concentration should always be above 2.2 mmol/L (40 mg%). Hypoglycemia may be asymptomatic or associated with a number of non-speciﬁc signs such as apathy, apnea, a weak or high-pitched cry, cyanosis, hypotonia, hypothermia, tremors and convulsions.39 The differential diagnosis includes other metabolic disturbances or sepsis. The possibility of hypoglycemia must be anticipated to prevent avoidable brain damage. All neonates undergoing surgery should have an infusion of 10% glucose at a rate of 75–100 mg/kg body weight per 24 hours and blood glucose levels should be monitored every 4–6 hours by Dextrostix estimation and/or by blood sugar determinations. Blood glucose level should be maintained above 2.5 mmol/L (45 mg%) at all times. The symptomatic infant should be treated urgently with 50% dextrose, 1–2 ml/kg intravenously, and maintenance i.v. dextrose 10–15% at 80–100 ml/kg/24 hours.

Table 5.2 Categories of hypoglycemia Limited glycogen stores Prematurity Prenatal stress Glycogen storage disease Hyperinsulinism IDM (infant of diabetic mother) Nesidioblastosis/pancreatic islet adenoma Beckwith–Wiedemann syndrome Erythroblastosis fetalis/exchange transfusion Maternal drugs Diminished glucose production SGA Rare inborn errors From Ogata,38 by permission.

Coagulation abnormalities 51

Hypocalcemia Hypocalcemia is usually deﬁned as a serum calcium value < 1.8 mmol/L. However, occasionally the ionized fraction of the serum calcium may be low, but without a great reduction of the total serum calcium level concomitantly and with the end result of clinical hypocalcemia. This may occur in newborns undergoing exchange transfusion, or in any surgical baby receiving bicarbonate. Hypocalcemia occurs usually during the ﬁrst few days of life, with the lowest levels of serum calcium seen during the ﬁrst 48 hours. The most common causes of neonatal hypocalcemia include decreased calcium stores and decreased renal phosphate excretion. The LBW infants are at greater risk, particularly if they are premature, or associated with a complicated pregnancy or delivery. Hypocalcemia may be asymptomatic or associated with non-speciﬁc signs such as jitteriness, muscle twitching, vomiting, cyanosis and convulsions. Asymptomatic hypocalcemia can be effectively treated by a continuous infusion of 10% calcium gluconate 75 mg/kg/day and can be prevented by adding calcium gluconate to daily maintenance therapy. The symptomatic patients should be treated by slow i.v. administration of 10% calcium gluconate, 6 ml in a LBW infant and 10 ml in a full-term infant, with monitoring of heart rate to prevent too rapid an injection. Serum calcium levels should be maintained within the 2.0–2.63 mmol/L (8–10.5 mg%) range.

Hypomagnesemia Hypomagnesemia may occur in association with hypocalcemia in SGA infants and neonates with increased intestinal losses. If there is no response to correction of calcium deﬁciency, a serum magnesium level should be obtained. The treatment of hypomagnesemia is by i.v. infusion of 50% magnesium sulphate 0.2 ml/kg every 4 hours until the serum magnesium level is normal (0.7–1.0 mmol/L).

Hyperbilirubinemia Jaundice in the newborn is a common physiological problem seen in 25–50% of all normal newborn infants and in a considerably higher percentage of premature and SGA infants.40 It is the result of a combination of shortened red cell survival, with a consequent increase in bilirubin load, and an immature glucuronyl transferase enzyme system with a limited capacity for conjugating bilirubin. This results in transient physiological jaundice which reaches a maximum at the age of 3–4 days, but returns to normal levels at the end of the ﬁrst week and the bilirubin level does not exceed 170 mmol/L.

Hyperbilirubinemia in the newborn may have a pathological basis such as severe sepsis, Rh and ABO incompatibilities and congenital hemolytic amemias. Neonatal hemolytic jaundice usually appears during the ﬁrst 24 hours of life, whereas physiological jaundice, as mentioned before, reaches a peak between 2 and 5 days of life.41 Other causes for prolonged hyperbilirubinemia, including those often associated with surgical conditions are: biliary obstruction, hepatocellular dysfunction and upper intestinal tract obstruction. The diagnosis of extrahepatic biliary obstruction should be done as early as possible, because early operations for biliary atresia are essential to obtain good short-term as well as long-term results.42 The major concern in neonatal hyperbilirubinemia (high levels of unconjugated bilirubin) is the risk of kernicterus that can result in brain damage. Predisposing factors include: hypoalbuminemia (circulating bilirubin is bound to albumin), hypothermia, acidosis, hypoglycemia, hypoxia, caloric deprivation and the use of drugs (e.g. gentamicin, digoxin, furosemide). When the serum bilirubin concentration approaches a level at which kernicterus is likely to occur, hyperbilirubinemia must be treated. In most patients, other than those with severe hemolysis, phototherapy is a safe and effective method of treating hyperbilirubinemia. When the serum indirect bilirubin level rises early and rapidly and exceeds 340 mmol/L, hemolysis is usually the reason, and exchange transfusion is indicated.

COAGULATION ABNORMALITIES Coagulation abnormalities in the neonate should be sought preoperatively and treated. The newborn is deﬁcient in vitamin K and this should be given as 1 mg prior to operation in order to prevent hypoprothrombinemia and hemorrhagic disease of the newborn. Thus, 1 mg vitamin K should be administered by i.m. or i.v. injection to every newborn undergoing surgery. Neonates with severe sepsis, such as those with necrotizing enterocolitis, may develop disseminated intravascular coagulopathy with a secondary platelet deﬁciency. Such patients should be given fresh-frozen plasma, fresh blood or platelet concentrate preoperatively. Bleeding is one of the major risks associated with neonatal ECMO, a risk that has a particularly devastating outcome.43 In their group of 45 patients, Weiss and colleagues reported on 12 (27%) patients who sustained hemorrhagic complications.43 Most of these hemorrhages were intracranial and were the most serious complication. Other less frequent sites of bleeding included the cannulation site, the gastrointestinal tract and chest tube sites. Although the hemorrhage is related to systemic heparinization, no correlation was found between the activate clotting time or the amount of

52 Preoperative assessment

heparin used and the hemorrhagic complications.44 An increased risk of hemorrhage was associated with lower platelet counts, so that aggressive platelet transfusion remains important in preventing hemorrhagic complications using ECMO. Attempts at correcting any coagulopathy should be undertaken before the initiation of ECMO.21 Lately, there is an interest in developing heparin-bonded circuits, which would allow ECMO without systemic heparinization.22 The potential of an increased rate of intraventricular hemorrhage (IVH) has also been reported in term and preterm neonates following iNO therapy. INO leads to a prolonged bleeding time and an inhibition of platelet aggregation.31

LABORATORY INVESTIGATIONS A newborn undergoing surgery should have blood drawn on admission for the various investigations, including full blood count, serum sodium, potassium and chloride, urea, calcium, magnesium, glucose, bilirubin, and group and cross-match. Blood gases and pH estimation should also be obtained to assess acid–base state and the status of gas exchange. The availability of micromethods in the laboratory has minimized the amount of blood required to do the above blood tests. The coagulation status of infants who have been asphyxiated may be abnormal and should be evaluated.45 Neonatal sepsis can result in disseminated intravascular clotting and severe thrombocytopenia. A platelet count < 50 000/mm3 in the neonate is an indication of preoperative platelet transfusion. Blood cultures should be obtained wherever there is any suspicion of sepsis.

Adequacy of the intravascular volume and the function of the heart can be assessed by a central venous catheter (CVC), which can be inserted through the umbilical vein, internal jugular vein, subclavian and femoral vein. Usually, catheters are placed using the Seldinger technique.47 This central line is often mandatory and a basic monitoring for the anesthetist at the time of operation, and sometimes can be performed at the theater immediately before starting the operation. It is a useful instrument for ﬂuid resuscitation, administration of medication and central venous pressure monitoring. However, CVC lines are not free from risks. Infection rates of 2.3–5.3% are reported and duration of catheter placement is a risk factor for line infection.47 Most catheter-related bloodstream infections respond to appropriate antibiotic treatment and/or catheter removal.46 Critically ill neonates will require an arterial line especially at the time of operation, either because of the surgery, when it is expected to result in signiﬁcant ﬂuid shift and hemodynamic instability, or because of a signiﬁcant underlying cardiopulmonary disease of the newborn. This arterial line is for monitoring the hemodynamic and biochemical status, especially throughout the operative procedure. Right radial artery percutaneous catheterization is preferred because it allows sampling of preductal blood for measurement of oxygen tension. If the baby has already had an umbilical artery catheter, it is safer to use it strictly for the purpose of blood pressure monitoring and blood sampling and not for the administration of drugs. A good ﬁxation of all these venous and arterial lines is essential while these newborns have to be transported frequently, and reinsertion of these vascular lines can be very difﬁcult. In an emergency, temporary vascular access can also be obtained by the intraosseous route.46

VASCULAR ACCESS Most newborns with surgical conditions cannot be fed in the operative and early postoperative period. It is essential, therefore, to administer ﬂuids in these patients by the i.v. route. With the availability of 22–24-gauge plastic cannulas, percutaneous cannulation of veins has become possible even in small premature infants. Scalp veins and veins of the dorsum of the hand and palmar surface of the wrist are the most common sites used for starting i.v. infusion. With the improvements of techniques and equipment, it is now rarely necessary to perform a ‘cutdown’ in order to administer i.v. ﬂuids. Longer term venous access can be obtained with ﬁne percutaneous intravascular central catheters inserted at bedside without general anesthesia.46 The development of these silastic catheters of appropriate size has reduced the incidence of thromboembolic complications and made it possible to leave central venous catheters in place for long periods of time.28

FLUID AND ELECTROLYTES, AND METABOLIC RESPONSES Estimation of the parental ﬂuid and electrolyte requirements is an essential part of management of newborn infants with surgical conditions. Inaccurate assessment of ﬂuid requirements, especially in premature babies and LBW infants, may result in a number of serious complications.48 Inadequate ﬂuid intake may lead to dehydration, hypotension, poor perfusion with acidosis, hypernatremia and cardiovascular collapse. Administration of excessive ﬂuid may result in pulmonary edema, congestive heart failure, opening of ductal shunts, bronchopulmonary dysplasia and cerebral intraventricular hemorrhage. In order to plan accurate ﬂuid and electrolyte therapy for the newborn, it is essential to understand the normal body ‘water’ consumption and the routes through which

Renal function, urine volume and concentration in the newborn 53

water and solute are lost from the baby. In fetal life around 16 weeks’ gestation, total body water (TBW) represents approximately 90% of total body weight, and the proportions of extracellular and intracellular water components are 65% and 25%, respectively.49 At term, these two compartments constitute about 45% and 30%, respectively, of total body weight, indicating that (1) a shift from extracellular water to intracellular water occurs during development from fetal to neonatal life, and (2) relative TBW and extracellular ﬂuid volume both decrease with increasing gestational age.49 In very small premature infants water constitutes as much as 85% of total body weight and in the term infant it represents 75% of body weight. The total body water decreases progressively during the ﬁrst few months of life, falling to 65% of body weight at the age of 12 months, after which it remains fairly constant.50 The extracellular and intracellular ﬂuid volumes also change with growth. These changes are shown in Table 5.3. The objectives of parenteral ﬂuid therapy are to provide: • Maintenance ﬂuid requirements needed by the body to maintain vital functions • Replacement of pre-existing deﬁcits and abnormal losses • Basic maintenance requirement of water for growth. Maintenance ﬂuid requirement consists of water and electrolytes that are normally lost through insensible loss, sweat, urine and stools. The amount lost through various sources must be calculated to determine the volume of ﬂuid to be administered. Insensible loss is the loss of water from the pulmonary system and evaporative loss from the skin. Approximately 30% of the insensible water loss occurs through the pulmonary system as moisture in the expired gas; the remainder (about 70%) is lost through the skin.51 Numerous factors are known to inﬂuence the magnitude of insensible water loss. These include the infant’s environment (ambient humidity and ambient temperature52), metabolic rate,53 respiratory rate, gestational maturity, body size, surface area, fever51 and the use of radiant warmers and phototherapy.54 In babies weighing less than 1500 g at birth, insensible loss may be up to three times greater than that estimated for term infants.55 Faranhoff and colleagues found insensible

water loss in infants weighing less than 1250 g to be 60–120 ml/kg/day.56 Chief among the factors that affect insensible water loss are the gestational age of the infant and the relative humidity of the environment.57,58 The respiratory water loss is approximately 5 ml/kg/24 hours and is negligible when infants are intubated and on a ventilator.58 Water loss through sweat is generally negligible in the newborn except in patients with cystic ﬁbrosis, severe congestive heart failure or high environmental temperature. Fecal water losses are 5–20 ml/kg/day.

RENAL FUNCTION, URINE VOLUME AND CONCENTRATION IN THE NEWBORN The kidneys are the ﬁnal pathway regulating ﬂuid and electrolyte balance of the body. The urine volume is dependent on water intake, the quantity of solute for excretion and the maximal concentrating and diluting abilities of the kidney.51 Renal function in the newborn infant varies with gestational age and should be evaluated in this context. Very preterm infants younger than 34 weeks’ gestational age have reduced glomerular ﬁltration rate (GFR) and tubular immaturity in the handling of the ﬁltered solutes when compared to term infants. Premature infants between 34 and 37 weeks’ gestational age undergo rapid maturation of renal function similar to term infants with rapid establishment of glomerulotubular balance early in the postnatal period.59 The full-term newborn infant can dilute urine to osmolarities of 30–50 mmol/L and can concentrate it to 550 mmol/L by approximately 1 month of age. The solute for urinary excretion in infants varies from 10–20 mmol per 100 cal metabolized, which is derived from endogenous tissue catabolism and exogenous protein and electrolyte intake. In this range of renal solute load, a urine volume of 50–80 ml/100 cal would provide a urine concentration of between 125 and 400 mmol/L. If the volume of ﬂuid administered is inadequate, urine volume falls and concentration increases. With excess ﬂuid administration, the opposite occurs. We aim to achieve a urine output of 2 ml/kg/hour, which will maintain a urine osmolarity of 250–290 mmol/kg

Table 5.3 Changes in total body water (TBW) and body compartments during development Age Premature Newborn 3 months 1 year Adolescence Male Female

TBW (% body weight)

Extracellular ﬂuid (% body weight)

Intracellular ﬂuid (% body weight)

75–80 70–75 70 60

– 45 35 27

– 35 35 40–45

60 55

20 18

40–45 40

54 Preoperative assessment

(speciﬁc gravity 1009–1012) in newborn infants. For older infants and children, hydration is adequate if the urine output is 1–2 ml/kg/hour, with an osmolarity between 280 and 300 mmol/kg. Accurate measurements of urine ﬂow and concentration are fundamental to the management of critically ill infants and children, especially those with surgical conditions, and extensive tissue destruction or with infusion of high osmolar solutions. In these situations, it is recommended that urine volume be collected and measured accurately.

SERUM ELECTROLYTES AND METABOLIC RESPONSES IN NEONATAL SURGICAL PATIENTS Electrolyte and metabolic responses to surgical trauma in neonates must be assessed against the background of the normal metabolic responses of an infant to extrauterine life. Table 5.4 represents a reasonable composite of some of the changes occurring in the metabolism of electrolytes, nitrogen, water and calories in healthy newborn infants.60,61 Phase I lasts for 1–3 days after birth. In newborns with minimal oral intake, the salient metabolic features of this phase are the development of negative balances for electrolytes, water, calories, and nitrogen. The nitrogen balance observed during phase I depends on the stress incident to labor and delivery, and on caloric intake. Nitrogen excretion is accompanied by potassium excretion, and the potassium level is negative. During phase II, which is characterized by an increasing oral intake of nutrients, nitrogen and potassium balances become positive. Body weight begins to rise because of transition to positive caloric metabolism. Phase III is characterized by a further increase of body weight because of positive nitrogen, potassium, water and caloric balances.60 Physiological changes in ﬂuids, electrolytes and energy metabolism, during postnatal life, however, can vary with

different feeding regimens, gestational age, and other associated medical and surgical problems.62 Table 5.5 shows ﬂuid and electrolyte disturbances, their mechanisms and treatment of common neonatal surgical conditions.

PREOPERATIVE MANAGEMENT OF VARIOUS SURGICAL NEONATAL CONDITIONS Preoperative management is critical to the success of surgical intervention and the postoperative restoration of normal function. It has been observed that patients who have operations conserve sodium postoperatively.63 In fact, this sodium concentration is usually caused by hypovolemia, which has its genesis in preoperative dehydration, because of various surgical conditions. The remedy is to provide parenteral maintenance ﬂuid preoperatively when oral restriction of ﬂuid is required. Some patients may need ﬂuid resuscitation preoperatively, and their extracellular ﬂuid volume must be restored. Assessment of adequacy of the intravascular space can be done by measurement of pulse, blood pressure, capillary ﬁlling in the skin, core temperature, temperature of the skin, urine output, speciﬁc gravity and urinary sodium level. In addition to vital signs, an accurate weight, and especially changes in weight, electrolyte levels and calcium and blood gas analyses should be obtained. Attempts should be made to correct any abnormalities encountered during this assessment. Newborn surgical patients shift large amounts of protein and water into tissues or into potential spaces such as the peritoneal or pleural cavity. These so-called third-space losses are hard to quantify. Inadequate replacement of these losses can cause hypovolemia and shock. This is commonly seen in peritonitis (e.g. necrotizing enterocolitis, perforated viscus) and other congenital abnormalities such as gastroschisis and omphalocele. Infusion of colloid in the form of fresh-frozen plasma, 5% albumin, packed red cells,

Table 5.4 Metabolic and electrolyte changes of the healthy newborn* Variable

Phase I

Phase II

Phase III

Age Intake Body weight K+ metabolism Na+ metabolism Cl- metabolism H2O metabolism Urine volume N metabolism Caloric metabolism

1–3 days Low consumption of breast milk Decrease Negative balance Negative balance Negative balance Negative balance Small output Negative balance Negative balance

3–6 days Intake of breast milk rose progressively Begin to rise Positive balance† Positive balance Positive balance Negative balance Increased Positive balance Positive§

6–7 days Intake of breast milk stable Increase Positive balance Positive balance Positive balance ±Balance‡ Stable Positive balance Positive balance

From Wilkinson et al.,48 by permission. * This group of 10 male newborn babies include ﬁve who were healthy and ﬁve who suffered degrees of fetal distress. † Potassium probably gives the most sensitive indication of metabolic changes at this time of life. The day on which potassium balance ﬁrst became positive varied a good deal. ‡ Balance may be slightly positive or slightly negative. § Transition to positive balance. In preterm infants all three phases can last longer and have more profound changes.

Preoperative management of various surgical neonatal conditions 55

whole blood or plasma-like product is required to maintain intravascular integrity in the face of protein and ﬂuid losses. Enterocolitis complicating Hirschsprung’s disease or other intestinal obstructive lesions can cause massive losses of ﬂuid and electrolytes and result in hypovolemia, hyponatremia, metabolic acidosis and hypokalemia. In the presence of severe enterocolitis secondary to obstruction, with accompanying large ﬂuid losses into the intestine, adequate preoperative ﬂuid replacement is mandatory to ensure a reasonable outcome. Vomiting of gastric contents as a result of gastric outlet obstruction caused by a duodenal atresia, a

diaphragm or web, pyloric stenosis, intestinal bands, or malrotation, results in a chronic loss of gastric contents and primary hydrogen and chloride ions, in turn resulting in hypochloremic alkalosis. Chronic hypochloremic alkalosis results in hypokalemia. In renal compensation, hydrogen ions are conserved at the expense of potassium loss. Preoperative management of patients with gastric outlet obstruction includes ﬂuid replacement and at least potential correction of the hypochloremic alkalosis by infusion of chloride and potassium chloride (Table 5.5). This preoperative metabolic correction greatly enhances surgical outcome. Table 5.6 represents the

Table 5.5 Fluid and electrolyte disturbances in common neonatal surgical conditions Neonatal condition

Fluid and electrolyte disturbances

Mechanism

Treatment

Tracheo-esophageal ﬁstula

Mild dehydration Hyponatremia Dehydration, hypokalemia, hypochloremia, metabolic alkalosis

External loss of salivary secretions, lack of intake Loss of gastric secretions, hydrogen ions, potassium and chloride

Volume replacement with dextrose–saline Volume replacement with dextrose–saline and potassium chloride

Severe dehydration Hyponatremia Metabolic acidosis, hyperkalemia, high levels of BUN

Shift of ﬂuids into third space, Fast volume replacement loss of sodium in stool or Blood or blood products emesis. Low blood pressure Dextrose–saline with poor peripheral perfusion

Upper intestinal obstruction Duodenal atresia Malrotation (Ladd’s bands) Midgut volvulus

Mild to severe dehydration Hypothermia, hypochloremia, hypocalcemia

Loss of gastric and duodenal ﬂuids: hydrogen ions, chloride and bicarbonate

Low intestinal obstruction Ileal atresia Hirschsprung’s disease Imperforate anus

Dehydration, hyponatremia, metabolic acidosis, hypokalemia

Loss of ﬂuids into the intestine. Fluid replacement by Enterocolitis dextrose–saline, plasma and blood as needed

Abdominal wall defects Omphalocele Gastroschisis

Severe dehydration, metabolic acidosis, hyponatremia

Loss of serum from the intestinal wall in gastroschisis. Aspiration of large volume of bile by nasogastric catheter. Low perfusion

Pyloric stenosis Pyloric atresia Peritonitis Necrotizing enterocolitis Perforated viscous

Volume replacement with dextrose–saline and potassium chloride

Urgent ﬂuid replacement by plasma, albumin, Ringer’s lactate

Table 5.6 Electrolyte content of bodily ﬂuids* Fluid Gastric Pancreatic Bile Small intestine Ileostomy Diarrhea Sweat normal cystic ﬁbrosis

Na+

K+

Cl–

HCO3–

20–80 120–140 130–160 100–140 45–135 10–90

5–30 5–15 5–15 5–25 3–15 10–80

100–140 90–120 80–120 90–135 20–115 10–110

0 110 40 30 13–100 15–50

10–30 50–130

3–10 5–25

10–35 50–110

0 0

From Chesney and Zelikovic,64 by permission.* Values are mEq/L.

56 Preoperative assessment

electrolyte content of bodily ﬂuids, which are lost by various routes, and must be corrected with the appropriate balance to be replaced accurately. Bilateral obstruction uropathy exhibits a number of important and sometimes complex abnormalities of electrolyte metabolism and acid–base regulation. Depending on the severity of a lesion, patients can have dehydration, ﬂuid overload, hypernatremia, hyponatremia, hyperkalemia, renal tubular acidosis and azotemia with variable degrees of renal failure. Patients with water and salt-losing nephropathy need additional salt and water supplements. Patients with defective dilutional capacity and renal failure require ﬂuid restriction. Patients with renal tubular acidosis require bicarbonate supplementation with or without potassium exchange resins.

FLUID MANAGEMENT PROGRAM Based on a consideration of the sources of water loss, an average parenteral ﬂuid design for an infant receiving no oral feeding should provide about 40 ml of water per 100 cal metabolized for insensible loss and 50–80/100 cal for urine, with about 5 ml /100 cal for stool water, resulting in a total volume of 100–125 ml/100 cal for the maintenance ﬂuid losses under baseline conditions per 24 hours. LBW infants will require considerably more ﬂuid because of an increasing insensible loss. Neonates weighing less than 1000 g may need 160 ml/kg/24 hours and those over 1000 g may require 110–130 ml/kg/24 hours. With premature infants, a ﬂuid intake >170 ml/kg/24 hours is associated with an increased risk of congestive cardiac failure, patent ductus arteriosus and necrotizing enterocolitis. Serial measurements of body weight are a useful guide to total body water in infants. Fluctuations over a 24hour period are primarily related to loss or gain of ﬂuid, 1 g body weight being approximately equal to 1 ml water. Errors will occur if changes in clothing, dressings and tubes are not accounted for and if scales are not regularly calibrated. The assessment of hydration status in every newborn surgical patient is essential for the infant’s outcome. This can best be obtained by changes in body weight, measurement of urine ﬂow rate, concentration of urine, hematocrit and total serum protein. Estimation of serum electrolytes, urea, sugar and serum osmolarity gives an excellent indication of the hydration status.

REFERENCES 1. Harrison MR, Golbus MS, Filly RA. The Unborn Patient – Diagnosis and Management of the Foetus with a Congenital Defect. San Diego: Grune and Stratton, 1984.

2. Harrison MR, Scott NS, Flake AW. Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg 1993; 28:1411–18. 3. Harrison MR, Adzick NS, Jennings RW et al. Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 1990; 336:965–7. 4. Hirata GL, Medearis AL, Platt LD. Foetal abdominal abnormalities associated with genetic syndromes. Clin Perinatol 1990; 17:675–702. 5. Azick NS, Flake AW, Harrison MR. Recent advances in prenatal diagnosis and treatment. Pediatr Clin Am 1985; 32:1103–16. 6. Govaerts MJ. Perioperative considerations in paediatric anaesthesia. Pediatr Anaesth 1990; 3:353–7. 7. Mullins GC. Anaesthesia and intensive care in critically ill neonates. Paediatr Anaesth 1990; 3:361–6. 8. Cook RWI. The low birth weight baby. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990: 77–88. 9. Takayama JI, Teng W, Uyemoto J et al. Body temperature of newborns: what is normal? Clin Pediatr 2000; 39:503–10. 10. Silverman WA, Sinclair JC. Temperature regulation in the newborn infant. N Engl J Med 1966; 274:146–8. 11. Swyer PR. Heat loss after birth. In: Sinclair JC, editor. Temperature Regulation and Energy Metabolism in the Newborn. New York: Grune and Stratton, 1978: 91–128. 12. Muraji T, Tsugawa C, Nishijima E, et al. Gastrochisis: a 17 year experience. J Pediatr Surg 1989; 24:343–5. 13. Niermeyer S, Winkel JK, Van Reempts P et al. International Guidelines for Neonatal Resuscitation: An Excerpt From the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Pediatr 2000; 106:1–16. 14. Hey EN. The relation between environmental temperature and oxygen consumption in the newborn baby. J Physiol 1969; 200:589–603. 15. Ringer SA, Stark AR. Management of neonatal emergencies in the delivery room. Clin Perinatol 1989; 16:23–41. 16. Walker J, Cudmore RE. Respiratory problems and cystic adenomatoid malformation of lung. Arch Dis Child 1990; 65:649–50. 17. Dziedzic K, Vidyasagar D. Pulse oximetry in neonatal intensive care. Clin Perinatol 1989; 16:177–97. 18. Philippart AI, Sarnik AP, Belenky WM. Respiratory support in paediatric surgery. Surg Clin N Am 1980; 60:1519–32. 19. Schmitt M, Prevot J, Lotte E et al. Relevance of highfrequency ventilation in neonatal surgery. Pediatr Surg Int 1986; 1:55–9. 20. Milerad J, Walsh WF. Commentary on neonatal ECMO: a North American and Scandinavian perspective. Acta Paediatr 1995; 84:841–7. 21. Reis-Bahrami K, Sort BL. The Current Status of Neonatal Extracorporal Membrane Oxygenation. Sem Perinatol 2000; 24:406–17.

References 57 22. Anthony ML, Hardee E. Extracorporal Membrane Oxygenation. Saving tiny lives. Crit Care Nurs Clin N Am 2000; 12:211–17. 23. Toomasian JM, Bartlett RH. Neonatal ECMO registry. In: Handbook for the Seventh Annual Spring Workshop on Neonatal ECMO. USA: MI, Ann Arbor: 1988: 236. 24. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia. Is emergency operation necessary? J Pediatr Surg 1988; 23:731–4. 25. McCune S, Short BL, Miller MK et al. Extracorporeal membrane oxygenation therapy in neonates with septic shock. J Pediatr Surg 1990; 25:479–82. 26. Atkinson JB, Ford EG, Kitagawa H et al. Persistent pulmonary hypertension complicating cystic adenomatoid malformation in neonates. H Pediatr Surg 1992; 27:54–6. 27. Adolph V, Ekelund C, Smith C et al. Developmental outcome of neonates treated with extracorporeal membrane oxygenation. J Pediatr Surg 1990; 25:43–6. 28. Neubauer AP. Percutaneous central iv access in the neonate: experience with 535 silastic catheters. Acta Paediatr 1995; 84:756–60. 29. McCabe AJ, Wilcox DT, Holm BA et al. Surfactant – A review for pediatric surgeons. Pediatr Surg 2000; 35:1687–1700. 30. Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Sem Perinatol 2000; 24:387–95. 31. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs 2001; 61:27–39. 32. Heymann MA, Randolph AM. Control of the ductus arteriosus. Physiol Rev 1975; 55:62–78. 33. Fyler C, Lang P. Neonatal heart disease. In: Avery EB, editor. Neonatology. 2nd edn. Philadelphia: Lippincott, 1981: 443–4. 34. McNamara DG. Value and limitations of auscultation in the management of congenital heart disease. Pediatr Clin N Am 1990; 37:93–113. 35. Fyfe DA, Kline CH. Foetal echocardiographic diagnosis of congenital heart disease. Pediatr Clin N Am 1990; 37:45–67. 36. McEwan AI, Birch M, Bingham R. The preoperative management of the child with a heart murmur. Pediatr Anaes 1995; 5:151–6. 37. Brewer ED. Disorders of acid-base balance. Pediatr Clin N Am 1990; 37:429–47. 38. Cowett RM, Loughead JL. Neonatal glucose metabolism: differential diagnosis, evaluation and treatment of hypoglycemia. Neonatal Netw 2002; 21:9–19. 39. Lynch RE. Ionised calcium: paediatric perspective. Pediatr Clin N Am 1990; 37:373–89. 40. Maisels MJ. Neonatal jaundice. In: Avery GB, editor. Neonatalogy. 2nd edn. Philadelphia: Lippincott, 1981: 482. 41. Weber JL. Liver disease in childhood. Med (International) 1982; 1:748–51. 42. Ohi R, Nio M, Chiba T et al. Long term follow-up after

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surgery for patients with biliary atresia. J Pediatr Surg 1990; 25:442–5. Weiss RG, Ball WS, Warner BW et al. Mediastinal hemorrhage during extracorporeal membrane oxygenation. J Pediatr Surg 1989; 24:1115–17. Sell LL, Cullen ML, Whittlesey GC et al. Haemorrhagic complications uring extracorporeal membrane oxygenation: prevention and treatment. J Pediatr Surg 1986; 21:1087–91. Gregory GA. Anaesthesia for premature infants. In: Paediatric Anaesthesia. New York: Churchill Livingstone, 1983: 879. Wardle SP, Kelsall AWR, Yoxall CW et al. Percutaneous femoral arterial and venous catheterisation during neonatal intensive care. Arch Dis Fetal Neonatal Ed 2001; 85:119–22. Chiang VW, Baskin MN. Uses and complications of central venous catheters inserted in a pediatric emergency department. Pediatr Emerg Care 2000; 16:230–2. El-Dahr SS, Chevalier RL. Special needs of the newborn infant in ﬂuid therapy. Paediatr Clin N Am 1990; 37:323–36. Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta Paediatr Scand (Suppl) 1983; 305:7–11. Shaffer SG, Bradt SK, Hall RT. Postnatal changes in total body water and extracellular volume in the preterm infant with respiratory distress syndrome. J Pediatr 1986; 109:509–14. Boineau FG, Lewy JE. Estimation of parenteral ﬂuid requirements. Pediatr Clin N Am 1990; 37:257–64. Hey EN, Katz G. Evaporative water loss in the newborn baby. J Physiol 1969; 200:605–19. Roy RN, Sinclair JC. Hydration of the low birth weight infant. Clin Perinatol 1975; 2:393–417. Engle WD, Baumgart S, Schwartz JG et al. Insensible water loss in the critically ill neonate. Combined effect of radiant-warmer power and phototherapy. Am J Dis Child 1981; 135:516–20. Bell EF, Gray JC, Weinstein MR et al. The effects of thermal environment on heat balance and insensible water loss in low-birth weight infants. J Pediatr 1980; 96:452–9. Faranhoff AA, Wal M, Gruber HS et al. Insensible water loss in low birth weight in infants. Pediatrics 1972; 50:236–45. Hammarlun K, Sedin G, Stromberg B. Trans-epidermal water loss in newborn infants. Acta Paed Scand 1983; 72:721–8. Albanese CT, Rowe MI. Preoperative and postoperative management of the neonate. In: Spitz L, Coran AG, editors. Operative Surgery. London: Butterworths, 1995: 5–12. Shaffer SE, Norman ME. Renal function and renal failure in the newborn. Clin Perinatol 1989; 16:199–218. Wilkinson AW, Stevens LH, Hughes ZA. Metabolic changes in the newborn. Lancet 1962; 1:983–7.

58 Preoperative assessment 61. John E, Klavdianou M, Vidyasagar D. Electrolyte problems in neonatal surgical patients. Clin Perinatol 1989; 16:219–32. 62. Pierro A, Carnielli V, Filler RM et al. Partition of energy metabolism in the surgical newborn. J Pediatr Surg 1991; 26:581–6.

63. Winters RW. Fluid therapy for paediatric surgical patients. In Winters RW. The Body Fluids in Paediatrics. Boston: Little Brown, 1973: 595–611. 64. Chesney RW, Zelikovic I. Pre- and postoperative ﬂuid management in infancy. Pediatr Rev 1989; 11:153–8.

6 Anesthesia DECLAN WARDE

INTRODUCTION Over the past 60 years or so, provision of anesthesia for the neonate requiring surgery has developed from being a relatively haphazard affair to achieving the status of a recognized subspeciality. The improved survival rates seen following surgery, where even the smallest and sickest infants are concerned, have been due in no small part to advances in anesthetic management. Equally important has been an increased appreciation of the need for an efﬁcient smooth-working team. The success of neonatal surgery depends on maximum cooperation between surgeon, anesthetist, neonatologist, and nursing and paramedical personnel. It is appropriate therefore that everyone involved in the care of neonates, whether working inside or outside the operating theatre, should be familiar with the basic techniques used to maintain a favorable physiologic milieu in the face of surgical intrusion, while at the same time ensuring adequate anesthesia. This chapter will consider the preoperative evaluation and preparation of the surgical neonate, anesthetic equipment, choice of anesthetic agent and technique (with reference to the pharmacology of the newborn), induction of anesthesia and endotracheal intubation, maintenance and reversal of anesthesia, perioperative monitoring and ﬂuid therapy, the anesthetic implications of congenital anomalies and, ﬁnally, speciﬁc considerations for the premature infant undergoing surgery.

PREOPERATIVE PREPARATION AND EVALUATION Much neonatal surgery is performed on an emergency basis. However, operation is rarely so urgent as not to allow for adequate evaluation and stabilization beforehand. The cornerstone of preoperative anesthetic management is a detailed knowledge of the infant’s history combined with a thorough physical examination.

Consideration must also be given to the speciﬁc surgical procedure to be undertaken and its implications in terms of potential blood loss, monitoring requirements and postoperative care.

History Although many neonates requiring surgery are only a few hours old, considerable information that is useful as regards anesthetic management will have been accumulated by the time of the anesthetist’s visit. This information should be obtained from the parent(s) (if available) and medical and nursing colleagues. Of profound importance is an accurate estimation of gestational age, as prematurity has major implications for the anesthetist (see later). Trends in blood pressure and heart rate, body weight, ﬂuid intake and output, laboratory measurements, X-ray appearances and the extent of any respiratory support required will normally be readily available and are very helpful both in planning anesthetic technique and in anticipating problems. A knowledge of recent or current drug therapy is also important.

Physical examination The anesthetist should make a brief appraisal of the infant’s overall condition and follow this with a careful assessment of individual body systems. Overhydration or hypovolemia can be detected by assessment of skin turgor, the anterior fontanelle and liver size. Peripheral vasoconstriction may indicate either hypovolemia or acidosis. Jaundice will normally be self-evident, but anemia and cyanosis can be difﬁcult to detect in the neonate. Pulmonary function is also less easily evaluated than in older children and adults, but any of the following may indicate impending respiratory failure: nasal ﬂaring, tachypnea, chest wall recession, grunting respiration or apneic spells. Airway anatomy should be carefully assessed in order that potential difﬁculties with endo-

60 Anesthesia

tracheal intubation can be anticipated. One should look for other associated congenital anomalies in the surgical neonate. This is particularly so when examining the cardiovascular system (e.g. one-third of infants with esophageal atresia also have some form of congenital heart disease). Accurate preoperative neurological assessment is mandatory in infants presenting for anesthesia for neurosurgery.

Laboratory investigations Minimum laboratory data required includes full blood count, blood urea and serum electrolytes, blood glucose and calcium, coagulation proﬁle and urine speciﬁc gravity. Arterial blood gas analysis for pH, oxygen and carbon dioxide partial pressure (PO2 and PCO2), and bicarbonate levels is also frequently indicated. The preoperative hemoglobin level should be at least 12 g/dL – if lower, consideration should be given to transfusion with packed red blood cells prior to anesthesia and surgery. Any dehydration, hypovolemia, hypoglycemia, hypocalcemia, or hypo- or hyperkalemia should be corrected. pH, PO2, PCO2 and body temperature should be normalized.

transfer to the operating theater, as it is usually easier to maintain an infant’s body temperature in the ICU environment. Overall ﬁtness must be assessed in light of the urgency of surgery. This may require consultation between anesthetist, surgeon and other interested personnel. If transfer to the operating theater is considered to be unacceptably hazardous, for example in the case of some extremely ill and low birth weight (LBW) infants, it may be advantageous to undertake surgery in the ICU itself.1,2

TRANSFER TO OPERATING THEATER The time during which the neonate is transferred to the operating theater is one which is not without hazard. Risks are minimized if he or she is accompanied by experienced medical and nursing personnel and if the theater is close at hand. Transfer should be in either an incubator or an isolette with overhead heater to reduce heat loss. Any treatment in progress (e.g. i.v. ﬂuid or drug infusion, respiratory support) should be continued by the use of battery-operated infusion pumps and portable respiratory equipment. Monitoring should not be interrupted during this critical phase.

Premedication Sedative premedication is not used in neonates. However many pediatric anesthetists consider it advisable to administer an anticholinergic drug either prior to or at induction of anesthesia in order to reduce secretions (which interfere with the airway) and to protect against bradycardia (which may occur with hypoxemia or after halothane, succinylcholine or airway instrumentation). Atropine is the most widely used drug, usually in a dose of 0.02 mg/kg by i.v. injection immediately prior to induction. Prior to transfer to the operating theater, the anesthetist should conﬁrm that: • The infant has been fasting for at least 3 hours (but not for much longer unless an i.v. ﬂuid infusion is in progress) • Blood has been cross-matched (if indicated) • Vitamin K, 0.5–1 mg i.m., has been administered (to allow for possible deﬁciency in vitamin K-dependent clotting factors) • The stomach has been decompressed (especially in cases of intestinal obstruction) • Any premedication ordered has been given. Estimated blood volume, allowable blood loss and maintenance ﬂuid requirements should be calculated. Where it is anticipated that multiple vascular access routes will be required (e.g. for central venous pressure or direct arterial pressure monitoring), it may be advisable to establish these in the intensive care unit (ICU) before

OPERATING THEATER AND ANESTHETIC EQUIPMENT The prime objectives of neonatal anesthesia are the provision of sleep, analgesia, life support, intensive surveillance and appropriate operating conditions for the infant requiring surgery. In order for these to be achieved it is imperative that both operating theater environmental conditions and anesthetic equipment be appropriate. It has been shown that maximum heat loss occurs between the time of arrival of the neonate in theatre and the skin incision. Measures should be taken to minimize the risk and extent of this occurrence. Before the infant arrives, the theater, which should be draught free, should be warmed to a temperature of 24oC or 25oC. Once the baby is removed from the incubator or isolette, he or she should be placed on a water or air mattress which has been heated to 40oC and kept covered as much as possible – plastic drapes and blankets are particularly useful in this regard. The warming mattress used must be electrically safe and accurately monitored, have an easily adjustable thermostat and a fail-safe cutout device in the event of thermostat failure. If an overhead radiant heater is available, it should be set to maintain skin temperature at 36oC. Other measures which assist in maintaining body temperature during this critical period include warming and humidifying inspired anesthetic gases and warming i.v. and skin preparation ﬂuids.

Operating theater and anesthetic equipment 61

Breathing systems An appropriate anesthetic circuit for use in infants needs to be light, have minimal resistance and dead space, allow for warming and humidiﬁcation of inspired gases and be adaptable to spontaneous, assisted or controlled ventilation. The most widely used is the T-piece system designed by Philip Ayre3 and later modiﬁed by Rees4 (Fig. 6.1). Connectors and tubes should also offer minimal ﬂow resistance and dead space. Most endotracheal tubes used during neonatal anesthesia are manufactured of polyvinyl chloride. A knowledge of the probable diameter and length of tube appropriate for any given infant is highly desirable (Table 6.1), but must always be conﬁrmed clinically. The optimal diameter is the largest which will pass easily through the glottis and subglottic region and will produce a slight leak when positive pressure is applied. A convenient guideline for length of orotracheal tube from gum to mid-trachea is 7 cm for an infant weighing 1 kg, with an additional centimeter for each kilogram increase in weight.5 Use of an endotracheal tube of too large a diameter may result in tracheal wall damage, while excess length leads to endobronchial intubation. The presence of a cuff limits the diameter of tube which can be used, with consequent increased resistance to airﬂow. For this reason, uncuffed tubes are invariably used in neonates.

Once satisfactory positioning has been conﬁrmed visually and by auscultation of both lungs, the tube should be taped securely to prevent accidental extubation. Consideration should be given to secondary ﬁxation to the forehead to prevent rotational movement. Face masks are generally used for only brief periods in neonates, but should provide a good ﬁt and have a low dead space. The Rendell–Baker–Soucek mask remains popular (Fig. 6.2). Oral airways are not generally necessary except in cases of choanal atresia, but have the advantage of splinting the endotracheal tube and preventing lateral movement. The incidence of airway complications associated with the laryngeal mask airway (LMA) in infants is high.6 However the device can occasionally prove to be useful, especially when endotracheal intubation is difﬁcult.7–9

Figure 6.2 Rendell–Baker–Soucek masks

Laryngoscopes Because of the anatomical peculiarities of the infant’s airway, most anesthetists prefer to use a laryngoscope with a straight blade, lifting the epiglottis forwards from behind to facilitate intubation. The Miller number 0 and 1 blades are suitable in most cases. A modiﬁed laryngoscope which assists in maintaining oxygenation during laryngoscopy in infants and children has been described.10

Ventilators

Figure 6.1 Ayre’s T-piece with Jackson–Rees modiﬁcation

Table 6.1 Approximate diameter and length of endotracheal tubes for use in neonatal anesthesia Post-conceptual age (weeks)

Internal diameter (mm)

Length (cm) Oral Nasal

< 30 < 30–40 > 40

2.0–2.5 2.5–3.0 3.0–3.5

7–8 8–9 9–10

8–9 9–10 10–11

Most infants and children can be ventilated using standard adult ventilators provided the ventilator is of low internal compliance and equipped with pediatric breathing tubes. The ventilator should be capable of delivering small tidal volumes and rapid respiratory rates, and have an adjustable inspiratory ﬂow rate and inspiratory:expiratory ratio so that peak airway pressure is kept as low as possible.11 Pressure-controlled ventilation is widely used in order to minimize the risk of pulmonary barotrauma. A suitable temperaturecontrolled humidiﬁer should be incorporated in the inspiratory side of the ventilator circuit. The ability to deliver air/oxygen mixtures through ventilator or anesthetic circuit should be available.

62 Anesthesia

Monitoring equipment A complete range of monitoring equipment suitable for infant use is required.

CHOICE OF ANESTHETIC AGENT AND TECHNIQUE Neonates perceive pain, while even babies born at 28 weeks’ gestation mount a substantial and potentially harmful response to surgically induced stress.12,13 Thus, few would argue with the contention that adequate anesthesia should be provided for all infants undergoing surgery. The anesthetic agents employed are similar to those used for older children and adults. However the responses of the neonate to these potent drugs differ in a number of respects from those of older patients. An understanding of these differences is essential for the safe conduct of neonatal anesthesia and also inﬂuences choice of anesthetic agent and technique.

Inhalational agents Inhalation induction of anesthesia with nitrous oxide, oxygen and a volatile agent remains popular. Provided that respiration is not depressed, both induction of and emergence from anesthesia are rapid in infants. The reasons for this are multiple, but include the relatively higher cardiac output, greater alveolar ventilation, smaller functional residual capacity and larger proportion of vessel-rich tissues relative to body mass seen in the newborn infant.14–16 An additional consideration is that the minimal alveolar concentration (MAC) of inhaled agents required to prevent reﬂex responses to surgical stimulation varies with age.

stered (especially during controlled ventilation) and caution is advised. Like most other inhalational agents, halothane increases cerebral blood ﬂow with a consequent rise in intracranial pressure. This effect is minimal at low concentrations if controlled ventilation is employed. Halothane hepatitis has not been reported in newborn infants.

ISOFLURANE Despite its lower blood gas solubility coefﬁcient, inhalation induction with isoﬂurane is generally not as rapid or as smooth as with halothane. Indeed this agent has been shown to be associated with a signiﬁcant incidence of hypoxic episodes during inhalation induction of anesthesia in older children.25 Sedative premedication26 and use of a highly inspired isoﬂurane concentration from the outset27 both reduce the incidence of these adverse occurrences, but are relatively contraindicated in the surgical neonate. The respiratory depressant effects of isoﬂurane are similar to those of halothane. Once again MAC values are lower in the newborn28 and lower still in premature infants.29 Isoﬂurane has been shown to maintain systolic arterial pressure in the normal range even in preterm neonates and, unlike halothane, does not sensitize the myocardium to the effects of circulating catecholamines. It has considerable potentiating effects on non-depolarizing muscle relaxants, so that lower doses of the latter can be used. Metabolic degradation of the agent is minimal and recovery rapid. In summary, isoﬂurane is an excellent agent for maintenance of anesthesia, perhaps the agent of choice in the neonate, but halothane remains superior for inhalation induction.

ENFLURANE This agent is not widely used in neonatal and pediatric anesthesia because its irritant effects render it relatively unsatisfactory for inhalation induction.

HALOTHANE Halothane was for many years the most widely used volatile anesthetic for inhalation induction in infants and young children. This is largely because it is usually associated with a smooth induction without irritant effects on the airway. Like other potent inhalational agents, it leads to a dose-related depression of spontaneous respiration.17 This is particularly important in the neonate, in whom the ventilatory response to hypoxia is one of hypoventilation. Halothane MAC is signiﬁcantly lower in newborn infants than in those between 1 and 6 months of age and appears to be still lower in the fetus.18–21 The agent is considered by many to be a more potent depressor of cardiovascular function in infants and young children than in older patients, but its use does not appear to be associated with increased morbidity.22–24 However, hypotension can occur when high concentrations are admini-

DESFLURANE Airway irritant effects also render desﬂurane unsuitable for inhalation induction in pediatric practice. However recovery times in infants are shorter with this agent than those following use of other volatile anesthetics. The agent has been recommended for maintenance of anesthesia in the ex-premature infant prone to apnea and ventilatory depression.30

SEVOFLURANE Induction time with sevoﬂurane is shorter than with halothane in older children.31 However, this does not appear to be the case where infants are concerned.32 The agent has been reported to cause more respiratory depression than halothane in infants and young children, but perhaps not to a clinically signiﬁcant degree.33

Choice of anesthetic agent and technique 63

NITROUS OXIDE This gas does not provide adequate anesthesia when used alone with oxygen.13 It is most often employed as a carrier, which supplements potent volatile anesthetics, thereby reducing the concentration required and minimizing cardiovascular depressant effects. Animal work indicated that it might induce pulmonary vasoconstriction, with resultant increased right-to-left shunting in the newborn,34 but this does not appear to be so.35 It does cause moderate respiratory and cardiovascular depression. One limitation to the use of nitrous oxide in neonatal anesthesia is the fact that it is many times more soluble in blood than is nitrogen. As a result, the inhalation and subsequent diffusion of the gas causes an increase in the volume of compliant spaces. It follows that the agent should not be used in infants with congenital diaphragmatic hernia, lobar emphysema or necrotizing enterocolitis.

Intravenous agents THIOPENTONE Despite the fact that it was introduced to anesthetic practice over 60 years ago and that many supposedly superior agents have since been developed, this drug remains the preferred agent for i.v. induction in infants. The induction dose (ED50 3.4 mg/kg) is lower in neonates younger than 14 days of age than in older infants.35

after a similar time to that seen in adults (approximately 4 minutes). Because of the number of side effects, including bradycardia, hyperkalemia and triggering of malignant hyperpyrexia reactions associated with this agent, it has been suggested that its use in young infants should be re-evaluated.38 However, it remains pre-eminent in rapidly providing optimum conditions for endotracheal intubation, and is still very widely used.

Non-depolarizing muscle relaxants For many years it was generally agreed that newborn infants exhibited an increased sensitivity to these agents, but recent studies have demonstrated that full relaxation demands doses similar to those used in adults. A lower plasma concentration is required (presumably because of immaturity of the neuromuscular junction), but this is produced in any event by distribution of injected drug throughout the relatively larger extracellular ﬂuid compartment. Alterations in plasma protein binding may also play a role in determining dose requirements, which are much more variable than in adults.39 It follows that careful titration of dose against response is advisable and that these drugs should be administered slowly to neonates. Use of a peripheral nerve stimulator as a guide to degree of relaxation is strongly recommended.

PROPOFOL

ATRACURIUM AND VECURONIUM

Experience with this drug is somewhat limited in neonates. However it has been used successfully in the management of pyloric stenosis.36

These two agents were introduced because their duration of action was intermediate between that of suxamethonium and older non-depolarizing muscle relaxants such as pancuronium and because they offered increased cardiovascular stability. In addition, atracurium is attractive in that its metabolism is independent of hepatic and renal function, although it is dependent on pH and temperature. Recommended initial doses are 0.3–0.5 mg/kg for atracurium and 0.05–0.1 mg/kg for vecuronium. Because of their pharmacokinetic proﬁles, both drugs are suitable for use by continuous i.v. infusion, although atracurium infusion requirements show marked individual variation.40 Nightingale found the duration of effect of atracurium to be longer in infants younger than 3 days of age.41 Other studies have shown the dose–response curves of this agent to be parallel in infants, older children and adults and in fact demonstrate recovery times to be shorter in infants.42,43 Histamine release, an occasional problem with the drug in adults, has not caused problems in the pediatric population.41 Vecuronium, on the other hand, has been found to have a longer recovery time in infants compared to older children and adults and should be regarded as a longacting muscle relaxant in this age group.44

KETAMINE This agent is associated with greater cardiovascular stability than many other anesthetic drugs.37 However, its metabolism is considerably delayed in infants younger than 1 year of age. It has the advantages of having a profound analgesic effect and of being capable of being given by i.m. injection.

Neuromuscular blocking agents SUXAMETHONIUM Relatively higher doses (2 mg/kg) of this drug are required to produce full relaxation in infants than in adults (1 mg/kg). This is because of the neonate’s larger extracellular ﬂuid space, throughout which the drug is distributed. Suxamethonium is metabolized by plasma pseudocholinesterase. Although plasma levels of this enzyme are low in the ﬁrst 6 months of life, activity is adequate to metabolize the drug, and recovery occurs

64 Anesthesia

MIVACURIUM Mivacurium is a short-acting, non-depolarizing neuromuscular agent which is rapidly hydrolyzed by plasma pseudocholinesterase. The time course of block produced by the drug is more rapid in younger pediatric patients.45 Satisfactory intubating conditions are not achieved as quickly as with suxamethonium but serious side effects occur less frequently.

ROCURONIUM This agent causes more neuromuscular depression and has a longer duration of action during halothane anesthesia in infants than in children older than 2 years.46

d-TUBOCURARINE AND PANCURONIUM These drugs were widely used in neonatal anesthetic practice in the past but have largely been replaced by alternatives with a shorter duration of action. The cardiovascular effects of pancuronium are more pronounced than in adults and tachycardia may be a problem.

NARCOTIC ANALGESICS AND THEIR DERIVATIVES The neonate exhibits an exaggerated response to narcotic administration when compared with the older child.47 The reasons for this include immaturity of hepatic enzyme systems leading to impaired conjugation and glucuronide excretion48 and the greater permeability of the infant blood-brain barrier to these drugs.49 Morphine elimination half-life is prolonged in babies younger than 4 days old, while morphine clearance in the newborn in less than one-half that of older infants.50 In addition, neonates are more susceptible than adults to the respiratory depressant effects of morphine and its derivatives.49 It follows that where narcotic analgesics are administered to neonates, dosage regimens should be modiﬁed so that patient safety is not compromised. Recent evidence indicates that neonates do perceive and respond to pain and there is little doubt that the intraoperative administration of opiates to infants undergoing major surgery can be beneﬁcial.13 There can be no justiﬁcation for denying adequate analgesia to infants who are to be mechanically ventilated in the postoperative period. Morphine (0.05–0.1 mg/kg) and fentanyl (0.005–0.02 mg/kg) given intravenously are the two most widely used drugs, with the latter being particularly well tolerated hemodynamically.37,51 Intraoperative infusions of ultra-short-acting opioids such as remifentanil have been used successfully although recovery times were prolonged in some infants younger than 7 days old.52,53

In recent years, continuous infusions of i.v. morphine have been popular for provision of postoperative analgesia in ventilated infants and those nursed in highdependency units. Infusion rates above 0.01 mg/kg/hour are rarely necessary. Respiratory monitoring should be continued for 24 hours after discontinuation of the infusion. The situation with regard to other infants is more difﬁcult. It should be recognized that while failure to treat discomfort or pain effectively may have signiﬁcant long-term effects, overaggressive treatment has its own morbidity.54 The easy option is to avoid intra- or postoperative opioids altogether but one dose of codeine phosphate (1 mg/kg) given by i.m. injection is probably safe.55 Local anesthetic techniques (e.g. lumbar or caudal epidural block, intrathecal block, intercostal block, wound inﬁltration, etc.) can often be used as an alternative method of providing analgesia for these babies and will undoubtedly be more widely adopted in the future.

Regional anesthesia In recent times there has been a signiﬁcant increase in the use of regional anesthetic techniques as an alternative to general anesthesia in neonates. Local anesthetic blocks are safe and efﬁcacious and may be particularly valuable in the high-risk infant. Spinal and epidural routes, or a combination of both, have been used.56–60

Induction of anesthesia and endotracheal intubation Most pediatric anesthetists advocate that infants should have anesthesia induced and a muscle relaxant administered prior to attempts at endotracheal intubation. Awake intubation is less popular than in the past61 because it is considered that the ensuing hypertension62 and rise in anterior fontanelle pressure63 may contribute to the development of intraventricular hemorrhage, especially in premature infants and those with disorders of coagulation. The induction technique depends on the: (1) age, size and physical status of the infants, (2) relative hazard of regurgitation, and (3) personal preferences of the anesthetist. In most instances, i.v. induction followed by administration of a short-acting muscle relaxant is satisfactory. Inhalation induction is an acceptable alternative. In either case, i.v. access should be established beforehand and the induction itself should be preceded by a short period of preoxygenation. Intubation is best accomplished with the infant’s head extended at the atlanto-occipital joint. This position allows the straightest and shortest distance between the lips and larynx.64 The laryngoscope blade is inserted into the right side of the mouth, displacing the tongue to the left. As the blade is advanced the epiglottis comes into view. In the neonate this structure is long and ﬂoppy and it should be displaced anteriorly from behind to aid

Monitoring 65

visualization of the larynx. If difﬁculty is encountered, the little ﬁnger of the left hand can be used to press gently on the larynx to improve visualization. The use of an atraumatic but rigid bougie can also be extremely valuable in these cases. Once intubation has been achieved, one should carefully auscultate both lungs to check for equal air entry, and the endotracheal tube should be securely ﬁxed. While the indications for awake intubation are not as broad as they once were, the technique retains a limited place in neonatal anesthesia. The main advantage is that the baby can still breathe if attempts at intubation fail. If the anesthetist is inexperienced in dealing with neonates or if there is signiﬁcant upper airway obstruction (e.g. cystic hygroma, Pierre Robin syndrome), it may occasionally be safer to intubate prior to inducing anesthesia. Correct holding of the infant is essential if the maneuver is to be successful; an assistant should stabilize the head and shoulders during the intubation process. The endotracheal tube is inserted on inspiration – this facilitates intubation and minimizes laryngeal trauma. If it is considered at the time of induction of anesthesia that postoperative mechanical ventilation will be required, the tube should be inserted by the nasal rather than the oral route. It is difﬁcult to manipulate Magill’s forceps in the mouth of a small infant, but ﬂexing the neck usually facilitates passage of nasotracheal tubes.

Consideration should be given to the use of air/ oxygen mixtures in preterm neonates. I.v. analgesics are rarely indicated unless it is proposed to ventilate the infant in the postoperative period.

REVERSAL AND EXTUBATION If a volatile agent has been used for maintenance of anesthesia, it should be discontinued shortly prior to the end of surgery. Once surgery has been completed, residual muscle relaxation is reversed by either neostigmine (0.06 mg/kg) or edrophonium (1 mg/kg) combined with either atropine (0.02–0.03 mg/kg) or glycopyrrolate (0.01 mg/kg). Controlled ventilation is continued with 100% oxygen or with oxygen in air until spontaneous respiration has returned. Suctioning through the endotracheal tube is carried out if secretions are obviously present. The nostrils should be gently suctioned as routine. The infant should not be extubated until fully awake and breathing adequately. In most cases, reversal of neuromuscular blockade and resumption of spontaneous respiration occurs rapidly.65 If difﬁculty is encountered this may be due to hypothermia, acidosis or hypocalcemia, or the fact that an incremental dose of relaxant has been given too close to the end of surgery.

MONITORING MAINTENANCE OF ANESTHESIA Because of the vulnerability of the infant’s respiratory system, spontaneous respiration is not used for long periods in the anesthetized neonate. Mechanical ventilation helps to ensure adequate gas exchange and also leaves the hands of the anesthetist free to perform other tasks. Suitable ventilators have already been discussed and, depending on the particular machine available, may be set in either pressure- or volume-cycled modes. With the former, suitable settings would include a fresh gas ﬂow of 2–3 L/minute, peak airway pressure of approximately 20 cmH2O of water and a ventilatory rate of 30–40/minute. With the latter, a delivered tidal volume of approximately 10 ml/kg at a rate of 30–40 breaths/ minute is appropriate. Inspired gases should be warmed and humidiﬁed to prevent damage to the mucosal lining of the respiratory tract and to minimize heat loss. Manual ventilation allows rapid detection of airway obstruction or disconnection, and is particularly useful during thoracic surgery. The most widely used agents for maintenance of anesthesia in the neonatal population are isoﬂurane, sevoﬂurane and desﬂurane, usually combined with 50% oxygen in nitrous oxide, along with a small dose of relaxant.

The clinical condition of the anesthetized neonate can deteriorate more rapidly and with less warning than that of patients in any other age group. It follows that careful and continuous monitoring is essential. While no piece of machinery will adequately replace the careful anesthetist, there are a number of devices available which provide helpful information that cannot be gleaned by clinical means alone. The monitoring employed in any particular case depends upon the physical status of the infant and the surgical procedure to be undertaken. The following should be positioned prior to induction (and, indeed, regarded as the minimum equipment required for monitoring anesthetized neonates): • • • • •

ECG leads and electrodes Precordial or esophageal stethoscope Blood pressure cuff Core temperature probe Pulse oximeter probe.

Although its use in pediatric anesthetic practice has declined,66 the stethoscope is particularly valuable, allowing continuous monitoring of heart and breath sounds. In the neonate, the intensity of the heart sounds varies with the stroke volume so that an indication of cardiac

66 Anesthesia

output is provided. Use of a monaural earpiece greatly improves the comfort of the listener. Most neonates undergoing anesthesia and surgery require additional monitoring. The various options available will be discussed in relation to the particular body system being monitored.

Respiration Chest wall movement should be observed continuously if at all possible. When mechanical ventilation is employed, airway pressure and minute volume alarms are mandatory. It should not be forgotten that alarms can fail. Oxygenation and adequacy of gas exchange are monitored continuously by pulse oximetry and capnography. Serial arterial blood gas analysis is mandatory in critically ill infants undergoing major surgery.

Cardiovascular function Observation of peripheral perfusion and palpation of a peripheral pulse are both useful but may be difﬁcult to achieve because of problems of access. Blood pressure monitoring is essential because of the reduced cardiovascular reserve of the neonate and the risk of hypotension if high concentrations of inhaled anesthetics are used. Conventional measurement using an inﬂatable cuff combined with auscultation of the Korotkoff sounds is often difﬁcult. The use of automated oscillotonometry represents an advance, but concern has been expressed about the accuracy of the devices used when blood pressure is low. The cuff should be of an appropriate width (approximately 4 cm). If either the infant’s physical status or the type of surgery to be performed necessitates continuous monitoring of blood pressure, a suitable vessel (usually the right radial artery) should be cannulated, the cannula being connected to a pressure transducer by narrow-bore tubing. Central venous pressure monitoring is useful in infants with congenital heart disease, and also if signiﬁcant blood loss (and replacement) are anticipated. The right internal jugular vein is usually the simplest to cannulate. Monitoring of left atrial pressure and/or pulmonary capillary wedge pressure is rarely indicated in the neonate.

Fluid balance The goal of intraoperative ﬂuid management is to sustain homeostasis by providing the appropriate amount of parenteral ﬂuid to maintain adequate intravascular volume, cardiac output, and, ultimately, oxygen delivery to tissues at a time when normal physiological functions are altered by surgical stress and anesthetic

agents.67 Maintenance ﬂuid requirements vary considerably within the neonatal period itself, but may be taken as being approximately 4 ml/kg/hour for infants older than 5 days of age. Assuming there is no preoperative ﬂuid deﬁcit, an i.v. infusion set at the usual maintenance rate should be commenced prior to induction of anesthesia. In practice, this will usually have been done in the ward. The composition of the administered ﬂuid will vary according to the maturity of the baby and preoperative electrolyte and glucose levels. Because of the problems associated with hyperglycemic states in infancy, care should be taken with the use of 10% dextrose infusions.68,69 It is important to take into account the volume of drug dilutents administered during anesthesia and surgery when calculating ﬂuid balance. Blood and ﬂuid loss can be extensive and very difﬁcult to measure during neonatal surgery. The former is best estimated by the use of small volume suction traps, by weighing small numbers of surgical swabs before they dry out, and by serial hematocrit measurements. During lengthy surgery, serum electrolytes and blood glucose should be measured at regular intervals. Urine output may be monitored by the use of adhesive collecting bags or bladder catheterization. Estimated third space loss may be replaced by continuous administration of lactated Ringer’s solution at 3–5 ml/kg/hour. While volume replacement should be undertaken when blood loss is expected to exceed 5–10% of circulating blood volume, concern has been expressed regarding the cost–beneﬁt ratio of colloidal solutions such as albumin.70 Because of the high hematocrit level at birth, red cell replacement is seldom required during most routine neonatal surgical procedures. When required, the blood used should be as fresh as possible. The most convenient and accurate method of administration is by syringe, through a three-way tap in the i.v. line. Adequacy of volume replacement can be assessed by monitoring of blood pressure, central venous pressure, peripheral circulatory state and urine output.

ANESTHESIA FOR SPECIFIC SURGICAL CONDITIONS Esophageal atresia Once a diagnosis of esophageal atresia (with or without ﬁstula) has been made, the blind upper pouch should be continuously aspirated using a Replogle or similar tube. In general, operation may be safely delayed pending improvement of any aspiration pneumonia which has developed.71 Pre-thoracotomy bronchoscopy is practised in some centers and may inﬂuence subsequent management.72 Anesthesia is similar to that for other neonatal

Special considerations for the premature infant 67

procedures, but special care must be taken with positioning of the endotracheal tube, the tip of which should be located above the carina but below any ﬁstula present. Surgical retraction during the operation may compromise either respiratory or cardiac function, so that close monitoring is essential. If serious contamination has not occurred, extubation is usually possible at the end of the procedure.

Congenital diaphragmatic hernia This condition was formerly regarded as one of the great emergencies of pediatric surgical practice, but it is now generally agreed that operation should be postponed until adequate gas exchange has been obtained and the infant is hemodynamically stable.73,74 Positive pressure ventilation using bag and mask should be avoided prior to endotracheal intubation, as expansion of the viscera contained within the hernia will cause further lung compression. Nitrous oxide should be avoided for the same reason. A reasonable anesthetic technique includes controlled ventilation with fentanyl 0.01–0.02 mg/kg, intermediate-acting muscle relaxant and 100% oxygen or oxygen in air as required. Great caution should be exercised in the use of volatile anesthetic agents. Airway pressures should be kept as low as possible. Should advanced ventilatory techniques such as high-frequency oscillation be required in order to achieve preoperative stabilization, these may be safely continued during surgery.75,76 Most infants will require mechanical ventilation in the postoperative period.

Intestinal obstruction The various forms of neonatal intestinal obstruction account for approximately 35% of all surgical procedures in the newborn. The major anesthetic problems are those of ﬂuid and electrolyte imbalance (which must be corrected preoperatively), abdominal distension (causing respiratory embarrassment) and the risk of regurgitation and aspiration of gastric contents into the lungs. Following decompression of the stomach, a rapidsequence induction incorporating preoxygenation, thiopentone and succinycholine with gentle cricoid pressure is advised. Anesthesia is then continued in the usual way.

Exomphalos and gastroschisis Anesthetic concerns include heat and ﬂuid loss from the exposed bowel and the fact that closure of the abdominal wall defect may push the diaphragm cephalad, thus compromising respiratory function. Special care must be taken to keep heat loss to a minimum. Fluid requirements are much greater than in normal neonates. To maintain plasma oncotic pressure,

at least 25% of ﬂuid intake should be given as colloid. The extent of respiratory compromise can assist the anesthetist in advising the surgeon whether or not primary closure is feasible. A proportion of infants, especially after repair of gastroschisis, require postoperative mechanical ventilation.

Congenital lobar emphysema This condition may cause severe respiratory distress in the neonatal period. Induction of anesthesia for lobectomy should be as smooth as possible – struggling may trap large amounts of air in the affected lobe during violent inspiratory efforts.77 Nitrous oxide can also increase the volume of trapped air considerably78 and is contraindicated. Great care should be taken with controlled ventilation because of the risk of pneumothorax.

Myelomeningocele If the defect is large, heat and ﬂuid loss during surgery can pose problems and should be monitored as closely as possible. Surgery is carried out with the infant in the prone position and the chest and pelvis should be supported with pads so that the abdomen remains free from external pressure.

SPECIAL CONSIDERATIONS FOR THE PREMATURE INFANT Congenital defects occur more commonly in preterm infants, so that surgery is frequently required. Organs and enzyme systems are very immature and meticulous attention to detail during anesthetic and surgical management is imperative if survival rates are to be high. The large body surface area and lack of subcutaneous fat make maintenance of body temperature even more difﬁcult than in term infants, so that a high neutral thermal environment is essential. Respiratory fatigue occurs very easily and may be exacerbated by residual lung damage following mechanical ventilation, persistent fetal circulation and oxygen dependency. The response to exogenous vitamin K is less satisfactory than in term infants and there is an increased risk of bleeding. In addition, anemia is common because of reduced erythropoiesis, a short erythrocyte lifespan and iatrogenic causes such as frequent blood sampling. Fluid and electrolyte management can be difﬁcult – insensitive losses are high and hypoglycemia and hypocalcemia occur easily, while renal function and the ability of the cardiovascular system to tolerate ﬂuid loads are reduced. Premature infants with a history of idiopathic apneic episodes preoperatively are more prone than other infants to develop life-threatening apnea during recovery

68 Anesthesia

from anesthesia.79 It has been recommended that infants born prematurely who undergo anesthesia and surgery while less than 60 postconceptual weeks of age should have respiratory monitoring for at least 12 hours postoperatively in order to prevent apnea-related complications.80 I.v. caffeine 5 mg/kg given intravenously at induction appears to reduce the risk of apneic episodes, but respiratory monitoring is still required.81

REFERENCES 1. Besag FMC, Singh MP, Whitelaw AGL. Surgery of the ill, extremely low birth weight infant: should transfer to the operating theatre be avoided? Acta Paediatr Scand 1984; 73:594–5. 2. Frawley G, Bayley G, Chondros P. Laparotomy for necrotizing enterocolitis: intensive care nursery compared with operating theatre. J Paediatr Child Health 1999; 35:291–5. 3. Ayre P. Endotracheal anaesthesia for babies with special reference to hare-lip and cleft palate operations. Anesth Analg 1937; 16:330–3. 4. Rees GJ. Neonatal anaesthesia. Br Med Bull 1958; 14:38–41. 5. Tochen ML. Orotracheal intubation in the newborn infant: a method for determining depth of tube insertion. J Paediatr 1979; 95:1051. 6. Harnett M, Kinirons B, Heffernan A et al. Airway complications in infants: comparison of laryngeal mask airway and the facemask-oral airway. Can J Anaesth 2000; 47:315–18. 7. Bahk J-H, Choi I-H. Tracheal tube insertion through laryngeal mask airway in paediatric patients. Paediatr Anaesth 1999; 9:95–6. 8. Ellis DS, Potluri PK, O’Flaherty JE et al. Difﬁcult airway management in the neonate: a simple method of intubating through a laryngeal mask airway. Paediatr Anaesth 1999; 9:460–2. 9. Delrue V, Veyckemans F, De Potter P. Modiﬁcation of the LMA no. 1 for diode laser photocoagulation in expremature infants. Paediatr Anaesth 2000; 3:345–6. 10. Todres ID, Crone RK. Experience with a modiﬁed laryngoscope in sick infants. Crit Care Med 1981; 9:544–5. 11. Walker I, Lockie J. Basic techniques in anaesthesia. In: Sumner E, Hatch DJ, editors. Paediatric Anaesthesia. London: Arnold, 2000. 12. Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987; 317:1321–9. 13. Anand KJS, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery. Lancet 1987; I:243–7. 14. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants. Anesthesiology 1969; 30:388–94. 15. Cook DR. Neonatal anaesthetic pharmacology: a review. Anesth Analg 1974; 53:544–8.

16. Steward DJ, Creighton RE. The uptake and excretion of nitrous oxide in the newborn. Can Anaesth Soc J 1978; 25:215–17. 17. Hatch D, Fletcher M. Anaesthesia and the ventilatory system in infants and young children. Br J Anaesth 1992; 68:398–410. 18. Nicodemus HF, Nassiri-Rahimi C, Bachman L et al. Median effective doses (ED50) of halothane in adults and children. Anesthesiology 1969; 31:344–8. 19. Gregory G, Eger EI, Munson ES. The relationship between age and halothane requirement in man. Anesthesiology 1969; 30:488–91. 20. Lerman J, Robinson S, Willis MM et al. Anesthetic requirements for halothane in young children 0–1 month and 1–6 months of age. Anesthesiology 1983; 59:421–4. 21. Gregory GA, Wade JG, Beihl DR et al. Fetal anaesthetic requirements (MAC) for halothane. Anesth Analg 1983; 62:9–14. 22. Diaz JH, Lockhart CH. Is halothane really safe in infancy? Anesthesiology 1979; 51:S313. 23. Diaz JH. Halothane anesthesia in infancy: identiﬁcation and correlation of preoperative risk factors with intraoperative arterial hypotension and postoperative recovery. J Paediatr Surg 1985; 20:502–7. 24. Friesen H, Wurl JL, Charlton GA. Haemodynamic depression by halothane is age-related in paediatric patients. Paediatr Anaesth 2000; 10:267–72. 25. Sampaio MM, Crean PM, Keilty SR et al. Changes in oxygen saturation during inhalation anaesthesia in children. Br J Anesth 1989; 62:199–201. 26. Raftery S, Warde D. Oxygen saturation during inhalation induction with halothane and isoﬂurane in children: effect of premedication with rectal thiopentone. Br J Anaesth 1990; 64:167–9. 27. Warde D, Nagi H, Raftery S. Respiratory complications and hypoxic episodes during inhalation induction with isoﬂurane in children. Br J Anaesth 1991; 66:327–30. 28. Cameron CB, Robinson S, Gregory GA. The minimum anesthetic concentration of isoﬂurane in children. Anesth Analg 1984; 63:418–20. 29. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoﬂurane in preterm neonates. Anesthesiology 1987; 67:301–7. 30. Wolf AR, Lawson RA, Dryden CM et al. Recovery after desﬂurane anaesthesia in the infant: comparison with isoﬂurane. Br J Anaesth 1996; 76:362–4. 31. Kataria B, Epstein R, Bailey A et al. A comparison of sevoﬂurane to halothane in paediatric surgical patients: results of a multicentre international study. Paediatr Anaesth 1996; 6:283–92. 32. O’Brien K, Robinson DN, Morton NS. Induction and emergence in infants less than 60 weeks post-conceptual age: comparison of thiopental, halothane, sevoﬂurane and desﬂurane. Br J Anaesth 1998; 80:456–9. 33. Brown K, Aun C, Stocks J et al. A comparison of the respiratory effects of sevoﬂurane and halothane in infants and young children. Anesthesiology 1998; 89:86–92.

References 69 34. Eisele JH, Milstein JM and Goetzman BW. Pulmonary vascular responses to nitrous oxide in newborn limbs. Anesth. Analg 1986; 65:62–4. 35. Hickey PR, Hansen DD, Stafford M et al. Pulmonary and systemic haemodynamic effects of nitrous oxide in infants with normal and raised pulmonary vascular resistance. Anesthesiology 1986; 65:374–8. 36. Dubois MC, Troje C, Martin C et al. Anesthesia in the management of pyloric stenosis. Evaluation of the combination of propofol-halogenated anesthetics. Ann Fr Anesth Reanim 1993; 12:566–70. 37. Friesen RH, Henry DB. Cardiovascular changes in preterm neonates receiving isoﬂurane, halothane, fentanyl and ketamine. Anesthesiology 1986; 64:238–42. 38. Delphin E, Jackson D, Rothstein P. Use of succinylcholine during elective pediatric anesthesia should be reevaluated. Anesth Analg 1987; 66:1190–2. 39. Goudsouzian NG, Donlon JV, Savarese JJ et al. Reevaluation of dosage and duration of action of dtubocuraine in the pediatric age group. Anesthesiology 1975; 43:416–25. 40. Goudsouzian NG. Atracurium infusion in infants. Anesthesiology 1988; 68:267–9. 41. Nightingale DA. Use of atracurium in neonatal anaesthesia. Br J Anaesth 1986; 58(Suppl 1):32–36S. 42. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atracurium in paediatric patients. Br J Anaesth 1986; 55:117–21S. 43. Brandom BW, Woelfel SK, Cook DR et al. Clinical pharmacology of atracurium in infants. Anesth Analg 1984; 63:309–12. 44. Fisher DM, Miller RD. Neuromuscular effects of vecuronium (ORG NC45) in infants and children during N2O, halothane anesthesia. Anesthesiology 1983; 58:519–25. 45. Brandom BW, Meretoja OA, Simhi E et al. Age related variability in the effects of mivacurium in paediatric surgical patients. Can J Anaesth 1998; 45:410–16. 46. Driessen JJ, Robertson EN, Van Egmond J et al. The timecourse of action and recovery of rocuronium 0.3 mg × kg(–1) in infants and children during halothane anaesthesia measured with acceleromyography. Paediatr Anaesth 2000; 10:493–7. 47. Hain WR, Mason JA. Analgesia for children. Br J Hosp Med 1986; 36:375–8. 48. Cook DR. Paediatric anesthesia: pharmacological considerations. Drugs 1976; 12:212–21. 49. Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6:454–61. 50. Lynn AM, Slattery JT. Morphine pharmacokinetics in early infancy. Anesthesiology 1987; 66:136–9. 51. Yaster M. The dose response of fentanyl in pediatric anesthesia. Anesthesiology 1987; 66:433–5. 52. Eck JB, Lynn AM. Use of remifentanil in infants. Paediatr Anaesth 1998; 8:437–9. 53. Wee LH, Moriarty A, Cranston A et al. Remifentanil

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infusion for major abdominal surgery in small infants. Paediatr Anaesth 1999; 5:415–18. Wolf AR. Pain, nociception and the developing infant. Paediatr Anaesth 1999; 9:7–17. Purcell-Jones G, Dorman F, Sumner E. The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987; 42:1316–19. Mahe V, Ecoffey C. Spinal anesthesia with isobaric bupivicaine in infants. Anesthesiology 1988; 68:601–3. Shenkman Z, Hoppenstein D, Litmarrowitz I et al. Spinal anaesthesia in 62 premature, former-premature or young infants – technical aspects and pitfalls. Can J Anaesth 2002; 49:262–9. Krane EJ, Haberkern CM, Jacobson LE. Postoperative apnea, bradycardia and oxygen desaturation in formerly premature infants: prospective comparison of spinal and general anesthesia. Anesth. Analg 1995; 80:7–13. Williams RK, McBride WJ, Abajian JC. Combined spinal and epidural anaesthesia for major abdominal surgery in infants. Can J Anaesth 1997; 44:511–14. Somri M, Gaitini L, Vaida S et al. Postoperative outcome in high-risk infants undergoing herniorrhaphy: comparison between spinal and general anaesthesia. Anaesthesia 1998; 53:762–6. Duncan HP, Zurick NJ, Wolf AR. Should we reconsider awake neonatal intubation? A review of the evidence and treatment strategies. Paediatr Anaesth 2001; 11:135–45. Down SM, Roloff DW, Goldstein GW. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone. Lancet 1981; ii:215–17. Friesen RH, Honda AT, Thieme RE. Changes in anterior fontanel pressure in preterm neonates during tracheal intubation. Anesth Analg 1987; 66:874–8. Stephens CR, Ahlgren EW, Bennett EJ. Elements of Pediatric Anesthesia. Springﬁeld, Ill: Charles C. Thomas, 1970. Meakin G, Sweet PT, Bevan JC et al. Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology 1983; 59:316–21. Watson A, Visram A. Survey of the use of oesophageal and precordial stethoscopes in current paediatric anaesthetic practice. Paediatr Anaesth 2001; 11:437–42. Leelanukrom R, Cunliffe M. Intraoperative ﬂuid and glucose management in children. Paediatr Anaesth 2000; 10:353–9. Louik C, Mitchell AA, Epstein MF et al. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child 1985; 139:783–6. Bush GH, Steward DJ. Can persistent cerebral damage be caused by hyperglycaemia? Paediatr Anaesth 1995; 5:385–7. Anon. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. Br Med J 1998; 317:235–40. Spitz L, Kiely E, Brereton RJ. Esophageal atresia: ﬁve year experience with 148 cases. J Paediatr Surg 1987; 22:103–8.

70 Anesthesia 72. Kosloske AN, Jewell PF, Cartwright KC. Crucial bronchoscopic ﬁndings in esophageal atresia and tracheoesophageal ﬁstual. J Paediatr Surg 1988; 23:466–70. 73. Cartlidge PHT, Mann NP, Kapila L. Preoperative stabilisation in congenital diaphragmatic hernia. Arch Dis Child 1986; 61:1226–8. 74. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia: is emergency operation necessary? J Paediatr Surg 1988; 23:731–4. 75. Bouchut J-C, Dubois R, Moussa M et al. High frequency oscillatory ventilation during repair of neonatal congenital diaphragmatic hernia. Paediatr Anaesth 2000; 10:377–9. 76. Tobias JD, Burd RS. Anaesthetic management and high frequency oscillatory ventilation. Paediatr Anaesth 2001; 11:483–7.

77. Cote CJ. The anesthetic management of congenital lobar emphysema. Anesthesiology 1978; 49:296–8. 78. Eger EI, Saidman LJ. Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology 1965; 26:61–6. 79. Liu LMP, Cote CJ, Goudsouzian NG et al. Life threatening apnoea in infants recovering from anesthesia. Anesthesiology 1983; 59:506–10. 80. Kurth CD, Spritzer AR, Broennle AM et al. Postoperative apnoea in preterm infants. Anesthesiology 1987; 66:486–8. 81. Welborn LG, de Soto H, Hannallah RS et al. The use of caffeine in the control of post-anesthetic apnoea in former premature infants. Anesthesiology 1988; 68:769–98.

7 Postoperative management DESMOND BOHN

INTRODUCTION

MONITORING

The past two decades have seen major advances in the management of critically ill newborns. During this period we have seen the introduction of innovative treatments for acute hypoxemic respiratory failure including surfactant replacement therapy, extracorporeal membrane oxygenation (ECMO) and highfrequency oscillatory ventilation (HFOV) which have resulted in improved survival of both term and preterm infants. At the same time advances in surgical and anesthetic management have led to corrective surgery being performed on complex lesions both prenatally and in low birth weight (LBW) infants, placing a demand for higher levels of care in the postoperative period. While the surgery itself may be only of a relatively short duration, success or failure will inevitably depend on the level and skill of the postoperative care. There are some distinct differences in the physiology of the newborn infant compared to the older child which may impact on postoperative management. Pulmonary vascular resistance is elevated in the ﬁrst week of life, which increases the potential right-to-left shunting at ductal level. There are distinct differences in the coagulation system as plasma levels and activities are low at the time of birth and then increase in the ﬁrst few months of life. Total body water is higher in the newborn, especially the preterm infant and the glomerular ﬁltration rate (GFR) is low in the ﬁrst few days of life. Thermoregulation mechanisms are also poorly developed. The newborn increases cardiac output by increasing heart rate because stroke volume is relatively ﬁxed. Finally, there are important hormonal–metabolic responses to surgery which have major implications for analagesia and sedation during and after surgery. While a comprehensive review of these topics is beyond the scope of this chapter the signiﬁcance of these physiological changes to the postoperative care of the newborn will be discussed.

The key to being able to successfully manage a critically ill newborn is the ability to measure and then adjust physiological parameters. For that reason invasive and non-invasive monitoring assume an important role in management in the postoperative period. The newborn, especially the preterm infant, has little tolerance to changes in normal physiological parameters and therefore minimum monitoring requirements should include continuously recorded ECG, rectal temperature, blood pressure by Doppler or automatic non-invasive blood pressure cuff, measurement of respiratory rate and hourly urine output. In addition, in infants with compromised cardiorespiratory function, more sophisticated respiratory and hemodynamic monitoring is required.

RESPIRATORY MONITORING Blood gas measurement Monitoring of respiratory function in the postoperative period requires measurement of gas exchange. The most reliable and accurate method is to measure PaO2, PaCO2 and pH from an arterial sample. The common sites for invasive arterial monitoring are umbilical artery (newborns) and radial or dorsalis pedis arteries in the ﬁrst few months of life. In the newborn, a blood gas drawn from the right radial will measure pre-ductal PaO2 values, whereas the other sites will be post-ductal. On some occasions the left subclavian artery is juxta-ductal and will therefore measure similar values to the right. With the newer generation of automated blood gas machines, samples as small as 0.1 ml are sufﬁcient for a full blood gas and pH proﬁle. This is particularly important in premature infants in whom frequent sampling may necessitate ‘top up’ transfusions. An alternative method of measuring PaCO2, PaO2 and pH is to use ‘arterialized’

72 Postoperative management

capillary blood taken from an area of skin that has been vasodilated by warming, usually the heel. This technique is generally reliable for PaCO2 and pH. With arterial PaO2 levels above 60–70 mmHg, accuracy drops off considerably.

Transcutaneous blood gas monitoring The development of pulse oximetry has made it possible to measure arterial saturation and heart rate on a beatto-beat basis and has proved to be a reliable and effective method of monitoring and trending oxygenation.1,2 The absolute values do not correlate well with those measured at saturations of less than 70% and in low cardiac output states where there is inadequate perfusion for a pulse to be recorded by the probe.3 Careful sensor placement is important to prevent distortion by light and the probes are sensitive to light artifact. It is a useful monitor to record the rapid response of PO2 to interventions such as suctioning and changes in ventilation. Due to the shape of the oxygen hemoglobin dissociation curve, high PaO2 levels (>12.6 kpa) will not be accurately reﬂected by saturation measurements. In the premature neonate (<1000 gm), where high PaO levels may predispose to the development of retinopathy of prematurity (ROP), the transcutaneous PO2 (TcPO2) probe is the preferred method of monitoring oxygenation as it indirectly measures the actual PaO2. The TcPO2 technique uses a modiﬁed Clark electrode with a heating element that raises skin temperature to between 41°C and 44°C in order to augment cutaneous blood ﬂow. These devices correlate well with arterial oxygen in small infants who have little subcutaneous tissue, and are reliable where cardiac output and peripheral perfusion are good.4 However, quality declines in the older child and in those in low cardiac output states. Transcutaneous CO2 (TcPCO2) monitoring uses the modiﬁed Severinghous probe with a heating element, which heats the skin to 41–44°C.5 These have proved to be reliable in small infants. While transcutaneous PO2 and PCO2 monitoring are useful trending devices, absolute values should be occasionally checked against an arterial sample. Greater accuracy is obtained by careful maintenance of the probes and care in calibration and application to the skin. The risk of skin damage from the heating element requires that the measuring site be changed every 4–6 hours

MANAGEMENT OF THE INTUBATED PATIENT Tube size and position Newborns are most commonly managed with nasotracheal tubes rather than oral tubes unless there is some congenital abnormality of or injury to the nasal area that

precludes their use. They provide for greater patient comfort and acceptability and the tube may be more securely fastened to the face and upper lip. In terms of length, the tip of the tube should reach to the level of the clavicles on the chest ﬁlm. Tubes that extend lower may enter a main bronchus, especially during ﬂexion or extension movements of the head. A routine chest ﬁlm should be obtained immediately after intubation or change of tube position to ascertain correct placement. The proximal end of the tube should protrude sufﬁciently far from the nose so that the tube connector does not impinge upon the external nares. Severe excoriation of nares and erosion of cartilage can occur with longterm intubation. In selecting a tube of correct diameter, the size should be sufﬁcient enough to provide a small leak under positive pressure, but not large enough to provide an airtight seal. Tight-ﬁtting tubes left in situ for prolonged periods will lead to tracheal stenosis and vocal cord granuloma formation, requiring tracheostomy and extended postoperative care. At the same time, too large a leak will make positive pressure ventilation extremely difﬁcult. In the term newborn 3 mm, 3.5 mm or 4 mm tubes may be used depending on the size of the infant; 2.5 mm or 2 mm tubes may be used in premature infants, but these are prone to becoming blocked with secretions.

Endotracheal tube suctioning Routine suctioning to maintain the patency of the endotracheal tube and prevent atelectasis is of prime importance in newborns. However, even skillful suctioning can lead to a profound fall in PaO2 and bradycardia, especially in infants who are already hypoxemic. Consequently, prior to suctioning, all patients should have their lungs inﬂated with 100% oxygen by manual hyperventilation. A catheter of a size that does not occlude the lumen of the endotracheal tube should be chosen so that the suctioning does not generate large enough negative pressures to cause atelectasis. End-hole catheters should be used rather than the side-hole type, which can trap and injure the respiratory tract mucosa. Suction should only be applied while the catheter is being withdrawn and for not longer than a few seconds. Between each suctioning, the patient should be ventilated with 100% oxygen. The onset of bradycardia during suctioning is an immediate indication to stop and ventilate with oxygen, as it is almost always indicative of hypoxemia. Endotracheal suctioning should always be performed as a sterile procedure using surgical gloves and a sterile catheter. The objective should be to pass the catheter down as far as it will go to beyond the carina and down either one or the other main bronchus, at the same time stimulating the patient to cough. The catheter tip may be encouraged to pass down either one or the other side by

Mechanical ventilation 73

rotating the head to the opposite side. The presence of unduly thick secretions in the respiratory tract should alert one to the possibility of inadequate humidiﬁcation. Intrapulmonary hemorrhage increases the chances of endotracheal tube blockage substantially and indicates the need for more frequent suctioning.

Humidiﬁcation Humidiﬁcation is one of the least emphasized but most important aspects of respiratory care. The small diameter endotracheal tube in the newborn patient is notoriously prone to blockage from secretions, especially where they become inspissated due to inadequate humidiﬁcation. Too much humidiﬁcation leads to ‘rainout’, as the inspired gas cools during its passage between the humidiﬁer and the infant’s airway and can lead to the absorption of considerable amounts of water. The goal of optimal humidity is to deliver fully saturated gases (44 mg/L H2O) at a temperature of 37°C to the peak of the airway. This can only be achieved with the heated water bath type humidiﬁer as opposed to the nebulizer type, which has little application in neonatal practice. The temperature of the water bath must be raised above body temperature, to about 40°C in order to deliver gases at 35–37°C at the endotracheal (ET) tube. Between the humidiﬁer and the endotracheal tube, considerable condensation of water vapor may occur as the gases cool, which may impede gas ﬂow. This problem has been overcome to some extent with the newer humidiﬁers, which have a heated electric coil inside the inspiratory line. This maintains a consistent temperature throughout the inspiratory line by means of a dual servo mechanism with temperature sensors in both the water bath and at the patient’s airway. There is therefore less cooling of gases in the respirator tubing and inspired gas is delivered to the endotracheal (ET) tube fully saturated and at 37°C. The condenser humidiﬁer or ‘Swedish nose’ is also capable of supplying moisture and preventing heat loss from the respiratory tract. While obviously not as efﬁcient as the water bath type, it is particularly useful for patient transport or for providing humidity to infants who have been intubated for upper airway problems. As the condenser humidiﬁer becomes increasingly saturated, the airway resistance tends to rise and the humidiﬁer must be changed every 24 hours.

RESPIRATORY FUNCTION IN THE NEWBORN The respiratory system is probably the most vulnerable area in the maintenance of a normal physiological milieu. Abnormalities in the cardiovascular, renal and central nervous systems are rapidly reﬂected in changes in function of the respiratory apparatus, which in the

newborn is ill equipped to deal with. The chest wall itself is highly compliant and increasing respiratory efforts, due to a fall in lung compliance, result in increasing chest wall distortion and eventual apnea from respiratory muscle fatigue. Major abdominal or thoracic surgical procedures in the newborn render the infant particularly vulnerable to developing respiratory failure, as surgery frequently has an adverse effect on the mechanics of the respiratory system. Repair of congenital abnormalities such as gastroschisis or congenital diaphragmatic hernia (CDH) frequently result in rises in intra-abdominal pressure, upward displacement of the diaphragm and a fall in total thoracic compliance.4 Normal tidal respiration in the infant occurs around the closing capacity and therefore any loss of lung volume will result in further atelectasis and hypoxemia. Similarly, the use of inhalational anesthetic agents, narcotics and muscle relaxants will adversely affect diaphragmatic function not only during surgery, but have an effect which extends well into the postoperative period. In order to prevent respiratory compromise in the immediate postoperative period, infants undergoing major abdominal or thoracic surgery will beneﬁt from a period of ventilatory support, the duration of which will depend on the maturity of the infant, the underlying surgical problem and the presence or absence of disease or abnormalities within the lung itself.

MECHANICAL VENTILATION Mechanical ventilation of newborn infants came into widespread use in the 1970s, when it was appreciated that long-term intubation was both safe and feasible in small infants and that positive pressure ventilation was not necessarily damaging to the newborn lung. The initial concept was to adapt adult ventilators for use in the infant, using positive pressure to generate a gas ﬂow into the lung, sufﬁcient to expand alveoli by overcoming the opposing forces generated by the elastic properties of the lung (compliance) and the airways (resistance). The most commonly used ventilators in the newborn are the time-cycled, pressure-limited variety. The number of breaths delivered by the respirator is set by the operator while the duration of the inspiratory and expiratory phases of the respiratory cycle can be altered by adjusting the inspiratory time. The respirator cycles from inspiration to expiration when a preset pressure is reached. This preselected pressure is known as the peak inspiratory pressure (PIP), which may vary depending on the pressure needed to expand the lung by overcoming the compliance of the lung and the airway resistance. The airway pressure at end expiration (normally zero during spontaneous breathing) can be increased to 5–20 cmH2O, depending on whether positive end expiratory pressure

74 Postoperative management

(PEEP) is required to maintain lung expansion. The volume delivered by a pressure ventilator will change signiﬁcantly according to conditions within the thorax. A fall in compliance or a rise in airway resistance results in the ventilator rapidly reaching its preselected cycling pressure. A reduction in delivered alveolar ventilation will inevitably follow, which can only be overcome by increasing the preset pressure. If one also takes into account the fact that there is invariably a leak around the ET tube in a newborn infant, changes in compliance and resistance will also increase the amount of wasted ventilation escaping between the tube and tracheal wall. The alternative ventilation system is a time-cycled, volume preset respirator which will deliver a set tidal volume at a preselected rate. In certain machines, the operator chooses the minute volume and ventilatory rate and the tidal volume can be calculated from these two settings. Alternatively, in other types of respirators the tidal volume and rate are selected and the minute volume calculated. As with the pressure-type respirator, the duration of the inspiratory and expiratory time can be adjusted according to conditions within the thorax. A fall in compliance or rise in airway resistance will not result in a fall in alveolar ventilation as the machine will merely increase the pressure in order to overcome these changes. The respirator however will not compensate for leaks around the ET tube and a signiﬁcant proportion of the preset volume will be vented around the tube when there is a large leak. These ventilators are most commonly used for ventilating adult patients where cuffed ET tubes are used, but are increasingly used in children and newborns.

Oxygen uptake The diffusion gradient for oxygen within the lung is high as the PO2 in the pulmonary artery is (PvO2) 5.3 kpa compared with alveolar PO2 (PaO2) of 14 kpa on FiO2 0.21. Despite this favorable gradient, the alveoli must remain open for gas exchange to occur. In the normal lung, due to the hysteresis, the alveoli open during inspiration and remain open during most of expiration and only cease gas exchanging at end expiration. In the diffusely atelectatic lung, of which RDS is a prime example, the alveoli become unstable and tend to collapse at low lung volumes. The degree of alveolar expansion depends to a large part on mean airway pressure (Paw), which is a measure of the average pressure that the alveoli are exposed to during the respiratory cycle. This in turn is determined by a combination of the PIP, PEEP and duration of the inspiratory phase of the respiratory cycle. Attempts to improve oxygenation are based on the manipulation of one or more of these variables in order to increase Paw. The simplest and most time honored of these measures is to increase the amount of PEEP, which was ﬁrst introduced to improve oxygenation in RDS. Abnormalities within the lung that cause a large difference between PaO2 and PaOo2 (A-a DO2) may also be compensated for to a certain extent by increasing the FiO2. However, both oxygen and positive pressure have been implicated in causing the chronic lung injury (BPD) seen in newborns with respiratory distress syndrome (RDS). High PaO2 levels have also been implicated in the development of retinitis of prematurity (ROP). Consequently, there are good reasons for carefully monitoring and controlling oxygen therapy in the newborn.

RESPIRATORY GAS EXCHANGE Carbon dioxide elimination Adequate CO2 elimination depends on the ratio between CO2 production (metabolic rate) and alveolar ventilation (tidal volume – dead space). In the normal situation, the two sides of the equation balance and normal CO2 homeostasis is preserved. An increase in CO2 production can normally be met by increased alveolar ventilation and the newborn achieves this by increasing its respiratory rate. Similarly, abnormalities within the thorax will result primarily in an increase in respiratory rate rather than volume in order to achieve the same alveolar ventilation. In mechanical ventilation, the PaCO2 level can be controlled by adjusting both ventilator rate and the volume delivered by each respiratory cycle (alveolar ventilation = tidal volume – dead space × frequency). With a pressure preset ventilator, minute ventilation is increased by increasing the peak inspiratory pressure (PIP) and rate, while in the volume respirator PaCO2 is controlled by adjusting rate and delivered volume.

VENTILATOR MANAGEMENT OF THE NEWBORN Choosing the options for ventilatory management of the newborn is in a large part determined by conditions within the patient. The objective is to maintain gases within a physiological range (PaO2 8–12 kpa, PaCO2 5–6.5 kpa) using the lowest FiO2 and airway pressure compatible with that aim. This may be relatively simple where the lungs are normal, but may require a completely different strategy in the presence of abnormalities within the abdomen or thorax. Therefore one must take these considerations into account when selecting ventilator settings for the newborn infant. Generally speaking, the term infant with normal respiratory system compliance and airway resistance on a pressure-preset ventilator would require a PIP of 10–20 cmH2O, a rate of 30–40/minite, an FiO2 0.25–0.35 and an inspiratory to expiratory ratio (I:E ratio) of 1:2 or 1:2.5 and a minimum of 3–5 cmH2O PEEP as routine. Using a

Ventilator management of the newborn 75

volume respirator, a tidal volume of 8–10 ml/kg would be adequate in a newborn with normal lungs. Having selected these settings, the adequacy of gas exchange must be veriﬁed by an arterial blood gas sample to ensure that hyperventilation is avoided.

(IVH) and the need for pharmacological paralysis.9 The infants were stratiﬁed for birth weight and the results show there was no difference in outcome except for infants with a birth weight of greater than 2000 g who had a shorter duration of mechanical ventilation associated with the use of SIMV. There was also an increased use of ECMO therapy in the IMV group.

Synchronized ventilation Synchronized mechanical ventilation has evolved from the use of patient triggering in the assist/control mode of mechanical ventilation. The drawback to this system was that it was frequently not sensitive enough to pick up the small negative inspiratory efforts frequently seen in the tachypneic newborn infant. The concept of synchronized mechanical ventilation is to trigger the ventilator’s positive pressure early enough during inspiration to avoid stimulating active expiration against the triggered breath. This type of asynchrony may result in suboptimal gas exchange, increased risk of barotrauma and an increased incidence of intraventricular hemorrhage. One method of overcoming this is to use sedatives or neuromuscular blocking drugs, both of which carry with them an alternative set of problems. Neuromuscular blockade is associated with loss of vasomotor tone and circulatory insufﬁciency, while the immature drug metabolism of the newborn may result in a prolonged effect of sedation. A more ideal solution to this problem is to use a form of synchronized ventilation that does not compete with the patient’s own breathing pattern. Most of these systems have been adapted from designs incorporated into adult ventilators and they include synchronous intermittent mandatory ventilation (SIMV), pressure support ventilation, volume support ventilation and proportional assist ventilation (PAV). Most experience in neonatal intensive care has been with the SIMV mode, with which the ventilator senses either airway ﬂow or pressure and the set rate or mandatory breaths from the ventilator are triggered so they do not interfere with the expiratory phase of respiration. There are an increasing number of studies that have compared synchronized ventilation with conventional intermittent mandatory ventilation (IMV) in neonatal respiratory failure. Jarreau et al.6 have shown that patient triggering decreased the work of breathing in neonates compared with IMV and Donn et al.7 showed that ﬂow synchronization was associated with a shorter time to extubation and decreased patient charges compared with IMV in a randomized prospective trial. Other studies have compared SIMV with conventional IMV in newborn infants. Bernstein et al.8 found increased and more consistent tidal volumes were associated with the use of SIMV. In a large multicenter randomized, controlled trial which enrolled 327 term and preterm infants, SIMV and IMV were compared in terms of outcome (death or survival), need for supplemental oxygen at 28 days, incidence of intraventricular hemorrhage

Weaning from ventilation Weaning from mechanical ventilation has been considerably simpliﬁed by the widespread use of IMV and other forms of ventilatory-assist modes. With these systems the infant may take spontaneous breaths from a gas ﬂow provided either through a demand valve or from a separate spontaneous breathing circuit. In this manner the mandatory breaths are gradually reduced as spontaneous respiratory effort improves, until the infant is breathing entirely spontaneously through a constant positive airway pressure (CPAP) system. The pace of weaning depends on the type of surgery and any additional pathology within the lung, and is set by observing the spontaneous respiratory rate and the measured blood gas response to changes in ventilation settings. In order to tolerate the transition from CPAP to extubation, the infant should be on FiO2 0.4, PEEP 5 cmH2O, with normal blood gases. A more recent innovation has been the introduction of pressure support ventilation, with which each spontaneously initiated breath generates a positive pressure from the machine to a preset inspiratory level.10 This helps to overcome the ﬁxed resistance of small endotracheal tubes.

Hyperventilation and ventilator-associated lung injury Since the ﬁrst introduction of intubation and ventilation for the treatment of neonates with acute respiratory failure, the objective has been to adopt a pattern of ventilation designed to produce gas exchange within normal physiological parameters. Since the original description of the induction of a respiratory alkalosis to reverse ductal shunting in persistent pulmonary hypertension (PPHN),11 hyperventilation became one of the mainstays of treatment. Although there may be a shortterm beneﬁt from this approach, there have been no prospective trials that have shown an improved outcome with the use of hyperventilation. In addition, there is now increasing concern that this may result in serious adverse consequences. The high inﬂation pressures required to reduce the CO2 can frequently result in ventilator-induced injury to the lung, thereby compounding a pulmonary–vascular problem with a pulmonary– parenchymal one. There are numerous animal models of ventilator-induced lung injury where pulmonary edema, hyaline membrane formation and pulmonary epithelial

76 Postoperative management

cell injury can be produced in normal lungs with peak inﬂation pressures as low as 30 cmH2O. As few as six manual inﬂations using high pressure at the time of birth have been shown to induce lung injury in an animal model.12 Wung et al. in 1985 was the ﬁrst to suggest that PPHN could be treated effectively without the use of hyperventilation and showed excellent outcomes with pressure-limited ventilation and hypercarbia.13 This is true not only in the premature lung but also in the dysplastic lung of infants with CDH, which are equally vulnerable to injury.14 There are several series reporting improved survival using a pressure-limited strategy which does not use hyperventilation to treat ductal shunting.15–17 There is also increasing evidence that low PaCO2s may adversely affect cerebral blood ﬂow and injure the developing brain18 and may partly account for the alarmingly high incidence of neurosensory deafness seen in these infants.19–24 Conversely hypercarbia increases cerebral protection in experimental models of neonatal brain injury.18,25 The ﬁrst human randomized trial that addressed the issue of hypercarbia in neonates has shown a decrease in number of days on a ventilator and absence of adverse events when permissive hypercapnia was compared with the conventional approach.26 Finally, in terms of avoidance of ventilator-associated lung injury, there is increasing evidence that the use of nasal CPAP together with early intervention with surfactant improves outcome in premature infants with moderately severe forms of IRDS.27–29

ACUTE HYPOXIC RESPIRATORY FAILURE IN THE NEWBORN: ALTERNATIVE THERAPIES A number of innovative techniques have recently been introduced into the management of acute respiratory failure, which include high-frequency ventilation, inhaled nitric oxide (iNO), and, if all else fails, ECMO. It is very likely that a signiﬁcant number of these therapies are being resorted to as rescue therapy from ventilatorinduced injury. This speculation is supported by the ﬁgures from the Extracorporeal Life Support Organisation (ELSO) registry which show the annual number of cases is actually falling for the ﬁrst time since neonatal ECMO was ﬁrst introduced in the late 1970s. It is likely that we will recognize that the single most important advance in ventilator management will be the recognition that the solution is part of the problem and that the ventilator must adapt to the underlying pathophysiology of the lung rather than to outmoded physiological imperatives.

High-frequency oscillatory ventilation One of the prinicipal strategies for the prevention of ventilator-associated lung injury is the use of HFOV.

This has been tested in a large number of randomized, clinical trials in preterm infants. Although the original National Institute of Health (NIH) study30 suggested that there was an increased incidence of intraventricular hemorrhage associated with its use, subsequent trials have led to a general acceptance that it is a safe and effective form of ventilation without there being any clear demonstrable beneﬁt in terms of increased survival and decreased incidence of chronic lung disease.31–36 This may be because the lung recruitment strategies (the open lung approach) were not aggressive enough or introduced early enough. Most of the protocols in neonatal trials have used levels of mean airway pressure (MAP) of 1–2 cmH2O above that of conventional mechanical ventilation (CMV) increased in small increments. The PROVO trial in 1996,37 which was an early intervention study and used a clearly deﬁned lung recruitment protocol with all patients receiving surfactant, was the ﬁrst to show a reduction in chronic lung disease with HFOV (24 vs 44%), less surfactant usage and decreased hospital stays. However, the rates of chronic lung disease in this study do not compare favorably with a Japanese HFOV study published in 1993,35 in which the rates were 9% and 13%, respectively. This highlights the problem of comparing different modes of ventilation in small randomized studies in which an optimal ‘open lung’ approach with HFOV is compared to a conventional technique where little attempt was made to use a lung recruitment strategy. In addition, no study has compared HFOV with a conventional ventilation approach that uses an optimal lung-recruitment strategy. When this has been done in experimental animals HFOV have been shown to be equally effective in opening the lung.38,39 It should also be emphasized that surfactant-replacement therapy has made a major impact on the mortality rate from neonatal lung disease. Clearly, if one is to use HFOV, early intervention before the lung sustains signiﬁcant damage is key and has been demonstrated by the excellent results published by Rimensberger et al,40 in which premature infants at risk from IRDS were placed on HFOV in the delivery suite. The incidence of chronic lung disease, as deﬁned as oxygen dependency at 36 weeks’ postgestational age, was zero compared to 34% in historical controls. The optimal recruitment strategy also needs to be determined. Copying the recruitment maneuvers (30 cmH2O for 15 seconds) used in the experimental lung lavage model is frequently insufﬁcient to achieve optimal recruitment strategy in premature infants. Thome et al 41 has shown that lung volume recruitment on HFOV is both time and pressure dependent in these patients. He was able to show that stabilization of mean lung volume after modiﬁcation of mean airway pressure took 2–25 minutes (median 9 minutes) in premature infants. HFOV has also proved effective in the management of term and near-term infants with PPHN, meconium aspiration and in preoperative stabilization of infants with CDH.31,42–44

Acute hypoxic respiratory failure in the newborn: alternative therapies 77

High-frequency jet ventilation High-frequency jet ventilation (HFJV) was ﬁrst developed in clinical anesthesia to provide small tidal volume ventilation for procedures involving the larynx and tracheobronchial tree where the ability to achieve a normal CO2 with low airway pressures provided ideal operating conditions. Although HFJV and HFOV operate on the same physiological principles of very small tidal volumes delivered at high rates, they should not be considered as merely two variations on the same theme. HFJV uses a high-pressure gas source to deliver small tidal volumes at frequencies of 1–5 Hz. Apart from the slower rates used in HFJV, the other major difference is that expiration is passive in the former while it is active in HFOV. The published experience with jet ventilation in acute hypoxemic respiratory failure (AHRF) is considerably less than oscillation and until recently only documented its use as rescue therapy in patients with either hypoxemia despite high PEEP or an established air leak. The rationale for the switch is usually the avoidance of further barotrauma by the use of smaller tidal volumes while maintaining a high mean airway pressure, but with lower peak airway pressures. Improvements in oxygenation can be obtained by driving up the MAP but this usually involves some compromise to cardiovascular function because of the transmitted pressure. A randomized, controlled clinical trial of HFJV in neonates with pulmonary interstitial emphysema (PIE) has shown an improvement in PIE and lower mortality rate in infants treated with HFJV compared to conventional ventilation.45 In the past 2 years, several prospective randomized trials have compared HFJV in both premature and term infants with AHRF.46–48 The two studies on premature infants showed conﬂicting results. Keszler et al.46 found better pulmonary outcomes in patients randomized to HFJV without a difference in survival rate while Wiswell48 found no difference in pulmonary outcomes but an increased risk of death and intraventricular hemorrhage associated with the use of HFJV. Engle et al.,47 in a randomized trial in term and near-term infants found improved oxygenation without any difference in survival rate. There are some technical safety concerns about the adequacy of humidiﬁcation in this system as well as reported cases of tracheal damage (necrotizing tracheobronchitis) in severely ill newborn infants. In addition, the airway pressures measured from the catheter within the trachea during HFJV probably represent a serious underestimate of true MAP because of the Bernoulli effect and consequently there is likely to be a signiﬁcant amount of auto-PEEP present.

Inhaled nitric oxide As well as having a key role in the modulation of vascular tone, exogenously administered NO has been shown to

be a highly selective pulmonary vasodilator. When administered by inhalation, NO diffuses rapidly from the alveolus into the endothelial cell and the vascular smooth muscle, where it stimulates guanylate cyclase to produce cGMP. The systemic nitrodilators currently in clinical use work by a similar mechanism but their pulmonary vasodilator effects cannot be separated from the systemic effects. In the case of inhaled nitric oxide (iNO), the vasodilatory properties are conﬁned to the pulmonary circulation because the marked afﬁnity of NO for the hemmoiety of hemoglobin results in its rapid binding and inactivation as soon as it crosses the alveolar capillary membrane, which explains its highly selective effect on the pulmonary vascular bed. A series of randomized, controlled trials (RCTs) have shown that iNO improves oxygenation49–55 and decreases the need for ECMO56–58 in term and near-term infants with PPHN. Although the response may be very dramatic, by no means do all infants respond well to it. This may reﬂect the fact that respiratory failure in this group of patients is not always a single disease entity and individual responses will vary according to the underlying pulmonary pathophysiology. Those infants with pure right-to-left ductal shunting and little parenchymal lung disease would be expected to respond best, while the infant with extensive pulmonary parenchymal disease as a cause of their hypoxemia (e.g. in meconium aspiration) may have little response. Although patients with alveolar capillary dysplasia have a dramatic response, the outcome is always fatal.59 An interesting alternative approach to iNO is to enhance the effect of endogenous production of NO in the vascular endothelium by blocking the inactivation of cGMP by phosphodiesterase inhibition. Two phosphodiesterase inhibitors, dipyridamole and zaprinast, have been shown to decrease pulmonary vascular tone in newborn animal models of pulmonary hypertension,60,61 and both dipyridamole and sildenaﬁl have been successfully used to treat the rebound pulmonary hypertension associated with withdrawal of iNO.62–64 The combination of HFOV and iNO together has proved particularly effective in one RCT.55

Surfactant-replacement therapy Probably the most important advance in neonatal medicine in the past 20 years has been the introduction of surfactant-replacement therapy for the treatment of lung disease of prematurity. This has resulted in a reduction in neonatal mortality without a signiﬁcant impact on the incidence of chronic lung disease.65 This may be because it has not been used with an optimal ventilation strategy that minimizes ongoing lung injury. Also, there are important differences between synthetic and natural surfactants, the latter having surfactant proteins which may have important anti-inﬂammatory

78 Postoperative management

properties. In term and near-term infants the situation is less clear cut. These infants are not surfactant deﬁcient but it may be inactivated by lung injury. Human studies have shown that the use of surfactant replacement therapy in this patient population is associated with decreased need for ECMO.66

Non-invasive ventilation An important advance in the management of respiratory failure in the newborn has been the increasingly widespread use of non-invasive ventilation either in the form of a nasal mask or cannulae. The high gas ﬂow used in this system means that airway pressure remains positive throughout both the inspiratory and expiratory cycle. Functional residual capacity (FRC) is maintained, decreasing the work of breathing and preventing lung collapse. There is an additional potential advantage in that avoiding invasion of the airway reduces the risk of nosocomial lung infections. The system has proved effective in the treatment of lung disease of prematurity both as a primary mode of therapy and as a method of supporting infants after extubation.27–29, 67–70

OVERVIEW A large number of highly innovative therapies have been introduced into the management of neonates with acute respiratory failure in the past few years. Many of these have shown beneﬁt in terms of improvement in physiological parameters without having a signiﬁcant impact on overall mortality, possibly partly due to the fact that, in an age where neonatal mortality is at a low level, many of the studies are underpowered to be able to show a difference.71 When all else fails, we still have the safety net of ECMO therapy to fall back on. Most tertiary care neonatal centers are now reporting a decrease in ECMO usage by 50% or more and these numbers are conﬁrmed by data from the ELSO Registry. The economic impact from this is that hospital charges for neonates with acute respiratory failure who previously required ECMO therapy have now been reduced by 50% or more.72,73 Although this may seem to indicate signiﬁcant progress in this area, the proliferation of these innovative technologies outside the tertiary referral areas means that when these treatments fail, sicker infants are being referred to the ECMO centers for rescue therapy, a reality that needs to be factored in when evaluating these therapies.

improvement in survival seen over the past few years.15–17,74 Newborn infants presenting with this anomaly have a mixture of pulmonary hypolasia, i.e. reduced alveolar number, as well as pulmonary vascular disease consisting of a reduced pulmonary vascular bed and a reactive and potentially reversible component due to the increased smooth muscle in the small pulmonary arterioles. The dysplastic lungs of these infants are highly susceptible to pulmonary barotrauma caused by high peak inﬂation pressures. The end result is hyaline membrane formation and pulmonary alveolar hemorrhage.14 Improved survival has been noted in several centers where the focus has been on the use of low peak airway pressures with less emphasis paid to treatment of right-to-left shunting through the ductus arteriosus and PFO. Attempts to reverse this by inducing alkalosis with hyperventilation will only cause pulmonary barotrauma. Therefore the focus should be on maintaining a pre-ductal SaO2 greater than 90% and not treating right and left shunting at the ductal level with hyperventilation. The objective for mechanical ventilation should be to maintain the PIP at <25 cmH2O without necessarily maintaining a normal PaCO2. It is our practice in this center to switch to HFOV if the PIP is above 25 cmH2O on conventional ventilation as this is a less injurious mode of ventilation. The strategy with HFOV in CDH is very different to that used in other forms of neonatal lung disease. In this instance the lung is hypoplastic and not recruitable and therefore we use a mean airway pressure of no more than 14–16 cmH2O. With this approach we ﬁnd that HFOV is a very efﬁcient way of maintaining normal PaCO2 levels without inﬂicting further injury on the lung. Survival rates of >80% and decreased ECMO use have been reported by centers using this approach.75 Other centers have chosen to use other non-conventional ventilator strategies such as tracheal gas insufﬂation (TGI)76 which uses a very high gas ﬂow delivered through an intratracheal catheter. It is also our practice to obtain a cardiac echo on all CDH infants to rule out structural heart disease and to assess the degree of right-to-left shunting. In most infants the right ventricular pressure is elevated with either bidirectional shunting, indicating that right ventricular pressure is systemic, or pure right-to-left shunting in which case it is supra-systemic. INO has been used extensively in CDH, although it does not seem to be as effective as in other forms of PPHN.77 Other adjuncts to positive pressure ventilation used in this disease include surfactant therapy and prenatal steroids, although neither of these therapies have been of proven beneﬁt in prospective trials.

Ventilatory management of congenital diaphragmatic hernia

POSTOPERATIVE SEDATION AND ANALGESIA

The pre- and postoperative ventilator management of infants with CDH is one of the key factors in the

One of the most important advances in postoperative care in the past decade has been a far greater under-

Cardiovascular homeostasis in the newborn 79

standing of the need for analgesia and sedation in newborns who have had major surgery. There is now strong evidence that neonates exposed to multiple painful procedures either during intrauterine or early in extrauterine life exhibit acute physiological responses which are detrimental.78–80 This has been associated with an increased physiological stress response resulting in hypertension and an increased incidence of intraventricular hemorrhage in preterm newborns. The increased hormonal and metabolic responses to major operations and to painful stimuli associated with procedures in the ICU also have the potential to increase the incidence of morbidity and mortality.81–83 Given the limited endogenous reserves of carbohydrates, proteins and fats in the newborn, it is perhaps not surprising that in the stressed state these reserves are rapidly exhausted. There is also evidence that failure to blunt painful stimuli in the developing nervous system results in changes within the spinal cord with altered long-term sensitivity to pain.84 There are now a number of studies which show that the use of narcotics and anaesthetic drugs can blunt these responses and bring about a decrease in morbidity associated with both surgical procedures and painful interventions in the ICU.85,86 These include reductions in catecholamine levels, lower airway pressures during mechanical ventilation and less acute rises in blood pressure and pulmonary artery pressure.87–89 The most commonly used narcotic agents in neonatal practice are i.v. morphine or fentanyl infusions. These are commonly combined with i.v. benzodiazepines usually in the form of midazalam or lorazepam.

CARDIOVASCULAR HOMEOSTASIS IN THE NEWBORN Cardiac output is a product of heart rate times stroke volume with increases in output dependent on the ability to increase heart rate or vary stroke volume. Stroke volume in turn is inﬂuenced by three inter-related factors: 1 Pre-load or venous return that determines enddiastolic volume 2 After-load or the impedance to left or right ventricular output 3 Contractility or the contractile state of the myocardial muscle, which in turn depends on its end-diastolic ﬁber length and the speed of shortening for a given load. In the newborn, where the myocardium is relatively immature, there is little capacity to increase stroke volume. Therefore, cardiac output is to a large part rate dependent and the neonate will primarily compensate for a fall in output by increasing its heart rate. Blood

pressure reﬂects cardiac output poorly in this age group as this is maintained at the expense of increasing heart and vasoconstriction, until a sudden decompensation and hypotension occurs. In situations where hypovolemia is the cause of low output, a reduction in elevated heart rate is the best guide to the adequacy of volume replacement. Cardiac output may be directly measured in the newborn by using either the thermo or dye dilution, but both techniques require invasive monitoring. For most practical purposes, the combination of heart rate, blood pressure, urine output and peripheral perfusion provide a reasonably accurate estimation of cardiac output. This can be combined with serum lactate and mixed venous oxygen saturation (SvO2) drawn from a central venous line in more critically ill newborns. In these patients measurement of central venous pressure (CVP) is particularly useful in optimizing cardiac output by the adjustment of right atrial ﬁlling pressures. Central venous access may be established through the internal jugular, subclavian or femoral veins in the neonate; the complication rate associated with the different approaches is related to the experience and skill of the operator rather than the approach chosen.90,91 The cannulation of the radial, posterior tibial, dorsalis pedis or femoral arteries with a 22 or 24 gauge cannula will provide a reliable direct arterial pressure measurement together with access to sampling for blood gas, electrolytes and acid–base measurement. Umbilical arterial lines are satisfactory for short-term use only due to the potential to cause renal or gut ischemia if not positioned correctly. The initial approach to the infant with a low CO, indicated by tachycardia, vasoconstriction, oliguria and hypotension, is to increase pre-load by volume expansion with 10–20 ml/kg of crystalloid or albumin and then reassess the effect on the measured parameters assessed. The CVP measurement may prove very useful in this context, as repeat volume increments may be used to increase the ﬁlling pressures to as high as 12–14 mmHg in order to increase output (Fig. 7.1). Failure to raise output by increasing pre-load is an indication of an attempt to decrease after-load or increase contractility by the use of vasoactive drugs.

USE OF VASOACTIVE DRUG THERAPY In order that the correct therapeutic option is chosen when dealing with a low cardiac output state in the newborn, it is important to know what effects vasodilators and inotropes have on the circulation in this situation. Since the objective is improved oxygen delivery at tissue level, changes in heart rate, ﬁlling pressures and afterload, which in turn profoundly affect myocardial work and therefore oxygen consumption, should always be considered when electing to use a particular drug. While one could use a vasoconstricting agent to maintain

80 Postoperative management

Figure 7.1 Effect of increasing right atrial ﬁlling pressures, vasodilator drugs and inotropes on cardiac output (Frank–Starling curve)

blood pressure in an infant in low cardiac output, this would be unsuccessful in most circumstances because this could only be achieved at the expense of a greatly increased after-load, decreased tissue perfusion and oxygen delivery. The aim must be to move the depressed myocardial function curve upwards and to the left as depicted in the Starling curve (Fig. 7.1), either by increasing contractility or by reducing pre-load or afterload. In the case of contractility, this can be achieved by using an inotrope which may cause signiﬁcant increases in heart rate, which the neonate, with its relative freedom from ischemia, is able to tolerate reasonably well. The ideal vasoactive drug would be that which increased contractility and decreased after-load with no change in heart rate, while at the same time maintaining renal and splanchnic perfusion.92

INOTROPES Dopamine Dopamine is an endogenous precursor of norepinephrine with sympathomimetic properties. It has been shown to be useful in the management of shock associated with cardiovascular surgery, sepsis and severe asphyxia with demonstrable inotropic, vasoconstricting and renal vasodilating effects. It has a well-documented range of activity with selective vasodilatory effects on cerebral, mesenteric, coronary and renal vascular beds through stimulation of dopaminergic receptors in a dose range of 0.5–3.0 μg/kg/minute. As the dose increases from 3–10

μg/kg/minute, it directly stimulates β1 receptors of the myocardium causing a rise in blood pressure, CO and heart rate, in addition to indirect stimulation through the release of norepinephrine. As the dose increases from 10–20 μg/kg/minute, progressive α adrenergic stimulation negates the effect of β stimulation, causing a rise in systemic vascular resistance (SVR) and renal vasoconstriction. Dopamine has been shown to be an effective inotrope following cardiopulmonary bypass in children.93,94 Studies on the effective dose in neonates have generally been anecdotal and contradictory.95–99 Evidence has been presented for the need for high-dose dopamine to achieve a measurable clinical effect, yet others have shown demonstrable effects at low doses. On balance it would seem demonstrable clinical beneﬁt can be achieved with dopamine using modest doses (<8 μg/kg/min), with a titratible dose-response increase in effect and little likelihood of side effects. Dopamine can be expected to increase MAP, improve echocardiographically determined indices of ventricular function, and improve urine output with a low incidence of side effects at doses <10 μg/kg/minute. Its effect on ventricular ﬁlling pressures remains uncertain. Dopamine’s effect on systemic vascular resistance appears secondary to the effect on CO at doses <10 μg/kg/minute, where there will be a drop in SVR. At doses above 20 μg/kg/minute there will be an increase in SVR as the effects of dopamine become predominant (see Table 7.1).

Dobutamine Dobutamine is a synthetic analogue of dopamine with predominately β1 effect and relatively weak β2 and α receptor-stimulating activity. In addition, it does not seem to lead to indirect stimulation through release of norepinephrine. In adults at doses of 5–15 μg/kg/minute, it has been shown to increase contractility, CO and MAP, improve tissue perfusion, and unlike dopamine, results in a decrease in cardiac ﬁlling pressures. It has consequently found much favor in the treatment of low cardiac output states in adults with ischemic heart disease. Pulmonic and systemic vascular resistances uniformly fall. It therefore can be described as having pre- and after-load-reducing properties in addition to its inotropic effect. Experience of its use in children generally parallels that of the literature on adult use with an increase in cardiac index and MAP in a dose-dependent fashion with doses from 2–7.5 μg/kg/minute.100–102 Neonatal experience has usually been in the treatment of PPHN, but there is a tendency for signiﬁcant increases in heart rate as well as cardiac output to occur in small infants. As there is no selective renal vasodilating effect, there would appear to be little advantage to using the drug in preference to dopamine in the newborn.

Vasodilators 81

Epinephrine Epinephrine is the ﬁnal product of catecholamine synthesis and has been used in emergency resuscitation for a number of years. It stimulates both α and β receptors in a dose-dependent fashion; in low doses (0.05–0.1 μg/kg/minute) it affects predominately β receptors, resulting in inotropic and chronotropic effects. In higher doses (0.2–1.0 μg/kg/minute) it is a potent vasoconstrictor, the α stimulation increasing MAP and diastolic pressure. This latter effect is the key to its effectiveness in resuscitation, where it can be given as an i.v. bolus, endotracheally, or rarely, intracardiac injection can be used. Epinephrine is a potent inotropic agent for the newborn myocardium; its major disadvantages are tachycardia and an increased SVR. Renal vasoconstriction can impair renal function and mesenteric vasoconstriction may cause bowel ischemia. Although epinephrine is not commonly used as a ﬁrst-choice inotropic agent, there are instances where it can be very useful when the more commonly used inotropes fail to produce an effect. This is most likely due to overwhelming disease and in this instance we ﬁnd that increasing the dopamine to >30 μg/kg/minute rarely produces any improvement in output. In such instances we would commence an adrenaline infusion at 0.05 μg/kg/minute, increasing to 1 μg/kg/minute according to response, frequently combined with vasodilator therapy.

appropriate use of vasodilators will shift the heart to a more favorable Starling curve, so that there is an improved SV for a given ﬁlling pressure (Fig. 7.1). 3 A drop in ﬁlling pressure with preservation of MAP will improve coronary perfusion and thereby improved load tolerance 4 Decreased end-diastolic volume may favorably alter the compliance characteristics of the heart with less pronounced limitation to ﬁlling exerted by either ventricle on the other and on both ventricles by the pericardium. With the newborn infant functioning at a high level of performance and limited reserve capacities as described earlier, acute pre-load or after-load increase, in addition to that imposed by postnatal adaptation, may be particularly harmful. Volume loads from left-to-right shunts, excessive volume administration or vasoconstriction from pharmacologic therapy may all lead to profound cardiovascular decompensation. A number of investigators have documented success with after-load reduction in conditions where inotropes have failed or have described additional beneﬁt in function with the addition of vasodilators to inotropic therapy.103–105

Sodium nitroprusside

Norepinephrine is a potent vasoconstrictor with predominant α agonist effects. As such it is effective in raising blood pressure at the expense of raising after-load on the heart and decreasing peripheral perfusion. It therefore has no place in the routine treatment of low cardiac output. However, in vasodilated septic shock, as seen in Gram-negative sepsis, it can be effective in restoring perfusion to vital organs, the unwanted effects such as decreased splanchnic and renal perfusion notwithstanding. Its potent vasoconstrictor properties require it to be infused via a central vein to prevent skin ischemia and necrosis. The usual dose range is 0.01–0.1 μg/kg/minute.

Sodium nitroprusside (SNP) is a direct-acting arteriolar dilator that reduces SVR by predominantly affecting resistance vessels and in addition reduces ﬁlling pressures by increasing venous capacitance. It is given by continuous i.v. infusion due to its short half-life of 1–2 minutes and is light sensitive. Its effect reverses within minutes of discontinuation. It is metabolized to thiocyanate, which is excreted by the kidneys. Cyanide toxicity can potentially occur if conversion to thiocyanate is impaired with formation of cyanmethemoglobin and reduced red cell oxygen-carrying capacity. Since its predominant effect is on arteriolar resistance vessels and left ventricular (LV) after-load, there may be a reduction in MAP. The dose ranges from 0.5–7 μg/kg/minute. SNP is frequently combined with inotropic drugs, especially where high-dose dopamine or adrenaline infusions are being used, in order to counteract the unwanted vasoconstrictor effects.

VASODILATORS

Phosphodiesterase inhibitors

Norepinephrine

Vasodilators are thought to be of beneﬁt in low cardiac output states through a number of mechanisms: 1 By decreasing impedance to ventricular emptying, resulting in increased stroke volume and decreased end-systolic volume 2 Increasing venous capacitance decreases venous return and therefore end-diastolic pressure;

A more recent innovation in pharmacotherapy for the management of low cardiac output has been the introduction of the phosphodiesterase inhibitors which act by blocking the breakdown of cGMP. This represents an alternative pathway for increasing myocardial performance rather than the traditional route via catecholamines, which can lose their effectiveness due to downregulation of β receptor activity. They also have

82 Postoperative management

important vasodilator properties. There are several studies of the effective use of phosphodiesterase inhibitors in the treatment of low cardiac output following open heart surgery in infants.106–110 The most commonly used drug in this class is milrinone in a dose of 0.33–1 μg/kg/minute. The drug has a long half-life and its metabolism is prolonged in hepatic failure.111

FLUID MANAGEMENT AND RENAL FUNCTION Preserving normal ﬂuid and electrolyte homeostasis is a more signiﬁcant problem in the neonate compared with the older child, as the renal system is somewhat immature in the newborn. The glomerular ﬁltration rate (GFR) is lower in the preterm infant compared with the term infant. However, the term newborn is capable of producing a dilute urine (30–50 mOsm/L) and will maintain a positive sodium balance with normal levels of sodium intake.112 The kidney in the preterm infant, however, is inefﬁcient at conserving sodium. On the other hand, there is also resistance to the effects of ADH and the infant can only concentrate urine to 400–600 mOsm/L. The preterm neonate also has an increase in extracellular ﬂuid volume (ECFV) compared to the term infant and this tends to rapidly expand immediately after birth.113 Fluid balance in the neonate depends on the balance between ﬂuid loss (evaporative, renal and gastrointestinal tract (GIT)) and the intake required for maintaining normal homeostasis organ function and growth. When calculating normal ﬂuid requirements in the newborn, all these factors need to be taken into consideration. Full maintenance ﬂuid requirements for the non-ventilated term newborn start at 60 ml/kg/24 hours in the ﬁrst day of life and increase to 100–150 ml/kg/24 hours by 5–7 days of life in the form of a dextrose/saline solution. Losses from the gastrointestinal (GI) tract due to nasogastric suction should be replaced with normal saline. The stimulus of surgery, the use of anesthetic agents and narcotic drugs, positive pressure ventilation and CPAP will all result in inhibition of ADH secretion and the failure to excrete a dilute urine. The frequent use of hypotonic i.v. solutions results in the accumulation of electrolyte-free water and hyponatremia. In addition, IPPV with humidiﬁcation of the respiratory tract eliminates not only evaporative losses from the respiratory tract but frequently will result in a net ﬂuid gain. For this reason it is common practice to calculate the maintenance requirements for ﬂuid for an infant on a respirator as being 70% of normal requirements in order to prevent ﬂuid retention. A urine output of >1 ml/kg/hour is generally regarded as a manifestation of adequate renal function following surgical procedures in the newborn. However, a period of oliguria in the presence of normal renal function is

not uncommon in the immediate postoperative period, especially where positive pressure ventilation is being used. There is usually a spontaneous diuresis within the ﬁrst 3–5 days after birth but it should be remembered that 7% of normal infants will not pass urine in the ﬁrst 24 hours of life. Persistent oliguria or anuria on the other hand may be associated with renal failure due to either pre-renal, postrenal or intrinsic renal damage. Pre-renal failure is most frequently due to decreased renal plasma ﬂow associated with blood or ﬂuid loss or inadequate ﬂuid resuscitation preoperatively. A ﬂuid challenge of 20 ml/kg of isotonic ﬂuid or 5% albumin will frequently result in restoration of urine output. Although critically ill newborns are frequently hypoalbuminemic and the maintenance of colloid osmotic pressure would seem to be an important factor in decreasing tissue edema, there is some dispute as to the efﬁcacy of albumin compared with crystalloid solutions.114–117 A further ﬂuid bolus/boluses with or without a diuretic may be tried depending on CVP measurement if there is no initial response. Intrinsic renal failure is a more serious complication and more difﬁcult to manage. Causes include congenitally abnormal kidneys (cystic or dysplastic), prolonged intraoperative renal ischemia or vascular abnormalities of the kidney (arterial thrombosis associated with umbilical artery catheters, renal venous thrombosis secondary to dehydration and prolonged hypotension due to sepsis.118 Drugs such as indomethicin and aminoglycoside antibiotics can also cause intrinsic renal damage. This form of renal failure can be differentiated from pre-renal etiology by the ﬁnding of red cells, protein and casts in the urine in association with high urinary sodium losses. Management of acute renal failure consists of eliminating the underlying cause if possible, restricting ﬂuids to urine output plus insensible losses and treating hyperkalemia with dextrose infusions and potassium exchange resins. This is only likely to be a short-term solution as the ﬂuid restriction will also entail restricted calorie intake and a cycle of catabolism with protein breakdown and weight loss. Early institution of renal replacement therapy (RRT) is important in interrupting this process. Peritoneal dialysis is an effective method of removing ﬂuid and potassium in the newborn with persistent renal failure, but may not be feasible after major intraabdominal surgery. Various solutions with differing glucose concentrations are used depending on the requirement for ﬂuid removal. Dialysis is unlikely to be effective unless ﬁll volumes of 10–20 ml/kg can be tolerated without hemodynamic compromise. Efﬁcacy also depends on perfusion of the mesentry and works less well in shocked states. The application of continuous veno-venous hemoﬁltration in small infants has demonstrated that large amounts of ﬂuid can be removed while at the same time maintaining a high calorie intake with

Postoperative hemorrhage 83

i.v. alimentation. Although this requires the insertion of a large double lumen catheter into a central vein and the use of heparin, there are several published case series with good outcomes.119–122

TEMPERATURE REGULATION AND METABOLISM IN THE NEONATE Temperature To maintain a normal body temperature, the neonate has to balance heat loss with heat production. With a large body surface area to body weight ratio, the neonate tends to lose heat rapidly by: 1 Conduction due to direct contact with cold surfaces 2 Convection by the cooling effects of air currents on exposed skin 3 Radiation to nearby objects such as an incubator wall 4 Evaporation of ﬂuid from skin and respiratory tract. Failure to eliminate areas of heat loss result in the infant attempting to raise its heat production by metabolism of brown fat stores and glucose. The preterm infant is poikilothermic and will not defend its body temperature and is therefore particularly vulnerable to the effects of cold injury. These include acidosis, hypoglycemia, increased O2 consumption and weight loss. It is therefore of great importance that the critically ill neonate be protected from the effects of cold stress following surgery. Nursing the infant in an incubator with an internal temperature of 32–36°C will eliminate conductive and convective heat losses. Radiation can be reduced by using double-glazed incubators and evaporative heat losses reduced by humidiﬁcation. Incubators do however limit access to the critically ill infant whereas the radiant warmer bed, while less efﬁcient in conserving heat losses, does provide excellent access. Evaporative and convective heat loss may be reduced with this system by covering the infant with plastic cling ﬁlm stretched between the side walls of the warmer bed.123

METABOLISM IN THE NEWBORN Glucose and calcium Glucose metabolism is not well developed in the newborn period and the critically ill neonate is liable to develop hypoglycemia at times of acute stress, particularly the preterm infant. This may be as a result of: 1 Diminished glycogen stores (inadequate stores in the premature infant or depletion from catecholamine-

stimulated glycogen breakdown release in perinatal stress) 2 Hyperinsulinemia in infants of diabetic mothers 3 Inadequate glucose production in small for gestational age (SGA) infants. Failure to recognize and correct neonatal hypoglycemia will result in seizures and brain damage. In order to prevent this it is recommended that a minimum of 10% dextrose with saline be used in all maintenance ﬂuid infusions in the newborn after surgery. In addition the blood sugar should be regularly measured to prevent hypoglycemia (<1.1 mmol/L in the preterm and <1.7 mmol in the term infant). Persistent hypoglycemia may require further boluses and an increased infusion to 15% dextrose. Where the hypoglycemia is due to delay in glucose release from glycogen stores in the liver, the administration of glucagon 300 μg/kg or steroid may result in a rise in blood sugar.124 Infants receiving highconcentration dextrose infusions have increased blood insulin levels. Abrupt discontinuation of the infusion will result in rebound hypoglycemia and therefore the patient should be weaned gradually. Hypocalcemia is common in the newborn period, but measurements of the total serum calcium do not accurately reﬂect the level of ionized calcium (Ca++) in the blood. Levels of total serum Ca above 1.75 mmol/L rarely cause problems but levels below 1.5 mmol/L may result in seizures, apnea and low cardiac output. Critically ill infants in the ﬁrst 24–48 hours of life, infants of diabetic mothers and newborns who have undergone large volume blood transfusions are all at risk for developing hypocalcemia. Calcium infusions should be given preferentially through central venous lines because of the tendency to cause intense venous irritation and damage to skin.

POSTOPERATIVE HEMORRHAGE The coagulation mechanism in the newborn infant is less well developed than in the older child and adult. Hepatic immaturity leads to decreased levels of vitamin K and a reduction of the vitamin K-dependent coagulation factors (II, VII, IX, X), particularly in the preterm infant. Reductions in these factors do not normally result in impaired hemostasis in the healthy term infant as levels of only 20–30% of most coagulation factors are necessary for normal clot formation. Although the most common form of postoperative bleeding is ‘surgical’ in nature as a result of hemorrhage from small vessels, it may be compounded by a failure of normal coagulation mechanisms, especially in the sick preterm neonate. Normal clot formation in the newborn may also be somewhat inhibited by the fact that although the platelet numbers may be normal, there is frequently some degree of platelet dysfunction, as they demonstrate abnormal

84 Postoperative management

membrane activity and diminished thromboxane A2 activity. In addition, continuous hemorrhage with blood replacement may result in a consumptive coagulopathy due to depletion of clotting factors and platelets.125,126 The clinical approach to the diagnosis and management of the newborn should be based on differentiating between a surgical correctable bleeding problem and an underlying coagulation problem. In the case of nonsurgical bleeding, the PT, PTT, platelet count, ﬁbrinogen level and a measurement of d-dimers will differentiate between a disorder due to inadequate coagulative factor levels and disseminated intravascular coagulation (DIC). The infant with excessive bleeding due to DIC frequently is severely ill with an underlying sepsis, asphyxia or shock. Excessive oozing from puncture sites, gastrointestinal and petechiae are frequently seen. The PT and PTT are prolonged, the platelet count reduced and d-dimers are high. The premature infant is at high risk of developing severe intraventricular hemorrhage secondary to disorders of coagulation. The main objective in treatment is to correct the underlying cause and replace the coagulation factors with fresh frozen plasma (FFP) and platelet transfusions. Heparin was formerly advocated in the treatment of DIC, but has not been shown to be effective. More recently the use of exchange transfusion to remove toxins, d-dimers and provide coagulation factors has become widely accepted although randomized controlled trials have not been shown to decrease mortality.

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causes pulmonary vasodilation in the ovine fetus. Am J Physiol 1995; 269(2 Pt 2):H473–9. 61. Thusu KG, Morin FCr, Russell JA, Steinhorn RH. The cGMP phosphodiesterase inhibitor zaprinast enhances the effect of nitric oxide. Am J Respir Crit Care Med 1995; 152(5 Pt 1):1605–10. 62. Kinsella JP, Torielli F, Ziegler JW, Ivy DD, Abman SH. Dipyridamole augmentation of response to nitric oxide. Lancet 1995; 346:647–8. 63. Thebaud B, Saizou C, Farnoux C, Hartman JF, Mercier JC. Dypiridamole, a cGMP phosphodiesterase inhibitor, transiently improves the response to inhaled nitric oxide in two newborns with congenital diaphragmatic hernia. Intensive Care Med 1999; 25(3):300–3. 64. Atz AM, Wessel DL. Sildenaﬁl ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91(1):307–10. 65. Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328(12):861–8. 66. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998; 132(1):40–7. 67. Robertson NJ, Hamilton PA. Randomised trial of elective continuous positive airway pressure (CPAP) compared with rescue CPAP after extubation. Arch Dis Child Fetal Neonatal Ed 1998; 79(1):F58–60. 68. Davis P, Henderson-Smart D. Post-extubation prophylactic nasal continuous positive airway pressure in preterm infants: systematic review and meta-analysis. J Paediatr Child Health 1999; 35(4):367–71. 69. Dassieu G, Brochard L, Benani M, Avenel S, Danan C. Continuous tracheal gas insufﬂation in preterm infants with hyaline membrane disease. A prospective randomized trial. Am J Respir Crit Care Med 2000; 162(3 Pt 1):826–31. 70. Kamper J, Wulff K, Larsen C, Lindequist S. Early treatment with nasal continuous positive airway pressure in very low-birth-weight infants. Acta Paediatr 1993; 82(2):193–7. 71. Jobe A. Too many unvalidated new therapies to prevent chronic lung disease in preterm infants. J Pediatr 1998; 132(2):200–2. 72. Wilson JM, Bower LK, Thompson JE, Fauza DO, Fackler JC. ECMO in evolution: the impact of changing patient demographics and alternative therapies on ECMO. J Pediatr Surg 1996; 31(8):1116–22; discussion 1122–3. 73. Kennaugh JM, Kinsella JP, Abman SH, Hernandez JA, Moreland SG, Rosenberg AA. Impact of new treatments for neonatal pulmonary hypertension on extracorporeal membrane oxygenation use and outcome. J Perinatol 1997; 17(5):366–9. 74. Azarow K, Messineo A, Pearl R, Filler R, Barker G, Bohn D. Congenital diaphragmatic hernia—a tale of two cities: the Toronto experience. J Pediatr Surg 1997; 32(3):395–400.

References 87 75. Reyes C, Chang LK, Waffarn F, Mir H, Warden MJ, Sills J. Delayed repair of congenital diaphragmatic hernia with early high-frequency oscillatory ventilation during preoperative stabilization. J Pediatr Surg 1998; 33(7):1010–14; discussion 1014–16. 76. Wilson JM, Thompson JR, Schnitzer JJ, Bower LK, Lillehei CW, Perlman ND et al. Intratracheal pulmonary ventilation and congenital diaphragmatic hernia: a report of two cases. Journal of Pediatric Surgery 1993; 28(3):484–7. 77. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics 1997; 99(6):838–45. 78. Anand KJ. Neonatal stress responses to anesthesia and surgery. Clin Perinatol 1990; 17(1):207–14. 79. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology 1990; 73(4):661–70. 80. Anand KJ, Brown MJ, Causon RC, Christoﬁdes ND, Bloom SR, Aynsley-Green A. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg 1985; 20(1):41–8. 81. Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Pediatrics 1994; 93(3):379–83. 82. Barker DP, Rutter N. Stress, severity of illness, and outcome in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996; 75(3):F187–90. 83. Pokela ML. Effect of opioid-induced analgesia on betaendorphin, cortisol and glucose responses in neonates with cardiorespiratory problems. Biol Neonate 1993; 64(6):360–7. 84. Anand KJ. Pain, plasticity, and premature birth: a prescription for permanent suffering? Nat Med 2000; 6(9):971–3. 85. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1(8524):62–6. 86. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326(1):1–9. 87. Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol 1990; 39(2):191–2. 88. Vacanti JP, Crone RK, Murphy JD, Smith SD, Black PR, Reid L et al. The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 1984; 19(6):672–9. 89. Quinn MW, Wild J, Dean HG, Hartley R, Rushforth JA, Puntis JW et al. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Lancet 1993; 342(8867):324–7.

90. Groff DB, Ahmed N. Subclavian vein catheterization in the infant. J Pediatr Surg 1974; 9(2):171–4. 91. Prince SR, Sullivan RL, Hackel A. Percutaneous catheterization of the internal jugular vein in infants and children. Anesthesiology 1976; 44(2):170–4. 92. Keeley SR, Bohn DJ. The use of inotropic and afterloadreducing agents in neonates. Clin Perinatol 1988; 15(3):467–89. 93. Driscoll DJ, Gillette PC, McNamara DG. The use of dopamine in children. J Pediatr 1978; 92(2):309–14. 94. Lang P, Williams RG, Norwood WI, Castaneda AR. The hemodynamic effects of dopamine in infants after corrective cardiac surgery. J Pediatr 1980; 96(4):630–4. 95. DiSessa TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman WF. The cardiovascular effects of dopamine in the severely asphyxiated neonate. J Pediatr 1981; 99(5):772–6. 96. Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Habib DM et al. Pharmacokinetics of dopamine in critically ill newborn infants. J Pediatr 1990; 117(3):472–6. 97. Padbury JF. Neonatal dopamine pharmacodynamics: lessons from the bedside. J Pediatr 1998; 133(6):719–20. 98. Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Goldblatt E et al. Dopamine pharmacokinetics in critically ill newborn infants. J Pediatr 1987; 110(2):293–8. 99. Perez CA, Reimer JM, Schreiber MD, Warburton D, Gregory GA. Effect of high-dose dopamine on urine output in newborn infants. Crit Care Med 1986; 14(12):1045–9. 100. Perkin RM, Levin DL, Webb R, Aquino A, Reedy J. Dobutamine: a hemodynamic evaluation in children with shock. J Pediatr 1982; 100(6):977–83. 101. Driscoll DJ, Gillette PC, Duff DF, Nihill MR, Gutgesell HP, Vargo TA et al. Hemodynamic effects of dobutamine in children. Am J Cardiol 1979; 43(3):581–5. 102. Bohn DJ, Poirier CS, Edmonds JF, Barker GA. Hemodynamic effects of dobutamine after cardiopulmonary bypass in children. Crit Care Med 1980; 8(7):367–71. 103. Stephenson LW, Edmunds LH, Raphaely R, Morrison DF, Hoffman WS, Rubis LJ. Effects of nitroprusside and dopamine on pulmonary arterial vasculature in children after cardiac surgery. Circulation 1979; 60(2 Pt 2):104–10. 104. Butt W, Bohn D, Whyte H. Clinical experience with systemic vasodilator therapy in the newborn infant. Aust Paediatr J 1986; 22(2):117–20. 105. Benitz WE, Malachowski N, Cohen RS, Stevenson DK, Ariagno RL, Sunshine P. Use of sodium nitroprusside in neonates: efﬁcacy and safety. J Pediatr 1985; 106(1):102–10. 106. Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995; 23(11):1907–14. 107. Lawless S, Burckart G, Diven W, Thompson A, Siewers R. Amrinone in neonates and infants after cardiac surgery. Crit Care Med 1989; 17(8):751–4.

88 Postoperative management 108. Bailey JM, Miller BE, Kanter KR, Tosone SR, Tam VK. A comparison of the hemodynamic effects of amrinone and sodium nitroprusside in infants after cardiac surgery. Anesth Analg 1997; 84(2):294–8. 109. Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 1998; 86(2):283–9. 110. Reinoso-Barbero F, Garcia-Fernandez FJ, Diez-Labajo A, del Cerro MJ, Cordovilla G. Postoperative use of milrinone for Norwood procedure. Paediatr Anaesth 1996; 6(4):342–3. 111. Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998; 132(2):329–34. 112. Simpson J, Stephenson T. Regulation of extracellular ﬂuid volume in neonates. Early Hum Dev 1993; 34(3):179–90. 113. Engle WD. Evaluation of renal function and acute renal failure in the neonate. Pediatr Clin North Am 1986; 33(1):129–51. 114. Greenough A. Use and misuse of albumin infusions in neonatal care. Eur J Pediatr 1998; 157(9):699–702. 115. So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed 1997; 76(1):F43–6. 116. Kanarek KS, Williams PR, Blair C. Concurrent administration of albumin with total parenteral nutrition in sick newborn infants. J Parenter Enteral Nutr 1992; 16(1):49–53.

117. Greenough A, Emery E, Hird MF, Gamsu HR. Randomised controlled trial of albumin infusion in ill preterm infants. Eur J Pediatr 1993; 152(2):157–9. 118. Gouyon JB, Guignard JP. Management of acute renal failure in newborns. Pediatr Nephrol 2000; 14(10–11):1037–44. 119. Reeves JH, Butt WB, Sathe AS. A review of venovenous haemoﬁltration in seriously ill infants. J Paediatr Child Health 1994; 30(1):50–4. 120. Zobel G, Ring E, Kuttnig M, Grubbauer HM. Five years experience with continuous extracorporeal renal support in paediatric intensive care. Intensive Care Med 1991; 17(6):315–19. 121. Bambauer R, Jutzler GA, Philippi H, Jesberger H-J, Limbach H-G, Richter J et al. Hemoﬁltration and plasmapheresis in premature infants, 1988. 122. Bambauer R, Jutzler GA, Jesberger HJ, Lofﬂer G, Limbach HG, Graf N et al. Hemoﬁltration and plasmapheresis in newborns using a small blood pump system. ASAIO Trans 1989; 35(3):578–9. 123. Chahine AA, Ricketts RR. Resuscitation of the surgical neonate. Clin Perinatol 1999; 26(3):693–715. 124. Ogata ES. Carbohydrate metabolism in the fetus and neonate and altered neonatal glucoregulation. Pediatr Clin North Am 1986; 33(1):25–45. 125. Buchanan GR. Coagulation disorders in the neonate. Pediatr Clin North Am 1986; 33(1):203–20. 126. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12(1):95–104.

8 Fluid and electrolyte balance in the newborn WINIFRED A. GORMAN

INTRODUCTION Appropriate ﬂuid and electrolyte therapy is an essential part of good neonatal care. In order to deliver appropriate quantities of ﬂuid and electrolytes, a thorough understanding of ﬂuid and electrolyte balance in the newborn is essential.

WATER DISTRIBUTION IN THE FETUS AND NEWBORN Body composition alters progressively throughout pregnancy. The body of the very young fetus is composed of 92% water, of which 65% is extracellular and 25% intracellular; less than 1% of the birth weight is composed of fat. There are progressive changes throughout pregnancy as the amount of protein and fat in the body increase. In a fetus of 1000 g birth weight (approximately 28 weeks’ gestation) about 80% of its weight is comprised of water; by full-term the water content is 75% and by 3 months of age (weighing approximately 5000 g) it is 60%.1–3 The total intracellular water content of the fetus and newborn’s body increases directly in proportion to cell mass. In the very immature fetus early in pregnancy, 25% of the weight is intracellular water; this increases to 35% at birth and 40% by 3 months of age. The body fat content increases from about 1% in the very early fetus to 15% at birth and 30% at 3 months of age.1 Fat has a very low water content and this increase in body fat content contributes to the decrease in total body water content.1 The growth-retarded infant whose body content of fat is low, has a greater proportion of body weight as water than the appropriately grown infant.

FUNCTIONAL ADJUSTMENTS TO POSTNATAL LIFE Renal blood ﬂow Functional nephrons are ﬁrst present in the fetus at approximately 8 weeks’ gestation. Nephrons develop in a centrifugal pattern with juxtamedullary nephrons developing ﬁrst. The full complement of glomeruli is present by 34 weeks’ gestation. Renal blood supply arises from the aorta between T12 and L2, a relationship that remains constant between 24 and 44 weeks’ gestation. As the renal arteries divide into segmental end arteries, the renal tissue in their area of distribution is very vulnerable to ischemia, thus follows the recommendation that umbilical artery catheters should not be positioned between T12 and L3.4,5 The renal blood ﬂow and glomerular ﬁltration rate in utero increase gradually with gestational age. Although absolute values increase, blood ﬂow and ﬁltration normalized to fetal weight remain constant, indicating that growth of new nephrons accounts for these increases in the fetus. Vascular resistance is high in the fetal kidney and restricts renal blood ﬂow and glomerular ﬁltration in utero. The proportion of cardiac output that is distributed to the kidneys during fetal life is about 2–3%.4–6 It increases to about 6% during the ﬁrst week of life and approximates 15–18% during the ﬁrst month of life. In adults, the kidneys receive 20–25% of the cardiac output. The low renal blood ﬂow during fetal life results from a high renal vascular resistance. Renal function is modiﬁed substantially after birth as a result of cardiovascular and hormonal inﬂuences. Increased cardiac output and decreased renal vascular resistance are responsible for increased blood ﬂow to the

90 Fluid and electrolyte balance in the newborn

kidneys. For 24 hours after birth, total renal blood ﬂow remains unchanged; however, distribution of intrarenal blood ﬂow changes dramatically, in that there is a shift in blood ﬂow from the inner to the outer cortex. After the ﬁrst day of life, blood ﬂow continues to rise in the outer zone of the cortex, whereas blood ﬂow to the inner cortex remains unchanged. The factors controlling these alterations in renal ﬂow are not fully understood. Factors noted to have an inﬂuence include renal sympathetic innervation, circulating catecholamines, the renin– angiotension systems and prostaglandins.7–9

Glomerular ﬁltration rate Glomerular ﬁltration begins between 9 and 12 weeks’ gestation in the human fetus and is responsible for making urine which contributes to amniotic ﬂuid. In fetal sheep, the glomerular ﬁltration rate (GFR) increases by 2.5 times during the last trimester and parallels the rise in fetal body weight and kidney weight.7–9 At delivery there is a positive correlation between GFR and gestational age in newborns delivered between 27 and 43 weeks’ gestation.10 In the ﬁrst 24 hours after delivery, there is a threefold increase in GFR. This occurs despite the absence of an increase in total renal blood ﬂow to the kidneys or an increase in systemic blood pressure. As mentioned earlier, however, there are dramatic changes in intrarenal blood ﬂow distribution with an increase in blood ﬂow to cortical glomeruli.7,9 The increase in glomerular ﬁltration occurs only in the infant of greater than 34 weeks’ gestation. Infants born before this gestation period fail to demonstrate this rapid rise in GFR; rather only a slow increase with age occurs postnatally so that by 40 weeks’ gestation the preterm infant has a GFR comparable to that of the term infant. The low GFR that characterizes the premature neonate’s renal function makes him intolerant of excessive ﬂuid and electrolyte loads. 8,10–12 Changes in GFR at birth may be inﬂuenced by plasma adrenaline and noradrenaline.13,14 Alterations in renin– angiotensin, prostaglandin, arginine vasopressin15–17and plasma cortisol18 concentration also occur perinatally. Each of these or a combination of these hormones may inﬂuence glomerular ﬁltration by decreasing glomerular vascular resistance and recruiting superﬁcial cortical nephrons.

Water homeostasis The diluting segment of the distal tubule and ascending limb of the loop of Henle develops relatively early in nephrogenesis. When challenged with a water load both the term and the preterm infant can dilute their urine to osmolalities to 50 mOsm/kg and 70 mOsm/kg water. The glomerular ﬁltration, however, is low and this limits the quantity of urine that can be excreted even in

the presence of a potent dilutional capacity. Thus the newborn, both term and preterm, is at risk of ﬂuid overload if presented with more ﬂuid than the kidney can handle. The concentrating ability of the newborn kidney is limited by the osmolality in the medullary interstitium. The newborn kidney of both the term and preterm infant has relatively low osmolality in the renal medulla and this limits the effectiveness of the countercurrent concentrating mechanism in the loop of Henle.11,12 In the term infant, urine can be concentrated to a maximum of 600–700 mOsm/L, considerably less than that of 1200 mOsm/L in the older child or adult. Thus both the preterm and full-term newborn are unable to handle either ﬂuid deprivation or overload, thus underlining the need for accurate assessment of ﬂuid requirements.19 Immediately after birth a physiological acute isotonic volume contraction occurs with the corresponding postnatal weight loss. Weight loss is greater and lasts longer in infants with less advanced gestational age. This volume contraction occurs predominantly in the extracellular water. This has been shown to occur independently of the amount of ﬂuid given postnatally.20 Hartnoll et al.21 studied the inﬂuence of delaying routine sodium supplementation on body composition. Their ﬁndings suggest that early sodium supplementation before a physiologic weight loss had occurred impaired the normal loss of body water from the extracellular ﬂuid compartment and resulted in increased respiratory morbidity.

Insensible water loss Insensible water loss is the continuous invisible loss of water by evaporation that occurs from the skin and lung surface. Account must be taken of an infant’s estimated insensible water loss when estimating total ﬂuid requirements.22

SWEATING Sweating occurs to only a very limited extent in response to a thermal stimulus in the term infant, despite the fact that the full complement of sweat glands is present at birth. Preterm infants below 30 weeks’ gestation do not have thermal sweating in the immediate newborn period,23 despite the absence of well-developed sweat glands by about 28 weeks’ gestation.

TRANSEPIDERMAL WATER LOSS Evaporation of water from the skin surface occurs continuously by diffusion.24,25 The quantity of water lost is determined by a number of factors. First, the relative humidity of the infant’s surrounding atmosphere is a major inﬂuence, particularly in the preterm infant.

Functional adjustments to postnatal life 91

Skin maturation has an inﬂuence on the quantity of water lost by evaporation. The full-term infant has a well-developed layer of keratinized stratum corneum which protects him/her against excess water loss. Keratinization begins at 17 weeks’ gestation and progresses in a non-uniform way throughout gestation, occurring latest on the skin of the abdomen and back.25–27 Transepidermal loss of water from the skin of the preterm infant is greatly increased as gestational age decreases. This is the result of a large ratio of surface area to weight and an immature epidermal barrier to water. This loss from the skin is exaggerated by postnatal trauma to the skin, for example from adhesive tape applied to the skin for attachment of monitors. After birth regardless of gestation the skin matures and skin permeability to water falls. However, in the extremely preterm infant this maturation may be extremely slow and extra cellular water loss has been shown to be higher than normal at 28 days postnatal age.28,29

Prenatal steroids Omar et al. have demonstrated high insensible water losses in preterm infants with a mean gestational age of 26 weeks. Transepidermal water loss gradually decreased over the ﬁrst 7 days of life and was signiﬁcantly lower in infants whose mothers had received prenatal steroids. On the other hand Jain et al. failed to demonstrate any maturational effect of antenatal steroids on transepidermal loss in a group of preterm infants. 30–32 The relative humidity of the infant’s surrounding atmosphere has a major inﬂuence on transepidermal water loss as well as heat loss. Water and heat loss can be at least partially counteracted by humidifying the infant’s surrounding atmosphere within the ﬁrst few days of life.33

Respiratory water loss Respiratory loss represents 39% of insensible water loss in term infants. Inspired air becomes fully saturated with water in the upper respiratory tract. Some water is lost as this air is expired. Tachypnea increases water loss through respiration. The relative humidity of the air before inspiration also has an inﬂuence; the higher the humidity, the less water needs to be added and less is lost. Infants ventilated will have humidiﬁed air delivered and thus the respiratory water loss will be zero.34

Sodium regulation Maintenance of normal serum sodium is principally controlled by the kidneys. Sodium intake must be roughly equivalent to the infant’s needs if a normal serum sodium (135–140 mmol/L) is to be maintained.

Glomerular ﬁltration, as has been described, is low in the preterm infant and increases progressively with gestational age. The amount of sodium that can be excreted is limited by the GFR. In the full-term infant, GFR increases dramatically after birth; however, it does not reach adult levels until approximately 2 years of age. This results in a lower GFR of sodium in the newborn infant, particularly in the preterm infant. Thus the ability of the kidney to excrete a sodium load is diminished as compared with adults and falls progressively with decreasing gestational age.35–37 Tubular function also has a role in renal handling of sodium. At all levels of sodium intake, preterm infants have a higher fractional sodium excretion rate than fullterm infants.37 Extrauterine existence has an accelerating effect on tubular sodium reabsorption but not on GFR, whose maturation is related to postconceptual age. The preterm infant, because of having a low GFR, is unable to excrete a sodium load. This immature function also renders him unable to retain sodium where intake is restricted. Al-Dahhan and colleagues have shown that the preterm infant of less than 30 weeks’ gestation requires a minimum of 5 mmol/kg/day of sodium and the infant of 30–35 weeks’ gestation requires 4 mmol/kg/day to achieve a positive sodium balance and maintain normal serum sodium.36,37 Intestinal absorption of sodium in the very preterm infant is low and improves progressively with increasing gestational age.38 Newborns undergoing intensive care may gain signiﬁcant amounts of ﬂuid and sodium from drugs, bronchial lavage, and ﬂushing of catheters – sources that are often overlooked. Hypernatremia may occasionally result, especially in the very small infant. 39 Hartnoll et al. have studied the inﬂuence of delaying postnatal sodium supplementation in infants of less than 30 weeks’ gestation on body composition and respiratory morbidity. They have shown that delaying routine sodium supplementation in preterm infants lessens respiratory morbidity for as long as 28 days postnatally. This suggests that routine supplementation of sodium without looking at overall ﬂuid balance may be detrimental to the preterm infant who has a limited ability to handle a sodium load.40 Prenatal steroids induce maturation of renal tubular function. Infants who have been exposed to prenatal steroids have an earlier diuresis and natriuresis.30

Renal response to antidiuretic hormone The human fetal pituitary contains antidiuretic hormone (ADH) from 12 weeks’ gestation onwards. Labor and delivery are associated with a surge in ADH secretion. Cord blood levels are elevated. Both term and preterm infants are capable of an appropriate ADH response to stimuli. Although blood levels in newborn infants are

92 Fluid and electrolyte balance in the newborn

elevated to the same extent as in adults, the antidiuretic response to ADH is blunted because a lower concentration gradient in the renal medulla lessens its effectiveness. ADH receptors in the kidneys may also be low in the newborn. Excess ADH can, however, cause a drop in urine output and hyponatremia. 41,42 Factors that result in excess or inappropriate secretion of antidiuretic hormone (SIADH) in the newborn include birth asphyxia,43 painful surgery, hypoxia and severe lung disease. SIADH results in weight gain, hyponatremia and oliguria, with a high urine osmolality and usually a high urine sodium. Treatment is with ﬂuid restriction.

FLUID AND ELECTROLYTE MANAGEMENT Dramatic changes in body composition, skin, renal and neuroendocrine function occur with delivery. Infants admitted to a neonatal intensive care unit who are unable to exclusively feed orally require careful management of ﬂuid and electrolyte balance. Additional difﬁculties may occur if the infant is preterm and if, as frequently happens in babies requiring surgery, there are additional losses from the intestine or the kidneys as a result of a complex surgical problem. When planning maintenance ﬂuid therapy for an infant, all the variables that have already been discussed that may inﬂuence ﬂuid requirements must be taken into account. Any guidelines for ﬂuid and electrolyte therapy must be modiﬁed to suit an individual infant’s requirements. Table 8.1 gives some guidelines that may be used and modiﬁed appropriately.43 Increased ﬂuid requirements may occur in the following circumstances: • Low birth weight (LBW) infants. For the reasons outlined in this chapter the LBW infant, especially the very low birth weight (VLBW) infant, has a very high insensible loss of ﬂuid and thus increased requirements for water. • Phototherapy. Phototherapy increases insensible water loss by evaporation, thus ﬂuid intake should be increased by 10 ml/kg/day in the infant weighing >1500 g and 20 ml/kg/day with birth weights <1500 g.44,45

• Radiant warmer. Nursing in a radiant warmer increases insensible ﬂuid loss (by a mean of 0.94 ml/kg/hour 47) when compared with incubators. This increased water loss is not prevented by using a heat shield but may be prevented by using a plastic blanket.46–48 • Polyuric renal failure. In this rare occurrence, maintenance ﬂuids will require very frequent readjustment (see later). Maintenance ﬂuid therapy may need to be decreased in the following circumstances: • Inappropriate ADH secretion. This may occur following cerebral or pulmonary insult and results in hyponatremia, oliguria and high urine osmolality. Treatment is principally with ﬂuid restriction. • Congestive heart failure and oliguric renal failure are both associated with ﬂuid overload, and ﬂuid restriction is thus an essential part of management. • Patent ductus arteriosus. Closure may be helped by ﬂuid restriction. In assessing the infant’s water requirements, useful guides include changes in weight and urine output, speciﬁc gravity and osmolality, serum sodium and creatinine and blood urea, and osmolality. Normal urine output is 2–4 ml/kg/hour. In the ﬁrst 24 hours of life, urinary output may be very low, or even absent. During recovery from a severe illness associated with ﬂuid retention or edema, polyuria may occur. A physiological diuresis (water loss) of up to 10% of body weight occurs over the ﬁrst 4–5 days of life. This diuresis has the effect of decreasing total body water content, in particular extracellular ﬂuid volume. It is greater in the preterm infant whose total body water content is higher than that of the term infant. No attempt should be made to replace this ﬂuid. This water loss occurs despite usual ﬂuid intakes and is typically accompanied by a negative sodium balance even when sodium is provided; it occurs predominantly on days 2 and 3 of life.49 High ﬂuid intake increases the likelihood of symptomatic patent ductus arteriosus. 50 High ﬂuid intake and or high sodium intake may also increase the likelihood of respiratory complications both in the short term and in the longer term by increasing the frequency of bronchopulmonary dysplasia.51

Table 8.1 Guidelines for initial ﬂuid therapy

Birth weight (kg)

Dextrose (g/100 ml)

Fluid rate (ml/kg/day) <24 hours 24–48 hours >48 hours

<1.0 1.0–1.5 >1.5

5–10 10 10

100–150* 80–100 60–80

120–150 100–120 80–120

140–190 120–160 120–160

*VLBW infants frequently require even higher initial rates of ﬂuid administration and frequent reassessment of serum electrolytes, urine output, and body weight.

Fluid and electrolyte management 93

Prevention of excess water loss by humidifying the infant’s environment, especially if the infant is very preterm, lessens water loss and makes maintenance of ﬂuid balance easier.

Sodium balance No sodium is required during the ﬁrst 24 hours of life, during which time urine and sodium output are low. As discussed earlier, sodium supplementation of 2–4 mmol/kg/day should be given when weight loss of approximately 5–10% of birth weight has occurred. This can be given with a solution containing one-ﬁfth normal saline with dextrose to which additional electrolytes are added as required (Table 8.2).

Table 8.2 Maintenance electrolyte therapy kg/day Sodium Potassium Calcium

2–4 mmol 1–3 mmol 5–10 ml of 10% calcium gluconate (1.125–2.25 mmol calcium)

Hyponatremia may occur in the following circumstances: • Laboratory error • Excess antidiuretic hormone secretion, where low urinary loss of water results in dilutional hyponatremia • Large renal tubular losses of sodium as occurs in extreme prematurity or polyuric renal failure • Congestive heart failure with dilutional hyponatremia • Diuretic therapy with loss of sodium via the renal tubules • Hypoadrenalism: congenital Addison’s disease, septic shock with adrenal failure, salt-wasting adrenogenital syndrome • Maternal hyponatremia 52 • Factitious hyponatremia as a result of hyperglycemia or hyperlipidemia. Hypernatremia may occur in the following circumstances: • Laboratory error • High insensible water loss which is incompletely replaced • High urinary water losses which are not replaced • Maternal hypernatremia • Deﬁciency of antidiuretic hormone. In summary, sodium requirements ordinarily are 2–4 mmol/kg/day. The preterm infant with immature renal tubules and resultant high urinary sodium loss may

require up to 6 mmol/kg/day of sodium. This high urinary sodium loss may continue for up to 4 weeks of age. Serum sodium in the ill newborn, especially if i.v. ﬂuids are required, must be monitored at least once daily in the term baby and 2–3 times daily in the VLBW baby, and appropriate adjustments in ﬂuid therapy must be made to correct any abnormalities in serum sodium.53

Potassium balance Potassium is predominantly an intracellular ion. No potassium is required on the ﬁrst day of life. After this, intakes of 1–3 mmol/kg/day should replace losses and maintain a normal serum potassium of 3.5–5.8 mmol/L (Table 8.2). Potassium must not be given if renal function is compromised. It should be given only with great care in the VLBW infant whose ability to excrete potassium may be limited. Early non-oliguric hyperkalemia may occur in 30–50% of infants with birth weights <1 kg as a result of a potassium shift from intracellular to extracellular space. Hyperkalemia will be exaggerated by hypoxia, metabolic acidosis, catabolic stress and oliguria. The hyperkalemia may be severe enough to cause lifethreatening arrhythmias. 7,54–57 Hyperkalemia may occur in the following circumstances: • Laboratory error or hemolysis of blood sample • Severe metabolic acidosis: with each 0.1 pH drop in serum, serum potassium increases by 0.6 mmol/L • Tissue cell death with release of intracellular potassium • Acute renal failure • VLBW in the absence of renal failure • Adrenal insufﬁciency secondary to acute adrenal failure as in sepsis/shock or congenital adrenal hyperplasia • Severe hemolytic anemia.

TREATMENT OF HYPERKALEMIA (Fig. 8.1) The following guidelines may be used: • Remove all sources of potassium • Correct metabolic acidosis with i.v. sodium bicarbonate • Give calcium gluconate (10%) intravenously to correct hypocalcemia • Give potassium chelator: calcium resonium 1 g/kg, rectally, 6 hourly • Give glucose and insulin intravenously: infuse 10–15% dextrose with soluble insulin. Use cautiously as severe hypoglycemia may result unless infusion is carefully monitored and titrated • Give salbutamol infusion 4 μg/kg intravenously over 20 minutes.58

94 Fluid and electrolyte balance in the newborn Remove all sources of exongenous potassium (K+) Abn

(1) Support cardiac output, CaGluconate, NaHCO3, frusemide, Kayexelate (2) Glucose/Insulin

Abn

(1) CaGluconate, NaHCO3. Check for arrhythmia causes.

CV status

NI ECG

NI NI Abn

Repeat ECG

Rejoin algorithm at renal status

Renal status

Abn

(2) Glucose/insulin, frusemide. Consider repeating step (1) above. Kayexelate

(1) Kayexelate, frusemide (if oliguric) (2) Dialysis double volume exchange NI Yes

(1) NaHCO3, frusemide, glucose/insulin (2) Kayexelate

Yes

(1) Frusemide (2) Kayexelate or Glucose/Insulin

+

[K ] >8 mmol/L No Ongoing K release

No Watch or frusemide In general, if [K+] acceptable for 6 hours, cease therapy but continue monitoring. Drug doses: Calcium gluconate 10% 1–2 ml/kg i.v. Sodium bicarbonate 8.4% (NaHCO3) 1–2 mmol/kg i.v. (dilute to 4.2%) Frusemide 1 mg/kg i.v. Glucose/insulin Bolus: D10W 2 ml/kg and Actrapid 0.05 U/kg Infusion: D10W 2–4 ml/kg/hour and Actrapid 10 U/100 ml D10W or 5% Albumin @ 1 ml/kg/hour Calcium resonium 1 g/kg rectally, used cautiously in the setting of an immature ischemic GI tract. Figure 8.1 Hyperkalemia44 For a given algorithm outcome proceed by administering the entire set of treatments labelled (1). If unsuccessful in lowering [K+] or improving clinical condition, proceed to the next set of treatments, e.g. (2) then (3). (CV = cardiovascular; Nl = Normal, Abn = abnormal.) (Taken from Manual of Neonatal Care. eds Cloherty and Stark. With permission of Lippincott Raven Publishers, USA)

CAUSES OF HYPOKALEMIA Hypokalemia may occur in the following circumstances: • Laboratory error • Alkalosis lowers serum potassium by shifting the potassium load intracellularly, but does not lower total body potassium • Polyuric renal failure

• Gastrointestinal losses through vomiting or diarrhea or pooling of ﬂuid in a ‘third space’, such as dilated loops with intestinal obstruction • Diuretic therapy • Inadequate intake. Hypokalemia predisposes to cardiac arrhythmias, paralytic ileus, urinary retention and respiratory muscle paralysis. Thus potassium balance must be carefully

Fluid and electrolyte management 95

monitored, taking into account the inﬂuence that pH may have on the serum potassium, in that alkalosis shifts potassium which is predominantly an intracellular ion into the cells; acidosis has the reverse effect and both hyper- and hypokalemia will have adverse effects.

Acid–base balance Normal values for pH are similar to those in the adult; however Pco2 and serum bicarbonate are both slightly lower in the newborn infant than in the adult.59,60 The lungs and kidney play important roles in the maintenance of acid–base balance. The lung excretes volatile acid formed during metabolism as CO2. Respiratory failure will cause accumulation of CO2 and respiratory acidosis.

METABOLIC ACIDOSIS The normal kidney has a vital role in regulation of serum bicarbonate. In mature subjects serum bicarbonate is maintained at approximately 25 mmol/L, but preterm infants have a lower threshold.60The kidney also has an important role in the excretion of non-volatile acid (mainly sulphur containing amino acids) produced by metabolism. Causes of metabolic acidosis The causes of metabolic acidosis include: 1 2 3 4 5 6

Perinatal asphyxia Severe hypotension with impaired tissue perfusion Acute renal failure Acute diarrhea and dehydration Excess ileal loss Excess protein administration, e.g. excess amino acids in parenteral nutrition 7 Inborn errors of metabolism (e.g. organic acidemia). Acute metabolic acidosis is common in the critically ill newborn. Treatment is predominantly by treatment of the underlying cause. Sodium bicarbonate may be used for severe acidosis with pH < 7.1 by giving a dose of 1–2 mmol/kg of 4.2% sodium bicarbonate by slow infusion over 30–60 minutes. 61,62 Causes of metabolic alkalosis • Persistent vomiting causes hypochloremic alkalosis and body potassium depletion. This may occur with untreated pyloric stenosis or upper intestinal tract obstruction. Correction is by replacement of ﬂuid, sodium chloride and potassium. Rehydration and correction of depleted electrolytes will be followed by correction of the metabolic alkalosis. • Chronic respiratory acidosis as in bronchopulmonary dysplasia may cause renal re-regulation of sodium bicarbonate level at a higher threshold until pH is normal. Infants with chronic hypercapnia regularly have a serum bicarbonate level of > 30 mmol/L.

In chronic acidosis or alkalosis, the kidneys and lungs do work in tandem with the aim of normalizing pH.

Glucose homeostasis Glucose is the most important substrate for brain metabolism and whereas ketones, glycerol and lactate can be used, a continuous supply of glucose is essential for normal neurological function.63,64 Fetal blood glucose is identical to that of maternal blood glucose since passive transfer of glucose occurs across the placenta. Immediately after delivery, blood glucose falls to approximately 2.5 mmol/L (45 mg/100 ml) in the term infant. Following delivery a combination of hormonal responses (glucagon, growth hormone, thyroxin) and oral feeds or in their absence i.v. ﬂuids, serve to maintain blood glucose within a normal range. Surprisingly, there is no consensus regarding the deﬁnition of hypoglycemia in the neonate.63,64 Blood glucose levels between 2.5 mmol/L (45 mg) and 7.2 mmol/L (130 mg) are accepted as being very safe. Symptomatic hypoglycemia results in cyanosis, apnea, lethargy, seizures or coma. Blood sugar values represent a continuum and there is no speciﬁc value at which brain-damaging hypoglycemia will always occur.63,65 Cornblath recommends using operational ‘thresholds’ as an indication for intervention. These levels are not diagnostic of disease but act as a guideline for when to treat hypoglycemia.64 In the newborn requiring surgery, hypoglycemia is most commonly caused by vomiting or inadequate intake of ﬂuids. Other contributing factors may include prematurity, septicemia, hypothermia, or hyperinsulinism as may occur in an infant of a diabetic mother. Infants with Beckwith–Wiedemann syndrome who frequently may have omphalocele, commonly have elevated blood insulin levels and severe hypoglycemia. Blood sugar in the infant at risk should be monitored at the bedside using a bedside screening glucose analyzer. Blood sugar levels below 2–2.5 mmol/L should be acted upon by giving a feed or giving a bolus of i.v. 10% dextrose as appropriate for the individual infant. Signiﬁcant hypoglycemia should be conﬁrmed by laboratory blood sugar before deﬁnitive action, such as i.v. glucose is given. This is because all screening methods are not completely accurate at low blood sugar levels.

HYPERGLYCEMIA A blood glucose level above 14 mmol/L (250 mg) may cause a hyperosmolar state with glucosuria, osmotic diuresis and dehydration. The risk of intracranial hemorrhage at least in the infant of < 32 weeks’ gestation may be increased by this increased plasma osmolality. Hyperglycemia most commonly occurs in the VLBW infant who is receiving large amounts of ﬂuids to

96 Fluid and electrolyte balance in the newborn

counteract insensible loss and whose ability to metabolize dextrose or glucose is limited. If hyperglycemia occurs, 10% dextrose should be replaced by 5% dextrose. Rarely, infusion of small doses of insulin may be required to counteract intractable hyperglycemia.43

Calcium homeostasis Calcium is the ﬁfth most abundant element in the human body. It has a key role in many physiological processes, including activation and inhibition of enzymes, intracellular regulation of metabolic sequences, secretion and action of hormones, blood coagulation, muscle contraction and nerve transmission.65 Of total body calcium, 99% exists in bone, to which it gives structural support. Calcium is present in the extracellular ﬂuid in three fractions: 30–50% is bound to protein, principally albumin; 5–15% is complexed to citrate, lactate, bicarbonate and inorganic ions; and 5–15% is ionized – this is the metabolically active fraction of calcium. Calcium concentration reported as mg/dL can be converted to molar units by dividing by 4 (e.g. 10 mg/dL converts to 2.5 mmol/L)43,66–68 If serum albumin is low, total serum calcium falls, but the serum level of ionized calcium is unchanged. Hydrogen ions compete with calcium for albuminbinding sites; thus acidosis increases serum ionized calcium levels without inﬂuencing total serum calcium levels. Alkalosis has the reverse effect. Prenatally, calcium is actively transported across the placenta from mother to fetus against a concentration gradient, which results in fetal hypercalcemia at the end of the last trimester and immediately after birth. Cord serum calcium in the full-term infant is approximately 2.75 mmol/L.67 In healthy full-term infants, calcium concentrations decrease for the ﬁrst 24 to 48 hours and reach a low of 1.8–2.1 mmol/L. Thereafter calcium concentrations progressively rise to the mean values observed in older children. This transient drop in serum calcium is exaggerated in the preterm infant.

HYPOCALCEMIA This is deﬁned as a total serum calcium concentration of < 2.0mmol/L in the term infant and < 1.7mmol/L in the preterm infant.66 Normal serum ionized calcium in the newborn infant is 1–1.5 mmol/L.67–69 Causes of hypocalcemia 1 The majority of hypocalcemia occurs in the fullterm and preterm infant in the ﬁrst 3 days of life. It is frequently asymptomatic and transient. 2 Infants of diabetic mothers frequently are hypocalcemic. 3 Additional stresses such as birth asphyxia or septicemia may precipitate hypocalcemia.

4 Genetic disorders such as Di Georges sequence may include hypoparathyroidism which causes hypocalcemia. Less common causes would include maternal hyperthyroidism and frusemide therapy or hypomagnesemia. Clinical manifestations The majority of instances of hypocalcemia is asymptomatic. The symptoms when they occur include jitteriness and seizures. An electrocardiographic Q-Tc interval longer than 0.4 seconds may occur. Management Early asymptomatic mild neonatal hypocalcemia does not require treatment. Infants receiving i.v. ﬂuids should be provided with maintenance calcium gluconate. Brown and colleagues have shown that aggressive attempts at normalizing serum calcium in sick preterm infants may be ineffective and even hazardous, thus at the least in the ﬁrst week of life maintenance of serum calcium at a level of 2.0 mmol/L is adequate.70 Symptomatic hypocalcemia should be treated with a slow infusion of i.v. calcium gluconate. Extreme care should always be taken when infusing calcium as extravasation can cause severe burns to the surrounding skin and subcutaneous tissue. Emergency treatment of hypocalcemia is only required if the infant is symptomatic. Symptoms include jitteriness, seizures, lethargy, poor feeding and vomiting. Symptoms are uncommon at serum calcium levels above 1.8 mmol/L and become common at serum calcium levels below 1.5 mmol/L. Oral calcium supplements in the form of calcium Sandoz 2.5 ml (50 mg)/kg/day may be given with feeds if the infant on feeds has asymptomatic hypocalcemia, requiring treatment. Symptomatic hypocalcemia unresponsive to calcium therapy may be due to hypomagnesemia. This can be treated with 50% magnesium sulphate either intravenously or intramuscularly.71

PREOPERATIVE FLUID AND ELECTROLYTE PROBLEMS IN THE NEONATE Heird and Winters have summarized the metabolic responses of the normal neonate in the ﬁrst weeks of life.72 Preoperatively, infants with abnormalities requiring surgery, especially those of the gastrointestinal tract, may have a variety of electrolyte abnormalities.72–74 If there has been a delay in recognition of gastrointestinal obstruction and the infant has been vomiting for a period of time, he or she will be dehydrated. Upper intestinal obstruction, for example duodenal atresia, results in loss of hydrochloric acid from the stomach, and small amounts of sodium and potassium.

Fluid and electrolyte balance in septic shock 97

The kidney then conserves hydrogen ions at the expense of potassium and sodium. Bicarbonate is excreted by the kidney along with sodium and potassium and the urine pH is alkaline. Potassium and sodium depletion occur. As loss of potassium and sodium progress, and the body stores are diminished, the kidney ceases to excrete these ions with bicarbonate. Sodium and potassium are now conserved by the kidney and hydrogen ion is lost instead. A severe hypochloremic metabolic alkalosis now occurs. Correction must be with adequate ﬂuid-containing sodium chloride and potassium chloride, as body stores of all these ions are depleted. It is not necessary to correct alkalosis with ammonium chloride. Infants with lower intestinal obstruction, such as Hirschsprung’s disease or other intestinal obstructive lesions, may pool large amounts of ﬂuid and electrolytes in dilated intestinal loops; this may result in intravascular dehydration with hyponatremia, hypokalemia and metabolic acidosis. Neonates with necrotizing enterocolitis, peritonitis or septic shock may have ‘third space’ loss of ﬂuid into the peritoneum, pleural ﬂuid or interstitial tissues with resultant hypoproteinemia and marked interstitial edema. Additionally, many of these infants are ventilated, sedated and paralyzed. Immobility resulting from paralysis will accentuate peripheral pooling of interstitial ﬂuid. Intravascular dehydration and hypoproteinemia and hyponatremia will result. Preoperatively, the infant’s hydration should be assessed on the basis of weight, pulse, blood pressure, capillary ﬁlling time, blood urea and electrolytes and urine output, speciﬁc gravity and electrolyte content.

metabolic acidosis. Inappropriate secretion of ADH is common and results from pain and/or ventilation. This will result in ﬂuid retention and hyponatremia; thus care must be taken to avoid overhydration, which will encourage both of these. Respiratory acidosis should be corrected by appropriate ventilation. Metabolic acidosis may occur postoperatively in the infant who is persistently hypotensive or hypoxic or who has ongoing tissue necrosis (i.e. severe necrotizing enterocolitis). This must be addressed by correcting the underlying cause of acidosis and by giving sodium bicarbonate. Fluids lost through nasogastric suctioning or drainage must be replaced at regular intervals by normal saline with maintenance potassium added; if losses are from the small intestine it has been recommended that a small amount of bicarbonate is also added. Where large ﬂuid losses occur from aspiration, calculation of the electrolyte content of these ﬂuids may help plan replacement71,72 (Table 8.3). Most, though not all, investigators agree that some discernible degree of catabolic response in terms of nitrogen excretion occurs in neonates postoperatively. Thus early attention must be given to beginning parenteral nutrition in infants in whom early feeding is not foreseen. The term infant who will be fed enterally within 5 days need not be fed parenterally; however, the VLBW infant (<1500 g) who has very inadequate stores of nutrients must begin parenteral nutrition as soon as he/she is metabolically stable.

Table 8.3 Electrolyte composition of body ﬂuids

Body Fluid

Electrolytes (mEq/L) Na+ K+ CI-

HCO3

PH

Gastric Pancreas Bile Ileostomy Diarrhea

70 140 130 130 50

0 100 40 25–30 50

1 9 8 8 >7

Intraoperative management Careful attention to ﬂuid and electrolyte balance intraoperatively is essential and monitoring of blood pressure, pulse and temperature is also essential. During major procedures, intravascular lines should be used to monitor blood pressure and central venous pressure. Urine output should also be measured and oxygenation and ventilation with blood gases and pulse oximetry. Loss of ﬂuid and heat from exposed peritoneal surfaces should be taken into account and minimized by keeping the operating room sufﬁciently warm. Acute blood loss should be replaced.73

5–15 5 5 15–20 35

120 50–100 100 120 40

Adapted from Wait RB, Kahng KU. Fluids and electroylytes and acid–base balance. In: Greenﬁeld LJ, Mulholland MW, Oldham KKT et al., editors. Surgery ,Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott Co.,1993:22373,74

FLUID AND ELECTROLYTE BALANCE IN SEPTIC SHOCK

Postoperative management Patients who have been adequately managed pre- and intraoperatively will be well hydrated in the immediate postoperative period. If the infant has been hypotensive, transient renal failure with oliguria may occur and must be managed with ﬂuid restriction and correction of electrolyte abnormalities such as hyperkalemia and

Many surgical conditions predispose to sepsis and shock. These include necrotizing enterocolitis, Hirschsprung’s disease with enterocolitis, and volvulus. The risk of septicemia with hypotension is even higher if the infant is also preterm. Shock is a stage of acute cardiovascular dysfunction in which the delivery of oxygen and nutrients is insufﬁcient

98 Fluid and electrolyte balance in the newborn

to meet metabolic demands of the tissues. The mortality rate when shock occurs is high. Endotoxin appears to be the common etiological factor in septic shock.75,76 Metabolic substrates, i.e. oxygen, glucose and fatty acids, are available, but their utilization is impaired; multiple-organ failure is the result. Capillary permeability increases and ﬂuid and protein leak into the interstitial ﬂuid. This results in tissue edema, hypoproteinemia and a fall in intravascular ﬂuid volume. Pulmonary hypertension, followed by marked pulmonary edema, occurs with severe respiratory distress. Myocardial depression results in decreased cardiac output.

Clinical manifestations Bacterial septicemia is frequently fulminant and fatal. A high index of suspicion by the nursing and medical staff is essential. The initial presenting features are subtle and may be recognized only by an experienced nurse or doctor. The infant may merely appear ‘off color’. The early signs of sepsis include lethargy, irritability, apnea and temperature instability.

Management Shock must be reversed with rapid infusion of ﬂuid and colloid to replete the intravascular space. Normal saline or lactated Ringer’s solution at a volume of 10–20 ml/kg should be infused over 20–60 minutes.74 Inotropic agents should be infused to increase cardiac output – dopamine improves cardiac contractility (5–20 μg/kg/minute) and in a low dose (<5 μg/kg/minute) also increases blood ﬂow to the kidneys and the intestine; high doses have the opposite effect. Alternative drugs are dobutamine or isoproterenol. Patients with profound hypotension and myocardial depression may respond only to infusion of epinephrine or norepinephrine. Hyponatremia and hyperkalemia may occur and should be corrected as outlined earlier in this chapter. Hyperkalemia results from oliguria and tissue catabolism; hyponatremia results from increased total body water and inappropriate antidiuretic hormone secretion. There is controversy about the value of i.v. sodium bicarbonate for correction of metabolic acidosis. It is no longer recommended for resuscitation in newborns and although it may correct acidosis in hypotensive shocked infants, this has not been shown to result in improvement in blood pressure or perfusion.61

ACUTE RENAL FAILURE Acute renal failure is common in the seriously ill neonate requiring surgery. It may be prerenal as a result of severe

dehydration, hypotension, abdominal distension or sepsis. It may result from congenital severe intrinsic renal disease. It may be obstructive and result from severe obstruction in the urinary collecting system, e.g. urethral valves.76,77 Prerenal failure is the most common form of acute renal failure in the surgical neonate, and results from a severe decrease in renal perfusion usually as a result of profound hypotension from blood loss, sepsis, severe necrotizing enterocolitis or intestinal obstruction with loss of ﬂuid into dilated intestinal loops. Primary fascial closure of omphalocele or gastroschisis carries the risk of placing the abdominal contents under pressure, which may cause a reduction in cardiac output, hypotension, bowel ischemia, venostasis and postoperative renal failure. Limited data suggests that an intragastric pressure of >20 ml of mercury or an increase in central venous pressure of 4 ml mercury or more indicate the need of a staged repair using a pouch.78 Additionally, newborn infants with abdominal wall defects have signiﬁcantly increased ﬂuid requirements preoperatively as major insensible water losses occur when eviscerated bowel is exposed to air and a perioperative third space is frequently associated. These conditions also favor hypovolemia, hypoperfusion of the kidney and postoperative renal failure. Renal vein or renal artery thrombosis, if bilateral, may be associated with acute renal failure. Treatment is by early aggressive ﬂuid replacement until blood pressure normalizes and then by meticulous adjustment of ﬂuid and electrolyte balance, until recovery of renal function occurs. Peritoneal dialysis may be required until renal function recovers. Recovery is associated with a polyuric phase which also requires ongoing care with replacement of large amounts of water, potassium and sodium via the kidneys. Renal failure due to obstruction and congenital malformations is often associated with severe irreversible renal diseases not compatible with normal extrauterine life. The focus of care must initially be to decide on the appropriateness of active management. Further discussion of renal failure management is outside the scope of this chapter.

CONCLUSION Major changes in body composition and ﬂuid and electrolyte balance occur during the transition to extrauterine life. These changes are even more marked in the preterm infant. The newborn who has a disorder requiring surgery has additional possible disorders of ﬂuid and electrolyte balance. This chapter outlines some aspects of the normal transition in the term and preterm infant, and the additional complications that may occur for the infant requiring surgery. It also provides some guidelines for ﬂuid and electrolyte therapy.

References 99

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100 Fluid and electrolyte balance in the newborn 38. Al-Danhan J, Haycock GB, Chantler C, Stimmler L. Sodium homeostatis in term and preterm neonates. II Gastrointestinal aspects. Arch Dis Child 1983; 58:343–5. 39. Noble-Jamieson CM, Kuzmin P, Airede K. Hidden sources of ﬂuid and sodium intake in ill newborns. Arch Dis Child 1986; 61:695–700. 40. Hartnoll G, Betremieux P, Modi N. Randomised controlled trial of postnatal sodium supplementation on oxygen dependency and body weight in 25–20 week gestational age infants. Arch Dis Child Ed 2000; 82:F19–23. 41. Rees L, Brook C, Shaw J, Forsling M. Hyponatraemia in the ﬁrst week of life in preterm infants. Part I Arginine vasopressin secretion. Arch Dis Child1984; 59:414–22. 42. Gore Ervin M. Perinatal ﬂuid and electrolyte regulation: Role of arginine vasopressin. Semin Perinatalol 1988; 12(2):134–42. 43. Simmons CF Jr. Fluid and electrolyte management. In: Coherty JP, Stark AR, editors. Manual of Neonatal Care. Philadelphia: Lippincott-Raven, 1988:9,87–100. 44. William OH, Karecki H. Phototherapy and insensible water loss in the newborn infant. Am J Dis Child 1972; 124:230–2. 45. Bell EF et al. Combined effect of radiant warmer and phototherapy on insensible water loss in low birth weight infants. J Peds 1979; 94:810–13. 46. Baumgart S. Reduction of oxygen consumption, insensible water loss, and radiant heat demand with use of a plastic blanket for low birth weight infants under radiant warmers. Pediatrics 1984; 75:89–99. 47. Flenady VJ, Woodgate PG. Radiant warmers versus incubators for regulating body temperature in newborn infants. Cochrane Library. 48. Meyer M, Payton M, Salmon A, Hitchinson C, de Klerk A. A clinical comparison of radiant warmer and incubator care for preterm infants from birth to 1800 grams. Pediatrics 2001; 108:395–401. 49. Lorenz JM, Kleniman LI, Kotagal UR, Reller MD. Water balance in very low birth weight infants: relationship to water and sodium intake and effect on outcome. J Pediatr 1982; 101:423–32. 50. Bell EF, Wharburton D, Stonestreet BS et al. Effect of ﬂuid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med 1990; 302:598–604. 51. Brown E, Start A, Sosemoko I et al. Bronchopulmonary dysplasia: possible relationships to pulmonary edema. J Pediatr 1978; 92:982–4. 52. Singhi S, Kalghatgi S. Iatrogenic neonatal and maternal hyponatraemia following oxytocin and aqueous glucose infusion during labour. Br J Obstet Gynaecol 1985; 92:356–63. 53. Lorenz JM, Kleinman L, Ghazala A, Markarian K. Phases of ﬂuid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics 1995; 96(3):484–9. 54. Lorenz JM, Kleinman A, Markarian K. Potassium metabolism in extremely low birth weight infants in the ﬁrst week of life. J Pediatr 1997; 131:81–6.

55. Sato K, Kondo T, Iwao H, Honda S, Ueda K. Internal potassium shift in premature infant: cause of nonoliguric hyperkalaemia. J Pediatr January 1995; 126:109–13. 56. Stefano JL, Norman ME, Morales MC, Goplerud JM, Ishra OP, Delivoria-Papadopoulos M. Decreased erythrocyte Na+, K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonologuric hyperkalemia. J Pediatr 1993; 122:277–81. 57. Kluckow M, Evans N. Low systemic blood ﬂow and hyperkalemia in pretern infants. Journal Pediatr 2001; 139:227–31. 58. Murdoch IA, Dos Anjos R, Haycock GB. Treatment of hyperkalaemia with intravenous salbutamol. Arch Dis Child 1991; 66:527–8. 59. Schwartz GJ, Evan AP. Development of solute transport in rabbit proximal tubule. HCO and glucose absorbtion. Am J Physiol 1983; 245:F382–90. 60. Ramiro-Tolentino SB, Markarian K, Kleinman LI. Renal bicarbonate excretion in extremely low birth weight infants. Pediatrics 1996; 98(2):256–61. 61. Burchﬁeld DJ. Medication use in neonatal resuscitation. Clin Perinatol 1999; 26:683–91. 62. Cooper DJ, Walley KR, Wiggs BR et al. Bicarbonate does not improve haemodynamics in critically ill patients who have lactic acidosis. Ann Int Med 1990; 112:492–8. 63. Koh THG, Eyre JA, Aynsley-Green A. Neonatal hypoglycaemia – the controversy regarding deﬁnition. Arch Dis Child 1988; 63:1386–98. 64. Cornblath M, Hawdon J, William A, Aynsley-Green A, Ward-Platt M, Schwartz R, Kalhan S. Controversies regarding deﬁnition of neonatal hypoglycemia: Suggested operational thresholds. Pediatrics 2000; 105(5):1141–4. 65. Koh THG, Aynsley-Green A, Tarbit M, Eyre JA. Neural dysfunction during hypoglycaemia. Arch Dis Child 1988; 63:1353–8. 66. Scott SM, Ladenson JH, Aguanna JJ, Walgate J, Hillmann L. Effect of calcium therapy in the sick premature infant with early neonatal hypocalcemia. J Pediatr 1984; 104:747–51. 67. Pitkin RM. Endocrine regulation of calcium homeostatis during pregnancy. Clin Perinatol 1983; 10( 3):575–87. 68. Namgun GR, Bainbridge R, Cruz MR, Tsang RC.Disorders of calcium and phosphorous metabolism in infants and children. 1988; 12:253–71. 69. Solden SJ, Hicks JM. Pediatric reference ranges. Washington: AA Press, 1995:39. 70. Brown D, Steranka B, Taylolr F. Treatment of early-onset neonatal hypocalcemia, effects on serum calcium and ionized calcium. Am J Dis Child 1981; 135:24–28. 71. Tsang RC. Calcium, phosphorous and magnesium. Metabolism. In: Polin RA, Fox WA, editors. Fetal and Neonatal Physiology. Philadelphia: Saunders, 1995. 72. Heird WC, Winters R. The body ﬂuids in paediatrics. In: Winters R, editor. Fluid Therapy for the Pediatric Surgical Patient. Boston: Little Brown, 1983. 73. Rice HE, Caty MG, Glick PL. Fluid therapy for the pediatric surgical patient. Pediatr Clin N Am 1988; 45(Aug):719–27.

References 101 74. Wait RB, Kahng KU. Fluids and electrolytes and acid-base balance. In: Greenﬁeld LJ, MuljOlland MW, Oldham KT et al. editors. Surgery Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott Co., 1993:23. 75. Butt W. Septic shock. Pediatr Clin N Am Vol, 2001; 48(3):601–19. 76. Toth-Heyn P, Drukker A, Guignard JP. The stressed neonatal kidney: from pathophysiology to clinical

management of neonatal vasomotor nephropathy. Pediatr Nephrol 2000; 14:22–239. 77. Gouyon JB, Guignard JP. Management of acute renal failure in newborns. Pediatr Nephrol 2000; 14:1037–44. 78. Yaster M, Scherer T, Stone M et al. Prediction of successful primary closure of congenital abdominal wall defects using intraoperative measurements. J Pediatr Surg 1989; 24:1217–20

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9 Nutrition AGOSTINO PIERRO

INTRODUCTION The newborn infant is in a ‘critical epoch’ of development not only for the organism as a whole but also for the individual organs and most signiﬁcantly for the brain.1 Adequate nutrition in the neonatal period is necessary to avoid the adverse effects of malnutrition on morbidity and mortality2 and to minimize the future menace of stunted mental and physical development.1 The survival rate of newborn infants affected by isolated congenital gastrointestinal abnormalities such as intestinal atresia, meconium ileus, omphalocele and gastroschisis has improved considerably over the past 20 years and is now in excess of 90% in most pediatric surgical centers. It is impossible to accurately quantify the contribution of improved nutritional management on the survival rate of these neonates. However the introduction of parenteral nutrition and advancement in nutritional management are certainly among the main factors responsible for this improvement.

HISTORICAL BACKGROUND The ﬁrst person to attempt to deliver nutrition intravenously was Sir Christopher Wren, the architect of St Paul’s Cathedral in London. He used hollow goose quills to infuse wine into dogs. Claude Bernard in the 18th century infused numerous substrates into animals and laid down the foundations of the scientiﬁc understanding of carbohydrate utilization in humans. In the 1930s Elman3 delivered the ﬁrst successful infusion of protein hydrolysates in humans. In 1949, Rhoads and Vars developed an apparatus for the continuous i.v. infusion of nutrients into dogs.4 The ﬁrst report of successful total parenteral nutrition in an infant was published in 1944 by Helfrick and Abelson.5 During the next 20 years, total parenteral nutrition in infants and children was without success because the solutions could not be infused into peripheral veins and insufﬁcient calories were provided

to allow the administered amino acids to be anabolyzed.6 In 1968 Dudrick et al.7 described a method to implant a catheter in the superior vena cava to deliver nutrients for prolonged periods. Using this system, Dudrick et al. showed that adequate growth and development could be achieved in beagle puppies and in a surgical infant.7 Following these initial reports Filler et al. reported the ﬁrst series of surgical neonates with gastrointestinal abnormalities treated with long-term total parenteral nutrition (TPN).8 The ﬁrst systematic investigations on the use of i.v. fat emulsions were carried out in Japan during the 1920s and 1930s.6 However the use of i.v. fat emulsions did not gain popularity because of the serious toxic reactions that occurred. The major breakthrough in the clinical use of i.v. fat emulsions came in 1962, when Wretlind described the soybean fat emulsion Intralipid still in use in many centers.9 During the 1970s and 1980s studies have been conducted in neonates receiving TPN, which led to signiﬁcant improvements in the technique and reduction of complications. The last 10 years have seen considerable changes in the nutritional management of surgical neonates. Various investigators have highlighted the importance of introducing as soon as possible enteral nutrition in surgical neonates. The beneﬁcial effects of minimal enteral feeding on the immune system, infection rate and liver function have been elucidated.

BODY COMPOSITION Newborns grow very rapidly and have lower caloric reserves than adults, and therefore do not tolerate prolonged periods of starvation. The body composition of newborns is markedly different from that of adults. The total body water varies from 86% of body weight at 28 weeks’ gestation to 69% at 40 weeks’ gestation and 60% in adulthood. This decline in body water also reﬂects an increase in energy content of the body. The ratio between minimal metabolic rate to non-protein energy reserve is only 1:2 at 28 weeks’ gestation; it

104 Nutrition

decreases to 1:29 for term infants and 1:100 for the adult.1 This justiﬁes the urgent need after birth for adequate caloric intake in very-low-birth-weight (VLBW) infants. Full-term neonates have a higher content of endogenous fat (approximately 600 g) and therefore can tolerate a few days of undernutrition.

ENERGY METABOLISM Newborns have a signiﬁcantly higher metabolic rate and energy requirement per unit body weight than children and adults10 (Fig. 9.1). They require approximately 40–70 kcal/kg/day for maintenance metabolism, 50–70 kcal/kg/day for growth (tissue synthesis and energy stored), and up to 20 kcal/kg/day to cover energy losses in excreta11,12 (Fig. 9.2). Computerization and miniaturization of indirect calorimeters have allowed the noninvasive investigation of energy metabolism in neonates.10,11,13,14 The total energy requirements for a newborn fed enterally is 100–120 kcal/kg/day, compared to 60–80 kcal/kg/day for a 10-year-old and 30–40 kcal/kg/day for a 20-year-old. Newborns receiving TPN

require fewer calories (80–100 kcal/kg/day). This is due to the absence of energy losses in excreta and to the fact that energy is not required for thermoregulation when the infant is nursed in a thermoneutral environment using a double-insulated incubator. Although the energy expenditure may double during periods of activity, including crying, most surgical infants are at rest 80–90% of the time.11 Signiﬁcant differences in resting energy expenditure (REE) have been reported among full-term surgical newborns (range 33.3–50.8 kcal/kg/day),11 and between premature and full-term babies. A full-term infant requires 100–120 kcal/kg/day, and a premature infant 110–160 kcal/kg/day11,15 (Fig. 9.1). These variations in maintenance metabolism explain the different growth rates frequently observed in surgical neonates receiving similar caloric intakes, and probably represent differences in metabolically active tissue mass, i.e. organ and muscle size. Several equations have been published to predict energy expenditure in adults.16 In stable surgical neonates, REE can be predicted from parameters such as weight, heart rate and age using the following equation:13 REE(cal/min) = –74.436 +(34.661 × body weight in kg) + (0.496 × heart rate in b.p.m.) + (0.178 × age in days) (r=0.92; F = 230.07; signiﬁcance F<0.00001).

The major predictor of REE in the above equation is body weight, which is also the strongest individual predictor of REE, and which represents the total mass of living tissue. The other predictors are heart rate, which provides an indirect measure of the hemodynamic and metabolic status of the infant, and postnatal age, which has been shown to inﬂuence REE in the ﬁrst few weeks of life.

Operative trauma Figure 9.1 Total energy requirement according to age. (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

Figure 9.2 Partition of energy metabolism in surgical newborns (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

In contrast with adults the energy requirement of infants and children undergoing major operations seems to be modiﬁed minimally by the operative trauma per se. In adults, trauma or surgery causes a brief ‘ebb’ period of a depressed metabolic rate followed by a ‘ﬂow phase’ characterized by an increase in oxygen consumption to support the massive exchanges of substrate between organs.17 In newborns, major abdominal surgery causes a moderate (15%) and immediate (peak at 4 hours) elevation of oxygen consumption and resting energy expenditure and a rapid return to baseline 12–24 hours postoperatively.18 There is no further increase in energy expenditure in the ﬁrst 5–7 days following an operation.18,19 The timing of these changes corresponds with the postoperative increase in catecholamine levels described by Anand et al.20 The maximum endocrine and biochemical changes are observed immediately after the operation and gradually return to normal over the next 24 hours. Interestingly, infants having a major operation after the second day of life have a signiﬁcantly greater increase in resting energy expenditure than infants undergoing

Energy metabolism 105

surgery within the ﬁrst 48 hours of life. A possible explanation for this may be the secretion of endogenous opioids by the newborn. It has been suggested that nociceptive stimuli during the operation are responsible for the endocrine and metabolic stress response, and that these stimuli may be inhibited by opioids.20,21 This is supported by studies showing that moderate doses of opioids blunt the endocrine and metabolic responses to operative stress in infancy.20,21 The levels of endogenous opioids in the cord blood of newborns are ﬁve times higher than plasma levels in resting adults.22 Thus, it is possible that the reduced metabolic stress response observed in infants less than 48 hours old is related to higher circulating levels of endogenous opioids. This may constitute a protective mechanism blunting the response to stress in the perinatal period. Chwals et al.23 demonstrated that the postoperative increase in energy expenditure can result from severe underlying acute illness, which frequently necessitates surgery (i.e. sepsis or intense inﬂammation). Resting energy expenditure is directly proportional to growth rate in healthy infants, and growth is retarded during times of acute metabolic stress. These authors suggest that energy is utilized for growth recovery following the resolution of the acute injury response in surgical infants. The authors indicate that serial measurement of postoperative resting energy expenditure can be used to stratify injury severity and may be an effective parameter to monitor the return of normal growth metabolism in surgical infants. Studies in adult surgical patients have shown that operative stress causes marked changes in protein metabolism characterized by a postoperative increase in protein degradation, a negative nitrogen balance,24,25 and a decrease in muscle protein synthesis.26 Powis et al.27 investigated substrate utilization and protein metabolism kinetics in infants and young children who had undergone major operations. Patients were studied for 4 hours preoperatively and for the ﬁrst 6 hours following surgery. The respiratory quotient fell signiﬁcantly postoperatively, reﬂecting mobilization of endogenous fat. However there were no signiﬁcant differences in the rates of whole-body protein ﬂux, protein synthesis, amino acid oxidation and protein degradation, between the preoperative and postoperative time, indicating that infants and children do not increase their whole-body protein turnover after major operations. It is possible that infants and children are able to convert energy expended on growth to energy directed to wound repair and healing, thereby avoiding the overall increase in energy expenditure and catabolism seen in the adult.14,27,28

Critical illness and sepsis Nutritional problems in infants and children requiring surgery are not unusual. The real nutritional challenge is

not represented by the operation per se but by the clinical condition of the patient. Examples include intrauterine growth retardation (IUGR) in small-for-gestation-age (SGA) preterm infants, infants who have suffered massive intestinal resection for necrotizing enterocolitis, and infants with motility disorders of the intestine following surgery for atresia, malrotation and midgut volvulus, meconium ileus or gastroschisis. Nutritional integrity, particularly in the neonatal period, should be maintained regardless of the severity of the illness or organ failure, especially in neonates due to their limited energy and protein stores. Infants and children require nutrition for maintenance of protein status as well as for growth and wound healing. One considerable challenge in pediatrics is represented by nutritional support during critical illness and sepsis. Keshen et al.29 have shown that parenterally fed neonates on extracorporeal life support are in hypermetabolic and protein catabolic states. These authors recommend the provision of additional protein and non-protein calories to attenuate the net protein losses. Sepsis is an intriguing pathological condition associated with many complex metabolic and physiological alterations.30 Studies in adults have shown that the metabolic response to sepsis is characterized by hypermetabolism as documented by an increase in resting energy expenditure up to 49% above that predicted.31 In addition, increased tissue catabolism,31 gluconeogenesis and hepatic release of glucose32 have been described. Energy is largely derived from endogenous fat, and the increased protein catabolism provides precursors for enhanced hepatic gluconeogenesis.32 In adult patients with sepsis it has been shown that: 1 During the ﬁrst 10 days from the onset of sepsis, 67% of the protein loss derives from skeletal muscle; after this time protein loss is predominantly from viscera31 2 Fat mobilization is far greater than fat oxidation, implying considerable cycling.33 At a later stage in sepsis, impaired oxidative metabolism and major metabolic abnormalities develop34 and exogenous fat utilization may become impaired.35 The interaction between exogenous lipid administration, immune response and tissue catabolism deserves further investigation.34 The existing knowledge on the metabolic response to sepsis in infants is limited. A recent metabolic study in septic neonates with necrotizing enterocolitis by Powis et al.14 failed to show any increase in whole-body protein turnover, synthesis and catabolism. The metabolic rate and hormonal response to stress and sepsis in infants may be different from that of adults and therefore it is not possible to adapt recommendations made for adults to the neonatal population. It is possible that neonates divert the products of protein synthesis and breakdown from growth into tissue repair. This may explain the lack

106 Nutrition

of growth commonly observed in infants with critical illness or sepsis. Further studies are needed in this ﬁeld to delineate the metabolic response of neonates and children to trauma and sepsis, explore the relationship between nutrition and immunity and to design the most appropriate diet.

PARENTERAL NUTRITION Indications Parenteral nutrition should be utilized when enteral feeding is impossible, inadequate or hazardous for more than 4–5 days. The most frequent indication in neonatal surgery is intestinal obstruction due to congenital anomalies. Frequently after an operation on the gastrointestinal tract, adequate enteral feeding cannot be achieved for more than 1 week and parenteral nutrition becomes necessary. This modality of therapy has improved signiﬁcantly the survival rate of newborns with gastroschisis, a condition that requires i.v. administration of nutrients for 2–3 weeks. Parenteral nutrition is also used in cases of necrotizing enterocolitis, shortbowel syndrome, and respiratory distress.

Fluid requirements A newborn deprived of oral ﬂuids will lose body ﬂuids and electrolytes in urine, stools, sweat and evaporative losses from the lungs and skin. The insensible water losses from the skin are particularly high (up to 80–100 ml/kg/day) in LBW infants.36 This is due to the very large surface area relative to body weight, the very thin and permeable epidermidis, reduced subcutaneous fat, and large proportion of total body water and extracellular water.36 The preterm infant requires larger amounts of ﬂuid to replace the high obligatory renal water excretion due to the limited ability to concentrate urine. The maintenance requirements can be calculated as follows: water losses = insensible (lungs + skin) + urine + stool + sweat + drainages ﬂuid requirements = losses + water for tissue synthesis – water from oxidation

The average water losses in newborns weighing > 2.5 kg are 100 ml/kg/day. In neonates with a weight < 1.5 kg the losses can be as high as 170 ml/kg/day. The water for tissue synthesis can be calculated from the daily weight gain: if this is 20 g/kg and the total body water is 80%, then 16 g/kg/day of water is required. This amount of water requirement is approximately offset by the water production from fuel oxidation. In surgical newborns it is not unusual to see signiﬁcant water losses from gastric

drainage and gastrointestinal stoma. These should be replaced on a ml-per-ml basis. Factors that increase the ﬂuid requirements are: 1 2 3 4 5

Use of a radiant warmer Phototherapy Fever Respiratory distress I.v. feeding.

In order to reduce water losses it is important to use double-walled incubators, to place the infant in relatively high humidity, to use warm, humidiﬁed air via the endotracheal tube, and in premature babies to cover the body surface with an impermeable plastic sheet. On the ﬁrst day of life, preterm newborns weighing < 1.5 kg should receive 80 ml/kg/day. Term neonates with a weight exceeding 1.5 kg should receive 60 ml/kg/day. This amount should be increased progressively day-by-day adjusting the requirements on the basis of the individual needs. Daily weight, ﬂuid balance (intake–output), urine osmolality, and serum electrolytes help to deﬁne the patient’s water requirements. Complications such as patent ductus arteriosus, necrotizing enterocolitis, pulmonary edema, and bronchopulmonary dysplasia are related to overhydration of high-risk infants and can be avoided by a careful monitoring of the above-mentioned parameters.

Components of parenteral nutrition The parenteral nutrition formulation includes carbohydrate, fat, protein, electrolytes, vitamins, trace elements and water. The caloric needs for TPN are provided by carbohydrate and lipid. Protein is not used as a source of calories, since the catabolism of protein to produce energy is an uneconomic metabolic process compared to the oxidation of carbohydrate and fat which produces more energy at a lower metabolic cost. The ideal TPN regimen therefore should provide enough amino acids for protein turnover and tissue growth, and sufﬁcient calories to minimize protein oxidation for energy.

CARBOHYDRATE Glucose is the natural energy source for body cells and is the primary energy substrate in parenteral nutrition. The amount of glucose that can be infused safely depends on the clinical condition and maturity of the infant. The ability of neonates to metabolize glucose may be impaired by prematurity and low birth weight. Carbohydrate conversion to fat (lipogenesis) occurs when glucose intake exceeds metabolic needs. The risks associated with this process are twofold: accumulation of the newly synthesized fat in the liver,37 and aggravation of respiratory acidosis resulting from increased CO2 production, particularly in patients with compromised pulmonary function.38

Parenteral nutrition 107

Jones et al.39 have shown that in surgical infants receiving parenteral nutrition there is a negative linear relationship between glucose intake (g/kg/day) and fat utilization (oxidation and conversion to fat) expressed in g/kg/day (y=4.547–0.254x; r=–0.937; P<0.0001). From this equation it was calculated that ‘net fat synthesis from glucose’ exceeds ‘net fat oxidation’ when the glucose intake is greater than 18 g/kg/day (Fig. 9.3). Jones et al.39 have also found a signiﬁcant relationship between glucose intake and CO2 production (ml/kg/min) (y= 3.849+0.183x; r=0.825; P<0.0001). The slope of this relationship was steeper when glucose intake exceeded 18 g/kg/day (y=2.62+0.244x; r=0.746; P<0.05), than when glucose intake was less than 18 g/kg/day (y= 5.30+0.069x; r=0.264; P=0.461). The conversion of glucose to fat thus results in a signiﬁcantly increased production of CO2. Glucose intake exceeding 18 g/kg/day is also associated with a signiﬁcant increase in respiratory rate and plasma triglyceride levels. In summary: 1 Glucose intake is the principle determinant of carbohydrate and fat utilization. 2 The maximal oxidative capacity for glucose in surgical infants is 18 g/kg/day, which is equivalent to the energy expenditure of the infant. 3 If glucose is given in excess of maximal oxidative capacity: ∑ Net fat oxidation ceases ∑ Net fat synthesis begins ∑ The thermogenic effect of glucose increases and the efﬁciency with which glucose is metabolized decreases ∑ Carbon dioxide production increases, and respiratory rate increases ∑ Plasma triglyceride levels increase.

FAT Since the 1960s, safe commercial i.v. fat emulsions have become widely used. These preparations have a high caloric value (9 kcal/g of fat), prevent essential fatty acid deﬁciency,41,42 and are isotonic, allowing adequate calories to be given via a peripheral vein.43 A number of studies in both adults and infants have indicated that a combined infusion of glucose and lipids might confer a metabolic advantage over a glucose infusion alone, because it lowers the metabolic rate and increases the efﬁciency of energy utilization.44–46 Fat tolerance has been extensively studied by monitoring fat clearance from plasma. However, clearance from plasma does not imply that the fat is being utilized to meet energy requirements, since it may be being stored instead.40,47 Pierro et al. have studied i.v. fat utilization by performing an ‘Intralipid utilization test’.40 This consisted of infusing for 4 hours Intralipid 10% in isocaloric and isovolemic amounts to the previously given mixture of glucose and amino acids. Gas exchange was measured by indirect calorimetry to calculate the patient’s O2 consumption and CO2 production, and net fat utilization (Fig. 9.4). The study showed that: (1) surgical infants adapt rapidly (within 2 hours) to the i.v. infusion of fat; (2) more than 80% of the exogenous fat can be oxidized; (3) CO2 production is reduced during fat infusion as a consequence of the cessation of carbohydrate conversion to fat (lipogenesis).40 This study did not measure the rate of fat utilization during a mixed i.v. diet including carbohydrate, amino acids and fat. More recent studies on stable surgical newborns receiving ﬁxed amounts of carbohydrate and amino acids and variable amounts of i.v. long-chain triglycerides (LCTs) fat emulsion have shown that at a carbohydrate intake of

It is advisable therefore in stable surgical newborns requiring parenteral nutrition to not exceed 18 g/kg/day of i.v. glucose intake.39,40

Figure 9.3 Linear relationship between glucose intake and fat utilization (r=–0.9; P<0.0001). Lipogenesis is signiﬁcant when glucose intake exceeds 18 g/kg/day (Reprinted from Pierro et al. J Pediatr Surg 2002; 37(6):811–22), with permission from Elsevier Science)39

Figure 9.4 Intralipid utilization test: surgical newborns adapt very rapidly to the infusion of i.v. fat. At 2 hours after the administration of i.v. fat they utilize approximately 3 g/kg/day. The oxidation of exogenous fat is associated with a signiﬁcant reduction in CO2 production. Fat utilization open . symbols; CO2 production.V CO2 closed symbols) (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

108 Nutrition

15 g/kg/day (56.3 kcal/kg/day), the proportion of energy metabolism derived from fat oxidation does not exceed 20% even with a fat intake as high as 6 g/kg/day. At a carbohydrate intake of 10 g/kg/day this proportion can be as high as 50%.48 This study seems to indicate that during parenteral nutrition in surgical infants the majority of the i.v. fat infused is not oxidized but deposited. Net fat oxidation seems to be signiﬁcantly inﬂuenced by the carbohydrate intake and the resting energy expenditure of the neonate. When the intake of glucose calories exceeds the resting energy expenditure of the infant, net fat oxidation is minimal regardless of fat intake.48 In order to use i.v. fat as an energy source (i.e. oxidation to CO2 and H2O), it is necessary to maintain carbohydrate intake below basal energy requirements. Commonly used fat emulsions for parenteral nutrition in pediatrics are based on LCTs. The rate of i.v. fat oxidation during TPN can be theoretically enhanced by the addition to the i.v. diet of L-carnitine and/or medium-chain triglycerides (MCTs). Important differences have been observed between MCTs and LCTs with respect to physical and metabolic properties. MCTs are cleared from the bloodstream at a faster rate and are oxidized more completely for energy production than LCTs. Therefore, they seem to serve as a preferential energy source for the body. The current author has recently investigated the effects of MCT on i.v. fat utilization during TPN in stable surgical newborns. Two groups of surgical infants receiving TPN were studied: one group received LCT-based (100% LCT) fat emulsion and the other group received an isocaloric amount of MCT-based (50% MCT + 50% LCT) fat emulsion. In infants receiving carbohydrate calories in excess of measured resting energy expenditure (56 kcal/kg/day), net fat oxidation was not enhanced by the administration of MCT-based fat emulsion. Conversely in infants receiving carbohydrate calories below resting energy expenditure (41 kcal/kg/day), the administration of MCT fat emulsion increased net fat oxidation from 0.6±0.2 to 1.7±0.2 g/kg/day. The administration of MCT-based fat emulsion did not increase the metabolic rate of the infants.

PROTEIN In contrast to healthy adults who exist in a state of neutral nitrogen balance, infants need to be in positive nitrogen balance in order to achieve satisfactory growth and development. Infants are efﬁcient at retaining nitrogen, and can retain up to 80% of the metabolizable protein intake on both oral and i.v. diets.49–51 Protein metabolism is dependent upon both protein and energy intake. The inﬂuence of dietary protein is well established. An increased protein intake has been shown to enhance protein synthesis,52,53 reduce endogenous protein breakdown,54 and thus enhance net protein retention.50,54 The protein requirements of newborns are

between 2.5 and 3.0 g/kg/day. The nitrogen source of TPN is usually provided as a mixture of cristalline amino acids. The solutions commercially available contain the eight known essential amino acids plus histidine, which is known to be essential in children.55 Complications like azotemia, hyperammonemia, and metabolic acidosis have been described in patients receiving high levels of i.v. amino acids.36 These complications are rarely seen with amino acid intake of 2–3 g/kg/day.56 In patients with severe malnutrition or with additional losses (i.e. those with a jejunostomy or ileostomy), the protein requirements are higher.55 The inﬂuence of non-protein energy intake on protein metabolism is more controversial. Protein retention can be enhanced by giving carbohydrate or fat,57–62 which are thus said to be protein sparing. Although some studies have suggested that the protein-sparing effect of carbohydrate is greater than that of fat,57–59 others have suggested that the protein-sparing effect of fat may be either equivalent to, or greater than, that of carbohydrate.60–62 The addition of fat calories to the i.v. diet of surgical newborns reduces protein oxidation, protein contribution to the energy expenditure, and increases protein retention.62 In order to further investigate this positive effect on protein metabolism the author studied the various components of whole-protein metabolism by the combined technique of indirect calorimetry and stable isotope (13C-leucine) tracer technique. Two groups of neonates receiving isonitrogenous and isocaloric TPN were studied: one group received a high fat diet and the other a high carbohydrate diet.63,64 There was no signiﬁcant difference between the two groups with regard to any of the components of whole-body protein metabolism: protein synthesis, protein breakdown, protein oxidation/excretion, and total protein ﬂux. This study conﬁrms previous observations that infants have high rates of protein turnover, synthesis and breakdown, which may be up to eight times greater than those reported in adults. In newborns receiving parenteral nutrition, synthesis and breakdown of endogenous body protein far exceeded intake and oxidation of exogenous protein. Infants are avid retainers of nitrogen, and carbohydrate and fat have an equivalent effect on protein metabolism. This supports the use of i.v. fat in the i.v. diet of surgical newborns. The ideal quantitative composition of amino acid solutions is still controversial. In newborns, cysteine, taurine, and tyrosine seem to be essential amino acids. However the addition of cysteine in the parenteral nutrition of neonates does not cause any difference in the growth rate and nitrogen retention.50 The essentiality of the earlier mentioned amino acids could be related to the synthesis of neurotransmitter, bile salts and hormones. The consequences of failure to supply these amino acids may be poor long-term neurological or gastrointestinal function.65 The incidence of abnormalities of plasma aminograms during parenteral

Parenteral nutrition 109

nutrition is low. There are no convincing data at the moment to support the selection of one crystalline amino acid solution over another in newborns.

SPECIAL NUTRIENTS: GLUTAMINE Nutrients can modulate immune, metabolic and inﬂammatory responses. Of these nutrients, glutamine is of particular interest. Glutamine is the most abundant free amino acid in the body, where it plays fundamental physiological roles. It is the predominant amino acid supplied to the fetus through the placenta66 and it is normally present in the enteral diet. Glutamine can be synthesized in the human body in substantial amounts and therefore is usually considered to be non-essential. However, in patients with acute and long-term sepsis and/or trauma, glutamine stores decline. This may be due to a combination of reduced glutamine production, possibly reﬂecting low muscle glycogen levels, glucose intolerance, and increased glutamine utilization. During sepsis, the liver and immune system become major glutamine consumers such that net glutamine utilization exceeds production and glutamine becomes ‘conditionally essential’.67,68 In rats, glutamine oxidation supplies a third of the total energy requirement of the gut.69 In humans who have sustained multisystem trauma or sepsis, glutamine concentration is 15% higher in arterial blood than in portal blood, conﬁrming the selective uptake of glutamine in the gut.70 There are several reasons why glutamine may be beneﬁcial for critically ill patients receiving parenteral nutrition. Firstly, glutamine supplementation has been shown to be beneﬁcial, both in vitro and in vivo, for the immune system.71 Glutamine is thought to be an important fuel and regulator of protein synthesis for cells of the immune system. An in vitro study has shown that glutamine supplementation is directly correlated with the host response to a range of different antigens including microrganisms.72,73 Animal studies have demonstrated that the glutamine-supplemented diet compared to standard parenteral nutrition preserves immunity in the respiratory tract, reduces mortality to a lethal bacterial challenge and reduces central venous catheter infection.74 Until recently glutamine has been excluded from parenteral nutrition because of low solubility and instability in solution. However glutamine dipeptides with improved stability and solubility are now available, making it possible to add glutamine to parenteral

nutrition formulation.75 The effect of glutamine supplementation on the prevention of infectious complications has been examined in randomized trials in adult patients receiving either glutamine-supplemented parenteral nutrition or isonitrogenous isocaloric parenteral nutrition. These trials included patients undergoing elective operations for colorectal cancer, patients with multiple trauma,76 critically ill patients77 and patients undergoing bone marrow transplantation.71 All these studies showed that parenteral glutamine administration does reduce infectious complications. Secondly, glutamine has multiple effects on gastrointestinal function. Glutamine deﬁciency leads to gut atrophy and bacterial translocation.77–80 Several studies in animals have investigated the effects of supplementing nutrition with glutamine on the preservation of the gut mucosal barrier during stress.78,80–82 Glutamine prevents deterioration of gut permeability, prevents intestinal mucosal atrophy83 and preserves mucosal structure in patients receiving parenteral nutrition.84,85 Reduced nitrogen loss has been demonstrated in adult patients receiving glutamine-supplemented parenteral nutrition after major abdominal operations.86 Recent studies have shown that in a neonatal animal model, glutamine reverses the liver dysfunction caused by sepsis due to an increase in the production of glutathione, a major intracellular antioxidant, for which glutamine is an important precursor.87,88 There have been several trials of glutamine parenteral nutrition supplementation in adults. However, a recent Cochrane systematic review has identiﬁed only two published randomized, controlled trials of glutamine use in neonates 89,90 including one on parenteral nutrition supplementation.89 This trial did not identify any adverse effects attributable to glutamine.89 Glutamine administration was associated with a reduced duration of artiﬁcial ventilation, hospital admission and parenteral nutrition,89 but effects on immunity or infection and its generalizability to other settings or patient groups remains unclear.91

Guidelines for the prescription of parenteral nutrition The author’s recommendations for the prescription of parenteral nutrition in surgical neonates are summarized in Table 9.1. I.v. calorie intake should be progressively

Table 9.1 Parenteral nutrition formulation Component

Day 1

Daily increment

Maximum dose

Intravenous ﬂuid Carbohydrate Fat Amino acids

80–100 ml/kg/day 10 g/kg/day 1 g/kg/day 1 g/kg/day

According to patient’s needs 4 g/kg/day 1 g/kg/day 1 g/kg/day

180 ml/kg/day 22 g/kg/day 4 g/kg/day 3 g/kg/day

110 Nutrition

increased over a 5-day period. I.v. carbohydrate intake should be increased from 10 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 22 g/kg/day. I.v. amino acid intake should be increased from 1 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 3 g/kg/day. I.v. fat should be increased from 1 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 4 g/kg/day. Non-protein i.v. calorie intake, after achieving stabilization, should vary from 80–120 kcal/kg/day according to weight gain and individual needs.

Complications of parenteral nutrition The complications of parenteral nutrition can be classiﬁed as those that are: 1 2 3 4

Infectious Metabolic Mechanical Hepatic.

INFECTIOUS COMPLICATIONS In spite of signiﬁcant improvement in the management of parenteral nutrition including the introduction of nutrition support teams, recently published infection rates from large children’s hospitals indicate that between 5% and 37% of infants may develop sepsis while receiving parenteral nutrition.92–95 This may lead to impaired liver function,95,96 critical illness and removal of central venous catheters. It has always been assumed that the central venous catheter is the major portal of entry for micro-organisms causing septicemia in patients on parenteral nutrition.93 However, studies in animals97 and surgical neonates95 have reported microbial translocation (migration of micro-organisms from the intestinal lumen to the systemic circulation) during parenteral nutrition. In a study on surgical neonates on parenteral nutrition95 all but one episode of microbial translocation occurred in patients with elevated serum bilirubin levels (cholestasis). Pierro et al.96 have reported that almost half of the surgical infants on parenteral nutrition develop abnormal ﬂora and that all cases of septicemia were preceded by gut colonization with abnormal ﬂora.96 Furthermore, it has been reported 98,99 that parenteral nutrition itself impairs host defense mechanisms and contributes to the occurrence of infection.100 This may be due to individual components of the parenteral nutrition solution, such as lipid emulsion101–104 or due to lack of nutrients, such as glutamine, normally present in the enteral diet. Important factors in reducing the incidence of septic complications are the placing of i.v. catheters under strict aseptic conditions, preparing the parenteral nutrition solutions in pharmacy in aseptic conditions and using meticulous care when catheters are used.

Every 4 days, the dressing on the exit site of the i.v. line should be removed aseptically, the skin should be cleansed with an antiseptic solution, and a sterile dressing reapplied. A 0.22 μ ﬁlter can be placed in-line to remove particulate matter, such as calcium salts or micro-organisms that may have contaminated the solution. All i.v. tubing and the containers of infusate should be changed daily. Chlorexidine 0.5% in 70% alcohol solution should be applied to all joints in the circuit to prevent entry of micro-organisms. Sepsis should be suspected when infants on parenteral nutrition present clinical features of generalized inﬂammation including one or more of the following features: temperature instability, poor perfusion, hypotension, lethargy, tachycardia, respiratory distress, and fever. In these neonates blood culture should be performed from the central venous line and/or from a peripheral vein. The current author suggests starting blind therapy with a combination of teicoplanin and gentamicin at the onset of sepsis. The aminoglycoside can be stopped in case of a Gram-positive micro-organism. In cases of Gram-negative bacillary septicemia, the glycopeptide should be discontinued and replaced by a second- or third-generation cephalosporin. In case of fungemia, liposomal amphotericin B can be administered. If cultures prove to be negative, antibiotics should be discontinued unless the severity of the sepsis warrants a full 5-day course of treatment. In the majority of neonates (80–90%) with positive blood culture, the central venous catheter can be salvaged with a 7-day course of antibiotics. In those patients who do not respond to antibiotic treatment it is advisable to remove the central venous line and insert a peripheral cannula for peripheral parenteral nutrition and i.v. antibiotic administration. A new central venous line should be inserted at least 4–5 days after cessation of the clinical features of generalized inﬂammation.

METABOLIC COMPLICATIONS The metabolic complications most frequently observed in newborns receiving parenteral nutrition are listed in Box 9.1. These complications are related to inappropriate administration of nutrients, ﬂuid, electrolytes, and trace elements or to the inability of the individual patient to metabolize the i.v. diet. Hyperglycemia occurs frequently during the course of parenteral nutrition, particularly while the glucose concentration of the infusate is being increased. Unless 4+ glycosuria or osmotic diuresis occurs, the hyperglycemia is best left untreated because most patients will, within hours, produce adequate endogenous insulin to metabolize the carbohydrate load. The treatment of symptomatic hyperglycemia usually is reduction of the infusion rate. When hyperosmolality occurs, the osmolality of the infusate must be decreased; rarely, insulin will be required.

Parenteral nutrition 111 Box 9.1 Metabolic complications of TPN Carbohydrate administration Hyperglycemia Hypoglycemia Fatty inﬁltration of the liver Hyperosmolarity and osmotic diuresis Increased CO2 production Protein administration Hyperammonemia, azotemia Abnormal plasma aminograms Hepatic dysfunction Cholestatic jaundice Fat administration Hyperlipidemia Fat overload syndrome Displacement of albumin-bound bilirubin by free fatty acids Peroxidation and generation of free radicals Fluid administration Patent ductus arteriosus Pulmonary edema Electrolyte imbalance Sodium, potassium, cholorine, calcium, phosphate Trace element and vitamin deﬁciency

Hypoglycemia usually results from sudden interruption of an infusion containing a high glucose concentration. The treatment is i.v. glucose by bolus or infusion of a 10% solution. High doses of fat or an accidental rapid infusion of fat may lead to fat overload syndrome, characterized by an acute febrile illness with jaundice and abnormal coagulation. Treatment is symptomatic and lipid fusion must be discontinued.105,106 The i.v. administration of fat emulsion in premature infants seems to increase the incidence of bronchopulmonary dysplasia and retinopathy.107 Peroxidation in stored fat emulsions, occlusion stored fat emulsions, and the generation of free radicals during i.v. infusion of fat in premature infants have been reported.108 The release of free radicals may overwhelm the endogenous protective mechanisms, resulting in cellular damage.109

MECHANICAL COMPLICATIONS Mechanical complications related to the i.v. infusion of nutrients are not uncommon. Box 9.2 lists the mechanical complications reported in the literature. Extravasation of parenteral nutrition solution is a common complication of peripheral parenteral nutrition. The ﬁnal concentration of parenteral nutrition for peripheral infusion should not exceed 10% dextrose and 2% amino acids. Unfortunately even a low osmolarity solution is

Box 9.2 Mechanical complications of parenteral nutrition Extravasation of parenteral nutrition solution Blockage of the central venous line Migration of the central venous line Breakage of the infusion line Right atrium thrombosis Cardiac tamponade (perforation of right atrium or vena cava)

detrimental for peripheral veins leading to inﬂammation and extravasation of the solution. This can cause tissue necrosis and infection. Careful monitoring of the infusion site and use of infusion pumps sensitive to changes in pressure can alert the nurse and surgeon to the need for discontinuing the infusion and re-siting of the i.v. cannula. I.v. lines may become clogged from thrombus formation, calcium precipitates, or lipid deposition. A urokinase (5000 U/ml) ﬂush should be tried ﬁrst, allowing for a 20-minute dwelling time. If this is unsuccessful, 0.1 N hydrochloric acid (HCl) or ethanol 70% can be tried. Since the volume of neonatal lines is small, very limited amounts of the above agents need to be used (0.001–0.004 ml/cm). There is disagreement on the ideal position of central venous lines for parenteral nutrition in infants. Some authors advocate the atrium as the ideal position because this would give less chance of catheter dysfunction.110,111 Others believe that placement in the superior vena cava would reduce the risk of perforation.112,113 There are no controlled trials to advise against positioning the tip of the central venous line in the right atrium. The risk of thrombosis of the superior vena cava is not abolished by positioning the tip of the line in the right atrium. In the current author’s opinion, the tip of the central venous line can be positioned either in the superior vena cava or in the right atrium. In small preterm infants the distance between the superior vena cava and the right atrium is very small. Current imaging techniques with the use of i.v. contrast should be able to differentiate between tips of lines located in the superior vena cava from those located in the right atrium. In a survey of 587 CVLs inserted in neonates,114 cardiac tamponade was the cause of death in two neonates (0.3%). In most of the cases reported in literature of cardiac tamponade following CVL insertion, the perforation was thought to be in the right atrium.112,113,115 Cardiac tamponade should be suspected in any patient with a CVL whose condition deteriorates suddenly. Immediate chest X-ray and echocardiogram should be performed to support the diagnosis. However when the patient’s condition is deteriorating rapidly, a diagnostic (and therapeutic as well!) pericardiocentesis should be performed without waiting for other diagnostic measures.116

112 Nutrition

HEPATIC COMPLICATIONS The hepatobiliary complications related to parenteral nutrition remain serious and often life threatening. The commonest hepatobiliary complication of parenteral nutrition in surgical neonates is cholestasis. The incidence of parenteral nutrition-related cholestasis varies widely from as low as 7.4%117 to as high as 84%.118 The etiological factors for the development of cholestatic jaundice in infants requiring parenteral nutrition are still unclear. Peden et al.119 ﬁrst reported in 1971 the development of liver disease in a preterm infant who was receiving parenteral nutrition from birth until the infant’s death at the age of 71 days. At autopsy the infant’s liver revealed cholestasis, bile duct proliferation, and early cirrhosis. The association between cholestasis and parenteral nutrition has been subsequently criticized by Rager and Finegold,120 who from a series of autopsy studies concluded that early fasting, rather than parenteral supplementation, may contribute to impaired hepatobiliary function in the small premature infant. Since these initial reports there have been several other publications on parenteral nutrition-related cholestasis. The frequency of this complication seems to be diminishing.121 However this is probably related to the early initiation of oral feeding rather than to an improvement in the i.v. diet. The clinical presentation of parenteral nutrition-related cholestasis is fairly typical. The infants requiring long-term parenteral nutrition develop progressive jaundice. This is commonly preceded by elevation of biochemical non-speciﬁc tests of hepatic damage, function and excretion. Various clinical factors are thought to contribute to the development of parenteral nutrition-related cholestasis (Box 9.3). These factors include prematurity, low birth weight, duration of parenteral nutrition, immature entero-hepatic circulation, intestinal microﬂora, septicemia, failure to implement enteral nutrition, and number of operations.122,123 Parenteral nutritionrelated cholestasis is a diagnosis of exclusion without any speciﬁc marker yet available. Therefore infants with cholestasis who are receiving or have received parenteral Box 9.3 Patient risk factors for the development of parenteral nutrition-related cholestasis Age Prematurity Immaturity of biliary secretory system Absence of oral/enteral intake Septicemia Bacterial overgrowth in the small bowel Short bowel length Necrotizing enterocolitis Hypoxia Major abdominal operations General anesthesia

nutrition must have an appropriate diagnostic evaluation to exclude other entities. These include bacterial and viral infections, metabolic diseases and congenital anomalies.124 When serial ultrasound examination of liver and gallbladder is performed in infants receiving parenteral nutrition, biliary sludge and cholelithiasis can be detected. Sludge is a dense ﬂuid lying in the dependent portion of the gallbladder, which produces low amplitude echoes.124 The incidence of sludge formation increases with duration of parenteral nutrition. Gallbladder sludge appeared in 18 neonates (44%) after a mean period of 10 days of parenteral nutrition.125 Sludge can progress to ‘sludge balls’ and gallstones. Asymptomatic infants can develop biliary stones and spontaneous resolution of the stones has been described.125 Cholecystitis in infants receiving parenteral nutrition is rare. Serial liver ultrasound examinations of neonates and infants receiving parenteral nutrition are advisable to detect abnormalities and/or to follow the abnormal gallbladder content. Parenteral nutrition-related cholestasis is progressive unless parenteral nutrition is ceased and enteral feeding introduced. Hepatosplenomegaly and severe jaundice are characteristic features of advanced disease. Neither of these signs, however, are pathognomonic for this condition and the diagnosis of hemolytic anemias, infection and metabolic disease should be excluded.124 Portal hypertension may develop and indeed be fatal. Although the parenteral nutrition-related cholestasis resolves with time after discontinuation of parenteral nutrition, in a small percentage of cases it remains intractable and progresses to severe hepatic dysfunction and death.126 In spite of 20 years of clinical experience with parenteral nutrition and several studies in animals and humans, the etiology of parenteral nutrition-related cholestasis remains unclear. Different factors may contribute to the development of the disease. These include the toxicity of parenteral nutrients, lack of enteral feeding, continuous non-pulsatile delivery of nutrients and host factors. Most of the components of parenteral nutrition have been thought to be implicated in the pathogenesis of cholestasis. Hepatic damage from the components of i.v. diet may result from excessive nutrient administration, deﬁcient nutrient administration, toxicity of by-products, and abnormal metabolism in the neonate. The infant’s clinical status inﬂuences the likelihood of parenteral nutrition-related cholestasis development. Box 9.3 lists the most common risk factors. Parenteral nutrition-related cholestasis has a higher incidence in premature infants than in children and adults. This may be due to the immaturity of the biliary secretory system since bile salts pool size, synthesis, and intestinal concentration are low in premature infants in comparison with full-term infants.127 The clinical care of infants and children who require parenteral nutrition and develop progressive jaundice

Parenteral nutrition 113

represents a real challenge. The difﬁculty is compounded by the lack of a full understanding of the pathological mechanisms of parenteral nutrition-related cholestasis. None of the experimental animal models for the disease can be extrapolated to the clinical situation, since the histological ﬁndings in the liver of animals on parenteral nutrition are not similar to those found in the livers of affected human infants and children. Most of the recommendations for prevention and treatment are therefore empirical and often not based on substantial clinical evidence. Prevention of parenteral nutrition-related cholestasis is based on the early usage of enteral feeding and the administration of i.v. feeding only when appropriate and necessary. In most patients the cholestasis resolves gradually as enteral feedings are initiated and parenteral nutrition is discontinued. Continuation of parenteral nutrition is usually associated with exacerbation of the liver damage; therefore every effort should be made to introduce enteral feeding. It has been recently shown that minimal bolus enteral feeding (1 ml/kg) during parenteral nutrition in premature infants induces signiﬁcant gallbladder contraction and after 3 days of starting minimal enteral feeds, the gallbladder volume returns to normal.128 Unfortunately, as a consequence of gut dysfunction, enteral feeding is often not feasible. In these cases the provision of i.v. calories should not be discontinued since malnutrition and increased risk of infection may result. The calorie needs of the patient should be carefully assessed and overfeeding should be avoided. Maini et al.129 suggested that cycling the parenteral nutrition may diminish cholestatic hepatic changes in adults. This may explain the less frequent liver disease in children receiving their parenteral nutrition cyclically at home. Experience with this technique in premature infants is extremely limited but encouraging.130,131 Rebound hypoglycemia is a common complication of this approach. Modiﬁcation of the constituents of parenteral nutrition has been proposed but no prospective trial has demonstrated any beneﬁt in reducing or changing the intake of nutrients. Several reports have described the attempts to use drug therapy to treat or prevent parenteral nutritionrelated cholestasis. Antibiotics such as metronidazole have been proposed to decrease bacterial overgrowth, formation of secondary toxic bile acids and production of endotoxins.132 In a subsequent animal study, however, metronidazole administration did not prevent development of abnormal liver enzymes on parenteral nutrition.133 Choleretics such as phenobarbital have been used with negative results.130 Cholecystokinin has been administered to diminish the gallbladder stasis and promote bile ﬂow. Sitzmann et al.134 have demonstrated in a randomized, double-blind controlled study in adults receiving parenteral nutrition that cholecystokinin given intravenously daily prevents stasis and sludge in the gallbladder. Rintala et al.135 reported the reversal of parenteral nutrition-related cholestasis in seven infants

by i.v. administration of cholecystokinin three times a day for 3–5 days. However all the patients except one were completely weaned from parenteral nutrition before the treatment with cholecystokinin. In rabbits maintained on total parenteral nutrition, daily infusions of cholecystokinin decreased periportal inﬂammation and ﬁbrosis, maintained gallbladder emptying capacity, and improved organic anion secretion, although bile ﬂow and bile acid secretion were not improved, and hepatocyte damage persisted.136 Prospective studies are needed to investigate, in infants and children requiring parenteral nutrition, the effects of exogenous cholecystokinin administration on bile ﬂow and cholestatic jaundice. Ursodeoxycholic acid can be used in infants and children on parenteral nutrition to correct the decreased secretion of endogenous bile acids.121 Ursodeoxycholic acid is non-toxic and acts as a natural bile acid after conjugation. The efﬁcacy of this treatment has been demonstrated in rabbits and sporadic case reports in humans. Controlled studies showing that ursodeoxycholic acid actually decreases morbidity and mortality in infants on long-term parenteral nutrition have not been performed.121 Biliary sludge, cholelithiasis and cholecystitis have been reported with the use of parenteral nutrition. Biliary sludge often resolves with the initiation of enteral feedings and discontinuation of parenteral nutrition. Cholecystectomy is the treatment of choice for patients with acute and symptomatic cholelithiasis and cholecystitis. Rintala et al.137 have proposed laparotomy and operative cholangiography followed by biliary tract irrigation in patients with progressive cholestatic jaundice not responding to medical treatment. In some patients the hepatic disease may progress to cirrhosis, portal hypertension and hepatic failure. In selected cases small bowel and liver transplantation have been used. The introduction of tacrolimus has allowed clinical intestinal transplantation to become feasible. However infectious and immunological problems still cause signiﬁcant morbidity and mortality, even 1–3 years after transplantation.138 The author’s approach to the treatment of parenteral nutrition-related cholestasis is as follows. Once the diagnosis is established and other medical causes of jaundice have been excluded, an ultrasound of liver and extrahepatic biliary tree is repeated to exclude extrahepatic biliary pathology. If cholelithiasis and/or cholecystitis are present, a cholecystectomy with intraoperative cholangiogram is performed. If only biliary sludge is present, an operation is not performed, but serial ultrasound monitoring of the extrahepatic biliary tree is performed to detect stone formation. In the absence of gallbladder disease, the current author vigorously attempts to establish at least minimal bolus enteral feeding to stimulate endogenous cholecystokinin production. Elemental formulas containing medium-

114 Nutrition

chain triglycerides are used to improve intestinal fat absorption. Surveillance cultures of throat, rectum, and stool are taken to detect bacterial overgrowth. If present, selective decontamination of the digestive tract is carried out.139,140 The calorie requirements of the patients are carefully re-evaluated and the carbohydrate intake is limited to the patients’ resting energy expenditure (approximately 50 kcal/kg/day in a full-term neonate). The i.v. fat intake is discontinued for 14 days. If this produces a drop in serum bilirubin level, the lipid intake is limited to 0.5 g/kg/day on alternate days to provide essential fatty acids. Normal lipid intake is resumed if no changes are observed in serum bilirubin level. Complications from fat-soluble vitamins and/or trace element deﬁciencies are minimized with proper monitoring and supplementation. Attempts are made to cycle the i.v. infusion of nutrients by reducing the daily administration of parenteral nutrition to a maximum of 12 hours.

Monitoring of neonates on parenteral nutrition All infants receiving parenteral nutrition must have accurate monitoring of their nutritional state and growth, and for possible metabolic complications. Weight should be measured daily and plotted on a growth chart. Expected weight gain in the full-term newborn is about 20 g/day; acute changes usually reﬂect ﬂuid gain or loss. Head circumference is measured weekly, and length, monthly; these two are charted. Skinfold thickness (subscapular and triceps) and midarm muscle area measurements are not used routinely but are useful for patients on long-term parenteral nutrition in conjunction with other body dimensions141 to assess variations in body composition (total body fat and lean body mass). During the initial period while glucose, protein and fat are being introduced, and during periods of metabolic instability, ﬂuid balance, urine-speciﬁc gravity or osmolality, urine sugar and protein content, and the blood sugar level should be checked every 6 hours. The cumulative volume of blood taken for tests may become signiﬁcant and should be recorded.

Weaning from parenteral nutrition The transition to enteral feeding is begun as soon as intestinal function is judged to be adequate, bearing in mind that if feeding is advanced too quickly, this may compromise digestion and absorption, and increase ﬂuid, electrolyte and nutrient losses. Initial feeds should be hypo-osmolar and small in volume as discussed for enteral nutrition. Increases must be subtle. The parenteral nutrition infusion should be tapered progressively during the transitional period and dis-

continued only when at least 70% of the caloric needs are being tolerated enterally. If there is a severe relapse of malabsorption, enteral feeds should be discontinued until the gut has recovered, after which weaning is begun again.

ENTERAL NUTRITION The energy requirement of an infant fed enterally is greater than the i.v. requirement because of energy lost in the stools and the energy cost of diet-induced thermogenesis. Because individual requirements vary, the energy intake must be adjusted according to the infant’s growth. The protein requirements for full-term infants are 2.5–3.0 g/kg/day. Breast milk from the infant’s mother is preferred because of the anti-infectious protective functions142 and high content of non-protein metabolizable nitrogen, notably urea.143 A standard commercial formula is adequate for full-term infants with a functionally normal gastrointestinal tract, and will provide approximately 0.66 kcal/ml. Premature infants may require a special formula with calories, minerals (notably calcium) and proteins content adjusted for the special needs of these infants.15 Additional calories may be provided as glucose polymer or medium-chain triglycerides. The volume required for enteral feeds is 150–200 ml/kg, adjusted for individual needs. Following an operation, enteral feeds usually can be commenced as soon as there is continuity of function throughout the intestinal tract, demonstrated by the absence of bile in the nasogastric aspirate, a low volume of aspirate (below about 50 ml/day), and the appearance of green stools. The presence of bowel sounds indicates small bowel peristalsis but is not evidence of continuity of function. Infants who have fed before operation should be able to tolerate the same feed after operation. It is not necessary that the initial feed should be a dextrose solution. Feeds should be commenced in small volumes, every 2 or 3 hours, and increased incrementally as tolerated. Infants who are premature or too weak to take oral feeds will need to be fed by gavage. If bolus feeds are not tolerated, a continuous slow feed through a nasogastric tube beginning at 1 or 2 ml/hour is often successful. Gastro-esophageal reﬂux is common in newborns and continuous tube feeds are better tolerated in this situation. A nasoduodenal tube or feeding jejunostomy should be considered when gastric emptying is abnormal. Tolerance of feeds is monitored by recording gastric residual volumes, stool frequency and volume, and the presence or absence in the stool of blood, fat and reducing substances. Documenting the growth of the infant in terms of body weight and head circumference monitors the efﬁcacy of the feeding regimen (see monitoring).

References 115

When malabsorption is anticipated, for example in infants with meconium ileus or necrotizing enterocolitis, or with a shortened length of functional small intestine due to an extensive resection or a proximal enterostomy, a hydrolyzed casein formula may be better tolerated, especially if diluted to reduce the osmolality. An example is Pregestimil, beginning with a one-quarter- or onehalf-strength preparation.

Chemically deﬁned formulae If malabsorption persists, an appropriate speciﬁc formula should be introduced. A soy-based disaccharide-free feed is used when there is disaccharide intolerance resulting in loose stools containing disaccharides. For fat malabsorption, a formula containing MCTs should be used. An elemental formula may be indicated when there is severe malabsorption due to short bowel syndrome or severe mucosal damage as in necrotizing enterocolitis. These preparations contain amino acids, glucose and fats, including MCTs. Dipeptide preparations which include dipeptides as well as amino acids have the advantage of a lower osmolality, are well absorbed and have a more palatable taste.144 For persistent severe malabsorption, a modular diet may be neccesary.145,146 Glucose, amino acid and MCT preparations are provided separately, beginning with the amino acid solution and adding the glucose and then the fats as tolerated. Minerals, trace elements and vitamins are also added. These solutions have a high osmolality and if given too quickly may precipitate dumping syndrome, with diahorrea, abdominal cramps and hypoglycemia. It is important therefore to start with a dilute solution and increase slowly the concentration and volume of each component. This may take several weeks and infants will need parenteral nutritional support during this period. Infants recovering from neonatal necrotizing enterocolitis pose a particular problem as malabsorption may be severe and prolonged. These infants may have had their small bowel resected, in addition to which the remaining bowel may not have healed completely by the time feeds are begun. Feeding may provoke a relapse of the necrotizing enterocolitis and the author recommends a cautious feeding program beginning with 25% Pregestimil at a slow rate.

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10 Vascular access in the newborn JUDA Z. JONA

INTRODUCTION The establishment of specialized units for the care of the newborn, with advanced monitoring, ventilation techniques and support for the ill newborn, has markedly increased their chance for survival.1 Vascular access is one of the tools which has enabled neonatologists and surgeons to provide ongoing therapy for the babies, while at the same time securing avenues for invasive monitoring of the condition and progress of these very ill patients. The therapeutic advantages which the various catheters and cannulae provide include the ability to administer ﬂuids and electrolytes, blood products, drugs and sophisticated nutritional formulas. The monitoring beneﬁts derived from these catheters are mostly for obtaining blood samples for analysis, measuring arterial and venous pressures, and providing minute-by-minute control and response to the various therapeutic modalities, particularly ventilatory. Signiﬁcant clinical advances have been brought about by the introduction of sophisticated and miniaturized monitoring instruments that have been coupled with the development of new catheters and devices for their introduction.2

ARTERIAL CANNULATION Invasive cannulation of the arterial tree has been introduced into clinical medicine in the past three decades. Previously, arterial puncture was done infrequently and great reliance was entrusted to clinical evaluations and heel-stick blood sampling. The modern application of intra-arterial cannulation has provided a great advance in the care and management of newborns. It enables the clinician to monitor continuously the patient’s blood pressure and to obtain, at will, samples of arterial blood for blood gas analysis, which is so vital to the ventilatory and acid–base management of these babies. In addition, all sampling for laboratory tests can be performed without repeated puncture of the babies’ limbs. When

possible, we encourage percutaneous insertion of these catheters, since any surgical ‘cut’down’ has the disadvantages of providing an easy portal for infection, dislodgement and inability to reuse the site in the future.

Maintenance and complications As with all catheters and cannulas, the arterial one must be secured particularly ﬁrmly to the patient and the strictest aseptic handling maintained. Since intra-arterial devices are prone to thrombosis, in all instances, heparinization of the infusate must be used. We customarily use heparin at 1 u/ml, continuously infusing at a slow rate utilizing small-volume pumps. The combination of infusion/sensory apparatus (Spectramed transducer system) is used in our institution and permits sampling and ﬂushing without a need for line disconnection. Puncture site care is carried on at set intervals, which involves povidone-iodine repreparing and resecuring of the cannula. Dampening of the arterial tracing usually indicates malposition or microthrombi formation. In time, endothelial damage will promote more aggressive thrombus formation, but immobilization of the limb and site will reduce the chance of this happening. Complications can, at times, be serious and early recognition through continuous observation may prevent signiﬁcant ill effects. It is therefore advised that the site and the extremity as a whole be inspected frequently. An inadvertently disconnected arterial line may result in exsanguination. Peripheral ischemia, an uncommon problem, can be caused by vasospasm or microthrombic formation, which may become severe enough to cause loss of tissue or digits. This complication is more probable in babies with poor peripheral perfusion or in those on vasoactive drug therapy. Site, or systemic, infections are by far the most common complication. A sepsis rate of about 4% and local infections in 15–18% of patients have been reported.3,4 Careful site management and secure immobilization of the catheter may reduce the chance of infection.5

122 Vascular access in the newborn

Umbilical artery catheterization By and large, umbilical artery catheterization is performed by the neonatologist and/or the pediatrician and rarely an opportunity arises for the surgeon to perform this task. Much has been written in the medical literature6 concerning the technique and positioning of the catheter and the precautions one must take in order to avoid complications. This discussion will not deal with the routine umbilical artery catheterization, but rather with a variant of this technique which is employed quite commonly by pediatric surgeons and involves the transfer of the umbilical artery from its umbilical position to a para-umbilical anterior abdominal wall position. The need for this maneuver arises when one deals with the surgical correction of abdominal defects in babies who will require careful monitoring and prolonged ventilatory support. This is particularly true in premature infants in whom peripheral arterial cannulization is at times impossible and in whom continuous intra-aortic catheterization is essential. When babies with gastroschisis or omphalocele (exomphalos) are taken to the operating room for deﬁnitive primary or staged repair of their abdominal wall defect, it is readily found that direct umbilical artery catheterization is either impossible (omphalocele) or impractical, since these defects involve commonly the umbilical stump and its vicinity. In such situations, transfer of the umbilical artery is called for (Fig. 10.1).

forceps. An appropriately-sized catheter (3 Fr. or 5 Fr. gauge) should be on hand, which is speciﬁcally designed and measured for umbilical artery catheterization. A paramedian and somewhat inferior stab incision is done in an area which will be uninvolved in the surgical closure. A ﬁne-tip hemostat is then advanced through the thickness of the abdominal wall towards the free end of the artery. The artery is grasped and brought to the surface. Care must be taken in order not to twist or angulate the artery sharply, so that the catheter can be advanced smoothly in. The catheterization then progresses as it is done routinely and, at the ﬁrst convenient time, a radiograph is taken in order to ascertain the proper position of the catheter tip in the distal thoracic aorta (in some centers, distal abdominal aortic position is preferred). The cannula is secured to the artery with a 4-0 permanent ligature and is then anchored with the same ligature to the adjacent skin. Removal of the catheter, when its function is terminated, is simple and usually does not involve undue bleeding. When the umbilicus is unsuited for direct catheterization because of dryness or previous manipulations, one can attempt similar cannulation by tracing the infraumbilical course of one of the arteries and bringing it to the surface through a separate small extraperitoneal incision.7 (Fig. 10.2) At the institutions of the Children’s Hospital of Wisconsin and at the NICU–Evanston, this

UA

UV

RAM

UA

OPERATIVE TECHNIQUE At the onset of the operation, the surgeon will carefully dissect the course of the umbilical artery as it descends inferiorly from the umbilical stump towards its union with the iliac artery. This dissection, which is done just below the surface of the peritoneum, need not be carried for a long distance. With proper magniﬁcation, the umbilical artery is isolated as it is held with ﬁne-tip

Inc

UR (a)

(b)

Figure 10.1 Surgical transfer of the umbilical artery catheterization in a newborn with gastroschisis. Umbilical site (arrow head) transposed umbilical artery (arrow)

RAM

Pr

Figure 10.2 Infraumbilical cut down.The umbilical arteries (UA) are exposed through a transverse subumbilical incision (Inc). The arteries run on either side of the urachal remnant (UR) in an extraperitoneal (Pr) position. A. Location of incision. B. Cross-section representing the extraperitoneal – para urachal position of the UA. RAM: Rectus abdominal muscle; UV: Umbilical vein

Arterial cannulation 123

has occurred quite rarely and in most instances we would rather resort to peripheral arterial catheterization.

Radial artery cannulation Radial artery catheterization is a rather commonplace procedure in the hand of the neonatologist in providing access to intra-arterial monitoring. The percutaneous technique is the standard approach to the insertion of the cannula and it is successful in most instances when carried out by an experienced clinician. At times when this is impossible, the surgeon is called to assist in providing cutdown exposure and direct cannulation.

OPERATIVE TECHNIQUE After ascertaining that the circulation to the hand is present via both radial and ulnar arteries (the Tennell test), the baby’s forearm is positioned in pronation on a ﬁxation board with the hand slightly dorsiﬂexed (Fig. 10.3). All other extremities should be restrained in order to prevent unnecessary motion. The wrist area is thoroughly prepared with antiseptic solution and draped with sterile drapes. The position of the radial pulse is then determined and a short incision is made on the volar aspect of the wrist, slightly proximal to the joint. Although we prefer a small transverse incision, some surgeons may ﬁnd it more useful to make a small longitudinal one. Using only a blunt hemostat, the tissues are dissected in a longitudinal manner and the artery is isolated and elevated out of the wound over a ligature. At least 1 cm of artery should be exposed to view. An appropriately sized trocar needle/cannula (Angiocath Arrow or similar product) is then preloaded with heparin solution (10 μ/ml). With proper traction on the distal ligature, the artery is straightened and is held relatively taut (stretching it too much will reduce its calibre and make the insertion more difﬁcult). With the bevel of the needle

pointing upwardly, the artery is punctured and the needle introduced a short distance. Care must be taken and visual inspection must ascertain that the artery is not punctured through-and-through. The sheath of the cannula is then advanced over the needle into the artery and the needle withdrawn. Back-ﬂow of arterial (pulsatile) blood assures successful cannulation. At these institutions, it is recommended not to tie the ligature around the artery in order to prevent occlusion of the artery following the removal of the catheter. Two skin sutures are placed on either side of the cannula, which are used both to approximate the skin edges and also secure the cannula in its position. Tincture of benzoin is then lavishly applied and an adherent plastic sheath (Tegoderm or Opsite) is placed over the protruding part of the catheter and the connecting cannula in order to further secure it to the patient. With proper care, these catheters can be maintained for a long period of time. The complication rate following surgical cannulation of the radial artery should not be much greater than those experienced by the percutaneous technique, except that there is a slight increase of the chance of wound infection for which precautions must be undertaken.

Pedal artery cannulation When the radial arteries are found unsuitable for intraarterial monitoring, the author has used the vessels of the lower extremities, namely the dorsalis pedis and posterior tibial arteries. The former lends itself to percutaneous catheterization, whereas the latter may require surgical cut-down. Of the two, we prefer the posterior tibial artery, since it takes a straight course and it is easy to identify and cannulate. It is located just posterior to the medial malleolus, between the malleolus and the achilles tendon. The technique of insertion of the cannula into either of these two arteries is quite similar to the one done in the radial artery, and the longevity and complication rate of these cannulas are similar too.

Axillary artery cannulation

Figure 10.3 Radial artery cannulation. Note the position of the hand and the direct puncture of the artery without a cutdown (a similar puncture technique is used in peripheral vein cut-down)

The axillary artery is rarely used by the cut-down technique and is reserved mostly for intraoperative monitoring of extremely ill babies. This is done in situations where the peripheral pulses are weak and the need for immediate intra-arterial access exists. We prefer not to maintain these catheters for longer than a few hours because of the threat to the extremity from vasospasm and/or embolization. The technique involves abduction of the arm beyond 90° and ﬁxation of the skin over the medial aspect of the upper arm. Percutaneous insertion is done in the upper half of the arm towards the axilla. The need for surgical exposure of the artery for insertion has never occurred in our practice and we would rather resort to femoral arterial cannulation.

124 Vascular access in the newborn

Femoral artery cannulation The indication for using this route is similar to the one of the axillary route, namely, extreme situations when peripheral circulation is poor and immediate access is necessary. In cannulating the femoral artery, we prefer to use a Seldinger technique (over a guide wire) to make sure that the insertion of the cannula is precise and is positioned in the iliac system. Again, because of threat to the lower extremity from spasm and/or embolization, we prefer to use this route only in extreme emergencies and for as short a period as possible.

VENOUS CATHETERIZATION Artiﬁcial cannulation of the venous system in babies has been available for nearly half a century. Great advancements in utilizing this modality have occurred in recent years with the introduction of non-ferrous (plastic) catheters. The short-term application of i.v. therapy in the newborn is achieved via umbilical vein catheterization or through percutaneous puncture of a peripheral vein. These, however, are a temporary modality when ﬂuids and electrolytes, blood products and the need for exchange transfusion and drug therapy are required for a relatively short duration. Percutaneous catheterization of major veins is occasionally done, especially when the baby is extremely ill and the peripheral vascular bed is contracted. When this fails, surgical exposure and cannulation of various veins may become necessary. Needless to say, for longterm usage, there is near-universal agreement that the surgical mode of introduction is preferred over the percutaneous route.

Percutaneous cannulation As mentioned earlier, percutaneous cannulation is usually undertaken for short-term usage – generally not to exceed 1–2 weeks. This is the most common method of introduction for babies undergoing emergency neonatal operation and those who require short-term i.v. ﬂuid support and/or drug therapy.

Umbilical vein Catheterization of the umbilical vein is rather commonplace in most nurseries and neonatal units, and it can be achieved by trained hands with a great degree of success. There is a time limitation beyond which the umbilicus is unsuitable for further cannulation and in such instances the clinician must resort to other routes. Most physicians agree that umbilical vein catheterization should not be maintained for a lengthy period of time for the fear of

inducting portal vein thrombosis. It is preferred to advance the tip of the catheter along the umbilical vein through the ductus venosus into the proximity of the right atrium. This will permit the administration of a concentrated i.v. solution and reduce the risk of thrombosis. Proper positioning of the catheters and verifying its position by means of radiographs is essential. The technique of this catheterization is a standard neonatal procedure and will not be discussed here. In our surgical practice, umbilical vein catheterization is used most frequently in newborn babies who require resuscitation and transport to our institution over a distance, and in whom ﬂuid administration must be assured throughout the transport. In hospital, it is most commonly used in babies requiring exchange transfusion for various medical reasons. At times, during a course of major abdominal operation, one may need to establish a large bove i.v. channel mostly for an exsanguinating situation. Direct cannulation of the umbilical vein as it courses along the falciform ligament may be a life-saving operation. For that reason, if the umbilical vein has to be divided during the onset of the celiotomy, the vein should be divided in its subumbilical origin, in order to keep a workable length of vessel before it enters the liver parenchyma.

Peripheral veins Here again, percutaneous cannulation is a standard neonatal practice which will not be elaborated upon here, except to mention that the most commonly used veins are the ones on the dorsum of the hands and feet, the scap veins and the antecubital veins. The longevity of percutaneous catheters, however, are known to be short lived and many cannot be maintained far beyond 1 week.

Major vein cannulation8–10 At times of urgent resuscitation or when a neonate is about to undergo a major operation and a large volume of ﬂuid and blood products may be required, we prefer to introduce a larger bore cannulae into a more proximal vein. In their order of usage, we employ the external jugular veins, the internal jugular veins, the femoral veins and the subclavian veins. In our daily practice, however, the distal saphenous vein has been successfully cannulated percutaneously in the majority of babies with a 20-gauge cannula. At times, the vein at the ankle is not always visible, but with prior knowledge of its anatomical location, ‘blind’ introduction can be accomplished. The external jugular vein is our next choice. The insertion here is facilitated by slight lowering of the baby’s head. The introduction may necessitate a guide wire technique if this is found to be difﬁcult. The ﬁxation and maintenance of the external jugular cannula

Surgical introduction 125

is somewhat awkward and it is to be considered only intermediate in its longevity. The internal jugular vein is usually catheterized percutaneously in emergency situations; however, the operator must realize again that the catheter cannot be maintained for more than 1–2 weeks in this position. The technique involving internal jugular cannulation and the anatomical landmarks for its insertion have been described and will not be mentioned here.11 In general, we do not like to cannulate the femoral vein except under extreme situations, since the hazards of thrombosis and infection are quite high and we reserve this technique for very short time use, mainly during resuscitative maneuvers.

Percutaneous central catheter Percutaneous central venous catheterization through a peripheral venous site has gained popularity in our neonatal units. It is done through cannulation of a medium-sized peripheral vein (scalp or antecubital) and threading through it a soft and ﬁne Silastic catheter which is ‘carried’ by the circulation to a central position. This can be achieved even in the severely premature infant and through this ﬁne catheter, not only total parenteral nutrition but also blood and blood products can be administered. The system we use is called Per-Q-Cath, which incorporates a 1.9 Fr. gauge (23 ga) Silastic Elastomere catheter. Repeated radiographs and great patience is required to lead the catheter tip eventually through the superior vena cava to a position near the right atrium. The infection rate is comparable to our surgically implanted catheters. The peculiar organism frequently seen infecting these catheters when they are used in longterm total parenteral nutrition (TPN) is Malassezia furfur. It is an organism which is rarely seen as an offender of other types of catheter. There is excellent long-term satisfaction with this system and it has virtually replaced the need for surgical insertion in the ordinary nursery patient.

SURGICAL INTRODUCTION Peripheral vein cut-down With the advent of improved cannulas for percutaneous peripheral venous insertion, we have found that the need for peripheral cut-down has markedly diminished and nowadays it is reserved mostly for those who have an acute blood or ﬂuid loss, both causing hypovolemia and peripheral venous constriction. At times, just prior to a major surgical maneuver, in order to ensure a large caliber cannula for rapid blood and/or ﬂuid replacement, we are called upon to utilize this technique. The preferred sites of cut-down in order of frequency are the greater saphenous, just above the middle malleolus at

the ankle, the brachiocephalic vein, just above the lateral condyle of the wrist, the veins of the antecubital fossa and the saphenous vein at its proximal position below the femoral canal.

PROCEDURE After proper immobilization of the extremity and thorough skin preparation with povodone–iodine, a small amount of local anesthetic is inﬁltrated at the site. A small transverse incision is then made and the dissection is carried with a hemostat, dissecting bluntly in a longitudinal manner. When the vein is isolated, it is encircled with a small caliber ligature and it is then dissected free to a distance of approximately 1 cm. With traction on the distal ligature, the vein is elevated and is straightened, such that direct puncture of the vein can then be accomplished with a proper cannula that is sheathed over a metal needle (AngioCath). Care must be taken to keep the puncture site tangential enough in order not to penetrate the vein through-and-through, and for that reason strong traction on the ligature must be avoided. Once the cannula is advanced a short distance, the needle is withdrawn and the catheter is then advanced to its full length. A syringe with saline is then utilized to inject the solution into the cannula to make sure that it is positioned properly in the venous system. When this is conﬁrmed, the cannula is afﬁxed in place with the previously placed ligature (we prefer an absorbable material). The skin is then closed on either side of the cannula utilizing silk or nylon material and the cannula is further afﬁxed to the skin site too. A small amount of povodone–iodine ointment is then applied to the wound and the whole wound is dressed with an adherent plastic material (Tegoderm or Opsite) and infusion begun. At times when the vein needs to be dilated in order to accommodate a larger caliber cannula, we place two ligatures around the vein proximally and distally and then perform a small transverse venotomy, which should not exceed one-third of the diameter of the vein. With the help of a catheter introducer, which opens the venotomy site and at the same time dilates it as it is introduced farther into the vein (by virtue of being wedge shaped), a larger cannula can then be introduced (Fig. 10.4). The care and maintenance of these peripheral cutdowns is similar to all other peripheral intravenous sites. Immobilization is a key to prolongation of its service. By and large, we have found that introduction by the cut-down technique does not prolong the longevity over the percutaneous mode.

Central venous catheterization Parenteral nutrition is claimed to be one of the major contributors to the ever-improving survival rates of

126 Vascular access in the newborn

Figure 10.4 Catheter-introducing device opens and dilates the venotomy for catheter introduction

premature infants and neonates. The administration of hyperosmolar solution of glucose and proteins necessitated its introduction into a central vein, where immediate mixing of the i.v. ﬂuids with a large volume of blood can be achieved. This requires the positioning of the tip of the cannula as close to the right atrium as possible and, in some instances, within the lumen of the atrium itself. Parenteral nutrition is offered not only to the severely premature infant and those with debilitating nutritional problems, but more and more as a preventive measure to avert the protein wasting associated with prolonged gastrointestinal malfunction. Whenever possible, we prefer to insert the central cannula in the operating room, in a sterile environment, under general anesthesia, and with the availability of ﬂuoroscopic X-ray apparatus. When we are asked to perform this procedure on premature babies in the neonatal intensive care nursery, it is usually done in the unit itself without utilizing general anesthesia.12

SURGICAL PROCEDURE The patient is positioned supine on the operative table and a small rolled towel is placed under the baby’s shoulders, such that the neck can be extended and rotated away from the operative site. The area is thoroughly prepared and draped as for a regular operation. Care must be taken to expose the entire chest, so that the catheter can be tunnelled adequately. A slight head-down (Trendelenberg) position is advantageous when possible. If the external jugular vein is prominent, we prefer to use this vein rather than the internal jugular. Some centers have preferably used the common facial vein as the site of introduction. A small transverse incision is made in the

region of the desired vein and the vein is exposed with a curved hemostat, using blunt dissection in a longitudinal manner. When the external jugular vein is utilized, we prefer to dissect it to a point slightly behind the clavicle to avoid the branches which may be present between the insertion site and the subclavian vein. In exposing the internal jugular vein, the sternocleidomastoid muscle is split longitudinally between its two heads and the vein is carefully separated and elevated, making sure not to injure or trap the vagus nerve. In severely premature babies with a thin subcutaneous layer, we use a noncuffed catheter, otherwise a Dacron cuff (Broviac) is selected. We like to premeasure the catheter on the baby’s surface to a position slightly above the line of the nipples. A subcutaneous tunnel of 2–3 cm is created, usually from a site selected for being ﬂat and somewhat out of the way. Tunnelling via a large-bore i.v. cannula has been described previously,12 but many operators prefer other devices or techniques. The catheter is then advanced under ﬂuoroscopic control and positioned at the junction of the superior vena cava and the atrium or in a high atrial position. Insertion through the internal jugular vein is straight and usually the catheter assumes its expected route. However, insertion through the external jugular vein may cause the catheter at times to ascend along the internal jugular vein rather than descend towards the heart. If the catheter persists in its misdirected route, it is advisable to rotate the patient’s head towards the site of insertion in order to angulate the junction between the subclavian and internal jugular vein in such a way as to favor a descent of the catheter towards the heart. We then secure the catheter with absorbable suture material to the vein, making sure that we do not impair the ﬂow of the ﬂuid within the catheter itself. Before closing the wound, care must be taken to ensure that there are no sharp angulations of the catheter in the subcutaneous site, such that it will kink and occlude the ﬂow. The wound is closed in two layers, except in the severely premature infant, in which a single layer closure is done. The catheter is additionally secured with a nylon suture at the skin exit site in order to prevent early dislodgement. We prefer to circle the catheter once on the anterior chest wall before afﬁxing it with a see-through adherent plastic sheath (Tegoderm or Opsite). At all times, attention must be paid to preventing air from entering the catheter and the vascular system for fear of systemic embolization (Fig. 10.5a–d).

Inferior vena cava cannulation As mentioned earlier, this route is reserved mostly to the acute situation when immediate resuscitation due to hypovolemia mandates large-volume infusion. There are times, however, when the venous access to the superior vena cava and its tributaries have been utilized, yet the

Surgical introduction 127

(b)

(a)

(c)

(d)

Figure 10.5 (a) Positioning of the baby for the operation: the neck extended and the head rotated away from the site of insertion. (b) Subcutaneous tunnelling of the catheter through the lumen of a large venous catheter. (c) After appropriate venotomy, the catheter is introduced into the vicinity of the right atrium. (d) The completed procedure

patient is in urgent need of i.v. parenteral nutrition. In such instances, we have had to resort to catheterization of the central venous system through the inferior vena cava. The insertion is done through the proximal-most portion of the saphenous vein, just prior to its entrance into the common femoral or, as some authors prefer, via the inferior epigastric vein in the lower abdominal region. The technique of insertion is similar in either case and subcutaneous tunnelling must be undertaken either towards the middle thigh for the saphenous vein or to the ﬂank area in the inferior epigastric insertion. The catheter should be advanced past the hepatic veins into the inferior portion of the right atrium proper in order to assure proper mixing. Since thrombosis of the inferior vena cava may carry with it some visceral consequences, it may be advisable to heparinize the solution and/or the patient lightly. In some pediatric surgical centers they prefer initially to utilize the inferior vena cava route, mentioned here, and with proper

tunnelling, wound care and heparinization have incurred low complication rates.

Azygos vein and right atrium catheterization In several children in whom all peripheral sources for catheterization have been used, we have utilized the azygos vein or the right atrium directly. These operations are more involved and are rarely needed in the newborn patient. The azygos vein is approached through a right fourth intercostal posterolateral thoracotomy carrying the dissection in the extrapleural space, as is done for the exposure and repair of oesophageal atresia. Since this approach may obliterate some of the superior vena cava collaterals, in many instances we resort to direct right atrial cannulation. For right atrial catheterization, a formal right thoracotomy is needed and the catheter is positioned through the atrial appendage after securing

128 Vascular access in the newborn

an appropriately sized purse-string suture. Because of the constant motion of the heart, it is advised to leave a small amount of slack in the line within the pericardial chamber in order to prevent premature dislodgment.

Direct subclavian catheterization Direct subclavian catheterization has been attempted in infants for some time, although only recently has it gained widespread acceptance. Recent literature reported encouraging results regarding the length of use and the incidence of infection in such an insertion. In our practice it is used mostly in the anesthetized baby, who is about to undergo a major surgical procedure. The miniaturization of various kits for this purpose, provide for a safe and relatively easy introduction. Most employ the standard Seldingers’ method of insertion over a guide wire.13,14

Central venous line maintenance The early use of central venous catheters was fraught with many severe complications. We soon came to realize that a designated nurse who is completely in charge of the day-to-day care of these catheters would signiﬁcantly reduce the frequency of expulsion and the rate of infection of these lines. Numerous authors have attested to the beneﬁt derived from having such a person in the pediatric institution. Utmost sterility in connecting and disconnecting the i.v. lines must be maintained at all times. Participants must wash their hands, glove and don a face mask when handling the site. The care of these patients is conducted in such a way as to minimize the interruption of the line itself. The entire i.v. administration system is changed once daily at the same time as a new solution is given. The dressing over the site is changed every 3 days, again by the designated central venous line therapist, who scrubs the area thoroughly with povodone–iodine and applies a sterile dressing to the site. Careful inspection of the skin surrounding the site is mandatory. In severely premature babies, because of the fragility of the epidermis, the see-through adherent plastic sheath (Tegoderm, Opsite) is applied in surgery and is changed less frequently, probably once every 10–14 days.

Complications Technical complications of catheter insertion have been greatly reduced with the attention to details and more so with the routine use of X-ray imaging of the catheter tip position. Cardiac arrhythmias are seen occasionally; most frequently they are due to irritation of the endocardium by the tip of the catheter and/or the chemical impact of the concentrated i.v. solution. Keeping the tip

of the catheter in the superior vena cava/right atrial junction will minimize this problem. Metabolic complications can be greatly minimized by attention to prescribed administration procedures and will not be discussed here. The two most commonly encountered complications nowadays pertain to thrombosis and infection.15–17 In past years, before the widespread usage of Dacron cuffed catheters, catheter expulsion was seen with some regularity (approximately 5% of the time). Biochemical changes should be monitored regularly and corrected.

Thrombosis Catheter tip thrombosis is a rather frequent occurrence which is hallmarked by the inability to withdraw blood freely from the catheter. When this happens, ultrasound or echocardiography often will depict thrombus formation. If there is difﬁculty or cessation of ﬂow in the catheter, the utilization of urokinase or streptokinase (50 μ/kg/hour) may be necessary. Because of concerns for the sources from which UK or SK are obtained, the FDA in the USA has issued a warning for their use. We have switched exclusively to the use of tissue plasminogen activator (TPA), which is by far a more expensive drug.14 Enough volume should be instilled to ﬁll the catheter totally to just beyond its tip. In most instances, successful declotting of the line can be achieved. Small clots, which under observation remain stable need not be a cause for catheter removal, especially in babies in whom TPN therapy is required for a long time. All efforts must be made to maintain the catheter even if anti-thrombotic therapy must be employed repeatedly. Occasionally, a premature baby will manifest ‘consumption coagulopathy’ due to rapid growth of the thrombus. In such a situation, removal of the catheter and, at times, heparin therapy, may be needed.

Infection Line infection and bacteremia or fungemia are by far the commonest cause for premature removal of catheters. This is particularly true in premature babies and in those who are severely stressed. Patients with altered immune states or those who have been on massive wide-spectrum antibiotics are the prime candidates for fungal infection (primarily Candida albicans). The most common offending bacterium in catheter infection is Staphylococcus epidermidis. Where, in the past, this organism was thought to be a mere contaminant, it is recognized nowadays as a true pathogen and should be therefore treated accordingly. In babies who must have a central line for support, i.v. antibiotic therapy with vancomycin is ordinarily curative. It is preferable, however, to remove the catheter, since this will promptly eradicate the infection. Other organisms have occasionally been

References 129

isolated from the catheter and, if they are signiﬁcantly pathogenic, it is advised to remove the catheter as well. Bacterial infection of the subcutaneous tissue surrounding the catheter exit site has also been seen. If the infection remains localized, topical measures and speciﬁc systemic antibiotics may, at times, eradicate the infection without the need for catheter removal. C. albicans fungemia from a catheter source ordinarily must be treated with removal of the catheter.18 A short course of amphotericin B may be added to patients with a compromised immune system. Candida is a frequent offender in the neonatal period in our experience. Embolization of a severed catheter has occurred only once in our experience, and, in that particular patient, pulmonary arteriotomy was necessary in order to retrieve the catheter.

CONCLUSION Improved vascular access in premature and newborn babies has opened new avenues for monitoring and treatment of these precarious patients. With careful attention to the details of insertion and proper maintenance techniques, the complications from these devices can be markedly reduced. The evolution of the modern care of neonates is dependent on further miniaturization of invasive tools, the establishment of sophisticated and sensitive instruments and the abilities of the clinician to assimilate all the new data to improve the care of the newborn meaningfully.

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16. 17.

18.

complications. Radiol Clin North Am 1999; 37(6):1109–25. Chiang VW, Baskin MN. Use and complications of central venous catheters inserted in a pediatric emergency department. Pediatr Emerg Care 2000; 16:230–2. Band JD. Infections caused by arterial catheters used for hemodynamic monitoring. Am J Med 1979; 67:735. Rodgers MC. Diagnostic Tests and technology for Pediatric Intensive Care. In: Pediatric Intensive Care, Baltimore: Williams and Wilkins, 1987:1406–10. Hughes WT, Buescher ES. Umbilical Vessel Catheterization, Exchange Transfusion and Phototherapy. In: Pediatric Procedures, Philadelphia: W.B. Saunders, 1980: 122–7. Sherman N. Umbilical artery cutdown. J Pediatr Surg 1977; 12:723–4. Morgan WW, Harkins GA. Percutaneous introduction of long-term indwelling vascular catheter in infants. J Pediatr Surg 1972; 7:538. Filston HE, Johnson DG. Percutaneous venous cannulation in neonates and infants. Pediatrics 1971; 48:896–901. Bagwell CE, Salzberg AM, Sonnino RE, Haynes JH. Potentially lethal complications of central venous catheter placement. J Ped Surg 2000; 35:709–13. Hall DM, Geefhuysen J. Percutaneous catheterization of the internal jugular vein in infants and children. J Pediatr Surg 1977; 12:719–22. Jona JS. Central venous hyperalimentation in the severely premature baby. In: Puri P, editor. Surgery and Support of Premature Infant Basel: Karger, 1985; 58–65. Goff DB, Ahmed N. Subclavian vein catheterization in the infant. J Pediatr Surg 1974; 9:171–4. Filston HC, Grant JP. A safer system for percutaneous subclavian venous catheterization in newborn infants. J Pediatr Surg 1979; 14:564–70. Grisoni ER, Mehta SK, Connors AF. Thrombosis and infection complicating central venous catheterization. J Pediatr Surg 1986; 21:772–6. Vane DW, Ong B, Rescorla FJ et al. Complication of central venous access in children. Pediatr Surg Int 1990; 5:174–8. Warner BW, Gorgone P, Schilling S. Multiple purpose central venous access in infants less than 1000 grams. J Pediatr Surg 1987; 22:820–2. Salzman MB, Rubin L. Intravenous catheter related infections. Adv Pediatr Infect Dis 1995; 10:37–368.

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11 Radiology in the newborn NOEL S. BLAKE

INTRODUCTION In recent years there have been great advances in surgical techniques, anesthesia and intensive care of the newborn. Imaging modalities have reached a high level of sophistication and the number and range of invasive and interventional radiology techniques has greatly increased also. All these advances have given rise to greater demands on pediatric radiology departments which should be well staffed, funded and equipped to keep up with these developments. It is essential that both conventional radiographic and high-technology imaging facilities be used efﬁciently and rationally. A sequence of investigations should be applied using ﬁrst the simplest and least invasive and irradiating examinations. These may provide the diagnosis before progressing to more complex, invasive and expensive studies, even if they are readily available. Duplication of information obtained from various imaging modalities without inﬂuencing management of the patient should be avoided.

(a)

CONVENTIONAL RADIOGRAPHY Examinations in the newborn should be directed to achieving the required information with the minimum of handling or disturbance, maintaining body temperature and employing measures to limit radiation. Only relevant projections should be obtained in relation to the clinical problem and condition of the baby (Fig. 11.1a,b). Rooms for examinations in newborns should be kept warm – around 80°F (27°C) – and the baby should be removed from the warm protective environment of the incubator for the shortest possible time. Measures to reduce radiation include the use of rare earth-intensifying screens in the cassettes and carbon ﬁber table tops to give lower exposures and shorter times. The beam should be collimated to cover only the area necessary and gonad protection with lead shields is extremely important. Good radiographic technique is

(b) Figure 11.1 Dorsal decubitus view for suspected perforation in necrotizing enterocolitis. (a) Position of baby in incubator for horizontal beam exposure. (b) Resultant radiograph conﬁrming free intraperitoneal gas below anterior abdominal wall. This was achieved with minimal disturbance to the baby

essential to produce radiographs of high quality and avoid the unnecessary extra irradiation and disturbance of babies entailed in repeat exposure.1 Sufﬁciently welltrained and experienced radiographic technicians should be available to ensure high standards.

132 Radiology in the newborn

PORTABLE EXAMINATIONS In recent years a great increase in demand for portable radiographic examinations has occurred. The position of i.v. catheters and endotracheal tubes needs to be checked often and frequent examinations may be required in infants with severe respiratory problems on ventilation.2 Portable X-ray machines have become smaller, more maneuverable and give shorter exposure times. Very good radiographs can now be obtained in critically ill or premature neonates in intensive or special care units without removing them from their incubators. This protects them from heat loss and allows minimal handling. It follows that incubators chosen for special or intensive care baby units should be user-friendly for radiography. A good example of not adhering to the earlier mentioned guidelines is in the case of taking inverted lateral radiographs for anorectal anomalies. The baby is removed from the incubator and held upsidedown by the legs while the exposure is taken. Even apart from the trauma to the infant, it is difﬁcult to obtain a good true lateral view centered at the correct level. A prone lateral view with the buttocks elevated and using a horizontal X-ray beam is a far superior technique. The baby can be left comfortably in this position for a prolonged period to ensure that gas outlines the distal limit of the blind rectal pouch (Fig. 11.2). Lateral decubitus views of the chest or abdomen are readily performed with a horizontal beam, leaving babies in their incubators. Erect views to show pneumothorax or pleural effusion, or to demonstrate ﬂuid levels in dilated bowel loops or free intraperitoneal gas should no longer be necessary.

available as well as a fully equipped resuscitation trolley. Procedures should be carried out quickly but carefully. A satisfactory i.v. infusion should be ensured before commencing any invasive or interventional technique. Developments in computerized digital ﬂuorography in recent years have resulted in the potential for a marked reduction in radiation exposure, more rapid performance of dynamic contrast studies and greatly improved recorded images.3 Digital ﬂuoroscopy units also have the facility to provide a rapid series of exposures up to 8/second. This can be very useful in studies of the swallowing mechanism or of the airway. These images can be obtained with a multiformat camera from videotape recordings of the examinations. Some installations provide image enhancement, processing and digital subtraction facilities, which can be very useful in angiography. Advances in contrast media have occurred in recent years with the development of water-soluble non-ionic media. Such contrast agents can be used with increased safety intravenously, intrathecally for myelography and for gastrointestinal examinations to exclude leakage or obstruction. In cases with suspected aspiration, a nonionic medium can be used safely. By dilution, an isoosmolar solution can be achieved for even greater tolerance in the airway. A good example of this would be in a bolus injection in the upper esophagus in H-type tracheo-esophageal ﬁstula (Fig. 11.3).

FLUOROSCOPIC EXAMINATIONS For investigations in neonates the ﬂuoroscopy room should be warm, with oxygen and suction outlets readily

Figure 11.2 Newborn with imperforate anus in prone position in incubator, with buttocks elevated for lateral view with horizontal beam

Figure 11.3 Prone lateral radiograph of bolus injection in esophagus to demonstrate H-type tracheo-esophageal ﬁstula. Non-ionic contrast diluted to achieve almost iso-osmolar solution was used

Ultrasonography 133

ULTRASONOGRAPHY This relatively inexpensive imaging modality has transformed neonatal diagnosis, especially since readily portable, high-resolution, real-time units were developed. In premature or severely ill babies, sonography can be performed satisfactorily without removing them from their incubators. The principles of minimal handling and maintenance of body temperature apply. Examinations should be carried out efﬁciently to achieve a diagnosis and not aimed at producing ‘pretty pictures’. Antenatal diagnosis of surgical conditions is being made by obstetric sonographers with increasing frequency worldwide.4 Lesions such as hydrocephalus and spina biﬁda can be recognized, as well as cystic or obstructive renal disease and intestinal tract obstructions (Fig. 11.4). Abdominal wall defects such as exomphalos and gastroschisis can be demonstrated in utero also. When diaphragmatic hernia is diagnosed antenatally on sonography, the birth can be arranged in or close to a major pediatric surgery center. Antenatal interventional techniques have been developed recently using ultrasound guidance, e.g. the insertion of stents or to drain obstructed urinary tracts. Cranial sonography is now an integral part of any department dealing with newborn patients. Using realtime sector probes of high frequency, images of excellent detail are obtained. Hydrocephalus is accurately diagnosed and graded using sonography, and serial examinations are helpful in relation to the need for shunting.

Figure 11.4 Antenatal ultrasound image demonstrating duodenal atresia with distended stomach and duodenum (Courtesy of M. El Shaﬁe, Toledo)

One of the most important contributions of highresolution sonography is in the diagnosis and grading of intraventricular hemorrhage (IVH). Early diagnosis of minimal lesions can be achieved in infants at risk. The discovery of IVH can inﬂuence the decision to operate on a newborn with a congenital malformation if IVH is severe (Fig. 11.5). Sonography has a role in the investigation of mass lesions in the neck and mediastinum. Localization, delineation, relationship to surrounding structures and especially differentiation of cystic from solid lesions are the main features achieved (Fig. 11.6). Real-time sonography can be ideal for diagnosing lesions around the diaphragm, including phrenic nerve paralysis. Abdominal sonography is most frequently carried out in the newborn to diagnose or exclude renal disease. Lesions conﬁned to the kidneys include multicystic dysplastic kidney, polycystic disease and hydronephrosis due to obstructions at pelvi-ureteric, uterovesical or urethral valve levels. All these lesions are readily diagnosed with sonography, and severity of obstruction and renal damage can be indicated also. The kidneys are frequently involved in complex syndromes, e.g. VATER syndrome. The spectrum of renal anomalies varies from agenesis (Fig. 11.7) to crossed fused ectopic and duplex kidneys. In space-occupying lesions of the abdomen, sonography should be the ﬁrst investigation. It will differentiate cystic from solid lesions and will frequently give the complete diagnosis, e.g. congenital mesoblastic nephroma, or give a clear indication of the next logical examination. In neonatal jaundice, sonography has a role complementary to that of radionuclide imaging and may give the complete diagnosis, e.g. choledochal cyst. It can certainly demonstrate or exclude dilatation of the biliary duct system (Fig. 11.8).

Figure 11.5 Coronal section of baby with multiple surgical problems relating to VATER syndrome. Severe bilateral IVH is shown; this inﬂuenced surgical management, as there was complex congenital heart disease

134 Radiology in the newborn

(a) Figure 11.7 Renal agenesis. Absence of echo pattern of right kidney in transverse prone sonogram. There was no evidence of an ectopic kidney and absence was conﬁrmed on T-cells–DTPA scan

(b) Figure 11.6 Mediastinal bronchogenic cyst. (a) Chest ﬁlm showing mass in the left superior mediastinum. (b) Ultrasound section demonstrates echo-free cystic lesion

The development of Doppler, duplex Doppler imaging and, more recently, color ﬂow Doppler imaging has been a considerable advance. Doppler studies may have widespread application, e.g. cranial,5 and in intestinal hemodynamics in relation to potential necrotizing enterocolitis.6 In regard to surgical lesions in the newborn, the facility for vascular mapping can be very useful in abdominal masses or in arteriovenous malformations in any site.

Figure 11.8 Longitudinal ultrasound section demonstrating dilated biliary ducts in obstructive jaundice with large choledochal cyst

Recently, a role for color Doppler imaging has been described in cranial neurosurgical procedures intraoperatively.7

NUCLEAR MEDICINE With the great advances in ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI), fewer radionuclide examinations are carried out in major centers now. Functional rather than morpho-

Computed tomography 135

logical studies are usually required. Total and individual renal function can be accurately assessed, but imaging is less clear than in the older infant or child. Technetium DTPA for dynamic scanning is more frequently used and technetium DMSA is for static scans, to demonstrate renal parenchymal function. Hepatobiliary scintigraphy using technetium with derivatives of iminodiacetic acid (IDA) is the deﬁnitive investigation in neonatal jaundice. Excretion is enhanced if phenobarbital is used for 3 days before the examination. This test should differentiate between biliary atresia and other obstructive lesions, and neonatal hepatitis (Fig. 11.9). If the biliary tract is patent, the passage of isotope into the intestine is usually detected within 30 minutes. Imaging with gallium citrate or indium-labeled leucocytes for deep-seated abscesses would very rarely be required in the newborn. Such lesions should usually be detected with ultrasound or CT. Isotope bone scanning can be unreliable in neonatal osteomyelitis and septic arthritis. It is rarely performed in the newborn, but may be used to demonstrate widespread metastases in neuroblastoma. Iodine-131 metaiodobenzylguanidine (MIBG) is now an established isotope which is accumulated in neuroblastoma and other neural tumours. It demonstrates metastases as well as the primary tumour and would be useful in follow-up to assess response to therapy.

COMPUTED TOMOGRAPHY Computed tomography has become an established and vital imaging modality with broad application in the

Figure 11.9 Neonatal jaundice. Technetium HIDA scan demonstrating complete obstruction of common bile duct and accumulation of isotope in choledochal cyst (same case as Fig. 11.8)

newborn and should be available on site in any specialized pediatric unit. Sharp, clear images with high resolution, giving excellent anatomical detail, are achieved with the latest generation of CT scanners. Other features include reduced acquisition times with exposures even less than 1 second, and reduction of artifacts.8 However, radiation dose remains a disadvantage and CT should be reserved in the newborn for speciﬁc indications where sonography or conventional radiography provide insufﬁcient information. For complex cerebral lesions (Fig. 11.10), CT can be deﬁnitive but, if available, MRI now provides greater detail in the brain and spinal cord. Tumors in the neck, chest and abdomen can be fully evaluated with CT, giving accurate staging of malignant lesions and demonstrating metastases. Response of tumors to therapy can also be monitored accurately.9 Examinations should be carefully monitored and technique directed to the individual patient requirement. Oral and i.v. contrast should be employed where indicated and the facility to use alternatives to the standard axial projection may be availed of. Sagittal reconstruction images or direct sagittal or coronal sections may give optimal demonstration of lesions prior to surgery. In esophageal atresia, direct sagittal CT can demonstrate associated tracheo-esophageal ﬁstula and give accurate measurement of the gap between the esophageal segments.10 The baby is placed transversely in the opening of the CT gantry. It follows that a wide opening is advisable in a pediatric CT unit. In anorectal anomalies, a useful role for CT has been described in lesions of equivocal level in relation to the puboccygeal line.11 The method involves selected axial slices and coronal reconstructed images to give the exact level of the blind rectal pouch and also to display the muscle complex of the pelvic ﬂoor.

Figure 11.10 Axial CT brain scan showing gross ventricular distension and distortion. Note dense calciﬁcation in left parieto-occipital region consistent with the clinical diagnosis of toxoplasmosis. The calciﬁcation was not detected on sonography due to proximity to bone

136 Radiology in the newborn

MAGNETIC RESONANCE IMAGING In the relatively short time since the ﬁrst reports of its use in pediatrics appeared, MRI has improved dramatically. Anatomical sections of the body can now be displayed in multiple planes with excellent detail and without ionizing radiation. These are great advantages, especially in pediatrics.12 Recent developments have resulted in shorter acquisition times and smaller magnets of low ﬁeld strength, which are cheaper to buy, install and operate. Open magnets have been developed, giving easier access for manipulation of tubes or lines, and for resuscitation if necessary. In brain imaging, MRI exploits the 14% difference in water content between gray and white matter to demonstrate them much more clearly.13 The latest MRI scanners give exquisite detail in imaging the brain14 (Fig. 11.11) and spinal cord, for which it should be the investigation of choice for suspected space-occupying lesions. Myelography should rarely be necessary for spinal lesions if MRI is available as a non-invasive, radiationfree investigation (Fig. 11.12). In malignant masses in the thorax, abdomen or pelvis, the lesions can be characterized and accurately staged with MRI (Fig. 11.13). Recently antenatal ultrasound and MRI diagnosis of mesoblastic nephroma was described by Irsutti et al. Optimal demonstration was achieved in the coronal plane.15 Response of tumors to therapy can be more frequently monitored with safety using MRI than CT due to radiation exposure. Contrast enhancement of lesions using gadolinium DTPA is now well established. This can be excellent for detecting and characterizing intracranial lesions and tumors of the spinal cord.17 However, there would be limited application of this technique in the newborn in whom brain and spinal cord tumors are rare. Magnetic resonance spectroscopy is a non-invasive and non-irradiating technique with exciting potential. It

Figure 11.11 MRI axial brain scan. Hydrocephalus is shown with marked distension of posterior horns of lateral ventricles

Figure 11.12 Sagittal MRI section demonstrating myelomeningocele and almost entire spinal cord

Figure 11.13 Metastatic sacrococcygeal teratoma. Sagittal T2-weighted image deﬁnes intramedullary tumor expanding the spinal cord at thoracolumbar level

Interventional techniques 137

can be used to measure relative metabolite concentrations in vivo.18

INTERVENTIONAL TECHNIQUES A marked increase has occurred in recent years in the number, range and complexity of interventional procedures in pediatric as well as adult radiology practice. In the gastrointestinal tract, the reduction of intussusception by barium enema or air insufﬂation is long established. However, this is a rare condition in the newborn. The reduction of meconium ileus by Gastrograﬁn enema has been practiced for four decades now and the typical plain ﬁlm and contrast ﬁndings are well known. However, it is worth stressing that complications such as volvulus, peritonitis and perforation must be excluded before a Gastrograﬁn reduction is attempted. The ﬂuoroscopy room should be warm and an i.v. drip must also be checked. In some centers the Gastrograﬁn is diluted with saline to reduce its potential toxicity. The current author prefers to induce full-strength Gastrograﬁn to reﬂux through the ileocecal valve and then follow it with normal saline.19 This permits the full effect of the hypertonic contrast with good imaging in ileal loops while limiting the colonic concentration and total volume of Gastrograﬁn (Fig. 11.14). Balloon catheter dilatation of esophageal strictures in neonates following anastomosis for esophageal atresia is now established in major centers worldwide. The advantages of balloon dilatation over bougienage relate to marked reduction in shear force with radial force

mainly achieving the dilatation.20 An interventional role can apply in imperforate anus of equivocal level. A high or low anomaly is usually categorized with a combination of clinical inspection and plain radiographs, including a horizontal beam lateral view with buttocks elevated. However, an anomaly may appear to be high, with gas well above the pubococcygeal line without any clinical stigmata to support this, such as associated anomalies or sacral dysplasia (Fig. 11.15a,b). An un-

(a)

(b)

Figure 11.14 Gastrograﬁn enema in meconium ileus. Impacted meconium is shown in ileal loops with full concentration of contrast. Normal saline gives washout effect in rectum and distal colon

Figure 11.15 Percutaneous proctogram. (a) In prone lateral ﬁlm with buttocks elevated, gas appears to be arrested well above the pubococcygeal line. Note normal sacrum and there were no other anomalies except imperforate anus. (b) Contrast injected through cannula inserted into rectum has gravitated in lateral erect ﬁlm, conﬁrming a low rectal anomaly and avoiding an unnecessary colostomy

138 Radiology in the newborn

necessary colostomy can be avoided in some of these cases by performing a percutaneous proctogram. A cannula is inserted through the anal region under ﬂuoroscopic control and advanced anterior to the upper sacrum with the baby in the lateral position. Then 5 ml of water-soluble contrast is injected, followed by an erect lateral radiograph. The contrast gravitates and outlines the exact limit of the blind rectal pouch. An associated ﬁstula can also be demonstrated. Balloon dilatation of colonic strictures complicating necrotizing enterocolitis is another established interventional procedure. Percutaneous gastrostomy and placement of a feeding tube in the jejunum is a further useful technique being practiced in many centers. In urinary tract obstruction, percutaneous nephrostomy to relieve the obstruction is widely practiced and is ideally performed under ultrasound control. A single stab technique should be used and a pigtail catheter containing a long needle and stilette can be introduced directly now without using a guide wire. The sharp echo of the needle is readily identiﬁed as it is guided into the dilated collecting system (Fig. 11.16). The performance of biopsies of organs or lesions under ultrasound, ﬂuoroscopic or CT guidance is not strictly interventional, but the aspiration or drainage of abscesses or cysts certainly is. In general, ultrasound is more simple and cheaper to use and avoids irradiation. The role of imaging specialists in procedures involving treatment or inﬂuencing management of patients is rapidly expanding. These techniques often reduce discomfort and morbidity. Hospital stay is frequently shortened and interventional procedures tend to be much more cost-effective than the alternative conventional surgical approach.

Figure 11.16 Percutaneous nephrostomy in congenital pelviureteric obstruction. Note sharp bright echo of needle in grossly dilated renal pelvis

REFERENCES 1. Gyll C, Blake NS. Paediatric Diagnostic Imaging, London, Heinemann, 1986: 44–62. 2. Narla LD, Hom M, Loﬂand GK et al. Evaluation of umbilical catheter and tube placement in premature infants. Radiographics 1991; 11(5):849–63. 3. Wesenberg RL. Limiting radiation exposure a boon to paediatric imaging. Diagn Imag 1987; 5:138–43. 4. Cohen HL, Haller JO, Gross B. Diagnostic sonography of the foetus: a guide to the evaluation of the neonate. Pediatr Ann 1992; 21(2):87, 91–6, 98–9. 5. Raju TN. Cranial Doppler applications in neonatal critical care. Crit Care Clin 1992; 8(1):93–111. 6. Van Bel F, Van Zweiten P, Guit GL et al. Superior mesenteric artery blood ﬂow velocity and estimated volume ﬂow: duplex Doppler ultrasound study of preterm and term neonates. Radiology 1990; 174:165–9. 7. Barr LL, Babcook DS, Crone KR et al. Colour Doppler US imaging during neurosurgical and neuroradiologic procedures. Radiology 1991; 181(2):567–71. 8. Zimmerman RA, Gusnard DA, Bilaniuck LT. Paediatric craniocervical spinal CT. Neuroradiology 1992; 34(2):112–16. 9. Eggli DK, Close P, Dillon PW, Umlauf M, Hopper KD et al. Mesoblastic nephroma. Paediatr Radiol 2000; 30:147–50. 10. Tam PKH, Chan FL, Saing H. Diagnosis and evaluation of oesophageal atresia by direct sagittal CT. Paediatr Radiol 1987; 17:68–70. 11. Krasna IH, Nosher JL, Amorosa JL et al. Localisation of the blind rectal pouch in imperforate anus with the CT scanner. Paediatr Surg Int 1988; 3:114–19. 12. Harwood-Nash. MRI and pediatric neuroradiology: a present perspective. Eur Radiol 1991; 1:3–18. 13. Smith FW. The value of NMR imaging in paediatric practice. Paediatr Radiol 1983; 13:141–7. 14. Christophe M et al. Early MR detection of cortical and subcortical hypoxic-ischaemic encephalopathy in fullterm infants. Pediatr Radiol 1994; 24:581–4. 15. Irsutti M, Puget C, Baunin C, Duga I, Sarramon MF, Guitard J et al. Mesoblastic nephroma. Paediatr Radiol 2000; 30:147–50. 16. Stack JP, Antoun NM, Jenkins JP et al. Gadolinium – DTPA as a contrast agent in magnetic resonance imaging of the brain. Neuroradiology 1988; 30(2):145–54. 17. Rothwell CI, Jaspan T, Worthington BS et al. Gadolinium enhanced magnetic resonance imaging of spinal tumours. Br J Radiol 1989; 62:1067–74. 18. Hope PL, Moorcraft J. Magnetic resonance spectroscopy. Clin Perinatol 1991; 18(3):535–48. 19. Blake NS. Radiological and procedures. In: Gyll C, Blake NS, editors. Paediatric Diagnostic Imaging. London: Heinemann, 1986: 80–2. 20. McLean GK, LeVeen RF. Shear stress in the performance of oesophageal dilation: comparison of balloon dilation and bougienage. Radiology 1989; 172:983–6.

12 Immune system of the newborn DENIS J. REEN

INTRODUCTION The immune system, just like the endocrine and neural systems, is a major inducible biological response system. Its function is to protect the host against pathogenic attack. Nowhere during our entire lifespan are we subjected to more foreign antigenic stimuli for the ﬁrst time than during the early neonatal period, when the newborn passes from the relatively protected environment of the womb to the hostile world of pathogens. The newborn’s immune defense system is therefore a vital response mechanism essential for its protection in the new environment in which it ﬁnds itself. The human neonate, especially those born prematurely, is highly susceptible to serious infections with bacterial, viral and fungal pathogens, including some which do not ordinarily cause systemic disease in immunocompetent older children and adults. Neonates have increased morbidity and morality from bacterial infections, with the incidence of severe infection rising sharply in extremely premature newborn infants weighing less than 1500 g.1 Neonatal sepsis may account for as many as 30% of neonatal deaths.2 The onset of sepsis and meningitis occurs within the ﬁrst 10 days of life in 75% of term infants and 90% of preterm infants.3 The mortality rate from neonatal microbial sepsis varies between 30% and 50%, depending on the organism, immunocompetence of the host and associated complications present at diagnosis.4,5 This reduced capacity of neonates to deal with a variety of infectious agents has been attributed to the relative immaturity of their immune system.

IMMUNE RESPONSES The basis of an adequate immune response resides in the capacity of individual cells of the immune system to recognize and react to the myriad antigens with which we are in continuous contact. The hemopoietic system of pluripotent stem cells is the source of all the major cell

types, which are involved in the immune response. These cells include various lymphocyte sub-sets, macrophages, natural killer cells, monocytes and polymorphonuclear leukocytes. These cells are involved in a complex regulatory network of cell interactions which constitute an immune response, and whose function is to eliminate both self-aberrant molecules and cells, as well as to protect the host from microbial attack. Lymphocyte development occurs along two distinct pathways leading to the production of the two major lymphocyte populations, T-cells and B-cells, which have very different biological effector functions. The thymus is the site of development of T-cells, which are responsible for the range of effector functions collectively termed cellmediated immunity. Cell-mediated immunity ranges from the release of soluble factors such as cytokines, which regulate the activity of all cells of the immune system, to direct cytopathic effect of cytotoxic lymphocytes on viruses or tumor cells. B-lymphocytes, on the other hand, have a more restricted effector function, conﬁned to the synthesis and secretion of humoral antibodies in each of the immunoglobulin classes, IgG, A, M, D and E. More recently, B-lymphocytes have been shown to be capable of presenting antigen to T-cells.6 In man, the site of synthesis of B-lymphocytes is the bone marrow. The different regulatory and effector functions mediated by cells of the immune system represent the capabilities of populations of cells that can be recognized by the presence of different patterns of expression of cellsurface antigens. The availability of monoclonal antibody reagents for the recognition of lineage, differentiation stage, activation phase and effector function of different cell types has contributed enormously to our understanding of the extent of heterogeneity of different cell types within the immune system. This heterogeneity of cell types forms the basis for an international leukocyte typing classiﬁcation system (CD), utilizing monoclonal antibodies which recognize speciﬁc cell-surface markers in order to deﬁne individual leukocyte subsets.7 The more widely used CD antigens, for classifying immune effector cell types, are described in Table 12.1.

140 Immune system of the newborn Table 12.1 Cell surface antigens which identify leukocyte subtypes in the newborn Antigen

Function

T-cells CD2 CD3 CD4 CD5 CD7 CD8

LFA-3 receptor (adhesion) Associated with cell receptor Class II and HIV receptor Co-stimulatory Unknown Class I receptor

B cells CD19 CD20 CD21 CD72

Signal transduction Unknown C3d and EBV receptor (CR2) Ligand for CD5

NK cells CD16 CD56 CD94

IgG receptor (FcRIII) Isoform of N-CAM Unknown

Myeloid/monocytic cells C14 Unknown C15 Unknown CD32 IgG receptor (FcRII) CD35 C3b receptor (CRI)

It is now well established that T-lymphocytes do not recognize native antigen on any pathogen, but rather a processed form of the antigen, in association with self major histocompatibility antigens (MHCs), class I (HLAA,B,C) or class II (HLA-DR/Ia) molecules.8,9 This important processing of foreign antigen is carried out by one of a group of antigen-presenting cells which include macrophages, dendritic cells, Kupffer cells and some Bcells. The proper functioning of these accessory cells is therefore as central to an adequate immune response as that of speciﬁc effector cells, such as the T-lymphocytes. When antigen becomes localized and processed by the antigen-presenting, cell (APC), the complex interaction of APC, T-cells and B-cells begins, which eventually leads to speciﬁc immunological memory, both of T-cells and B-cells as well as to antibody production. Although B-cells can be directly activated by antigen, under experimental conditions, concomitant activation of T-cells is required for the clonal expansion of antigen-speciﬁc B-cells, leading to the generation of long-lived memory B-cells and immunoglobulin-secreting plasma cells.10,11

Cytokines As well as the series of cellular interactions of the immune response, there exists a range of soluble factors, most of them products of lymphoid cells that are critical to the proper functioning of an immune response. Among the major molecular components of the immune

system are the immunoglobulins, cytokines and proteins of the acute phase response and complement system. While immunoglobulin and complement have long been recognized as potent effector molecules of the immune response, the realization that the whole family of cytokine peptides are important regulators of the immune system has only more recently been recognized. The term ‘cytokine’ is used to describe a group of peptides with potent immunoregulatory effects, which are produced and utilized, by individual cells of the immune system, to communicate with each other and to control the environment in which they operate. A description of some of the major characterized cytokines is listed in Table 12.2. Present evidence suggests that cytokines are of immense importance in controlling both local and systemic immune responses, inﬂammation and the regulation of hemopoiesis.12,13 Their most important function appears to be at local level, modulating the behavior of adjacent cells in a paracrine fashion,13 or the cells that secrete them, in an autocrine fashion.14 In addition, especially in the case of TNF-α, IL-1 and IL-6, cytokines may effect endocrine-like activity on distant organs or tissues.15 Cytokines have important biological activity which can be of major clinical beneﬁt, such as stimulation of antimicrobial function, promotion of wound healing and myelostimulation.16,17 With such diverse biological function, an exaggerated or prolonged secretion of these peptides may be detrimental for the host. Speciﬁcally, aberrant secretion of cytokines, such as TNF-α and IL-1, are thought to be responsible for the hemodynamic changes in the host during septic shock and in cachexia of chronic disease.18,19 The availability of recombinant DNA techniques to produce cytokines in almost unlimited quantities and the production of speciﬁc antagonists such as soluble cytokine receptors and IL-1 receptor antagonists, are leading to new and exciting therapeutic potential for these molecules. It is beyond the scope of this chapter, however, to discuss in great detail the enormous complexity of immune regulation ranging from antigen recognition to speciﬁc immune competence to acquired tolerance. However, the basic principles described earlier are fundamental to the proper functioning of the immune response in the newborn.

T-cell responses Many components of the neonate’s immune system are compromised at birth. Several studies in the literature have questioned the stage of maturity of circulating lymphocytes in the newborn. Some parameters of T-cell function in cord blood, however, have been shown to be normal or similar to those of healthy older children. These include the quantity and proportion of Tlymphocytes,20 lymphocyte response to mitogens,21 and

Immune responses 141 Table 12.2 Cytokines Name

Principal cellular source

Principal cellular target

IL-1α+β IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-8 IL-10 IL-12 IL-13 TNF-α TNF-β IFN-α IFN-β IFN-γ TGF-β GM-CSF

Macrophages, ﬁbroblasts, endothelial cells T-cells T-cells T helper cells T helper cells Fibroblasts Stromal cells Macrophages T-cells, activated monocytes Macrophages T helper cells Macrophages, ﬁbroblasts T-cells Macrophages, ﬁbroblasts Fibroblasts T-cells, NK cells T-cells, macrophages, platelets T-cells, endothelial cells

Thymocytes, endothelial cells, neutrophils, T-cells, B-cells T-cells, B-cells Multipotential stem cells T-cells, B-cells, mast cells, macrophages B-cells, eosinophils B-cells, ﬁbroblasts, hepatocytes B-cells Neutrophils T-cell subsets, macrophages T-cells, NK cells B-cells Many cells type Many cells type Many cells type Many cells type Macrophages, T-cells, B-cells Many cell types Multipotential stem cells

production of certain cytokines such as IL-2.22 However, other newborn cellular immune functions have been reported to be depressed. These include, PHA-induced cytotoxicity,23 lymphotoxin production24 as well as reduced cAMP levels.25 The literature, however, would also appear to contain a number of contradictions with respect to reporting many aspects of immune function in the newborn. Such contradictions, which are not uncommon in describing immune function in clinical disease, often arise from the diversity of analytical approaches to quantifying the immune response. There are some studies which have suggested that the percentage of T-lymphocytes in the newborn period is signiﬁcantly lower 1 day and 5 days after birth, compared to adult levels.26 However, the lymphocyte subsets attain normal distribution values by 20 days of age. While lymphocyte responsiveness to mitogens such as PHA has been shown to be equal to that of adult values in the newborn, spontaneous lymphocyte blastogenesis of newborn lymphocytes is signiﬁcantly greater than that of adult lymphocytes.26 This probably reﬂects an ongoing in vivo immune responsiveness in the newborn to its new antigenic environment following delivery. Premature infants of very low birth weight, have signiﬁcantly reduced mitogen responsiveness.27 The autologous mixed lymphocyte response or the proliferative response to mitogenic antibodies such as OKT3 (CD3) monoclonal antibody is diminished in newborns.28,29 There is also evidence, however, that cord blood T-cells can respond to antigens such as Candida and streptokinase to which the mother has been sensitized, as well as reports of fetal reactivity in the absence of a maternal response.30,31 This suggests that the newborn may be sensitized to antigen in utero. Newborn infants, immunized with BCG, are

capable of manifesting delayed-type hypersensitivity responses on subsequent tuberculin skin testing.32 The overall characteristic that distinguishes newborn T-cells from other T-cells at different stages of development is that they are recent thymic emigrants, not long after exiting the thymus.33

Lymphocyte phenotype Functional aberrations of the T-cell system of the newborn have also been characterized using monoclonal antibodies to cell-surface antigens of the CD system of lymphocyte determinants (see Table 12.1). Lymphocyte phenotyping has been used to identify major T-cell proﬁle differences in the newborn compared to adults. There has been a reported incidence of up to 25% of cord blood lymphocytes co-expressing both CD4 helper T-cell and CD8 suppressor T-cell surface markers.34 Cells of this double positive phenotype are common in the thymus, where they are considered to be the precursors of mature helper and suppressor T-cells. However, more recently, using more sensitive ﬂow cytometry-based analytical techniques, workers investigating cord blood samples failed to detect the presence of doubly labelled CD4/CD8-labelled cells.35 Other markers of an immature phenotype of newborn T-cells have been described. The CD38 antigen, which is a marker of immature thymus-derived T-cells, as well as activated lymphocytes, is present in the majority of newborn cord blood lymphocytes.36 This thymocyte-like membrane phenotype can be modulated by the inﬂuence of thymic hormones in vitro.37 In addition to the presence of CD38 thymocyte-associated antigen,

142 Immune system of the newborn

human cord blood contains T-cells of the unusual phenotype which include peanut agglutinin-positive/ CD8-positive as well as some CD3-positive CD1apositive lymphocytes.38 Like CD38, CD1a is a marker present on early thymocytes.38 CD1a-positive cells are especially present in preterm and antenatally stressed infants.39 While the neonate has adequate numbers of CD4 helper T-cells, cord blood T-cells are deﬁcient in their ability to provide help for antibody production, probably at the level of altered cytokine production.40,41 The cellular basis for this functional defect is reﬂected in other phenotypic markers of functional activity. More than 90% of cord blood T-cells carry the CD45RA+ ‘virgin’ cell phenotype marker, compared with 50% of adult T-cells which express CD45RA+.42 In contrast, less than 10% of cord blood lymphocytes express the CD45RA− ‘memory’ T-cell marker compared to a 50% level of expression in adult T-cells.43 This major imbalance in the ratio of CD45RA+/CD45RA−, CD4positive T-cells in the newborn compared to adults may help explain some of the functional differences of newborn cells compared to adult lymphocytes. Regulatory factors contributing to the differences in functional activity and the different phenotypic proﬁles of newborn T-cells compared to adults require further investigation in order to arrive at a fuller understanding of the mechanisms involved.

B-cell responses The newborn’s capacity to produce antibody is signiﬁcantly reduced, both quantitatively and qualitatively, compared to that of an adult. Newborn B-lymphocytes poorly differentiate into immunoglobulin-producing cells.44,45 The mechanisms controlling this aspect of B-cell immunocompetence in the newborn is unknown. Many studies have focused on the ability of cord blood lymphocytes to terminally differentiate into IgG-, IgA- and IgM-producing plasma cells in response to mitogens. However, a delay occurs in B-cell differentiation, resulting in decreased production of plasma cells, markedly diminishing the secretion of antibody, and restriction of secreted antibody to IgM isotype.46 Cord blood Blymphocytes, unlike adult B-cells, usually are unable to differentiate into immunoglobulin plaque-forming cells when cultured with pokeweed mitogen alone, or with killed Staphylococcus aureas Cowan 1 alone.47 However, it appears that these two stimuli can act synergistically to induce a signiﬁcant in vitro plaque-forming cell response in cord blood B-cells. The relative inadequacy of IgG and IgA antibody synthesis cannot be attributed to the lack of precursor Bcells, since lymphocytes bearing these immunoglobulin classes on the surface are present in the fetus and on cord blood B-cells.48,49 The impaired capacity to undergo IgG or IgA synthesis has been attributed to immaturity of

cord blood B-cells, since their activation by polyclonal activators, like pokeweed mitogen, lipopolysaccharide or Epstein–Barr virus, generally results in moderate or reduced levels of IgM synthesis with no IgA, IgG or IgE production.45 However, the question of T-cell immaturity as a signiﬁcant factor in the restricted imunoglobulin isotype production of cord blood B-cells has to be taken into account.40,41 Cord blood mononuclear cells produce normal levels of IgE in vitro, when cultured in the presence of IL-4, indicating that the B-cells are mature in their capacity to switch to IgE-producing cells.50 The defect observed may be associated with the failure of cord blood T-cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis, both in vitro and in vivo.51 An inadequacy of newborn T-cell help for plasma cell isotype switching to IgG and IgA immunoglobulin-producing cells is also suggested by the observation that IgG and IgA antibody responses are more dependent upon T-cell help than are IgM responses. In a series of experiments, co-culturing adult T-cells and newborn T-cells with adult or newborn B-cells, the addition of adult T-cells greatly enhanced the pokeweed mitogen-driven responses of newborn mononuclear cells, which included IgG and IgA responses.52,53 Cord blood T-cells, however, did not show augmentation of B-cell differentiation when co-cultured with nonT-cells from adults. These data, looked at collectively, would indicate that deﬁcient T-cell function as well as possible deﬁciencies of B-cell function exist in the newborn. The defect in immunoglobulin production may also be contributed to, of course, by suppressor T-cell activity of newborn lymphocytes or even by enhanced suppressor activity of newborn monocytes. The newborn also possesses a major population of CD5-positive52 B-cells, which are only commonly found in patients with autoimmune diseases. It appears that these cells, in the newborn, uniquely express the activation antigens 4F2 and CD25.54 The signiﬁcance of these activated CD5positive B-lymphocytes is however unclear. A particular function of these cells is the production of natural polyspeciﬁc autoantibodies.55 A possible role for these cells in the newborn may therefore be the inﬂuencing of emerging B-cell speciﬁcities.

IMMUNOGLOBULINS The presence of physiological hypogammaglobulinemia has been noted by several investigators in preterm and term infants. Neonates have low levels of IgA and IgM immunoglobulins because of the poor ability of these immunoglobulin classes to cross the placenta.56 Furthermore, all IgG sub-classes are not equally transferred across the placenta, especially the IgG2 and IgG4 subclass levels, which are therefore also relatively low in the newborn.54 The neonate is consequently very susceptible to pyogenic bacterial infections since most of the antibodies that opsonize capsular polysaccharide

Conclusion 143

antigens of pyogenic bacteria are contained in the IgG2 sub-class and IgM immunoglobulin subfraction. Neonates, even during overwhelming sepsis, do not produce type-speciﬁc antibodies.57 This impairment in antibody production appears to be secondary to the defect in the differentiation of B-lymphocytes into immunoglobulin-secreting plasma cells and T-lymphocyte-mediated facilitation of antibody synthesis. There is a marked limitation in infant antibody responses to most bacterial capsular polysaccharides.58 This limitation prevents successful infant immunization with Hib polysaccharide vaccines,59 which fortunately can be circumvented by use of conjugate vaccines shown to be immunogenic in infants.60

ACCESSORY CELLS The crucial role of monocytes/macrophages in the immune response resides in their accessory cell and immunoregulatory functions of both humoral and cellular immunity. Human cord blood contains almost three times as many monocytes as adult blood does and major changes occur in the levels of monocytes during the ﬁrst few weeks of life. Newborn macrophages show poor resistance against facultative intracellular organisms. Newborn monocytes exhibit marked heterogeneity with respect to density. This heterogeneity in density is reﬂected in functional responses in different population of newborn monocytes.61 The most dense population of newborn monocytes appear to have helper function for antibody production, while suppressor function resides in the less dense populations.62 Neonatal blood monocytes are also characterized as having a much lower frequency of class II molecular expression than adult monocytes, which may be related to the selective incapacity of neonates to secrete signiﬁcant levels of IFN-γ.63 The precise role of the monocyte in the newborn’s unique susceptibility to infections with various agents, remains a challenging area for future study. Dendritic cells are the primary antigen-presenting cells for optimum sensitization of naive T-cells to antigen. Newborn dendritic cells have been shown to be deﬁcient in IL-12 (p35) expression, a key regulator of Th1-type Tcell responses.64 The critical role of the neutrophil in host defences against microbial infection has long suggested that defects in this particular cell type might be the cause of the increased susceptibility of the newborn to serious bacterial infections. Recent advances in our understanding of the molecular basis of cell adherence and phagocytosis have provided us with greater insight into the role of the neutrophil in the newborn’s defense system. Numerous in vitro abnormalities include decreased chemotaxis, leukocyte adherence, bacterial killing and depressed oxidative metabolism.65,66 However, most of these neonatal neutrophil functions have been carried out on cord blood, which contains immature forms of

the cells, and therefore care must be taken in interpreting some of the data. Oxidative metabolic function of cord blood monocytes, measured by chemiluminescence, has been shown to be depressed 12–36 hours after birth.67 Cytoskeletal actin polymerization has also been shown to be altered in neonates.68 Decreased adherence of neonatal neutrophils may be caused, at least in part, by the decreased expression of adherence glycoproteins, or by decreased ﬁbronectin content in the plasma membrane of polymorphonuclear leukocytes.69 Humoral defects have also been found in neonates, which may help explain the decreased levels of chemotaxis reported in neonatal polymorphonuclear leukocytes. Such altered humoral factors include decreased levels of complement components70 and ﬁbronectin.71 Phagocytosis by neutrophils from healthy term newborns has been studied by a number of investigators using a wide range of micro-organisms. The general consensus appears to be that neonatal neutrophils exhibit normal phagocytosis of opsonized particles as well as particles that required no opsonization. The major opsonic role of neutrophils for the uptake of antibody or complement-coated micro-organisms is reﬂected in their expression of a number of receptors both for antibody (Fc-receptors) and complement (CR receptors). In newborn cord blood, the levels of these receptors are similar to those in adult polymorphonuclear leukocytes.72,73 The level of expression of Fc receptors is signiﬁcantly more upregulated in response to in vitro stimuli such as f-met-leu-phe (FMLP) on adult PMNs compared to newborn PMNs.68 As is the case with many aspects of lymphocyte and monocyte function we are only beginning to appreciate the subtleties of molecular regulation that may inﬂuence polymorphonuclear leukocyte function as part of the immune responses in the neonate.

CONCLUSION In fetal and neonatal life, many aspects of the immune system reveal several in vivo and in vitro dissimilarities compared to the adult immune system. It is clear that the abnormalities of the immune defense system of the newborn could predispose the infant to serious and often overwhelming bacterial and fungal infections. The molecular and cellular basis for these abnormalities, while partially explained by many of the observations described in this chapter, still remains relatively unclear. The prospects for more speciﬁc and selective immunological intervention as part of the treatment of the immunocompromised neonate undergoing surgery will beneﬁt enormously from ongoing research into the biological basis of immuno-insufﬁciency of the newborn.

144 Immune system of the newborn

REFERENCES 1. Pyati SP, Pildes RS, Rama-murthy RS et al. Decreased Mortality in neonates with early onset group B streptoccocal infection: reality or artifact? J Pediatr 1981; 98:625–7. 2. Wasserman RL. Neonatal sepsis: the potential of granulocyte transfusion. Hosp Pract 1982; 75:95–104. 3. Quie PG. Neonatal septicaemia. Antibiot Chemother 1976; 21:128–34. 4. Gonzalez LA, Hill HR. The current status of intravenous gammaglobulin use in neonates. Pediatr Infect Dis J 1989; 8:315–22. 5. Placzek MM, Whitelaw A. Early and late onset neonatal septicaemia. Arch Dis Childh 1983; 58:728–31. 6. Myers CD. Role of B-cell antigen processing and presentation in the humoral immune response. FASEB J 1991; 5:2547–53. 7. Schlossman ST, Boumsell L, Gilks W et al. Leukocyte Typing V, Oxford University Press, Oxford,1995. 8. Meuer SC, Schlossman SG, Reinherz EL. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T-cells recognise products of different major histocompatibility complex regions. Proc Nat Acad Sci USA 1982; 79:4395–9. 9. Germain RN. The ins and outs of antigen presentation. Nature 1986; 322:687–9. 10. Melchers F, Anderson J,Curbel CM et al. Regulation of B lymphocyte replication and maturation. J Cell Biochem 1982; 19:315–21. 11. Singer A, Hodes RJ. Mechanisms of T-cell–B-cell interaction. Ann Rev Immunol 1983; 1:211–42. 12. Hamblin AS. Lymphokines, IRL Press, Oxford, 1988. 13. Whicker JT, Evans SW. Cytokines in disease. Clin Chem 1990; 36/7:1269–81. 14. Lucas C, Bald LN, Fandly BM et al. The autocrine production of transforming growth factor- during lymphocyte activation: a study with a monoclonal antibody based ELISA. J Immunol 1990; 145:1415–22. 15. Nijsten MW, de Groot ER, ten Duis HJ et al. Serum levels of interleukin-6 and acute phase responses. Lancet 1987; 2:921. 16. Fong Y, Moldawer L, Shires GT et al. The biological characteristics of cytokines and their implication in surgery injury. Surg Gynec Obstet 1990; 170:363–78. 17. Leary AG, Ikeubuchi K, Hirai T. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1a. Blood 1988; 71:1759–63. 18. Beytler B, Mylsark IW, Cerami A. Passive immunisation against cachectin/Tumor necrosis factor protects mice from the lethal effect of endotoxin. Science 1985; 229:869–71. 19. Schoham S, Davernne D, Cady AB et al. Recombinant tumor necrosis factor and interleukin-1 enhance slowwave sleep. Am J Physical 1987; 253:142–9.

20. Tosato G, Magrath IT, Koski IR, Dooley NJ, Blaese RM. Bcell differentiation and immunoregulatory T-cell function in human cord blood lymphocytes. J Clin Invest 1980; 66:383–8. 21. Puri P, Blacke P, Ren DJ. Lymphocyte transformation after surgery in the neonate. J Paediatr Surg 1980; 15:175–7. 22. Hayward AR, Kurnick J. Newborn T-cell suppression: early appearance, maintenance in culture and lack of growth factor suppression. J Immunol 1981; 125:50–3. 23. Lubens RG, Gard SE, Soderberg-Warner M, Stiehm R. Lectin dependent T lymphocytes and natural killer cytotoxic deﬁciencies in human newborn. Cell Immunol 1982; 74:40–3. 24. Eife RF, Eife G, August CS et al. Lymphotoxin production and blast cell transformation by cord blood lymphocytes: dissociated lymphocyte function in newborn infants. Cell Immunol 1974; 14:435–9. 25. Gupta S, Shwartz SA, Good RA. Subpopulation of human Tcell lymphocytes. VII cellular basis of concanavalin A induced T-cell mediated suppression of immunoglobulin production by B-lymphocytes from normal humans. Cell Immunol 1978; 44:242–9. 26. Puri P, Reen DJ. Host defences in the newborn. Mod Probl Paediatr 1985; 23:13–33. 27. Chandra RK. Inﬂuence of nutrition-immunity axis on perinatal infections. In: Ogra PL, editor. Neonatal Infection. New York: Grune and Stratton, 1984: 229–45. 28. Zamkoff FW, McKenas D, Davy FR. The autologous mixed lymphocyte reaction in cord blood lymphocytes: altered kinetics and magnitude of proliferative response compared to the adult autologous mixed lymphocyte reaction. J Clin Lab Immunol 1985; 16:87. 29. Papadogiannakis N, Johnsen SA, Olding LB. Monocyte regulated hypo responsiveness of human cord blood lymphocytes on OKT3, monoclonal antibody induced mitogenesis. Scand J Immunol 1986; 23:91. 30. Gill TJ, Rabin BS, Kunz HW et al. Immunological aspects of maternal-fetal interactions. In: Cooper MD, Dayton DH, editors. Development of Host Defences. New York: Raven Press, 1977: 287–302. 31. Pabst HF, Godel JC, Spady DW et al. Transfer of maternal speciﬁc cell-mediated immunity to the fetus. Clin Exp Immunol 1987; 68:209–14. 32. Lawton AR, Cooper MD. Ontogeny of immunity. In: Stiehm ER, editor. Immunologic Disorders in Infants and Children. Philadelphia: WB. Saunders, 1989. 33. Hassan J, Reen DJ. Human recent thymic emigrantsidentiﬁcation, expansion, and survival characteristics. J Immunol 2001; 167:1970–6. 34. Foa R, Giubellino M, Fierro M et al. Immature TLymphocytes in human cord blood identiﬁed by monoclonal antibodies: a model for the study of the differentiation pathway of T-cells in humans. Cell Immunol 1984; 89:194–201.

References 145 35. Reason DC, Ebiasawaaa M, Saito H et al. Human cord blood lymphocytes do not simultaneously express Cd4 and Cd8 cell surface markers. Biol Neonatel 1990; 58:87–90. 36. Clement LT, Vink PE, Bradley GE. Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate. J Immunol 1990; 145:102–8. 37. Gerli R, Bertotto A, Spinozzi F et al. Thymic modulation of CD38 (T10) antigen on human cord blood lymphocytes. Clin Immunol Immunopathol 1987; 45:323. 38. Maccario R, Ferrari FA, Ciana S et al. Receptors for peanut agglutinin on a high percentage of human cord blood lymphocytes: Phenotype characterisation of peanut positive cells. Thymus 1981; 2:239. 39. Meccario R, Nespoli IO, Mingrat G et al. Lymphocyte subpopulations in the neonate: identiﬁcation of an immature subset of OKT8-positive, OKT3-negative cells. J Immunol 1983; 130:1129–32. 40. Splawski JB, Lipsky PE. Cytokine regulation of immunoglobulin secretion by neonatal lymphocytes. J Clin Invest 1991; 88:967–77. 41. Watson W, Oen K, Ramdahin R et al. Immunoglobulin and cytokine production by neonatal lymphocytes. Clin Exp Immunol 1991; 83:169–74. 42. Clement LT, Vink PE, Bradley GE. Novel immunoregulatory function of phenotypically distinct sub-populations of CD4+ cells in the human neonate. J Immunol 1990; 145:102–8. 43. Erkeller-Yuuksel FM, Deneys V,Yuksel B et al. Age-related changes in human blood lymphocyte subpopulation. J Pediatr 1992; 120:216–22. 44. Wu LYF, Blanco A, Cooper MA et al. Ontogeny of B Lymphocyte differentiation induced by pokeweed mitogen. Clin Immunol Immunopathol 1976; 5:208–17. 45. Hayward AR, Lawton AR. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T and B cell. J Immunol 1977; 115:1213. 46. Bird AG, Britton S. A new approach to the study of B lymphocyte function using an indirect B cell activator. Immunotl Rec 1984; 45:41. 47. Miller KM, Pittart WB, Sorenson RU. Cord blood B cell differentiation: synergistic effect of pokeweed mitogen and Staphylococcus aureus on in vitro differentiation of B cells from human neonates. Clin Exp Immunol 1984; 56:415. 48. Andersson U, Bird AG, Britton S et al. Humoral and cellular immunity in humans studies at the cell level from birth to 2 years of age. Immunol Rev 1981; 57:5. 49. Durandy A, Fisher A, Griscelli C. Active suppression of B lymphocyte maturation by two different unborn T lymphocyte subsets. J Immunol 1979; 123:2646. 50. Pastorelli G, Rousset F, Pene J et al. Cord blood B-cells are mature in their capacity to switch to IgE producing cells in response to interleukin-4 in vitro. Clin Exp Immunol 1990; 82:114–19.

51. Finkelman SD, Katona IM, Urban JF et al. IL4 is required to generate and sustain in vivo IgE responses. J Immunol 1988; 141:2335–41. 52. Hayward AR, Lawton AR. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T- and B-cells. J Immunol 1977; 119:1213–17. 53. Clough JD, Mims LH, Strober W. Deﬁcient IgA antibody responses to arsanilic acid bovine serum albumin (BSA) in neonatally thymectomised rabbits. J Immunol 1971; 107:1624–9. 54. Durandy A, Thuillier S, Forbveille M et al. Phenotypic and functional characteristics of human newborns Blymphocytes. J Immunol 1990; 144:60–5. 55. Raveche ES. Possible immunoregulatory role for CD5+B cells. Clin Immunol Immunopathol 1990; 56:135–50. 56. Cates KL, Rowe JC, Ballow M. The premature infant as a comprised host. Curr Probl Pediatr 1983; 13:5–63. 57. Rijkers GT, Sanders EA, Breukels MA, Zegers BJ. Infant B Cell responses to polysaccharide determinants. Vaccine 1998; 16:1396–4000. 58. Holmes SJ, Granoff DM. The biology of Haemophilus inﬂuenzae type b vaccination failure.J Infect Dis 1992; 165 Suppl A:S121–8. 59. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Fiegrist CA. Combined vaccination of Haemophilus inﬂuenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354:2063–8. 60. Goriely S, Vincart B, Stordeur P, Vekemans J, Willems F, Goldman M, De Wit D. Diﬁcient IL-12 (p350 gene expression by dendritic cells derived from neonatal monocytes. J Immunol 2001; 166:2141–6. 61. Mills EL. Mononuclear phagocyte in the newborn: their relation to the state of relative immunodeﬁciency. Am J Pediatr Haematol Oncol 1983; 5:189–98. 62. Khansari N, Fuiderberg HH. Functional heterogeneity of human cord blood monocytes. Scand J Immunol 1984; 19:337–42. 63. Byson YJ, Winter HS, Gardm SE et al. Deﬁciency of immune interferon production by leukocytes of normal newborns. Cell Immunol 1980; 58:191–206. 64. Sztein MB, Steeg PS, Stiehm R et al. Modulation of human cord blood monocyte DR antigen expression in vitro by lymphokines and interferons. In: Oppenheim JJ, Cohen S, editors. Interleukins, Lymphokines and Cytokines. New York: Academic Press, 1983: 299–305. 65. Beltas S, Goetza B, Spere CP. Decreased adherence, chemotaxis and phagocytic activities of neutrophils from pre-term neonates. Acta Paediatr Scand 1990; 79:1031–8. 66. Anderson DC, Huges BJ, Edwards MS et al. Impaired chemotaxigenesis by Type III group B streptococci in neonatal sera: relationship to diminished concentration of speciﬁc anticapsular antibody and abnormalities. Pediatric Research 1983; 17:496–520. 67. Miels EI, Thompson T, Bjorksten B et al. The Chemiluminescence response and bactericidal activity of

146 Immune system of the newborn polymorphonuclear neutrophils from newborns and their mothers. Paediatrics 1979; 63:429–34. 68. Hilmo A, Howard TH. F-actin content of neonate and adult neutrophils. Blood 1987; 69:429–949. 69 Anderson DC, Becker-Freeman KL, Herdt, B. Adnormal stimulated adherence of neonatal granulocytes: impaired induction of surface Mac-1 by chemotactic factors and secretogogues. Blood 1987; 70:740–50. 70. Thonson U, Trudsson L, Gustavis B. Complement components in 100 newborns and their mothers determined by electro-immunoassays. Acta Path Microbiol Scand Immunol, C, 1983; 91:148–50.

71. Gerdes JS, Douglas SD, Kolski GB et al. Decreased ﬁbronectin biosynthesis by human cord blood mononuclear phagocyte in vitro. J Leuk Biol 1984; 34:91–9. 72. Fleit HB. Fc and complement receptor (CR1 and CR3) expression on neonatal human polymorphonuclear leukocytes. Biol Neonate 1989; 55:156–63. 73. Smith JB, Cambell EE, Ludomirsky A et al. Expression of the complement receptors CR1 and CR3 and the type III Fcγ receptor on neutrophils from newborn infants and from newborn infants and from fetuses with Rh disease. Pediatr Res 1990; 28:120–6.

13 Hematological problems in the neonate OWEN P. SMITH

INTRODUCTION The neonatal period is a time of rapid ﬂux and hematological problems that present during this time as a result of a genetic defect, immaturity or stress and present a major diagnostic and therapeutic challenge to the neonatologist and hematologist alike. The recent explosion in molecular biological techniques has allowed the elucidation of the molecular and cellular mechanisms that give rise to the disorders of platelets, coagulation proteins, and red cells that present in the newborn. Because of the space allotted it is hoped that this chapter will give the reader a broad understanding and appreciation of the major hematological disorders seen in the neonatal period, especially those involving platelets and clotting proteins.

PLATELETS The normal range of the platelet count is similar in fetal life to that seen in adulthood, being in the range of 150 × 109/L to 400 × 109/L. Neonatal thrombocytopenia, deﬁned by a blood platelet count of below 150 × 109/L is common, with a reported frequency of approximately 0.9% in unselected newborns, and 40% in infants in intensive care units.1–3 The differential diagnosis of thrombocytopenia in the neonatal period is similar to thrombocytopenia in older children with a number of exceptions that include the inherited thrombocytopenia group and those that arise due to pathophysiological events unique to the antenatal and perinatal periods. It is important to remember to conﬁrm that the low platelet count is genuine by careful inspection of the blood sample and smear before initiating further investigations. Once established, the approach to the diagnosis of thrombocytopenia should be tailored to the individual infant and mother. For example, assessment of the child’s general well-being is very important as healthy neonates usually have an immune or an inherited

etiology, whereas the presence of lymphadenopathy, hepatosplenomegaly, mass lesions, hemangiomas, bruits and congenital anomalies will point towards a totally different spectrum of causes. It should also be emphasized that obtaining a detailed maternal history to include bleeding problems, pre-eclampsia and drug ingestion in present and past pregnancies and any history of viral infections, or connective tissue disease will save time and indeed unnecessary investigations. The causes of thrombocytopenia are divided into two broad categories: inherited and congenital thrombocytopenia.

INHERITED THROMBOCYTOPENIA The inherited thrombocytopenias comprise a group of platelet formation abnormalities in which platelet numbers are reduced. In the vast majority of patients the platelet count is only mild to moderately reduced (50 × 109/L and 100 × 109/L) and therefore, signiﬁcant spontaneous hemorrhage tends not to be problematical. There are however, a small number of notable exceptions where spontaneous bleeding is a prominent clinical feature of the syndrome. These include Wiskott–Aldrich syndrome (WAS), amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii, where the platelet count is usually very low, and in Bernard–Soulier syndrome (BSS) and Chediak–Higashi syndrome, where there is also a marked platelet dysfunction.4 Immunemediated thrombocytopenia is a major differential diagnosis in children with low platelet counts, and therefore making the correct diagnosis of these conditions is important as it usually prevents the useless and potentially dangerous prescribing of immunosuppressants such as corticosteroids.4,5

BERNARD–SOULIER SYNDROME This is the best characterized inherited thrombocytopenia which has, in association, abnormal platelet

148 Hematological problems in the neonate

function. Typically, there is moderate to severe thrombocytopenia, a prolonged bleeding time and platelet morphology usually reveals ‘giant’ forms. BSS is inherited as an autosomal recessive manner with the underlying molecular defects due to quantitative or qualitative defects in platelet membrane receptors.

PSEUDO-VON WILLEBRAND’S DISEASE This is an autosomal dominant disorder characterized by mild intermittent thrombocytopenia, mild bleeding, absence of high molecular weight von Willebrand factor (vWf) multimers, and increased ristocetin-induced platelet aggregation. It can be differentiated from type 2B vWd, where the mutation resides in the vWf protein by spontaneous aggregation of the patient’s platelets with normal plasma4 (see later).

TYPE 2B vWD This subtype of vWd is clinically and biochemically very similar to pseudo-von Willebrand’s disease (pseudovWd). Type 2B is usually diagnosed by the increased platelet agglutination induced by low concentratons of ristocetin.4

MONTREAL PLATELET SYNDROME This syndrome is characterized by thrombocytopenia, large platelets, spontaneous platelet aggregation, and a reduced response to thrombin-induced aggregation. It can be distinguished from BSS by its autosomal dominant inheritance and a normal platelet agglutinability response to ristocetin.4

GRAY PLATELET SYNDROME This is an extremely rare autosomally inherited syndrome characterized by a markedly reduced platelet alpha-granule content but normal dense bodies and lysosomes. Other features include a prolonged skin bleeding time, morphologically large platelets and highly variable platelet aggregation proﬁles. The thrombocytopenia and bleeding symptoms are usually mild.4,6

PARIS–TROUSSEAU SYNDROME This is a recently described autosomal dominant syndrome comprised of mild thrombocytopenia, a moderate hemorrhagic tendency, giant alpha-granules in a subpopulation of platelets, bone marrow micromegakaryocytes with enhanced megakaryocyte apoptosis and a deletion of the distal part of chromosome 11 at position 11q23 (del (11)(q23.3;qter)).4,6

WISKOTT–ALDRICH SYNDROME WAS is inherited as an X-linked recessive trait and is characterized by eczema, microthrombocytopenia and combined immunodeﬁciency. It is often fatal by the early

teens due to infection, lymphoreticular malignancy or bleeding. Hemorrhagic events in this syndrome are common during the ﬁrst 2 years of life and the reason for this is multifactorial.4,6 Wiskott–Aldrich syndrome variants (X-linked thrombocytopenia) This is a heterogeneous group of thrombocytopenic disorders with X-linked inheritance. The thrombocytopenia is usually less severe in WAS variants and requires no treatment.4,6 Oculocutaneous albinism – Hermansky-Pudlak & Chediak–Higashi syndromes Oculocutaneous albinism denotes a group of inherited disorders characterized by reduced or absent pigmentation of the skin, hair and eyes. Whilst the majority of these patients have an isolated platelet storage pool defect, in some an accompanying low platelet count can occur.4,6 Hermansky-Pudlak syndrome is an autosomal recessive disorder with the classic triad of oculocutaneous albinism (tyrosinase positive), platelet dense-body or combined dense-body and alpha-granule storage pool deﬁciency, and depositions of ceroid-like material in the monocyte–macrophage system. The bleeding tendency is usually mild (related to the storage pool defect and not thrombocytopenia, as the latter is not a feature syndrome), however, excessive bleeding following tooth extractions and tonsillectomy is the rule.4,6 The features of Chediak–Higashi syndrome include: partial oculocutaneous albinism, presence of giant granules in all granule-containing cells, neutropenia, peripheral neuropathy, and platelet storage pool deﬁciency, which usually involves the dense bodies. Thrombocytopenia usually occurs during the accelerated phase of the disease, which involves the development of pancytopenia, hepatosplenomegaly, lymphadenopathy, and extensive tissue inﬁltration with lymphoid cells.4,6

MAY–HEGGLIN ANOMALY This is an autosomal dominant disorder, characterized by giant platelets, variable thrombocytopenia and Dohle-like inclusions within granulocytic cells including monocytes. Platelet function has been reported to be normal in some and impaired in others.4

ALPORT VARIANTS Alports syndrome is associated with the ﬁndings of sensorineural deafness (usually high-tone deafness), hematuria, cataracts and progressive renal failure. The disorder is heterogeneous with the majority having autosomal dominant inheritance. Many variants of Alports syndrome have been described; the three types associated with thrombocytopenia include: Epstein’s syndrome, Fechtner syndrome and Sebastian platelet syndrome.4

Inherited thrombocytopenia 149

Inherited bone marrow failure syndromes THROMBOCYTOPENIA WITH ABSENT RADII Thrombocytopenia with absent radii (TAR) is a rare, autosomal recessive disorder that is usually diagnosed at birth as the vast majority of these patients are thrombocytopenic and have the pathognomonic physical sign of bilateral absent radii. Other skeletal abnormalities involving the ulnae, ﬁngers and lower limbs are also seen but are much less common. TAR differs from Fanconi anemia in several ways; the absent radii are accompanied by the presence of thumbs, the thrombocytopenia is the only cytopenia, there is absence of spontaneous or clastogenic stress-induced chromosomal breakage and evolution to aplastic anemia and leukemia have not been reported.4,7 The majority of children with TAR have recurrent signiﬁcant bleeding episodes in the ﬁrst 6 months of life.4,7 Intracerebral and gastrointestinal hemorrhage are the usual causes of mortality with previously one in four of these children dying by 4 years of age. The majority of these deaths however, occur in the ﬁrst year of life. The mainstay of treatment is judicious use of single-donor platelet concentrates aiming to keep the platelet count above 20 × 109/L, especially in the ﬁrst year of life as this is the time of maximum morbidity and mortality.4,7

AMEGAKARYOCYTIC THROMBOCYTOPENIA Amegakaryocytic thrombocytopenia (AMEGA) is an extremely rare disorder of infancy and early childhood. The thrombocytopenia is non-immune, usually severe and early bone marrow examination shows a normal karyotype, with absent or greatly reduced numbers of megakaryocytes. Platelet transfusions are the main therapeutic intervention from diagnosis.7

FANCONI ANEMIA A premalignant disorder, Fanconi anemia (FA) is inherited as an autosomal recessive trait, with genetic heterogeneity and a gene frequency of about 1 in 600. Thrombocytopenia is usually the ﬁrst cytopenia to appear but rarely in the neonatal period.7

TRISOMY SYNDROMES Moderately severe thrombocytopenia is seen in some cases of trisomy 18 syndrome, trisomy 13 syndrome and to a lesser extent in trisomy 21. Both trisomy 13 and 18 are usually diagnosed at birth as the associated abnormalities are usually quite striking. The majority of these cases die in the neonatal period from non-hemorrhagic sequelae.4

Congenital thrombocytopenia Congenital thrombocytopenia is deﬁned as a low platelet count at birth not resulting from the association of a speciﬁc gene defect, accounting for the majority cases of

neonatal thrombocytopenia. Thrombocytopenia is a common ﬁnding in sick neonates, however, and since the introduction of automated cell counters it is now considered a relatively common (approximately 1%) ﬁnding in apparently normal infants.8 In the vast majority of cases, the thrombocytopenia results from increased platelet destruction, which can arise by several mechanisms, the majority of which are not known.

IMMUNE THROMBOCYTOPENIA Immune-mediated thrombocytopenia is usually seen in term babies that are clinically well and may be responsible for one-third of cases of thrombocytopenia seen in the general neonate population.9 There are two broad groups of conditions: those mediated by an alloimmune mechanism and those with associated autoimmune phenomena.

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Neonatal alloimmune thrombocytopenia (NAIT) This arises following maternal sensitization to paternal antigens present on fetal platelets. It occurs in approximately 1 in 1500–2000 births, with the mother having a normal platelet count and negative history for bleeding.9 The maternal alloantibody produced does not react with the mother’s platelets but crosses the placenta and destroys fetal platelets. NAIT typically presents as an isolated severe thrombocytopenia in an otherwise healthy child at birth. Severe thrombocytopenia may be present early in gestation and at least 20% of cases suffer intracranial hemorrhage.8 Widespread petechial hemorrhage is present in more than 90% of cases, while cephalohematomata, hematuria and gastrointestinal bleeding occur in a signiﬁcantly smaller number of children.1,4,9 Typically, the platelet count spontaneously returns to the normal range within 3 weeks after birth. The mainstay of treatment for affected infants is washed, irradiated, maternal platelet concentrates.

MATERNAL AUTOIMMUNE THROMBOCYTOPENIA Autoimmune thrombocytopenia (AIT) is due to the passive transfer of autoantibodies from mothers with isolated immune thrombocytopenic purpura (ITP) or it may be seen in association with conditions that have immune dysregulatory features such as maternal systemic lupus erythematosus, hypothyroidism and lymphoproliferative states.9 Approximately 1 in 10 000 pregnancies are complicated by maternal ITP. The risk of signiﬁcant infant morbidity and mortality is minimal, as the infant platelet count is rarely less than 50 × 109/L, ICH rarely, if ever, happens and when it does occur it is not related to birth trauma.9

INTRAUTERINE INFECTIONS (TORCH SYNDROMES) Intrauterine viral infections rarely produce severe thrombocytopenia (< 20 × 109/L) and therefore,

150 Hematological problems in the neonate

therapeutic intervention in the form of platelet concentrate and/or antiviral therapy are only indicated when there is active bleeding, or surgical intervention is being considered.10 In the vast majority of cases the platelet count returns to the normal range within 2–4 weeks after birth but may persist to 4 months of age.

GIANT HEMANGIOMA SYNDROME (KASABACHMERRITT SYNDROME) Kasabach-Merritt syndrome (KMS) is the association of giant cavernous hemangiomata and disseminated intravascular coagulopathy. The consumptive coagulopathy which is seen in approximately 25% of cases of KMS is usually low grade and compensated. However, acceleration into the fulminant form, which is characterized by hypoﬁbrinogenemia, raised d-dimers, red cell microangiopathy and severe thrombocytopenia is not uncommon. Fortunately, spontaneous regression of these tumors occurs in the majority of patients. Treatment modalities that have been used with varying degrees of success including corticosteroids, surgical resection, alpha-interferon, embolization, and radiotherapy. Replacement therapy with platelets, ﬁbrinogen concentrate, fresh-frozen plasma (FFP), cryoprecipitate and antiﬁbrinolytic drugs and antiplatelet agents have a role in the fulminant phase of severe forms.4

HYPERCOAGULABLE STATES Consumptive thrombocytopenia, mainly secondary to DIC following thrombin generation can be the ﬁrst manifestation of an acquired or inherited hypercoagulable state.11

Miscellaneous conditions Other associations of neonatal thrombocytopenia including maternal pre-eclampsia, maternal use of drugs, disseminated intravascular coagulation, primary microangiopathic hemolytic anemias, including hemolytic uremic syndrome, transient abnormal myelopoiesis (TAM) associated with Downs’ syndrome hemophagocytic lymphohistiocytosis, osteopetrosis, congenital leukemia, metastatic neuroblastoma and are covered in more detail elsewhere in the book.

COAGULATION PROTEINS Plasma levels of many of the hemostatic coagulation factors are lower in newborns than in older children and adults.12–15 At the end of gestation, a healthy, normal newborn should have approximately half the adult values of the vitamin K-dependent coagulant factors (factors II, VII, IX and X) and contact factors (factors XII, and XI, prekalikreinin and high molecular weight kininogen).12–15

In pre-term infants these levels are even lower. The natural anticoagulants, antithrombin and protein S are also approximately 50% at term with a similar relationship to gestational age.12–15 The plasma levels of the procoagulant co-factors, factor V and factor VIII and ﬁbrinogen are the same in term infants as is in adults. Like the coagulation system the ﬁbrinolytic system is also physiologically immature in the neonate.12–15

Inherited bleeding disorders Hemophilia A (factor VIII deﬁciency) is the second most common inherited bleeding disorder in man with a frequency of approximately l:5000 male births.16 Hemophilia B or factor IX deﬁciency is approximately one-sixth as common as that of hemophilia A. When there is a family history of hemophilia, it is usually diagnosed early in newborns as the condition is usually suspected. However, one-third to one-half of all individuals with hemophilia A and B arise from the de novo mutations and it may be some time before a ﬁrm diagnosis is made as a signiﬁcant number of these children will be seen in the general pediatric setting.16 Hemophilia has a worldwide distribution, and affects individuals in all racial groups. Hemophilia A and B are clinically indistinguishable. In the severe form the phenotype is characterized by bleeding into the joints and soft tissues. Both the factor VIII and factor IX genes were cloned over l5 years ago and as a result Recombinant factor VIII and factor IX are the treatment of choice.16 Hemorrhagic complications in moderate and severe hemophilia A and B may become obvious after birth, especially if the male child is circumcised. Severity and type of bleeding is related to the absolute level of circulating plasma VIII:C. A minimally effective level for hemostasis is about 25–30% for hemophilia A and 20–25% for hemophilia B. Those with severe deﬁciency (less than l%) usually experience repeated and often spontaneous hemorrhage. While muscular skeletal bleeding is by far the commonest clinical event, other spontaneous hemorrhagic manifestations frequently occur and may be life threatening. Successful treatment in acute or potentially acute (pre-surgical) bleeding is usually achieved with adequate and prompt factor replacement therapy. The level of factor concentrate required to achieve adequate hemostasis will depend on the type of bleeding.16

Other coagulation factor deﬁciencies Deﬁciencies of all coagulation factors have been described. However, it should be remembered that the number of patients with hemophilia A greatly outnumber all of the others put together. Common features to these rarer forms of coagulation factor deﬁciencies

Coagulation proteins 151

have variable bleeding and autosomal recessive inheritance.16,17

way, and platelets; these children also have signiﬁcant platelet function defects.16

ACQUIRED BLEEDING DISORDERS

CONGENITAL HEART DISEASE

The acquired coagulation disorders are far more common than the inherited disorders and are usually associated with multiple coagulation factor deﬁciencies.

A signiﬁcant number of children with congenital heart disease will have coagulation defects. It should be remembered however that in children with cyanotic heart disease with associated polycythemia, the elevation in PT/APTT may be spurious, i.e. may be secondary to a sampling defect as there will be an alteration in the plasma anticoagulant ratio, especially when the hematocrit level is greater than 60%.16

VITAMIN K Vitamin K is crucial for the function of procoagulant factors II, VII, IX and X and the natural anticoagulants protein C and protein S. Vitamin K itself is recycled and when this process is blocked as with warfarin administration, these vitamin K-dependent factors are not produced in adequate amounts.16,18

HEMORRHAGIC DISEASE OF THE NEWBORN This syndrome usually occurs on the second to fourth day of life as a result of decreased synthesis of vitamin Kdependent factors. The etiology of vitamin K deﬁciency in newborns is multifactorial to include reduction of vitamin K stored in the fetus and neonate, functional immaturity of the liver, lack of bacterial synthesis of vitamin K in the gut and low amounts of vitamin K in breast milk.16,18 Most neonates now are given vitamin K at birth. Exceptions to the rule are those children with known G6PD deﬁciency in the family as a signiﬁcant number of these patients will develop frank hemolysis. In those children who present with frank bleeding, vitamin K and infusions of FFP can be given to arrest the blood loss.

LIVER DISEASE The coagulopathy associated with liver disease is complex, involving reduced synthesis of vitamin Kdependent procoagulant factors, non-vitamin Kdependent procoagulant factors, structually abnormal coagulation proteins and a reduced amount of natural anticoagulants.19 A signiﬁcant number of these patients are also vitamin K deﬁcient because of an associated malabsorption. It should also be noted that these patients are usually thrombocytopenic and even though the platelets do circulate, they are usually dysfunctional. Correcting the coagulopathy usually involves replacement of vitamin K, addition of FFP and when volume restriction is imperative, then factor concentrates such as factor VII concentrate and prothromplex concentrate can be given along with platelets and DDAVP.19

CARDIOPULMONARY BYPASS The coagulopathy associated with cardiopulmonary bypass is multifactorial, involving activation of the contact pathway, ﬁbrinolytic pathway, tissue factor path-

VON WILLEBRAND’S DISEASE Von Willebrand disease (vWd) is the commonest inherited bleeding disorder in man with a gene prevalence of approximately 1% of the population.16 There is signiﬁcant phenotypic heterogeneity even among members of the same family. The majority of individuals have type 1 vWd with type 3 vWd being seen in 1–2 per million of the population. Bleeding tends to be predominantly mucocutaneous, so called ‘wet purpura’, the commonest type being epistaxis, easy bruising, gum bleeding following tooth brushing and in adolescent girls, heavy menses. Bleeding into joints is rare and typically only seen in individuals with severe type 3 disease, where the circulating plasma FVIII levels are usually around 2%. The main objective of treatment is to correct the two laboratory hallmarks of the disease, namely, prolonged bleeding time and low FVIII level.16 As most patients have a quantitative defect it is possible to stimulate endogenous release with i.v. DDAVP (Desmopressin). While this treatment is inexpensive and infection free, it does have a number of rare side effects, notably hyponatremia and seizures especially in very young children. Failure to respond occurs in approximately 10–15% of patients, and in those who do not respond, a signiﬁcant number become refractory when the drug is given over an extended period of time (tachyphylaxis).16

Thrombotic states The fetus and neonate are less efﬁcient in generating thrombin and thus thrombotic disease in early childhood is rare and when seen is either secondary to an acquired prothrombotic state or indeed the child has inherited gene defects predisposing to clot formation.12–15,20 When it does occur in childhood it can be fatal or associated with several sequelae such as amputation, organ dysfunction and post-phlebitic syndrome.20 The peak incidence for these thrombotic events is undoubtedly the neonatal period, where the use of indwelling catheters in tertiary care pediatrics is almost the norm.20

152 Hematological problems in the neonate

Acquired states CENTRAL VENOUS CATHETER DEVICES Central venous catheter devices have revolutionized the intensive care management of neonates requiring indwelling vein or artery catheterization. Unfortunately, thrombosis related to their placement continues to be a therapeutically challenging complication in terms of diagnosis, prophylaxis against thrombosis and also treatment of established thrombosis within the catheter. Once clot formation occurs the catheter may be salvaged using either/or antithrombotic or antiﬁbrinolytic agents. However, it should always be remembered that these therapeutics pose special risks in the neonatal age group. It should also be remembered that whilst, although very uncommon, death from venous thromboembolic disease in young children does occur. Therefore early detection of such thrombotic events and adequate treatment are absolutely mandatory in this group of children.

RENAL ARTERY AND VEIN THROMBOSIS Renal artery thrombosis especially in the neonatal period is commonly associated with umbilical artery indwelling on umbilical artery catheters.20 It may be difﬁcult to diagnose and hypertension and heart failure may be the presenting clinical features. There is usually extension of the thrombus to other vascular beds such as the aorta. Its incidence can be as high as one in six neonates and factors that can reduce its incidence include prophylactic anticoagulants, using a smaller size catheter and also concentration of ﬂuids infused.20 Both medical and surgical approaches have been used with variable outcome. Renal vein thrombosis is more common than renal arterial thrombosis in the newborn period. It is associated with birth asphyxia, dehydration, hypotension, cyanotic heart disease, polycythemia, and babies born to diabetic mothers. The commonest presenting features are ﬂank swelling followed by hematuria, microscopic hematuria, renal dysfunction and thrombocytopenia. Usually ultrasound will reveal renal enlargement with or without evidence of venous thrombosis. The use of anticoagulants and thrombolytic agents in this condition continue to be evaluated.20 Survival rates in babies are as high as 80% and renal status after recovery ranges from normal function to renal atrophy, hypertension and chronic renal failure.

ACQUIRED PROTEIC C/S DEFICIENCY Purpura fulminans is a term used to describe an acute, often lethal, syndrome of DIC and purpuric skin.21 Inherited and acquired abnormalities of the protein C pathway, especially protein C deﬁciency, are mainly responsible for the majority of patients with this clinical syndrome.21–23 The treatment of choice is protein C replacement.

ACQUIRED ANTITHROMBIN DEFICIENCY Acquired deﬁciencies of antithrombin have been associated with a large number of diseases, which in turn have an increased rate of venous and arterial thrombosis. Antithrombin concentrates are available and are the treatment of choice during the acute phase of the disease.20

MISCELLANEOUS CONDITIONS Other associations of neonatal thrombosis include: necrotizing enterocolitis, respiratory distress syndrome, heparin-induced thrombocytopenia/thrombosis syndrome (extremely rare in neonates), antiphospholipid antibodies and lupus anticoagulant, extracorporeal membrane oxygenation (ECMO), hemolytic uremic syndrome , birth asphyxia.20

Inherited thrombotic states Genetic defects within the protein C pathway account for the majority of cases of inherited thrombophilia.23

PROTEIN C AND PROTEIN S DEFICIENCY Hereditary protein C (PC) and protein S (PS) deﬁciency (homozygosity or compound heterozygosity) are associated with a high venous thromboembolic risk at birth or in the ﬁrst few months of life. First clinical manifestation is usually skin purpura mainly affecting extremities and in some cases massive large vessel thrombosis can also be a presenting feature. Optimum therapy involves factor replacement (PC concentrate in PC deﬁciency or FFP in PS deﬁciency) and heparin in the acute phase and oral anticoagulation in the long term.23

ANTITHROMBIN III DEFICIENCY Reducing functional defects is also associated with a high risk of venous thromboembolic disease. The homozygous state is extremely rare and appears to be incompatible with life. Presentations of antithrombin deﬁciency in neonates include myocardial infarction at birth, aortic thrombosis, saggital sinus thrombosis and cerebral thrombosis.20

OTHER INHERITED THROMBOPHILIAS Several other inherited gene defects have been associated with increased propensity to clot formation, the commonest being activated protein C resistance (APCR) and factor VR506Q/factor V Leiden, factor II gene variant (prothrombinG20210A), hyperhomocysteinemia.20

Management The indications for use of anticoagulants in infants and children have changed dramatically over the past 20

Anemia 153

years with major advances in tertiary pediatric care such as ECMO, cardiopulmonary bypass, hemodialysis and the use of intra-arterial and i.v. indwelling catheters.20,24,25 The choice of anticoagulant is dependent upon the duration of anticoagulation and therefore in the acute phase heparins, either unfractionated or low molecular weight forms are used, whilst in the longer term oral anticoagulants are the treatment of choice. In more speciﬁc disease states such as inherited or acquired protein C or antithrombin deﬁciencies, factor concentrate replacement as an adjuvant hemostatic support is used more and more. It should be remembered that because the hemostatic system in infancy and throughout childhood is constantly maturing, the anticoagulant effects of unfractionated heparin and warfarin are not predictable and therefore are deemed age dependent.

ANEMIA

usually diagnosed by testing the blood group of the mother and baby together with the presence of maternal allo-antibodies and a positive Coomb’s test. If HDN is due to Rhesus antibodies, the number of circulating nucleated red cells is often very high and thrombocytopenia may be present in those severely affected. If HDN is due to ABO incompatibility, the Hb is often normal and the nucleated red cell count is rarely elevated; however, there are very large numbers of spherocytes, in contrast to a relative paucity of spherocytes in Rhesus disease.

AUTOIMMUNE HEMOLYTIC ANEMIA This is a very uncommon cause of neonatal anemia and it arises when auto-antibodies produced in the mother are directed against fetal red cell antigens causing hemolysis in a similar fashion to neonatal thrombocytopenia secondary to AIT.27

INFANTILE PYKNOCYTOSIS There is a gradual decrease in hemoglobin (Hb) level following birth and throughout the ﬁrst 2 months. This is termed ‘physiological anemia’ and it is a direct consequence of changes in red cell production reﬂecting the increase in oxygenation with adaptation to pulmonary respiration, together with redistribution of blood ﬂow following birth and changes in red cell production.26 When the level of Hb is below the ‘physiological anemic’ range, then a pathological neonatal anemia is present.26 Whilst the majority of cases of anemia occurring in the neonatal period are acquired, a number of inherited disorders that involve gene defects of hemoglobin, red cell membrane and enzymes also present during this period.27 Anemia, whether it be acquired or inherited may present as an incidental ﬁnding on a blood count performed for other reasons, with non-speciﬁc signs of pallor, tachypnea and/or tachycardia, failure to thrive, jaundice, splenomegaly or bleeding. If the anemia is due to a hemolytic process, the jaundice is almost always present.

Acquired anemia

This transient acquired disorder typically presents with jaundice, mild hepatosplenomegaly and anemia in a term baby within a few days or weeks of birth.27 It is not an uncommon cause of moderate anemia in the ﬁrst few weeks of life in term infants. The cause is unknown but some cases appear to be due to selenium deﬁciency. The Hb may fall to as low as 4 g/dL and many neonates require one or two red cell transfusions before the condition resolves spontaneously around 4–6 weeks of age.27

BLOOD LOSS Anemia due to blood loss is the commonest cause of neonatal anemia in pre-term infants. In most cases this is iatrogenic and due to frequent blood sampling. In term infants, blood loss is also not an uncommon cause of anemia and is often occult. This is the commonest cause of otherwise unexplained neonatal anemia. Blood loss may occur before or around delivery due to fetomaternal hemorrhage or twin–twin transfusion; it may occur as a result of bleeding from a ruptured cord or abnormal placenta or there may be bleeding into the baby.

ALLO-IMMUNE HEMOLYTIC ANEMIA Hemolytic disease of the newborn (HDN) is caused by transplacental passage of maternal allo-antibodies.27 The commonest allo-antibodies causing severe hemolytic disease of the newborn are: anti-D, anti-c and anti-Kell, which produce hemolysis in fetuses which carry the D, c and Kell antigens respectively.27 The allo-antibodies are acquired either as a result of blood transfusion prior to or during pregnancy or as a result of allo-immunization during the pregnancy itsesf. Allo-immunization due to anti-D affects around 1200 pregnancies per year and causes at least 50 deaths every year in the UK.27 HDN is

ANEMIA OF PREMATURITY Almost all preterm infants have anemia, the etiology of which is usually multifactorial with reduced red cell lifespan and inappropriately low erythropoietin production being the most important contributing factors.28–31 The best approach is prevention. Whilst blood transfusion is usually carried out especially in babies of less than 28 weeks’ gestation or those requiring prolonged mechanical ventilation, the amount of allogeneic red cell exposure can be signiﬁcantly reduced by reducing blood tests in the child, giving folate and iron to all preterm

154 Hematological problems in the neonate

infants, appropriate use of erythropoietin and compliance with peer reviewed transfusion guidelines.

APPROACH TO MANAGEMENT Only severe or moderate neonatal anemia should be treated with blood transfusion and this decision is made on clinical grounds as well as the Hb in accordance with peer-reviewed guidelines.31 HDN always resolves albeit it may take 1–2 months and in the ﬁrst couple of weeks of life the hemolytic process may be so brisk that the high bilirubin necessitates phototherapy to prevent kernicterus. Blood transfusion may also be required for infantile pyknocytosis and for neonatal anemia due to blood loss.

RED CELL ENZYME DEFICIENCIES These are usually straightforward to diagnose in the neonatal period. A G6PD assay should be performed in cases of prolonged or severe jaundice unless there is an obvious alternative cause. Pyruvate kinase deﬁciency is also diagnosed by assaying red cell enzyme levels; PK assays should be performed in cases of unexplained hydrops, those with hemolytic anemia of unknown cause, and where there is a family history.

MISCELLANEOUS CONDITIONS Other inherited conditions that can present as anemia in the neonatal period include Diamond–Blackfan anemia,32 Pearson’s syndrome,33 congenital dyserythopoietic anemia, 34Aase syndrome, and osteopetrosis.27

Inherited anemia As stated earlier, if the anemia is due to a hemolytic process, jaundice is almost always present. When the hemolytic process is secondary to a red cell membrane disorders then jaundice is usually accompanied by mild to moderate splenomegaly. Jaundice is also frequently seen in neonates with inherited red cell enzyme deﬁciencies, however in glucose-6-phosphate dehydrogenase (G6PD) deﬁciency anemia is not usually present and the hyperbilirubinemia is thought to be most likely of hepatic origin. Most of the hemoglobinopathies, apart from alpha-thalassemia major and hemoglobin-H (HbH) disease do not cause neonatal jaundice.27

RED CELL MEMBRANE DEFECTS These can be difﬁcult to diagnose in the neonatal period especially in the case of the commonest type, hereditary spherocytosis (HS), where the classic blood ﬁlm morphology of numerous spherocytes is indistinguishable from that seen in ABO incompatibility. Spherocytes are also seen in the neonatal period with consumptive coagulopathy, birth asphyxia and when there was signiﬁcant placental insufﬁciency. A positive family history of HS, usually the best piece of additional information that is needed to make the diagnosis as osmotic fragility testing in this age group, is not reliable and should be postponed until the child is between 6 and 12 months of age. Hereditary elliptocytosis is straightforward to diagnose from peripheral red cell morphology.

HEMOGLOBINOPATHIES As globin chain synthesis is in a state of ﬂux between late fetal life and following birth, diagnosing hemoglobinopathy is fraught with difﬁculty in the neonatal period. The hemoglobinopathies that cause neonatal anemia include alpha-thalassemia major (Hb Barts hydrops fetalis) and HbH disease. In sickle cell syndromes the Hb is normal.

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anticoagulant pathway. Thromb Haemost 1993; 70:29–35. Aiach M, Borgel D, Gaussem P et al, Protein C and protein S deﬁciencies. Semin Hematol 1997; 34:205–16. Schlegel N, Hurtund-Roux MF, Beuaﬁls F. Anticoagulation for neonates, infants and children. In: Doupremepuich C, editor. Anticoagulation. 1st edn. New York: SpringerVerlag, 1994, 226–47. Manco-Johnson MJ. Diagnosis and management of thromboses in the perinatal period. Semin Perinatol 1990; 14:393–402. Bifano EM, Smith F, Borer J. Relationship between determinants of oxygen delivery and respiratory abnormalities in preterm infants and anemia. J Pediatr 1992; 120:292–7. Reilly I. Red cell disorders. In: Smith OP, Hann IM, editors. Essential Paediatric Haematology. 1st edn. London: Martin Dunitz, 2002, 168–84. Stockman JA, Anaemia of prematurity: determinants of the erythropoietin response. J Pediatr 1984; 105:786–91. Stockman JA. Anaemia of prematurity: current concepts in the issue of when to transfuse. Pediatr Clin North Am 1986; 33:111–15. Stockman JA, Garcia JF, Oski FA. The anemia of prematurity: factors governing the erythropoietin response. N Engl J Med 1977; 296:647–50. Keyes WG, Donohue PK, Spivak JL et al. Assessing the need for transfusion of premature infants and the role of hematocrit, clinical signs, and erythropoietin level. Pediatrics 1989; 84:412–17. Janov AJ, Leong T, Nathan DG et al. Diamond–Blankfan anemia: natural history and sequelae of treatment. Medicine (Baltimore) 1996; 75:77–82. Rotig A, Cormier V, Blanche S et al. Pearson’s marrowpancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 1990; 86:1601–03. Shalev H, Tamary H, Shaft D et al. Neonatal manifestations of congenital dyserythropoietic anemia type 1. J Pediatr 1997; 131:95–8.

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14 Genetics in neonatal surgical practice ANDREW GREEN

NATURE AND STRUCTURE OF A GENE Genetics is traditionally deﬁned as the science of biologic variation, and has been a scientiﬁc discipline for over 100 years. Human genetics makes up a large part of the ﬁeld of genetics, but the principal laws of genetics are universal, and apply equally to all species, including humans. Mendel’s studies in the 19th century were originally felt to have no relevance to humans, and it is only in retrospect that their importance can be seen. Many of the principles of genetics were discovered through the study of smaller organisms, such as bacteria, yeast and fruit ﬂies. The basic genetic mechanisms of cell division, development and differentiation happen in the same way in widely divergent species. Therefore it is impossible to look at human genetics in isolation, and there are large amounts of information from lower species which have bearing on human disorders. The study of the genetics of small organisms has had a profound impact on our understanding of human development, and of how human diseases develop. It is likely that such basic science will continue to contribute signiﬁcantly to the understanding of human genetic disease. This chapter will attempt to outline the basic elements of genetics, describe the types of genetic tests now available to help in neonatal diagnosis, and give an approach to the diagnosis of congenital abnormalities. The basic unit of inheritance for any species is the gene. The original concept of a gene arose long before the relationship between genes and nucleic acids was ever understood. A gene was considered to be a stable heritable element, which conferred a particular property or phenotype onto an individual organism. This element was passed on to subsequent generations of a particular species, and the nature of the phenotype varied according to the nature of the gene. The concept of dominant and recessive traits, which will be discussed later, was derived from studies of inheritance patterns, long before the molecular basis of the gene was understood. A gene can also be considered in another way, as a speciﬁc length of deoxyribonucleic acid (DNA), which

encodes a particular function, in most cases the synthesis of a protein. This also is a stable heritable unit. Each cell in an organism, regardless of its function, has the entire set of genes for that particular organism, but only a proportion of those genes will be active. DNA is found in the nucleus of every cell of an organism as a double helix (Fig. 14.1). Each strand of the double helix has a backbone of alternating phosphate and deoxyribose sugar molecules, with the sugars attached to the 5¢ and 3¢ hydroxyl groups of the phosphate group. Attached to the sugar molecule, lying within the helix, is one of four nitrogen-containing nucleic acid bases. Two of these bases, adenine (A) and P

O

O

O H

O

C 5'

H

BASE

4' H H 3' O –

O

H H

1'

2' H

P

O

O H

C 5'

H

O BASE

4' H H 3' O –

O

P

H H

1'

2' H O

O H H

C 5' 4' H H 3' O

O BASE H H

1'

2' H

Figure 14.1 Structure of a DNA chain. The deoxyribose and phosphate residues are linked to form the sugar-phosphate backbone of DNA

158 Genetics in neonatal surgical practice

guanine (G), are purines, and two are the smaller pyrimidines cytosine (C), and thymine (T). The A and T bases pair together by hydrogen bonding, and the G and C bases similarly pair by hydrogen bonds (Fig. 14.2). The two strands of the double helix are held together by paired A-T or G-C bases of opposite strands of the double helix. The DNA strand can be read in only one direction from 5¢ (left hand) to 3¢ (right hand). The two strands of DNA are complementary to each other, and the sequence of one strand can be predicted from its opposite. If one strand reads 5¢-CAGCGTA-3¢, then the opposite strand must read 5¢-TACGCTG-3¢. The doublestranded sequence would then be written as follows:

to the template strand of DNA. The replication system builds a new strand of DNA based on the template. The new double helix formed as a result will contain one original strand, and a newly synthesized complementary second strand. This is the basic mechanism of DNA replication in all species. Thirdly, the double helix provides a basis for repair of damaged DNA. A damaged base can be replaced, knowing its complementary base is present on the opposite strand. Damage to the sugar-phosphate backbone can also be repaired using the opposite strand as a template.

DECODING THE INFORMATION IN DNA

5¢-CAGCGTA-3¢ 3¢-GTCGCAT-5¢

The simplicity of the double helix structure allows for several important functions for DNA. Firstly, huge amounts of information can be stored in the strand of DNA. If a molecule of DNA is 1 million bases long, then there are 41 000 000 possible sequences for that stretch of DNA. A genome is the complete DNA sequence of an organism. In humans, the estimated genome size is 3 × 109 base pairs (bp). The human genome contains a huge amount of coded information, of which as yet only a small part is known. Secondly, the double helix provides a framework for DNA replication. One strand of DNA acts as a template for the synthesis of a new strand of DNA. The double helix unwinds, allowing DNA replication enzymes access

G

C T

A

G

C

A

A

T

T G

C

Figure 14.2 Double-helix structure of DNA. The double helix of deoxyribose and phosphate molecules is held together by paired purine and pyrimidine bonds

About 90% of the DNA in the human genome does not code for any speciﬁc property. Only about 10% of the genome actually contains coding information in the form of a gene. In simple terms, the genetic code in DNA is transcribed into a molecule called messenger RNA (mRNA). The mRNA is then translated into a protein, which carries out the function encoded by the speciﬁc DNA. A gene has several distinct elements (Fig. 14.3). The major part of the gene is divided into coding regions, called exons, and non-coding regions called introns. Just before (5¢) the ﬁrst exon, there is a promoter which indicates where transcription of a gene should start. There can be several promoters for one gene, and different promoters can be used according to the tissue in which the gene is being expressed, in other words the promoter is tissue speciﬁc. Further 5¢ of the promoter, there can also be enhancers or suppressors, which can increase or decrease the level of transcription of the gene. Not all of the mRNA will code for protein, as some exons will code for mRNA that does not directly encode protein. These areas, known as untranslated regions, can be either at the start (5¢) or the end (3¢) of the mRNA. To express the DNA code, mRNA is used. There are several different types of RNA, but mRNA is the most important in decoding DNA. There are three differences between RNA and DNA. Firstly, the sugar backbone of RNA contains ribose rather than deoxyribose. Secondly, mRNA exists as a single strand, and remains more unstable. Thirdly, in RNA the base uracil (U) is used instead of thymine (T), whereas the other three nucleic acids remain the same. The DNA code in most genes is expressed as a protein, which is a peptide made of the building blocks of individual amino acids. Each amino acid is coded for by a sequence of three DNA bases, known as a codon. For some amino acids, there is more than one codon (Table 14.1). A long series of DNA codons in a gene will thus code for an entire protein. The mRNA codons coding for amino acids are identical to DNA codons, with the substitution of U for T. There is a tightly controlled mechanism for the generation of protein from a DNA template.

Decoding the information in DNA 159 5' untranslated region Exon Intron

Promoters Transcription enhancers initiation site

3' untranslated region

5'

3' AUG translation initiation site

Stop codon (UGA)

Coding region

AAAAAAAA(N)

5' cap

Polyadenine tail

Mature mRNA

Figure 14.3 An idealized gene

Table 14.1 The genetic code

First position

U amino acid

Second position C amino acid A amino acid

G amino acid

Third position

U

UUU UUC UUA UUG CUU CUC CUA CUG AUU AUC AUA AUG GUU GUC GUA GUG

UCC UCU UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG

UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG

U C A G U C A G U C A G U C A G

C

A

G

Phe Phe Leu Leu Leu Leu Leu Leu Ile Ile Ile Met Val Val Val Val

Ser Ser Ser Ser Pro Pro Pro Pro Thr Thr Thr Thr Ala Ala Ala Ala

To decode a gene into protein, the DNA is ﬁrst transcribed into mRNA. A strand (the ‘sense’ strand) of the DNA double helix is used by the enzyme RNA polymerase to synthesize a complementary strand of mRNA. Transcription of mRNA starts from the 5¢ end of the ﬁrst exon of the gene, until the end of the most 3¢ exon. The intervening introns are initially included and the ﬁrst molecule is known as pre-mRNA. The intronic RNA sequences are spliced out, and a 3¢ polyadenine tail is added, producing mature mRNA. The mature mRNA is then transferred from the nucleus to the ribosome to be used as a template for the production of protein. The mature mRNA has both 5¢ and 3¢ untranslated regions. Protein synthesis does not begin at the 5¢ end of the mRNA, but at the ﬁrst 5¢ AUG codon, which codes for the amino acid methionine. Protein translation stops at

UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC AAA AAG GAU GAC GAA GAG

Tyr Tyr Stop Stop His His Gln Gln Asn Asn Lys Lys Asp Asp Glu Glu

Cys Cys Stop Trp Arg Arg Arg Arg Ser Ser Arg Arg Gly Gly Gly Gly

the ﬁrst truncation codon (usually UGA) thereafter (Fig. 14.3). In the ribosome, amino acid-speciﬁc transfer molecules, called transfer RNAs, bind a free molecule of their speciﬁc amino acid. The binding is carried out by an anti-codon in the tRNA, which is complementary to the mRNA that codes for that speciﬁc amino acid. Using its anti-codon, the tRNA binds the speciﬁc mRNA codon for its amino acid. By a complex machinery, the amino acid is then added to a growing peptide chain which will eventually form the mature protein (Fig. 14.4). The 5¢ end of the mRNA corresponds to the NH2 (amino terminus) of the protein, and the 3¢ end of the mRNA corresponds to the COOH (carboxyl terminus) of the protein. Many proteins in higher species are modiﬁed after translation by the addition of phosphate or lipid groups.

160 Genetics in neonatal surgical practice 5'

mRNA 3' C

C

A

A

G

A C

G U

A C

G

G

U

G

U

G

A

C

C

G

G

G

Ribosome

U C U

U G

C Glutamic acid

Transfer-RNA

Arginine

G

Valine

Proline

Figure 14.4 Diagram of protein synthesis from mRNA

CHROMOSOMES AND CELL DIVISION The ﬁrst coiling of DNA is in the form of the double helix. However, there are subsequent higher orders of coiling and packaging of DNA. The ﬁrst order gives a loop of about 146 bp in size, wound around a histone protein. The complex is known as a nucleosome. The highest order of coiling of a large DNA molecule, with its associated histones and other proteins is known as a chromosome. A chromosome consists of one very long double helix of DNA, containing very many genes in millions of base pairs. Humans are diploid, that is to say they have two copies of every chromosome. The normal human chromosome complement is 46, made up of 22 pairs of autosomes (non-sex chromosomes) and two sex chromosomes, either X and Y in a male, or two X chromosomes in a female. Each member of a pair of autosomes contains the same genetic information. The pair of X chromosomes in a female will contain the same genetic information, but X and Y chromosomes in a male only have a small amount of genes in common. A normal human metaphase karyotype is shown in Fig. 14.5. When cells divide, the genetic content must also be duplicated so that the daughter cells have the correct genetic material. Most cell division occurs as mitosis, where one cell divides to give two cells genetically identical to that parent. This is the process which allows the formation of a complete human being from one fertilized embryo, and is also the process by which the cells of many organs are constantly renewed. Mitosis is one short period during a carefully programmed cell cycle (Fig. 14.6). After mitosis, the cell may enter a resting phase (G0), or go on to divide again (G1). A cell in G1 will then go on to synthesize new DNA as described earlier (S phase). There is then a second gap phase (G2) followed by mitosis (M). Prior to mitosis the cell can be said to be in interphase, during which the chromosomes are very elongated. Just before mitosis, in S phase, the chromosomes are dupli-

Figure 14.5 A normal male karyotype

G0 phase

M phase

G2 phase

G1 phase

S phase

Figure 14.6 Cell cycle

cated, and begin to condense as two (sister) chromatids per chromosome. This condensation phase is known as prophase. In the next phase, metaphase, the condensed chromatids line up along the plane of the cell, and spindle ﬁbers develop between the centromeres (narrow waist of each chromatid), and the polar centrioles. Standard analysis of human chromosomes is carried out in metaphase. The chromatids separate, starting from each centromere, and pass to the new daughter cell, in

Chromosome analysis 161

the step called anaphase. By the telophase, the chromatids have reached to opposite poles of the dividing cell, and division completes. Meiosis is the form of division required to form gametes (sperm or oocyte). Gametes are haploid, with only one of each chromosome, 23 chromosomes in the case of humans. This allows the formation of a new diploid organism from two haploid gametes. Meiosis occurs in two stages: meiosis I and meiosis II. The ﬁrst phase of meiosis I, prophase I, is similar to that in mitosis, with the appearance of two condensed chromatids which have duplicated. At this stage, crossing over of genetic material from one chromatid to another can occur. It is estimated that about 1–2 cross-overs occurs per chromosome in each meiosis. This introduces further genetic diversity, ensuring that the inherited chromosomes are different from the chromosomes of the parent. Metaphase I then occurs, where chromatids do not separate, but go to the opposite ends of the cell in anaphase I and telophase I. The cells at this stage are still diploid. The second meiotic division then occurs, where chromatids condense again in prophase II, and line up along the axis of the dividing cell in metaphase II. The chromatids then separate, passing to opposite ends of the cell in anaphase II. The new cells are then haploid, with 23 chromosomes, and the chromatids elongate into thin strands in telophase II.

CHROMOSOME ANALYSIS To examine chromosomes from a patient (a karyotype), dividing cells in culture must be examined. These cells are usually lymphocytes, amniotic ﬂuid cells, or ﬁbroblasts. Cells are arrested in the metaphase stage of mitosis, and stained in such a way that the chromosomes are easily visualized. The usual technique used is Gbanding (using a Giemsa stain), which gives a characteristic positive and negative banding pattern to each chromosome. Each chromosome has a constriction, called a centromere, dividing the chromosome into a short arm (p) and a long arm (q). Each arm has a number of prominent bands, which can then be subdivided into smaller bands. The gene for the ABO blood group is localized to chromosome 9q34. The gene thus lies in the fourth sub-band from the centromere (q34) of the third band from the centromere (q34) on the long arm (q34) of chromosome 9 (9q34). Chromosome abnormalities can broadly be classiﬁed into abnormalities of chromosome number, or a rearrangement of a normal number of chromosomes. The critical issue in most cases for determining the signiﬁcance of a chromosome abnormality is whether the abnormality gives rise to an excess or deﬁciency of the normal diploid state (aneuploidy).

Abnormalities of chromosome number are relatively common, but many are not recognized, as they may result in the early loss of a pregnancy. Triploidy (69 chromosomes) and tetraploidy (92 chromosomes) are relatively common causes of early pregnancy loss. Trisomy, the presence of a single extra chromosome (47 chromosomes), is also a common cause of miscarriage. Speciﬁc trisomies can give rise to an affected neonate, the commonest being trisomy 21 (Down syndrome), trisomy 13 (Patau’s syndrome) and trisomy 18 (Edwards’ syndrome). All these trisomies usually occur as a result of autosomal non-dysjunction in meiotic division of the oocyte. In non-dysjunction, the speciﬁc chromatids fail to separate, resulting in an extra chromosome in one oocyte, and no chromosome in the opposite gamete. A fertilized embryo from the oocyte with an extra chromosome will therefore be trisomic. The fertilized oocyte with an absent chromosome will be monosomic, and be lost as an early miscarriage. Non-dysjunction tends to occur more frequently with increasing maternal age. Non-dysjunction can occur in the male germline, but rarely produces viable offspring. There are numerous types of chromosome rearrangements, the commonest of which are shown in Fig. 14.7. Pericentric and paracentric chromosome inversions are usually balanced, and inherited without any phenotypic effect. Paracentric inversions are usually associated with a low risk of producing a liveborn unbalanced karyotype, but pericentric inversions may carry a higher risk. Insertions, duplications, deletions, isochromosomes and ring chromosomes are all usually aneuploid and associated with signiﬁcant clinical abnormalities. Reciprocal translocations occur where there is exchange of genetic material from one arm of a chromosome in return for genetic material from a different chromosome. Reciprocal translocations are usually balanced, without any clinical effect, but may carry a risk of having a child with problems due to an unbalanced karyotype. Another type of translocation occurs between the acrocentric chromosomes (13–15, 21 and 22), where there is no appreciable coding material on a very small short (p) arm. This is known as a Robertsonian translocation. Robertsonian translocations are one of the commonest human chromosome translocations, and in the balanced form have no clinical effect. A Robertsonian translocation involving chromosomes 14 and 21 is shown in Fig. 14.8. Those who carry a Robertsonian translocation involving chromosome 21 may be at signiﬁcantly higher risk of having a child with Down syndrome as an unbalanced product of the translocation. The same applies to a lesser extent for those carrying a Robertsonian translocation involving chromosome 13, and a subsequent risk of a child with Patau’s syndrome. The nomenclature for reporting a chromosome analysis is strict, and needs to be read carefully. A karyotype is reported initially as the number of chromosomes,

162 Genetics in neonatal surgical practice Normal

Pericentric inversion

Paracentric inversion

Deletion

Isochromosome

A

A

A

B

C

B

B

C

C

B

D

C

C

D

D

C

D

D

Figure 14.7 Different types of chromosome anomaly. A–D represent notional chromosomal loci

D

Reciprocal translocation

Ring chromosome

A

B B A

C C D D

Balanced Robertsonian 14/21 translocation

Normal

14

14

14 21

21

21

Figure 14.8 Robertsonian translocation

regardless of whether those chromosomes are normal or not. The sex chromosomes are then described. If there is no further abnormality, the report is then complete. Any further abnormality is added after the sex chromosomes. A normal male karyotype is thus 46,XY. A male with non-dysjunctional Down syndrome will have the karyotype 47,XY,+ 21, an extra unattached chromosome 21. A male with Down syndrome due to a Robertsonian translocation between chromosomes 14 and 21 will have the karyotype 46,XY,t(14;21), and his carrier mother will have a karyotype 45,XX,t(14;21). A standard laboratory chromosome analysis will be performed on G-banded chromosomes, which will detect many common and less common chromosome abnormalities, and in most cases no further laboratory

work is required. However, recombinant DNA technology has allowed new techniques for chromosome analysis, based on the hybridization of ﬂuorescently labelled fragments of DNA to the DNA of chromosomes, prepared in a standard fashion, immobilized on a glass slide. The slides can then be visualized by eye using a ﬂuorescent microscope, or indirectly by generating an image of the hybridization on computer. This technique is known as ﬂuorescent in situ hybridization (FISH). The information which can be gained from this technique depends on the origin of the fragments of DNA hybridized to the chromosome preparation. Labelled whole chromosome ‘paints’, consisting of DNA exclusively from one chromosome are now commercially available. For example, whole chromosome paints can be used to identify the origin of extra chromosomal material which cannot be identiﬁed using G-banding techniques. Whole chromosome paints are also helpful in determining the origin of subtle complex translocations. It is also now technically possible to use a chromosome 21 paint on uncultured cells in interphase, to look for trisomy 21. A cell would show three ﬂuorescent nuclear dots, representing three chromosomes 21, as opposed to two in the normal situation. Fluorescently labelled small DNA fragments, corresponding to 40–50 kb of DNA from a speciﬁc chromosomal region, can also be hybridized to metaphase chromosomes. Chromosomal deletions which cannot be detected within the resolution of conventional cytogenetic analysis, can be detected by the FISH method. A normal karyotype will give two hybridization signals:

Patterns of inheritance 163

one from the same part of each chromosome. A karyotype containing a submicroscopic chromosomal deletion involving the segment of the chromosome corresponding to the 50 kb DNA fragment will only give one hybridization signal. An example would be the submicroscopic deletion of chromosome 22q11 which occurs in most cases of the Di George spectrum, which can only be seen by FISH analysis of chromosomes. FISH diagnosis of submicroscopic chromosomal deletions is likely to become available for a variety of speciﬁc clinical syndromes.

PATTERNS OF INHERITANCE Single-gene disorders have one of three principal modes of inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. Other rare forms of inheritance include X-linked dominant, and mitochondrial disorders, as well as disorders due to abnormalities of genetic imprinting. Disorders caused by inheritance of unstable elements of DNA are now increasingly being recognized (see later).

Autosomal dominant inheritance Autosomal dominant disorders are characterized by vertical transmission from parent to child, and the hallmark of these conditions is male-to-male transmission of the disease (Fig. 14.9). Those affected with an autosomal dominant disorder have an alteration in one or other copy of their two genes responsible for that condition. Each child of a person with an autosomal dominant disorder has a 50:50 chance of inheriting the gene responsible for the condition from its parent. There are many examples of autosomal dominant disorders, including neuroﬁbromatosis 1 and 2, familial adenomatous polyposis coli, myotonic dystrophy, and

II:1

II:6

III:3

III:4

I:1

I:2

II:2

II:3

II:4

II:5

III:1

III:2

Huntington’s disease. There can often be variability in both expression and penetrance of autosomal dominant disorders. For example, neuroﬁbromatosis 1, an autosomal dominant condition, will almost always manifest in someone who has an altered neuroﬁbromatosis 1 gene. This means that the condition has almost complete penetrance. However, different people can manifest the condition in different ways, with some people showing mild skin lesions, and others with severe intracerebral complications. This means that the expression or expressivity of the condition is very variable. In contrast, only 80% of those who have a single altered gene for the rare hereditary form of retinoblastoma will actually develop an eye tumor. The penetrance in this situation is 80%, but the expression of the altered gene is consistent, as manifested by a retinoblastoma. Autosomal dominant disorders are not commonly seen in neonatal surgical practice. A list of the more frequent conditions is outlined in Table 14.2.

Autosomal recessive inheritance When a child is diagnosed with an autosomal recessive disorder, then both copies of a particular gene responsible for the condition are altered. Both its parents are therefore carriers for that condition, with one normal and one altered gene. Two of the child’s four grandparents is also a carrier, and it is likely that many of the child’s relatives are also unknowingly carriers (Fig. 14.10). In most cases, being a carrier for an autosomal recessive condition has no effect on that person. When both parents are carriers for an alteration in the same gene, then there is a 25% or 1 in 4 chance for each of their children to be affected by the condition. The risk of a healthy carrier sibling of having a child with the same condition depends on the chances of that sibling’s partner also being a carrier. A child of a person with an autosomal recessive disorder will automatically be a carrier. The child’s chances of being affected will depend upon whether its unaffected parent is a carrier for an alteration in the same gene.

= affected Note male-to male transmission and non-penetrance in II:4

Figure 14.9 Autosomal dominant inheritance

= affected = heterozygous carrier

Figure 14.10 Autosomal recessive inheritance

164 Genetics in neonatal surgical practice Table 14.2 Autosomal dominant disorders in neonatal surgical practice System affected

Condition

Gastrointestinal

Hirschsprung’s disease (some cases) Beckwith–Wiedemann syndrome with exomphalos (some cases) Pyloric stenosis (some cases)

Genito-urinary

Vesico-ureteric reﬂux

Skeletal

Stickler’s syndrome Most craniosynostosis syndromes Achondroplasia Osteogenesis imperfecta Limb reduction defects (some cases)

Cardiac

Holt-Oram syndrome Noonan’s syndrome 22q11 microdeletion syndrome

Other

Retinoblastoma

Autosomal recessive disorders are commonly encountered in neonatal practice, and the nature of the disorder depends on the population being seen. Each regional population has its own recessive disorder, where the frequency of carriers for that disorder is highest. For instance, cystic ﬁbrosis is a very common autosomal recessive disorder in western Europe, whereas sickle cell anemia is the commonest autosomal recessive disorder in west Africa. Common examples of autosomal recessive conditions include cystic ﬁbrosis, sickle cell anemia, several of the mucopolysaccharidoses, beta-thalassemia, spinal muscular atrophy and congenital adrenal hyperplasia (Table 14.3). Prenatal diagnosis is available for many of these conditions.

X-linked recessive inheritance In X-linked recessive inheritance, the condition affects almost exclusively males, and females can be carriers (Fig. 14.11). The classic examples of such conditions are hemophilia A and B, Duchenne and Becker muscular dystrophy, and Hunter syndrome. Table 14.3 Autosomal recessive disorders in neonatal surgical practice System affected

Condition

Metabolic

Cystic ﬁbrosis α-1-antitrypsin deﬁciency

Skeletal

Short-rib polydactyly syndrome Jeune’s syndrome Robert’s syndrome

Genito-urinary

Infantile polycystic kidneys Meckel-Gruber syndrome

Endocrine

Congenital adrenal hyperplasia

= affected male = carrier female

Figure 14.11 X-linked recessive inheritance

The daughters of a man with an X-linked recessive condition are all obligate carriers. The sons of a man with an X-linked condition are all normal, as they inherit his Y chromosome, and not his X chromosome. When a woman is a carrier of an X-linked condition, each of her sons has a 50:50 chance of being affected, and each of her daughters has a 50:50 chance of being a carrier. There can be a relatively high mutation rate for some X-linked recessive conditions, and affected boys may not have any family history of the condition. About one-third of cases of boys with Duchenne muscular dystrophy occur as a result of new mutations. Prenatal diagnosis is available for a wide range of X-linked recessive diseases. The more common X-linked disorders in neonatal practice are shown in Table14. 4.

Polygenic inheritance Many congenital conditions do not have a clear mode of inheritance, and can be classed as polygenic or oligogenic, where a disease may arise as a result of the effects of several genes. A good example is cleft lip and palate,

Patterns of inheritance 165 Table 14.4 X-linked recessive disorders in neonatal surgical practice System affected

Condition

Neurological

Hydrocephalus with aqueduct stenosis (some cases)

Hematological

Hemophilia

Skeletal

Amelogenesis imperfecta

Endocrine

Androgen insensitivity syndrome

Metabolic

Adrenoleucodystrophy

which usually occurs in the absence of a family history. However, monozygotic twins have a high concordance for cleft palate, suggesting a genetic inﬂuence. A similar model applies to the genetics of neural tube defects, which arise as a result of the combination of several environmental and genetic factors.

Other forms of inheritance There are also much rarer forms of inheritance, including X-linked dominant, which can be hard to tell apart from autosomal dominant, except that females will be more mildly affected, and there is no male-to-male transmission. An example of an X-linked dominant condition is hypophosphatemic rickets. Mitochondrially inherited diseases show a very unusual pattern of inheritance. Most of the proteins in the mitochondria are encoded for by nuclear genes, but the mitochondria also contain their own small genome of 18 kb, with many copies per cell. The mitochondrial genome replicates independently and far more frequently than the nuclear genome. Several important mitochondrial proteins are encoded by the mitochondrial genome. Mitochondria are only inherited via oocytes, and not sperm. Therefore, where a gene alteration is in the mitochondrial genome, it will pass exclusively down the female line, but both males and females can be affected. The children of an affected male will not inherit their father’s mitochondrial gene alteration. Children with mitochondrial disorders can present with many varied symptoms, including myoclonic seizures, acute acidoses, muscle weakness, deafness or diabetes. A number of point mutations and deletions in the mitochondrial genome have been described in patients with a wide variety of conditions, including myoclonic epilepsy with lactic acidosis and stroke-like episodes (MELAS) or myoclonic epilepsy with ragged red ﬁbers on muscle biopsy (MERRF). To complicate matters further, Leber’s hereditary ophthalmopathy is a mitochondrially inherited condition, with a characteristic mitochondrial mutation, but the expression appears to have an X-linked recessive inﬂuence. Some conditions show a phenomenon known as genetic imprinting. An imprinted gene has been marked

during meiosis, to indicate the parent from which it comes. For some genes, it appears to be important not only to inherit two copies of that gene, but to inherit one from each parent. Some genes may be silenced, depending upon which parent has passed on that gene. A good example is the presence of a small deletion of chromosome 15q, which has a different effect, depending upon which chromosome 15 is deleted. If the deletion occurs on the chromosome inherited from a child’s normal father, the child will develop Prader-Willi syndrome. If the deletion occurs on the chromosome inherited from a child’s normal mother, the child will develop a completely different clinical condition, Angelman’s syndrome. The genes in this area of chromosome 15 are therefore imprinted. In addition, if a child has two maternal copies of chromosome 15 (maternal disomy), but no paternal copy, he or she will also develop Prader–Willi syndrome. Other conditions which show imprinting effects include Russell-Silver syndrome, Beckwith-Wiedemann syndrome, and the rare condition of transient neonatal diabetes mellitus. A new molecular mechanism for genetic disease has been described, of inherited unstable triplet repeat expansions. At least nine different conditions are caused by this phenomenon. In one of these genes, a normal person has a stable number of a repetitive element of three bases of DNA (for example 20 copies of a CAG repeat) in a particular gene. In that case the gene functions normally and the children of that person have the same number of repeats in their gene. An affected person has an increased number of repeats (say 100 copies) in that gene, and the affected children of that person have more serious disease, with perhaps 200 repeats in the gene. The molecular genetic ﬁndings appear to be the genetic correlate of the phenomenon of anticipation, where a condition appears to worsen from generation to generation. The most extreme example is that of congenital myotonic dystrophy, where a minimally affected mother can have a profoundly affected infant. In this case, there is a small repeat expansion of say 150 repeats in the mother, increasing to many hundreds of repeats in her affected infant. This molecular mechanism is responsible for Fragile X syndrome, Huntington’s disease, Friedreich’s ataxia,

166 Genetics in neonatal surgical practice

several forms of spinocerebellar ataxia, and probably several other conditions.

MOLECULAR GENETIC ANALYSIS FOR SINGLE-GENE DISORDERS Laboratory tests for single-gene disorders have been available for a considerable amount of time. Hemoglobin electrophoresis for sickle cell anemia and thalassemia, and enzyme assays for Tay-Sachs’ disease are very effective in resolving clinical issues in individual families. However, an increasing number of speciﬁc DNA-based tests can now be used in diagnosis and prediction of single-gene disorders. The two major techniques used in molecular genetic analysis are the polymerase chain reaction (PCR) and Southern blotting techniques. PCR is a technique which allows ampliﬁcation of a speciﬁc genetic region in large quantities from a small amount of DNA template (Fig. 14.12). The DNA sequence of the region to be ampliﬁed must be known, so that synthetic pieces of singlestranded DNA (oligonucleotide primers) corresponding to the region can be designed and manufactured. The oligonucleotide primers are added in great excess to the DNA template, along with a thermostable DNA polymerase, and free nucleotides (A,C,T,G). The mixture is heated up to cause the two strands of template DNA to separate, and then cooled. As the DNA cools, the oligonucleotides bind to the template sequence, and are extended by the polymerase. A new copy of the template DNA is thus produced. The cycle is repeated 30–40 times, with an exponential increase in the amount of the target sequence.

DNA generated by PCR can be used in many different ways to detect an abnormality in the sequence. There are numerous techniques which are used to screen PCR products for mutations, such as single-stranded conformational assay (SSCA), or denaturing gradient gel electrophoresis (DGGE). In some cases the complete sequence of the PCR product can be directly determined. Speciﬁc PCR assays for mutations have been developed, such as the ampliﬁcation resistant mutation system (ARMS) test, or the use of a speciﬁc DNA restriction enzyme which recognizes a known mutant DNA sequence. Southern blotting is a more protracted procedure involving the digestion of a relatively large amount of DNA by a restriction enzyme. The digested DNA is then electrophoresed through an agarose gel, giving a smear of DNA of different sizes. The DNA is then transferred (blotted) and ﬁxed to a membrane. The ﬁxed DNA is then hybridized to a labelled DNA probe speciﬁc for the gene to be analyzed, and the speciﬁc sizes of DNA to which the probe binds allows determination of the ‘genotype’ (Fig. 14.13). This test is often superseded by PCR technology. There are different degrees to which molecular genetic tests can contribute to clinical diagnosis. Some speciﬁc molecular genetic tests can be used to detect a known pathogenic DNA mutation, and give a diagnosis, even without any knowledge of the patient’s clinical status. For instance, the PCR detection of the ΔF508 deletion in both copies of a person’s cystic ﬁbrosis (CFTR) gene immediately gives a diagnosis of cystic ﬁbrosis. Such Digested DNA separated on agarose gel

DNA transferred and fixed to membrane

+

Primers

Heat

Sequence to be amplified Separation of strands

–

Cycle 1

Primers Membrane hybridized with radiolabelled specific DNA probe

Heat

Separation of strands

Heat

Separation of strands

Figure 14.12 Polymerase chain reaction (PCR)

Radiolabelled probe binds to specific sequences detected by autoradiography

Cycle 2

Cycle 3

Figure 14.13 Southern blotting and hybridization

A clinical genetic approach to diagnosis of malformation syndromes 167

direct mutation tests are possible where both the gene responsible for a condition has been isolated, and speciﬁc pathogenic mutations have been identiﬁed. Similarly a PCR test detects a deletion of exons seven and eight in both alleles of a gene called SMN on chromosome 5q in almost all children with spinal muscular atrophy. Southern blot analysis of DNA from infants with congenital myotonic dystrophy shows a very large expansion in a triplet repeat DNA sequence in the myotonin kinase gene on chromosome 19, as described earlier under ‘Other forms of inheritance’. In other cases, molecular genetic diagnosis can point towards a diagnosis, without conﬁrming it. For instance, the presence of a single ΔF508 CFTR gene mutation in a child with a history suggestive of cystic ﬁbrosis increases the likelihood of the child being affected. In some cases, where either a gene is not known, or very few gene mutations have been identiﬁed in a known gene, gene tracking studies can be performed in a family to predict whether a person in that family is affected. This is known as linkage analysis. Such a study requires careful clinical examination of several family members, to establish whether they are affected or unaffected. Where their clinical status is clear, DNA samples are then obtained. Gene tracking analysis in the family uses the property of normal variation in a gene between different people. Some genetic areas show wide variation between individuals, and a DNA marker from such an area, which can detect many variations, is described as being polymorphic. Each variant of a polymorphic marker is known as an allele. There are now thousands of polymorphic markers covering most of the human genome, and such markers can be found very close to most known genes. There are several types of polymorphic DNA markers, including markers characterized by different numbers of speciﬁc DNA-cutting enzymes recognition sites or restriction fragment length polymorphisms (RFLPs). Other markers detect the variation in number of anonymous elements of repetitive DNA and are called microsatellites or minisatellites. If the two alleles of a polymorphic marker can be distinguished, to discriminate between the two copies of that particular chromosome from where the marker comes, then the marker is informative in that individual. Where a gene location is known but the actual gene has yet to be found, the alleles of informative markers which lie on either side of the gene will be inherited along with each copy of the gene in question. This can be used to predict a child’s clinical status. If one set of alleles is found in the affected members of the family, but not in those unaffected, then the presence or absence of these alleles in the at-risk individual can be used to predict their chances of being affected. An example of linkage analysis for an autosomal recessive disorder is shown in Fig. 14.14. This form of linkage analysis is often used in families with X-linked recessive

2,3

2,4

1,2

3,4

2,3

1,4

?

= affected = carrier Alleles 2 and 3 are associated with a gene mutation and can be used to predict the status of another sib

Figure 14.14 Linkage analysis in an autosomal recessive disorder using an intragenic polymorphic marker

conditions such as Duchenne muscular dystrophy, to predict whether a woman is a carrier. Such linkage analysis can also be used in prenatal diagnosis. Of its nature, linkage analysis is more prone to error than direct mutation testing. This can be due to difﬁculties in assessing a person’s clinical status, and because of the possibility of recombination between the polymorphic markers. However, with the rapid advances in molecular genetics, many more mutations are being found in many different genes, and linkage analysis is often superseded by direct mutation testing. There are many new molecular genetic tests being developed, with the rapid advances in human molecular genetics. It is impossible to cover all such tests in the space available in this chapter, but it is clear that new genetic tests will alter the clinical management of many neonatal conditions.

A CLINICAL GENETIC APPROACH TO DIAGNOSIS OF MALFORMATION SYNDROMES Deﬁnitions One child in 40 (2.5%) is born with a signiﬁcant congenital anomaly and 20–25% of perinatal and childhood mortality is accounted for by congenital anomalies. Only a small number of these anomalies will occur as part of a speciﬁc genetic syndrome. A list of common congenital anomalies and approximate birth incidence is shown in Table 14.5. Awareness of the possibility of a genetic or syndromal association for anomalies is very important for management of the patient, and for advising the whole family. A distinction has also to be drawn between several different forms of abnormality, with appropriate deﬁnitions. A disruption can be deﬁned as an anomaly which is caused by an interference in the structure of a normally

168 Genetics in neonatal surgical practice Table 14.5 Examples of major congenital anomalies

Urethral obstruction, e.g. valve

Renal agenesis

Type

Birth incidence (per 1000 births)

Cardiovascular Ventricular septal defect Atrial septal defect Patent ductus arteriosus Fallot’s tetralogy

10 2.5 1 1 1

Central nervous system Anencephaly Hydrocephalus Microcephaly Lumbosacral spina biﬁda

10 1 1 1 2

Gastrointestinal Cleft lip/palate Diaphragmatic hernia Esophageal atresia Imperforate anus

4 1.5 0.5 0.3 0.2

Limb Transverse amputation

2 0.2

Urogenital Bilateral renal agenesis Polycystic kidneys (infantile) Bladder extrophy

4 2 0.02 0.03

developing organ. A good example would be the digital constrictions and amputations caused by amniotic bands. A deformation can be deﬁned as an anomaly which is caused by an external interference in the structure of a normally developing organ. An example would be talipes equinovarus caused by chronic oligohydramnios, perhaps from an amniotic leak. A malformation can be deﬁned as an anomaly which is caused by an intrinsic failure in the normal development of an organ. Common examples would be congenital heart disease, cleft lip and palate, and neural tube defects. A dysplasia is an abnormal organization of cells in a tissue, often speciﬁc to a particular tissue. For example, achondroplasia is a skeletal dysplasia caused by a mutation in the FGFR3 gene. Most dysplasias are singlegene disorders. A sequence can be deﬁned as a group of anomalies which arise due to one single event. An example would be Potter’s sequence. Potter’s sequence (Fig. 14.15) is the group of anomalies consisting of pulmonary hypoplasia, oligohydramnios, talipes, cleft palate, and hypertelorism. All of these anomalies arise as a result of the failure of urine production in the fetus. The cause of Potter’s syndrome and failure of urine production could be posterior urethral valves, dysplastic or cystic kidneys, or renal agenesis, all of which can have genetic, non-genetic or chromosomal origins. Pierre Robin sequence is the

Reduced urinary output Chronic amniotic leak Oligohydramnios Squashed facial features

Dislocated hips talipes Pulmonary hypoplasia

Death

Figure 14.15 Potter’s sequence

grouping of cleft palate, micrognathia and glossoptosis, which can have at least 30 different causes. A sequence therefore does not have a speciﬁc cause or inheritance pattern. An association can be deﬁned as a clustering of anomalies, which is not a sequence, and which occur more frequently than by chance, but has no prior assumption about causation. A good example is the association of VATER (vertebral anomalies, anal abnormalities, tracheo-esophageal ﬁstula, and radial or renal anomalies). There is no clear cause for VATER, although it can rarely occur in people with chromosome 22q11 microdeletions, and can also rarely be mimicked by Fanconi’s anemia. A syndrome is a description of a group of symptoms and signs, and a pattern of anomalies, where there is often a known cause or an assumption about causation. The looser deﬁnition of ‘syndrome’ to describe an anomaly should be avoided. The term can include chromosomal disorders such as Down syndrome, or single-gene disorders such as van der Woude syndrome, which can cause cleft lip and palate with lower lip pits.

An approach to diagnosis When a child is born with a congenital anomaly, several particular aspects of the history need to be explored. A good family history must be taken, with reference not only to a history of the same anomaly, but other anomalies as well. A family history must include documentation of pregnancy losses, stillbirths and neonatal deaths. Any history of potential teratogens in the pregnancy should be looked for, considering the likely embryological timing of the anomaly. Teratogens can include medications, recreational drugs, maternal diabetes and prolonged maternal hyperthermia. If a child has one congenital anomaly, a very careful examination should be carried out to check for any other more subtle abnormalities or for dysmorphic facial features, e.g. to check for hydrocephalus in an infant with

Further reading 169

a spinal meningomyelocele. If there is more than one malformation or signiﬁcant dysmorphology, a chromosomal analysis should be requested, as chromosomal aneuploidy is a well-recognized cause of multiple malformations. A clinical genetic opinion should also be sought, as a clinical geneticist can often help greatly in achieving a diagnosis, as well as in counselling parents about the likelihood of recurrence of similar problems in other family members. A diagnostic approach to congenital anomalies is outlined in Fig. 14.16. Deformations and disruptions need to be excluded ﬁrst. If the pattern of malformations ﬁts into a well-described sequence, then a cause for that sequence should be sought. If the anomalies do not ﬁt into a sequence, then a syndrome or association diagnosis should be attempted. If a syndrome diagnosis is achieved, it is important to remember that syndromes can be caused by chromosomal disorders, single-gene (monogenic) disorders, or by environmental agents (teratogens). The majority of congenital anomalies have a polygenic or multifactorial origin, and most are isolated (non-

Congenital anomalies

Malformation

Deformation

Malformation sequence

Multiple anomalies not explained by a sequence

Disruption

Malformation syndrome

Chromosomal

Monogenic

Teratogenic

Cause unknown

Figure 14.16 A diagnostic approach to congenital anomalies

syndromal). The causes of congenital abnormalities are outlined in Table 14.6, and it is important to note that about 50% do not have a clear cause. Nonetheless, parents and families want an explanation as to the origin of their child’s anomaly, and it is therefore worthwhile to pursue a diagnosis wherever possible. This chapter is an introduction to the concepts and principles of genetics in neonatal surgical practice. It is not intended to be a comprehensive review of syndromes. Further information can be obtained from the bibliography later, and from many Internet sources.

Table 14.6 Causes of congenital anomalies Type

Relative frequency

Genetic Chromosomal Single gene Multifactorial/polygenic

6% 7.5% 20–30%

Environmental Drugs, infections, maternal illness

5–10%

Unknown

50%

Total

100%

FURTHER READING 1. Watson JD, Hopkins NH, Roberts JW, Steitz JA, Weiner AM. Molecular Biology of the Gene. 5th edn. Menlo Park, CA: Benjamin Cummings Publishing Company, 1993. 2. Strachan T, Read AP. Human Molecular Genetics. Oxford: BIOS Publishers, 1996. 3. Lewin B. Genes V. Oxford: Oxford University Press, 1994. 4. Connor M, Ferguson-Smith M. Essential Medical Genetics. 5th edn. Blackwell Scientiﬁc, Oxford 1997. 5. Mueller RF, Young ID. Emery’s Elements of Medical Genetics. 10th edn. Churchill Livingstone, Edinburgh 2001. 6. Online Mendelian Inheritance in Man. A list of genetic disorders and the latest genetic developments for each condition. Website http://www3.ncbi.nlm.nih.gov /Omim.

170 Genetics in neonatal surgical practice

GLOSSARY 3-prime 5-prime Acrocentric Allele Aneuploidy Anti-codon Autosomal dominant Autosomal recessive Base pair Centromere Chromatid Codon Diploid DNA marker Enhancers Exon Expression FISH Gamete Genetic imprinting Haploid Haplotype Histone Interphase Intron Isochromosome Karyotype Linkage analysis Meiosis Metaphase Microsatellite marker Minisatellite marker Mitosis Non-dysjunction Nucleosome Oligonucleotide primers Paracentric inversion PCR Penetrance Pericentric inversion Promoter Prophase

Distal end of a gene, as indicated by the bond at the 3rd hydroxyl group of the deoxyribose sugar Proximal end of a gene, as indicated by the bond at the 3rd hydroxyl group of the deoxyribose sugar A chromosome with effectively only a long arm – chromosomes 13,14,15,21, and 22 A genetic variation of a gene or DNA marker An excess or deﬁciency of chromosomal material An element of transfer RNA which binds a speciﬁc amino acid Inheritance pattern characterized by transmission through several generations, male-tomale transmission, and a 50:50 risk to the children of any affected person. Inheritance pattern characterized by several affected members of the same generation, with carrier parents and a 1:4 recurrence risk where both parents are carriers Unit of double-stranded DNA Element of chromosome involved in chromosome replication, found as a constriction in the chromosome Condensed chromosome found just before mitosis Three base pair element of DNA encoding an amino acid A complement of two copies of each chromosome per cell A piece of DNA corresponding to a speciﬁc gene or chromosomal segment Elements of DNA which are involved in increasing gene transcription A part of a gene which is transcribed into mRNA The way in which a gene fault manifests clinically Fluorescent in situ hybridization – a new and powerful technique for studying speciﬁc chromosomes or regions of chromosomes A germ cell – sperm or oocyte The marking of a gene according to which parent has passed the gene to its child A complement of one copy of each chromosome per cell (as in sperm or oocyte) A pattern of alleles of DNA markers representing one of the two copies of a chromosomal region A DNA-binding protein important in chromosomal folding Phase of mitosis in which the chromosomes are very elongated The part of a gene between the exons which is not transcribed into mRNA An abnormal chromosome made up of two long or two short arms of a normal chromosome An analysis of the chromosome complement of a cell type The use of polymorphic DNA markers to perform gene tracking studies within a family The process of cell division to give haploid germ cells Phase of mitosis in which the chromosomes are very condensed and easier to analyze A DNA marker which detects variation in number of an anonymous small repetitive element of DNA A DNA marker which detects variation in number of an anonymous medium repetitive element of DNA The normal process of cell division to give two diploid copies of a cell A failure of meiosis, giving two copies of a chromosome in one gamete, and no copy of a chromosome in the other gamete The combination of a histone and its bound DNA Small lengths of synthetic single-stranded DNA of a speciﬁc sequence A rearrangement of chromosomal material within one arm of a chromosome Polymerase chain reaction – a method of generating large amounts of speciﬁc DNA from a small amount of target sequence The number of people known to carry a gene mutation who manifest the condition A rearrangement of chromosomal material around the centromere of a chromosome Element of a gene which is necessary to activate gene transcription Phase of the cell cycle where condensation of the chromosomes occurs, just before metaphase

Glossary 171

Reciprocal translocation Restriction enzyme Restriction fragment length polymorphism Ribosome Ring chromosome Robertsonian translocation Southern blotting Suppressor Telophase Telomere Transcription Translation Triploidy Trisomy X-linked recessive

Exchange of chromosomal segments between different chromosomes An enzyme which cuts double-stranded DNA at a speciﬁc unique short DNA sequence A genetic variation between two copies of the same gene, where one gene may have one copy of a restriction enzyme recognition site, and the other has two copies. This variation can be detected using PCR or Southern blotting. Area of the cell where mRNA is converted into protein An abnormal chromosome in which the tips of the long and short arms have fused A fusion of two acrocentric chromosomes A process of immobilizing DNA to nylon membrane for genetic analysis A DNA element which reduces the expression of a gene The last phase of mitosis The end of a chromosome The process of converting DNA into mRNA The production of protein from a DNA sequence Three of each chromosome, i.e. 69 chromosomes in man One extra chromosome, i.e. 47 chromosomes in man Inheritance characterized by affected males in several generations, and by female carriers

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15 Ethical considerations in newborn surgery JACQUELINE J. GLOVER AND DONNA A. CANIANO

INTRODUCTION In caring for the extremely premature neonate with surgical disease or the infant with multiple, life-threatening congenital anomalies, pediatric surgeons often encounter difﬁcult ethical decisions about the use of advanced, life-sustaining treatments and operative interventions. The imperative to utilize new technology is tempered with concerns about quality of life, informed parental decision making, and access to scarce medical resources. Pediatric surgeons, families and communities ask the difﬁcult ethical question: ‘We can do this particular intervention, but, should we?’ This chapter provides the pediatric surgeon with ethical guidelines to utilize in clinical situations in which therapeutic decisions contain uncertainty or conﬂict and the next steps in the management of an infant that poses challenges for the parents and physicians.

DEFINING THE BEST INTERESTS STANDARD Since neonates and infants cannot make decisions about the appropriate use of technology based on their own personal values, the central ethical question is framed in pediatrics as, ‘What is in the best interests of this infant?’ An answer requires a unique and complex ethical framework that combines a concern for who makes the decision and what decision is appropriate. In the USA, parents are presumed to be the appropriate decision makers for their infants,1 but they are not unqualiﬁed decision makers. Parents and pediatric surgeons must work together to make decisions that are in the ‘best interests’ of infants.2 The term ‘best interests’ is meant to capture a balancing of the beneﬁts and burdens to this infant of a particular intervention.3 In the mainstream medical culture in the USA, the term ‘best interests’ was developed to focus attention on the need to assess the beneﬁts and burdens of treatment for a particular infant from the infant’s perspective. In an

effort to be as objective as possible, only the direct pain and suffering associated with an infant’s condition and/or proposed treatment was to be considered in conjunction with the beneﬁt of continued life. The standard was proposed as a very strict one, regarding treatment as beneﬁcial and in the infant’s best interest unless the infant was dying, the treatment was medically contraindicated, or continued life would be worse for the infant than an early death. A central feature of this narrow understanding of best interests includes its childcenteredness, understood to mean the exclusion from consideration of the negative effects of an impaired infant’s life on other persons, including parents, siblings and society. A second key feature is its emphasis on the infant’s concrete experience of burden in the form of pain and suffering. In addition to the difﬁculties associated with assessing the burdens experienced by an infant, a narrow best interests standard cannot be applied to neonates and infants with neurological deﬁcits so severe as to exclude the possibility of experience of any sort. Infants, who are not responsive to outside stimuli, for example, cannot experience pain and therefore cannot be burdened in the same way as conscious infants. Some ethicists have appropriately pointed out that absence of pain is not the only morally relevant feature.4 A ‘relational potential’ standard is necessary to augment a best interests standard. It is not morally obligatory to sustain life without any capacity for human relationship, even though life is not burdensome per se. Just as the presence of pain unable to be relieved can preclude the attainment of those basic human goods that make life worth living, so the absence of fundamental human capacity can render a life devoid of the same basic human goods.5 For the last few decades, the best interests standard has enjoyed prominence in pediatric ethics in the USA, although its limitations have also been clearly articulated. Critics argue that an infant’s interests are unknowable, that an interests appeal can yield counterintuitive results, and others’ interests also deserve consideration.6

174 Ethical considerations in newborn surgery

For those who favor a best interests standard, it is a way to focus attention on the patient as the primary loyalty of the health care professional, to maximize beneﬁt to the patient,7 to insure that the lives of the disabled are not undervalued, and to guarantee that justice in the form of principles of non-discrimination are applied.4 However, reliance on a narrow best interests standard fails to take into account other moral features that are a necessary part of ethical decision making in pediatrics. The term has been used to oversimplify a distressingly complex set of moral problems. The more one can render an ethical decision unidimensional, and the more factors one can exclude from consideration beforehand, the easier the choice becomes.5 An expanded understanding of best interests must take into consideration several competing ethical values. One value is respect for family autonomy or selfdetermination. Families ought to have the freedom to make important choices about family welfare independent of others. It is not so much that families have a right to make important decisions for their infants, as it is that families have the responsibility to make decisions and provide the necessary ﬁnancial and other types of support. Families are an essential unit of care that is both valuable in themselves, and instrumentally valuable to meet the social goal of caring for children. Since families are presumed to love their children and desire to do what is best for them, they have a unique claim to the decision-making role. Also, families have to live with the consequences of the health care decisions that are made. In a very real sense, the families’ interests are linked with the interests of the neonate or infant.8 An attempt to starkly separate infant and family interests is artiﬁcial and diminishes rather than enhances an understanding of the infant’s well-being. One can understand how the best interests standard developed in the context of imperiled newborns, where there is great uncertainty and no one has a longstanding relationship with the infant. The objectivity sought is comprehensible only because the infant is a stranger to all. Yet even in the case of newborns, most authors agree that parents should be the primary decision makers.9 If family interests were irrelevant, it would be difﬁcult to make sense of such a presumption. Given this presumption in favor of parental decision making, and the fact that most infants are not strangers to their parents, a best interests standard would be better understood to include a more comprehensive understanding of a child-centered decision, one made by a family whose daily lives involve the love and care of their infant. Additionally, the search for the ‘best’ interests of the infant apart from the family has several negative consequences. First of all, it can antagonize parents and turn all parties into adversaries. It can also cut off discussion and planning rather than improve it. Families may not feel free to discuss difﬁculties, and important needs may go unmet. Rather than search for some artiﬁcial ‘best’

interest, all parties should acknowledge the complex goal of promoting the infant’s well-being and the necessary interdependence of families in that endeavor. To exclude the family in a concept of child-centeredness is to reduce the infant to only a physiological organism and wellbeing to pathophysiological function. Another value that is in tension with respect for family decision making is respect for professional integrity. Since ‘best interests’ also contains an important focus on the uniquely medical interests of the infant, professional judgement plays an important role in describing and evaluating the beneﬁts and burdens of health care interventions.10 Pediatric surgeons have independent obligations to the infants who are their patients, to promote their well-being and protect them from harm. They have a professional obligation to promote life and quality of life, and to avoid such harms as killing, premature death, pain and suffering. Yet even based on so-called medical facts, decisions are a complex amalgam of what the infant’s alternative futures will be like, how likely it is that these futures can be gained, and what the infant has to endure to get there. An infant’s present interests in being free from undue burdens must be weighed against all future interests.11 A third important value is that of justice as nondiscrimination.4 How do we understand the interests of a child in himself or herself, independent of how others may value him or her? What does society owe its children as a matter of justice? Infants do not only belong to their families, but they also are members of their community. Communities have an obligation to protect the most vulnerable among them, especially if they are vulnerable to the neglect and abuse of their families. All infants deserve a certain level of health care, independent of what their families might choose for them. The principle of justice also has another important component that is in direct conﬂict with the highly individualistic interpretation of ‘best interests’. In fact, a ‘best interests’ standard is an attempt to narrowly focus decisions on the patient himself or herself and to avoid greater issues of the just distribution of health care resources, but this is impossible. Families and communities struggle to consider what they owe each child, but also to consider what is fair for this child and all children together. Resources of time, effort, services and money are limited within families and communities. Each must consider the impact of choices on the availability of resources for others. There is no doubt that questions of distributive justice are among the most difﬁcult ethical issues that families, professionals, and communities must face. But they will never be resolved if they are simply ignored in the decision-making process. The authors agree that allocation decisions are best made at levels other than at the bedside, as in the formulation of insurance plans and governmental policies. But these corporate allocation decisions will always have implications for bedside care, and must not be ignored.

Applying the best interests standard 175

An expanded ‘best interests’ standard is an attempt to balance the beneﬁts and burdens of a health care intervention according to the values of the parents, pediatric surgeons and the larger society. It should be clear that the model described represents its application in the dominant medical culture in the USA. Firstly, other cultures and countries may have a different understanding of what constitutes family and necessarily include others besides parents. Perhaps others, such as family elders, are the persons designated as decision makers. Secondly, this particular model is based on western notions of the importance of informed consent and respect for the autonomy (self-determination) of the patient, and the family in the case of pediatrics. In other cultures and countries, families may not see their role as decision makers at all, but only in terms of doing what the doctor orders. Also, other cultures and countries may emphasize other core values such as responsibility to the larger family and community rather than autonomy (self-determination). Finally, the model described presumes a certain access to technology that is primarily available in developed nations. A concern for quality of life is different in developed nations where the issue may be the result of technology that is able to save life of diminished quality, as opposed to developing nations where diminished quality of life may be primarily a consequence of inadequate access to basic health care services.

APPLYING THE BEST INTERESTS STANDARD How does the best interests standard work in practice? It must be remembered that the term is just a place holder for a complex structure of values that must themselves be interpreted and applied. It is not possible to use the label ‘best interests’ and expect it to do the moral work for us. It is always necessary to discuss the particular beneﬁts and burdens of an intervention, according to the evaluations of all the parties involved. No one party has a privileged view of the best interests of the infant. Consider for example, an infant born with an imperforate anus. There are no associated anomalies and the infant cannot survive without operative correction. The pediatric surgeon recommends surgery to the parents because surgery would be in the best interests of their infant. The pediatric surgeon means by the use of the term, that the possible beneﬁts to the infant (life, restoration of function, reduction of pain and suffering) outweigh the possible burdens (time in the hospital away from family, risk of death associated with anesthesia, pain and suffering associated with testing and interventions, and risk of compromised function). The calculation of best interests is based on the infant’s diagnosis, prognosis, available treatment options, and the likelihood of their success. The anomaly is fatal without

intervention, and the surgery is relatively low risk with a high likelihood of success. The pediatric surgeon wishes to preserve professional integrity by fulﬁlling the ethical obligations to promote the infant’s welfare by saving the infant’s life and restoring function, and protecting the infant from harm. The pediatric surgeon is acting upon the values of what it means to be a ‘good physician’. Most parents would agree that surgery for an imperforate anus is in the best interests of their infant. Out of their values to be ‘good parents,’ they strive to promote their infant’s welfare and cope with the burdens placed on their infant and upon themselves. Most parents would agree that the outcome is good (life and restored function), and the surgery has a high likelihood of success with minimum burden (surgery, recovery time, and associated costs). Parents who refused such surgery in the USA would most likely be accused of medical neglect, and the power of the state would most likely be used to insure that the infant received the necessary care. In other situations, a pediatric surgeon and parents may agree that stopping life-sustaining treatment would be in the best interests of a particular infant. For example, consider the case of a 23-week-old infant weighing 600 g who develops necrotizing enterocolitis (NEC). Following an operation for NEC that leaves 25 cm of jejunoilieum, the infant develops a grade IV intraventricular hemorrhage, worsening lung disease, and ongoing sepsis. In this case, the mortality rate of the condition is very high, and the infant’s quality of life is affected by the associated neurological and pulmonary complications. A pediatric surgeon and parents would be justiﬁed in withdrawing life support and instituting comfort care for this infant. It could be argued that it would be inappropriate to subject this already vulnerable infant, with little or no potential to interact with the environment, to the substantial burdens of life-sustaining technology for devastating bowel disease. None of the treatments for devastating bowel disease, such as further surgery, the use of total parenteral nutrition (TPN), or a bowel transplant, would improve the infant’s neurological condition. With little or no opportunity to experience things such as pleasure or comfort that we regard as beneﬁts, inﬂicting pain or separation from family could be viewed as disproportionally burdensome or not necessary according to a relational potential standard. Although most health care professionals and parents would agree that further interventions are not in this infant’s best interests, some parents would disagree and insist that ‘everything possible be done’. In the USA, it is a very difﬁcult matter both ethically and legally to stop life-sustaining treatment over the objections of the parents.12 Conﬂict resolution depends on a trusting relationship between the pediatric surgeon and the family. The family must be able to trust the pediatric surgeon so that they can rely on the pediatric surgeon’s judgment. This trust begins with the pediatric surgeon’s honesty: the

176 Ethical considerations in newborn surgery

commitment to disclose all relevant information, to insure that families understand what is being said and to respond to the questions and concerns of the family. Pediatric surgeons must also be compassionate, feeling for the infant and with the family as they endure this critical illness. The family needs to know not only that the pediatric surgeon cares for and about them and their infant, but that the pediatric surgeon will not abandon them on this difﬁcult journey. It is vital in these so-called ‘futility’ cases, to understand just what the family means when they say ‘everything possible is being done’. The conﬂict may be a matter of misunderstanding the diagnosis and prognosis and such false expectations can be often corrected with open, ongoing communication. But sometimes there is a real conﬂict between the values of the pediatric surgeons and the values of the family.

3 Solicit value data from all involved parties. Do conﬂicts exist among the values of the parents, other family members and the physicians? Has the basis for the conﬂict been identiﬁed? 4 Deﬁne the available treatment options. With each option, what is the likelihood of cure or amelioration? What are the risks of an adverse effect? What is a minimum level of professionally acceptable treatment? 5 Evaluate possible treatment options and make a recommendation. Justify your choice according to the values of various parties. 6 Achieve a consensus resolution. Have all parties articulated their viewpoint? Would more factual information help to resolve any disputes? Would a mediator (ethics consultant, ethics committee, or other trusted third party) be helpful?

Taking a values history

Most of the time, ethical conﬂicts between pediatric surgeons and parents can be resolved with further communication, negotiation, and accommodation. But sometimes the conﬂict is so severe that the pediatric surgeons should consider appealing to an outside resource such as an ethics committee or withdrawing from the case based on conscientious objections. The threshold is high for involving the courts in a decision about surgery for a neonate or infant. Pediatric surgeons should invoke the power of the state to secure treatment for an infant only when that treatment is universally regarded as beneﬁcial and the appropriate standard of care, making parental refusal equivalent to medical neglect, as in the previously cited case of the infant with an imperforate anus. The classic case for court intervention involves treatment for a life-threatening condition in which the beneﬁts are substantial and the burdens minimal, such as court-ordered blood transfusions for pediatric patients.14 Courts are also not the appropriate venue when parents demand treatments that the pediatric surgeon regards as not being in the best interests of the infant. Conﬂicts are resolved best at the bedside among the parties who know the infant and the circumstances, and those who will live with the consequences of the decision.

Because families may differ in how they make value judgments about what constitutes an acceptable quality of life for their infants, it is essential to be able to elicit information about values and preferences from families. The authors have found the following questions useful. The questions are intended as subject guides only; each clinician must translate the questions into his or her own style: 1 What is your understanding of your baby’s current condition? 2 How has your baby’s illness affected your family? 3 What is most important in the care of your baby? 4 What do you fear the most? What would you like to avoid? 5 What are your family’s sources of strength and support?

Guidelines for ethical decision making Ethical dilemmas most often arise when parents and pediatric surgeons disagree about what constitutes an acceptable quality of life or what constitutes the best interest of the infant. Whose judgment should prevail? Pediatric surgeons can help insure that their ethical judgments are reliable through the application of an organized process.13 There are multiple versions available in the ethics literature, but they generally all contain the following components: 1 Identify the decision makers. Are the parents involved? Are there non-parental legal guardians? Do the parents have the capacity to make a decision? Who are the involved clinicians? 2 Gather the relevant medical facts. What is the diagnosis? What is the prognosis? Are additional tests necessary for further clariﬁcation? Is there necessary information to be gathered from other clinicians?

ROLE OF CULTURE IN DECISION MAKING The ethical concept of best interests that has been articulated is largely dependent upon the authors’ own experiences in the medical culture in the USA. Some of the most difﬁcult ethical issues that the authors’ have personally faced involve a conﬂict between this western medical notion of best interests and families making decisions for their infants from within other cultures. The following case illustrates how culture may affect parental decisions and the patient–physician relationship.

Role of culture in decision making 177

Case study MS is a 25-day-old infant born at 26 weeks’ gestation, weighing 650 g. He was stable on 50% oxygen and minimal ventilatory settings. He was on continuous feedings using a premature formula. At 25 days of age the infant developed acute abdominal distention, intolerance to feedings, and bloody stools. Urgent consultation with the pediatric surgeon was requested. A radiograph showed diffuse pneumatosis. He was mottled, acidotic, and hypotensive. His laboratory values showed a white blood cell count of 2000, hemoglobin of 7 mg%, and a platelet count of 6000. He received packed red cells and platelets. Blood cultures were drawn and he was started on triple antibiotics. The parents agreed to bedside peritoneal drainage. After 36 hours, MS was clinically stable and the pediatric surgeon advised laparotomy. The parents refused the operation. MS’s parents are from Nigeria and are in the USA on student visas. They have two other healthy children, aged 3 and 5. They plan to return to their native country in 6 months. Both parents visit daily and are concerned about their son. Both the father and mother speak English, but the father’s English is slightly better than the mother’s. Sometimes the father has to translate information for the mother and translate the mother’s statements for the doctors. They ask appropriate questions and seem to understand their son’s medical condition, prognosis, and alternatives for treatment. They desire that their son live, but are strongly opposed to TPN, especially since this technology is not available in Nigeria. They acknowledge that MS is gravely ill and are accepting of his probable death. They say that they agreed to the use of all the previous medical technology because they thought it would save their son’s life. But a life dependent on medical technology is too burdensome. They were expecting that their son would be able to live normally once he got out of the hospital. The parents explain that they have a strong faith in God, and God will decide if their son lives or dies and they will accept whatever happens. They believe that it is not in their power to alter God’s will by the continued use of technology to support a life ‘that was not meant to be’ and that if the boy is not able to eat like a normal infant, than it is better that he go to God. They are supported in this belief by their Nigerian minister and congregation. They have clearly stated their intention to return to Nigeria where life-sustaining technology, such as TPN and specialized nutritional formulas, are unavailable. In addition, in their native country pediatric specialists are unavailable to provide medical and surgical care for an infant with a poorly functioning intestine. What should the pediatric surgeon do? Some may be tempted to resolve this conﬂict in a very legalistic fashion dependent on western notions of medical neglect and their attendant professional obligations to turn to the courts for proper resolution.

Simply stated, ‘You are in the USA – our cultural norms get to override your cultural norms.’ In that sense, this case is no different from any other case that raises the issue of the limits of parental discretion in medical decision making. A narrow best interests standard would seem to require overriding the parents’ decision and forcing the operation. According to informed medical judgment, the infant will most likely die without the surgery, while there is a reasonable probability that the infant’s life can be saved by resection of the diseased bowel. To say that the infant is better off dead is to substantially undervalue the lives of persons with disabilities, including this infant. Some would argue that this case is similar to the case of the infant with an imperforate anus or an infant needing a blood transfusion. To allow this family to choose non-treatment would violate the principle of justice as nondiscrimination. However, there is something particularly compelling about such cases that call participants to value and respect cultural differences. Both the parents and pediatric surgeons are struggling to fulﬁll their role-speciﬁc obligations to be good parents and good physicians. But they literally see their roles quite differently. It is culture that provides the ‘lens’ for each of us to view the world. One deﬁnition of culture states: ‘Culture is a set of guidelines (both explicit and implicit) which individuals inherit as members of a particular society, and which tells them how to view the world, how to experience it emotionally, and how to behave in it in relation to other people, to supernatural forces or gods, and to the natural environment. It also provides them with a way of transmitting symbols, language, art and ritual. To some extent, culture can be seen as an inherited “lens”, through which individuals perceive and understand the world that they inhabit, and learn how to live within it. Growing up within any society is a form of enculturation, whereby the individual slowly acquires the cultural “lens” of that society. Without such a shared perception of the world, both the cohesion and the continuity of any human group would be impossible.’15

It seems obvious from this deﬁnition that there is no way to talk about best interests from outside a cultural perspective. All of our discussion, then, is in some sense cross-cultural. The narrow explication of best interests represents the perspective of the USA, and perhaps predominantly the powerful status of its medical and legal culture. A Nigerian anthropologist commenting on this case might point out that the USA has several unique cultural features. People in the USA tend to think that there is nothing worse than death – at least for a child or young person. Children are to be viewed as little adults – as individuals ﬁrst and then only secondarily as members of a family or community, essentially independent of their

178 Ethical considerations in newborn surgery

families rather than dependent. Their right to grow up and to ultimately make their own choices is primary. US culture is very action oriented: when in doubt – act. The USA is also obsessed by the development and perceived power of technology. Technology and knowledge are primary goods. But the central question is not really whether or not we have a cultural perspective, but whether we can judge some perspectives as better than others. This raises the difﬁcult ethical question of cultural relativity. Cultural relativity refers to the following claims: (1) all moral judgments are relative to the culture in which they arise; (2) moral judgments across cultures are signiﬁcantly different; and (3) there is no way to rank moral judgments across cultures.16 The well-respected physician – ethicist, Edmund Pellegrino, accepts that culture is essential in the context of medical and ethical decisions, but that there are also features of human beings as human beings according to which we can judge among cultures.17 It can be argued that there are some universal features that all cultures either should or would accept. An example would be that moral communities must allow democratic processes and cannot be oppressive.18 The philosopher, Sara Ruddick, identiﬁes three universal maternal interests that are applicable regardless of the particular form they take in a culture. These maternal interests include: (1) preservation; (2) growth; and (3) acceptability.19 Other ethicists identify universal moral principles that underlie our commitments to be tolerant of cultural diversity.20,21 Without some principle of respect for persons, for example, there would be no reason to prefer tolerance of cultural differences. A cultural perspective is particularly important to ethical theorists, who support the inclusion of context and relationship in an ethical analysis, and to those of us working in clinical settings. As Carl Elliot writes: ‘Ethical concepts are tied to a society’s customs, manners, tradition, institutions – all of the concepts that structure and inform the ways in which a member of that society deals with the world. When we forget this, we are in danger of leaving this world of genuine moral experience for the world of moral ﬁction – a simpliﬁed, hypothetical creation less suited for practical difﬁculties than for intellectual convenience.’22

The authors wish to support an ethical analysis that includes culture as an important feature, but also acknowledges the role of the application of universal ethical principles. Like Pellegrino, the authors accept that there are some ethical principles that apply to all humans based on their humanity. Culture is necessary to understand what these principles mean and how they are applied with respect to each of the parties in the conﬂict. It is possible to be respectful of cultural differences and at the same time acknowledge that there are limits. What remains critical is the perceived degree of harm; some

cultural practices may constitute violations of fundamental human rights.23 It is useful to return to the above case and apply the process for ethical decision making with special attention to its cross-cultural features.

CASE ANALYSIS The ethical question in this case is: what should the pediatric surgeon do for MS? What role should culture play in the deliberations? The family in this case clearly values their son’s life and his quality of life. They also value the impact of this infant’s life on their other children, the life of the family as a whole, and their plans to return to their native country. They accepted the initial use of technology in the care of their premature son, in the hope that it would deliver a ‘normal’ infant, free of future dependence on medical technology. They are clear that for them, in a cultural and religious sense, a life dependent on TPN, specialized nutritional feedings, and the prospect of bowel transplantation is unacceptable. For the pediatric surgeon and the other members of the health care team, the preservation of this infant’s life is a goal, but the quality of his life is also a consideration. The laparotomy will allow the pediatric surgeon to assess the severity of the NEC, the amount of diseased bowel, and the prognosis for MS to have functional intestine without the need for prolonged TPN. There are basically three options available in this situation. First, the pediatric surgeon can go forward with all the care that it takes to save this infant’s life. This would include surgery, the use of TPN for as long as necessary, and all efforts to preserve the life of MS, including the possibility for bowel transplantation. This would more than likely include going to court to force the parents to consent to the operation and having a guardian appointed to make medical decisions for MS. This option could result in the permanent loss of parental rights and placement of the infant in the care of the state. In the second option, the pediatric surgeon performs the operation in the hope that there is sufﬁcient residual bowel without the need for long-term TPN and bowel transplantation. If there were clearly not enough viable bowel, MS would be provided with comfort care and allowed to die. If there were sufﬁcient residual bowel, care would proceed as appropriate. A difﬁculty arises if there is a questionable amount of bowel and a trial of TPN would seem to be appropriate. The pediatric surgeon could resect the diseased bowel and proceed with a trial of TPN, discontinuing the use of TPN when it is clear that the bowel is not going to function normally. The third option is not to perform the operation. The infant could be maintained on current levels of support to see whether his bowel will heal on its own, or a comfort care plan could be initiated that would allow the infant to die sooner rather than prolonging the dying process.

Role of culture in decision making 179

The authors think that the ﬁrst option is outside the range of moral justiﬁcation and should not be recommended. The infant is critically ill with a disease that carries high rates of mortality and morbidity. Nontreatment for MS does not rise to the standard of medical neglect. The strongest argument for insisting on treatment rests on the claim that this infant is a member of the community, not only a member of his family. If families will not or cannot take proper care of their children, then we will step in to do so. But who is this ‘we’? If there is no such community support, or insofar as the broader community fails in this responsibility, then the community’ s claim on the family’s choice is diminished. In this case, the Nigerian community (here or in Nigeria) does not make demands on the parents’ choice. They do not see themselves as able, or obligated, to provide these services to MS. But in what sense is MS and his family a member of the US community? An argument can be made that they are community members by virtue of their residence. Yet they are planning to return to Nigeria. The argument that treatment must be forced because of community obligations seems diminished by their departure. We will not be around to provide the support we claim is necessary. But will we provide the necessary support even if they stay? Is it possible for them to stay? Our community claims also seem diminished insofar as the family’s student visa is not renewed, or access to health and social services is limited based on their foreign status. To claim that we are discharging our community obligations only by saving the child’s life, seems to greatly distort the notion of community. But a ﬁnal consideration needs to be mentioned. Couldn’t we discharge our community responsibility by keeping the child here and placing him up for adoption? Then he certainly would become a full member of our community and the concerns raised earlier would no longer apply. Such an action could clearly state that we believe the only appropriate parental choice is to try and save the infant’s life. To choose anything else is to act as bad parents who should be replaced. Yet are they really bad parents? Such a judgment clearly raises serious concerns about cultural norms of parenting, and fails to take culture into consideration. From the parent’s cultural perspective, good parents would not choose surgery and neither would good physicians. This is not standard of care in Nigeria. But how should culture ﬁgure into the deliberations of the pediatric surgeon? It obviously cannot simply be ignored in a grand act of medical and parental imperialism. Also, we should not pay lip service to cultural perspectives, accepting the unusual and exotic only when it also ﬁts into our own value framework. For example, this family could make the choice based on their cultural values only if there were a much higher mortality rate associated with the infant’s condition.

Finally, respect for different cultures cannot simply be some kind of ultimate trump. Automatically deferring to any choices based on cultural differences is to ignore the central values of our own culture. Ironically, it would be a violation of respect for cultural diversity in that our own cultural values are ignored. An attempt at negotiation and compromise is to be preferred. The authors think that the pediatric surgeon should recommend surgery under the second scenario, saving the infant if possible, letting the infant die if appropriate, and negotiating a trial of TPN if necessary. But if this is not acceptable to the parents, the pediatric surgeon should respect the parents’ decision not to have surgery and proceed with a plan of care aimed at keeping the infant comfortable until he either improves or dies. A decision by a pediatric surgeon to conscientiously withdraw from this patient’s care out of concern for his or her own central values, should be respected. The second option is supported by the health care professionals’ and the family’s values. Surgery could save the infant’s life, which all parties value, but it would do so under conditions of a quality of life that are acceptable to the family. Some health care professionals may have problems with this option if a trial of TPN is necessary. It is difﬁcult to establish how long a trial of TPN should last. This difﬁcult negotiation must consider what is medically feasible and also acceptable to the family. Also, many believe that there is a distinction between decisions not to start treatments (withholding) and decisions to stop treatments (withdrawing). Although this distinction is psychologically powerful, it is not ethically or legally valid in the US.23 If health care professionals and parents have sufﬁcient justiﬁcation based on the balance of beneﬁts and burdens not to start a treatment, then they have the same justiﬁcation to stop a treatment once begun. There is a hidden danger in maintaining this distinction between not starting and stopping medical and surgical treatments. Sometimes trials of therapy are not initiated when they are appropriate out of fear that the therapy cannot be stopped once it has begun. Others argue that the provision of nutrition and hydration is different than other medical interventions, such as ventilators and dialysis, which are ‘extraordinary’ and ethically can be withheld or withdrawn. According to this view, the provision of nutrition and hydration is ordinary and is always morally required. The attempt to classify categories of interventions independent of their application to the care of an individual patient is misguided. So-called ‘ordinary’ treatments like antibiotics and the medical provision of hydration and nutrition, can be disproportionally burdensome to certain infants and may be ethically forgone (withheld or withdrawn).24 Many physicians and parents have particular values around the importance of feeding, regarding feeding tubes and TPN as morally equivalent to bottle or breast feeding an infant or to sharing a meal. Yet the provision of TPN is not readily comparable to feeding an infant or

180 Ethical considerations in newborn surgery

to a shared family meal. There are important differences. When hydration and nutrition are provided through medical means, they must be assessed according to the same principles used to evaluate any medical intervention. Decisions must be based on a careful evaluation of the proportionality of the possible beneﬁts and burdens. For this family, TPN is not only burdensome because of the risk of frequent infections and the likelihood of progressive liver disease, but because of what feeding through technology means in their culture, and the ﬁnancial and social burdens to the entire family. The health care team in the USA cannot allocate this family’s scarce resources for them, or for their country of origin.

SUMMARY The best interests standard is a complex amalgam of the values of pediatric surgeons, families, and broader societies. As health care itself becomes increasingly multicultural and international, the need for cross-cultural ethical dialogue increases. There are no ultimate trump cards, just a genuine need for what one philosopher calls ‘communitarian perspectivalism.’16 Any healthy, growing and self-renewing culture continually subjects itself to self-evaluation and evaluation by others. In this regard, the authors wish to point to the need for greater attention to the value of justice in the provision of health care around the globe. This chapter represents a tendency to look at the developed nations and evaluate the issue of not providing the most that can be done. This is obviously an ethical problem for the rich. What about the bigger ethical problem of not providing the basic minimum to infants everywhere – the ethical problem of not providing what poor parents want for their children and cannot afford? Certainly ethical dialogue needs to include what children around the globe are owed as a matter of justice – of fundamental human rights. Access to global health care resources is a problem that affects all persons. The contribution of the medical marketplace to the disproportionate allocation of health care that exists cannot be ignored. Medicine must take responsibility for the emphasis on expanding new technologies in the market rather than meeting basic public health needs, and the disproportionate burden it may place on the economies of developing nations or nations committed to universal access to health care. A global cross-cultural perspective is essential to help expand the concept of ‘best interests’ to include a necessary public health focus.

REFERENCES 1. American Academy of Pediatrics Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995; 95:314–17.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment, 1983, 197–229. 3. The Hastings Center Research Project on the Care of Imperiled Newborns. Hastings Center Report 1987; 17:5–32. 4. McCormick R. To save or let die: the dilemma of modern medicine. JAMA 1974; 29:172–6. 5. Arras JD. Toward an ethic of ambiguity. Hastings Center Report 1984; 14:25–33. 6. Brody H. Commentary. Hastings Center Report 1988; 18:37–39. 7. Bartholome WG. Commentary. Hastings Center Report 1988; 18:39–40. 8. Nelson JL. Taking families seriously. Hastings Center Report 1992; 22:6–12. 9. Ruddick W. Questions parents should resist. In: Kopelman LM, Moskop JC, editors. Children and Health Care: Moral and Social Issues. Dordrecht: Kluwer Academic Publishers, 1989, 221–9. 10. Baylis F, Caniano DA. Medical ethics and the pediatric surgeon. In: Oldham KT, Colombani PM, Foglia RP, editors. Surgery of Infants and Children. Philadelphia: Lipincott-Raven, 1997, 281–388. 11. Buchanan A, Brock D. Deciding for Others: The Ethics of Surrogate Decision Making, Cambridge University Press, Cambridge, 1989, 83–135. 12. Annas GJ. Asking the courts to set the standard of emergency care – the case of Baby K. N Engl J Med 1994; 320:1542–5. 13. Glover JJ, Caniano DA. Ethical issues in treating infants with very low birth weight. Seminars in Pediatric Surgery 2000; 9:56–62. 14. American Academy of Pediatrics Committee on Bioethics. Religious objections to medical care. Pediatrics 1997; 99:279–281. 15. Helman CG. Culture, Health and Illness. Wright Publishing, London, 1990, 2–3. 16. Garcia J. African-American perspectives, cultural relativism, and normative issues: some conceptual questions. In: Flack HE, Pellegrino ED, editors. AfricanAmerican Perspectives in Biomedical Ethics, Washington, DC: Georgetown University Press, 1992, 11–66. 17. Pellegrino ED. Intersections of western biomedical ethics. In: Pellegrino ED, Corsi PMP, editors. Transcultural Dimensions in Medical Ethics, Frederick, Maryland: University Publishing Group, 1992, 13–19. 18. Sherwin SL. No Longer Patient: Feminist Ethics and Health Care, Temple University Press, Philadelphia, 1992, 248–9. 19. Ruddick S. Maternal thinking. In: Trebilcot J, editor. Mothering: Essays in Feminist Theory, Totowa, New Jersey: Rowan & Allanheld, 1983, 213–30. 20. Beauchamp T. Response to Garcia. In: Flack HE, Pellegrino ED, editors. African-American Perspectives in Biomedical Ethics, Washington DC: Georgetown University Press, 1992, 67–8.

References 181 21. Macklin R. Ethical relativism in a multicultural society. Kennedy Institute of Ethics Journal 1998; 8:1–22. 22. Elliot C. Where ethics comes from and what to do about it. Hastings Center Report 1989; 22:28–35. 23. American Academy of Pediatrics Committee on Bioethics

Guidelines on foregoing life-sustaining medical treatment. Pediatrics 1994; 93:532–6. 24. Nelson LJ, Rushton CH. Foregoing medically provided nutrition and hydration in pediatric patients. J Law Med Ethics 1995; 23:33–46.

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16 Minimally invasive neonatal surgery ASHLEY VERNON, TIMOTHY KANE AND KEITH E. GEORGESON

INTRODUCTION The application of minimally invasive surgical techniques to neonates has developed in parallel with its adult counterpart. Limitations in the miniaturization of endosurgical instruments have resulted in a lag in the development and popularity of minimal-access procedures in infants. Signiﬁcant recent advances in the downsizing of surgical instrumentation and the development of reliable and safe techniques have broadened the applicability of endoscopic surgery in neonates. Despite the growing use of minimally invasive procedures in neonates, much of the current literature supporting the safety and applicability of thoracoscopy and laparoscopy is based on case reports and relatively small clinical series of patients. With the growing experience in neonatal endoscopic surgery, it has become clear that neonates tolerate minimally invasive procedures well but have speciﬁc sensitivities to minimal-access invasion that must be recognized in order to achieve successful results. These special sensitivities will be discussed individually in the appropriate sections of this chapter.

THORACOSCOPY The application of thoracoscopy in infants and children began over 20 years ago.1 Currently, the most frequently performed thoracoscopic procedures for infants and children have been for the purpose of pulmonary biopsy for interstitial lung disease. Thoracoscopy has also been used for more extensive pulmonary resections utilizing either segmentectomy or lobectomy for congenital pulmonary lesions including sequestrations, lobar emphysema and cystadenomatoid malformations have been associated with low morbidity rates.2 Bronchogenic cysts, esophageal duplications, thoracic ganglioneuromas and neuroblastomas have been approached

using thoracoscopic methods with excellent visualization and access to these lesions.

Anesthetic consideration in thoracoscopy Like the adaptation of endoscopic instruments for thoracoscopic neonatal operations, the techniques of using anesthesia during delivery have also evolved to ensure patient safety and optimize surgical visualization during thoracoscopy. Peripheral i.v. access is usually adequate for safe thoracoscopy in neonates. Central venous access, although rarely necessary, should be placed on the side of planned thoracoscopy to avoid the potential for bilateral pneumothoraces. Other monitoring devices needed during thoracoscopy include continuous electrocardiography, non-invasive blood pressure monitoring, temperature monitoring, and end-tidal carbon dioxide (ETCO2) measurement. Since ETCO2 monitoring is often inaccurate during thoracoscopic procedures, especially during single-lung ventilation with its physiologic alterations due to dead space and shunt fraction, transcutaneous CO2 monitors are useful and provide a greater margin of safety for thoracoscopic procedures.3 A major problem associated with general anesthesia and positive-pressure ventilation during thoracoscopy is the impairment of visualization and surgical access by lung expansion. In the neonate, single-lung ventilation using selective mainstem intubation of the contralateral bronchus is the primary method used to overcome this problem.4 Other methods of single-lung ventilation include the use of bronchial blockers and cuffed endotracheal tubes. Double-lumen tubes are not available in sizes appropriate for neonates. It is important to monitor the patient for the development of signiﬁcant hypercapnia or hypoxia during one-lung ventilation because this anesthetic technique sometimes results in inadequate oxygenation and ventilation and must be abandoned. If single-lung ventilation cannot be achieved or is not well tolerated by the infant, double-lung ventilation with

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the addition of low-ﬂow (1 L/minute), low-pressure (4–8 mmHg) infusion of CO2 into the thorax on the operative side will often adequately compress the lungs and optimize visualization. This technique is surprisingly well tolerated by most neonates. The major risks of creating this artiﬁcal pneumothorax are the development of hypercarbia and hypoxia due to inadequate ventilation, the sudden onset of hypotension due to inadequate venus return, and the potential development of CO2 embolism. Cardiovascular changes of hypotension and bradycardia are usually quickly reversible by stopping insufﬂation, relieving the pneumothorax and administering ﬂuids to increase pre-load.

Diagnostic thoracoscopy Thoracoscopy for diagnostic purposes is infrequently utilized in the neonate. Most neonatal diagnoses are made by the thoughtful use of diagnostic imaging. However, in carefully selected circumstances, excellent visualization of intrathoracic anatomy can be obtained using thoracoscopy.

Biopsy or resection of lung lesions Pulmonary biopsy is one of the most common operations performed thoracoscopically in infants. Thoracoscopic biopsy has been shown to be useful in the diagnosis of interstitial lung disease, metastatic lesions, or infectious disease of unknown origin. Lung biopsy in neonates is usually performed with a loop ligature placed snugly at the base of the biopsy specimen. The lung peripheral to the ligature is excised sharply leaving a 5 mm cuff. Placement of a chest tube through an access trocar site is optional but recommended. Another effective biopsy technique is to seal the base of the biopsy specimen with an endoscopic Ligasure coagulator (Valleylab, Tyco Healthcare (Boulder, Colorado)). The specimen is then removed peripheral to the coagulated tissue. Thoracoscopic approaches have also been used for resection of congenital cysticadenomatoid malformations and congenital lobar emphysema. The segment or lobe is removed using the Ligasure for sealing of the lung and vessels. Suture ligation is used to secure the bronchus.

safest approach has been ﬁrst to evacuate the cyst followed by subtotal resection of the cyst. Removal of the cyst lining on the esophageal wall completes the procedure. Reinforcement of the esophageal wall is then performed, when needed, using interrupted sutures.8 Mediastinal dissections are almost always carried out with an esophageal dilator in place to minimize potential trauma to the esophagus.

Closure of patent ductus arteriosus There have been multiple reports of thoracoscopic closure of patent ductus arteriosus (PDA). The ﬁrst such report appeared in 1991. Initially, the majority of patients were older than 2 months or over 4 kg in weight.9 As the instrumentation for video-assisted thoracoscopic PDA ligation has improved, the application of this technique in smaller and smaller patients has grown.10 Burke et al.11 has shown that endoscopic PDA ligation in infants weighing <2500 g is safe and effective; in 34 patients there were no operative mortalities. Conversion to open thoracotomy was required in 11%, usually due to difﬁculty in visualization of the PDA.11 The incidence of procedure-related complications of endoscopic PDA ligation such as residual ductal ﬂow and recurrent laryngeal nerve injury are similar to those of open techniques.11

Esophageal atresia Several pediatric surgical groups have demonstrated the ability to repair esophageal atresia with tracheoesophageal ﬁstula using thoracoscopic methods. Some of the observed complications have been anastomotic leaks

Mediastinal masses Thoracoscopic resection of bronchogenic cysts and esophageal duplication cysts have become commonplace in the neonate.5–7 Complete resection of bronchogenic cysts by a thoracoscopy approach is usually straightforward. Adjacent structures are clearly visualized and avoided. Occasionally, esophageal duplication cysts and the esophagus share a common wall. In these cases, the

Figure 16.1 Ligation of TEF and repair of esophageal atresia. Note the clip (arrow) on the tracheo-esophageal ﬁstula. The esophageal anastomisis was performed thoracoscopically

Laparoscopy 185

and stenoses. It is too early to judge whether this technique will be as beneﬁcial as the standard open thoracotomy method of tracheo-esophageal ﬁstula repair. Perhaps this is an area that will beneﬁt from the development of microscopic robotic instruments.

Diaphragmatic hernia repair The repair of Bochdalek and Morgagni diaphragmatic hernias using thoracoscopic methods has been described in anecdotal case reports, usually in older infants and children. Repair of symptomatic congenital diaphragmatic hernias in the newborn has not yet been described. Video-assisted plication for eventration of the diaphragm or phrenic nerve paralysis has become commonplace. No large series have been reported to date but the success of thoracoscopic diaphragmatic plication appears to be equivalent to that of open methods.

LAPAROSCOPY Pneumoperitoneum CO2 has been shown to be a useful insufﬂating gas in adults and infants because it is nonﬂammable, has moderate absorption and has predictable and nontoxic physiological effects when absorbed. The physiological effects of CO2 pneumoperitoneum may be more pronounced in infants than in larger patients. Interest in studying these effects has grown as more laparoscopic procedures are being applied to patients in this age group. Two primary reasons have been proposed for the pronounced effects of CO2 pneumoperitoneum in neonates when compared to adults. Higher levels of dissolved CO2 are seen in neonates during laparoscopic procedures (as signaled by increased end-tidal CO2). This response is thought to be due to an increased peritoneal absorptive surface area in comparison to body weight. Secondly, the absorption of CO2 through the peritoneal surface may be more efﬁcient in neonates. The efﬁciency is likely to be due to decreased fat and closer proximity of the blood vessels to the peritoneal lining. The result is hypercapnia and respiratory acidosis if not anticipated. For the most part, the hypercapnia associated with CO2 pneumoperitoneum is overcome by increasing minute ventilation and ‘blowing off ’ CO2 during the laparoscopic procedure. Some evidence suggests that the ventilatory rate may need to be increased by between 20–30% (Tan, 1992)12 and up to 50–75%13 to maintain normocarbia. In a series of 65 laparoscopic neonatal procedures (in patients 2–30 days old), hyperventilation was necessary to correct elevated end-tidal CO2.14 The

major postoperative risk is that the neonate will be unable to maintain increased ventilatory effort during the immediate postoperative period when CO2 levels are still high, but the diaphragm is sluggish due to inhaled and i.v. anesthetic agents. Prolonged postoperative intubation and ventilation may be necessary in some neonates after the pneumoperitoneum has been evacuated.

Increased intra-abdominal pressure It has been shown in adults that increased abdominal pressure can be tolerated to levels of 15 mmHg. At this level of intra-abdominal pressure, there is usually no compromise to venous return. In fact, at low levels of intra-abdominal pressure the venous return is actually augmented as blood is ‘squeezed’ out of the splanchnic venous bed. The cardiovascular effects of increased abdominal pressure may be different in neonates. An animal neonatal model using newborn piglets was used to study the cardiovascular effects of increased abdominal pressure. Using a pulmonary artery catheter, a progressive decrease in cardiac index was noticed in this neonatal model as pressure was increased above 15 mmHg. At higher pressures, in addition to inferior vena caval (IVC) compression, collaterals are also compressed, accounting for even more profound hypotension than would be explained by IVC compression alone. This study documents the sensitivity of the newborn piglet to increased abdominal pressure and emphasizes the importance of maintaining somewhat lower pressures in human neonates.15 Gueugniaud et al.16 studied 12 healthy infants aged 6–30 months using transesophageal echo aortic Doppler. With a pneumoperitoneum of 10 mmHg and increased minute ventilation to prevent hypercapnia, they noted a decrease in cardiac performance (67% reduction in aortic blood ﬂow and stroke volume) and an increase in systemic vascular resistance (162%). These changes were not associated with any deleterious cardiac effects in the short period of study. Others have found no clinically signiﬁcant effects with short procedures and pneumoperitoneum of less than 15 mmHg. Tobias et al.17 studied 53 children aged 1 month to 7 years who underwent diagnostic inguinal laparoscopy. End-tidal CO2 increased from 32 to 35 and normalized within 10 minutes postoperatively. The patients did not require hyperventilation and ventilatory settings were unchanged during the investigation. These minimal alterations in vital signs were attributed to the brief surgical times, limiting intra-abdominal pressure to 15 mmHg, and avoiding the Trendelenburg’s position. Sfez (1995)18 studied 25 children undergoing laparoscopic fundoplication with over two-thirds of the patients having underlying respiratory disease. Of the

186 Minimally invasive neonatal surgery

patients included in the study, 25% had transient hypoxia postoperatively and three patients had positional hypotension and bradycardia. Upward displacement of the paralyzed diaphragm following creation of pneumoperitoneum can lead to pulmonary atelectasis, which might not be clinically apparent perioperatively owing to positive-pressure ventilation (PPV). With resumption of spontaneous ventilation, however, these patients can become hypoxemic and require PPV until the collapsed lung reexpands.

Abdominal access There are some reports of an increased incidence of access injuries in infants due to the proximity of important intra-abdominal structures in small patients. The insertion of the Veress needle or initial trocar into major vessels can be avoided by strict adherence to the basic principles of insertion. Although there has been no trocar insertion technique proven to be the safest, it appears that the radially expanding trocars are safe. We prefer to use a radially expanding trocar as the initialaccess trocar. Reusable trocars can then be more safely inserted under direct vision. Slippage of trocars can be a major problem, especially in pediatric laparoscopic surgery.19 These complications can be managed in a variety of effective ways. Our preference is to use the radially expanding 5 mm trocars. For trocars 4 mm and smaller, the authors use reusable trocars and suture them to the abdominal wall using a rubber cuff made from a red rubber catheter. The catheter is cut to a 1 cm length segment, slipped over the end of the trocar and positioned at the appropriate level on the trocar. The trocar can then be moved in and out relative to the cuff.

Abdominal procedures Although laparoscopic surgery has been somewhat slower to progress in neonates than in older patients, there are a few laparoscopic procedures that are routinely performed at selected centers. There is a large amount of experience in pyloromyotomy, fundoplication, colon and pelvic procedures.

Figure 16.2 Laparoscopic pyloromyotomy. Note the absence of bleeding and the intact pyloric mucosa

Overall, laparoscopic pyloromyotomy has an acceptable complication rate and operative time which is equivalent to that with the open procedure. Fujimoto et al.23 noted that there are signiﬁcantly lower levels of IL-6 in patients undergoing laparoscopy as compared to those undergoing open pyloromyotomy, implying decreased surgical stress. The major drawback of the laparoscopic procedure is that it is currently more costly than its open counterpart. In a series of 301 patients undergoing pyloromyotomy at The Children’s Hospital of Alabama, Birmingham, Alabama (129 laparoscopic and 172 open pyloromyotomies), operative times were shorter for the laparoscopic group (23.5 minutes) compared to those of the open group (28.5 minutes). Additionally, the postoperative length of stay was shorter for the laparoscopic group (31.4 hours) compared to the open group (41.1 hours). The complications were similar for both groups, with ﬁve perforations and one incomplete pyloromyotomy in the laparoscopic group and four perforations in the open group. The cost per patient for the laparoscopic group was signiﬁcantly higher than for the open group: $4240±$1626 vs $3786±$1405 (P<0.05). In conclusion, laparoscopic pyloromyotomy has become a commonplace procedure. It appears to be equally as safe and effective as open pyloromyotomy. The advantages appear to be a faster recovery, a shorter hospitalization time, equivalent operative times, and better cosmetic outcomes. Despite these advantages, the cost of laparoscopic pyloromyotomy continues to be higher than for the open procedure and this remains the current focus for improvement.

Pyloromyotomy Fundoplication Alain et al. ﬁrst described laparoscopic pyloromyotomy in 199120 and subsequently reported 70 other patients in 1996.21 Downey22 reviewed 226 pyloromyotomies published up to the time of his review in 1998. This cumulative review revealed perforation rates and operative times similar to those obtained with the open procedure.

Laparoscopic fundoplication is being performed with increasing frequency in neonates. A study conducted at three children’s hospitals reviewed the fundoplications performed on all patients younger than 3 months of age or weighing less than 3 kg. Information was compiled on

References 187

104 patients of whom 82 had a gastrostomy tube placement in addition to the fundoplication. The mean patient age was 68 days and the mean operative time was 60 minutes. Eleven complications occurred in these 104 patients. Four complications were related to the laparoscopy, four to the gastrostomy, one to poor patient selection, and two to the fundoplication. One patient with a malpositioned gastrostomy tube had emesis at the time of the report; otherwise all patients had no clinical evidence of gastro-esophageal reﬂux with a mean followup of 5 months. There was one death from a gastrostomy tube leak in an infant with trisomy 18. This study shows that laparoscopic Nissen fundoplication can be done safely and effectively in very young patients. Care should be taken to apply fundoplication only to those patients who cannot be safely or adequately treated using medical management.

Other upper gastrointestinal procedures

Endorectal pull-through

Pelvic pathology

Laparoscopy-assisted endorectal pull-through for Hirschsprung’s disease is being performed in increasing numbers of the neonatal record.24–26 The procedure is performed using three small abdominal ports. The transition zone is identiﬁed by seromuscular biopsies obtained laparoscopically. In patients with a rectosigmoid colon transition zone, the intra-abdominal portion of the aganglionic bowel is devascularized using a hook electrocautery. In patients with the longer segments of aganglionic colon, a pedicle preserving the marginal artery is fashioned as far proximal as necessary to bring the colon pedicle down without tension to form the neorectum. The rectal mobilization is performed transanally using an endorectal sleeve technique. The anastomosis is performed transanally 0.5 cm above the dentate line. The early clinical outcomes after a one-stage laparoscopy-assisted endorectal pull-through have been reported in 80 patients aged 3 days to 96 months and appear to reduce perioperative complications and postoperative recovery time.25 Most of these patients were too young to evaluate fecal continence. However, the author’s impression is that fecal continence after this procedure is equivalent to that after procedures performed in an open fashion. Successful techniques for performing laparoscopy-assisted Duhamel and Swenson pull-through procedures have also been reported in neonates. Endoscopic assisted pull-through for high imperforate anus27 also deserves a mention. This procedure is useful in patients with intermediate- and highimperforate anus. The anatomy of the pelvic ﬂoor is seen clearly using the laparoscope. The perineal dissection is aided by transillumination of the perineal muscles using an intra-abdominal light source. The senior author has performed 20 of these operations. The follow-up is too short to obtain information regarding continence.

A variety of treatment options for ovarian cysts can be pursued laparoscopically. These options include decompression, excision, fenestration, oophorectomy, and adnexal detorsion and ﬁxation.28–33 The use of laparoscopic dissection of the pelvic portion of a sacrococcygeal teratoma has been described by Bax and van der Zee.34 The author’s have also performed the pelvic dissection laparoscopically in two patients with sacrococcygeal teratoma and concur with Bax that the intra-abdominal and pelvic portions of teratomas are expediently managed with laparoscopic assistance.

Laparoscopic procedures for malrotation have been performed in many pediatric surgical centers. The operation is technically simple. The duodenum is released from Ladd’s bands starting just distal to the pylorus and the dissection is continued distally. Further bands are also released to allow the cecum to fall over the left side of the abdomen. We have attached the distal duodenum and proximal jejunum to Gerota’s fascia on the right side using interrupted sutures to help maintain a widened mesentery. The follow-up is too short to tell whether the diminished adhesion formation caused by the laparoscopic approach will allow late volvulus. Other conditions which have been corrected laparoscopically in the neonate include the repair of duodenal atresia and division of obstructive bands.

CONCLUSION Neonatal minimally invasive surgery is becoming an increasingly effective tool for infants requiring surgical correction of their afﬂictions. Eventually, the authors are conﬁdent that most intracavitary surgical conditions in neonates will be approached using these techniques.

REFERENCES 1. Rodgers BM, Moazam F, Talbert JL. Thoracoscopy in children. Ann Surg 1979; 189(2):176–80. 2. Rothenberg SS. Thoracoscopy in infants and children. Semin Pediatr Surg 1998; 7(4):194–201. 3. Tobias JD, Wilson Jr WR, Meyer DJ. Transcutaneous monitoring of carbon dioxide tension after cardiothoracic surgery in infants and children. Anesth Analg 1999; 88(3):531–4. 4. Tobias JD. Thoracoscopy in the pediatric patient. Anesthesiol Clin North America 2001; 19(1):173–86, viii.

188 Minimally invasive neonatal surgery 5. Michel JL et al. Thoracoscopic treatment of mediastinal cysts in children. J Pediatr Surg 1998; 33(12):1745–8. 6. Schier F, Waldschmidt J. Thoracoscopy in children. J Pediatr Surg 1996; 31(12):1640–3. 7. Dillon PW, Cilley RE, Krummel TM. Video-assisted thoracoscopic excision of intrathoracic masses in children: report of two cases. Surg Laparosc Endosc 1993; 3(5):433–6. 8. Rodgers BM. Thoracoscopic procedures in children. Semin Pediatr Surg 1993; 2(3):182–9. 9. Rothenberg SS et al. Thoracoscopic closure of patent ductus arteriosus: a less traumatic and more costeffective technique. J Pediatr Surg 1995; 30(7):1057–60. 10. Laborde F et al. Video-assisted thoracoscopic surgical interruption: the technique of choice for patent ductus arteriosus. Routine experience in 230 pediatric cases. J Thorac Cardiovasc Surg 1995; 110(6):1681–4; discussion 1684–5. 11. Burke RP et al. Video-assisted thoracoscopic surgery for patent ductus arteriosus in low birth weight neonates and infants. Pediatrics 1999; 104(2 Pt 1):227–30. 12. Tan PL, Lee TL, Tweed WA. Carbon dioxide absorption and gas exchange during pelvic laparoscopy. Can J Anaes 1992; 39(7):677–81. 13. Liu SY et al. Prospective analysis of cardiopulmonary responses to laparoscopic cholecystectomy. J Laparoendosc Surg 1991; 1(5):241–6. 14. Fujimoto T et al. Laparoscopic surgery in newborn infants. Surg Endosc 1999; 13(8):773–7. 15. Lynch FP et al. Cardiovascular effects of increased intraabdominal pressure in newborn piglets. J Pediatr Surg 1974; 9(5):621–6. 16. Gueugniaud PY et al. The hemodynamic effects of pneumoperitoneum during laparoscopic surgery in healthy infants: assessment by continuous esophageal aortic blood ﬂow echo-Doppler. Anesth Analg 1998; 86(2):290–3. 17. Tobias JD et al. Cardiorespiratory changes in children during laparoscopy. J Pediatr Surg 1995; 30(1):33–6. 18. Sfez M, Guerard A, Desruelle P. Cardiorespiratory changes during laparoscopic fundoplication in children. Paediatr Anaesth 1995; 5(2):89–95. 19. Bax NM, van der Zee DC. Trocar ﬁxation during endoscopic surgery in infants and children. Surg Endosc 1998; 12(2):181–2.

20. Alain JL et al. [Pyloric stenosis in infants. New surgical approaches]. Ann Pediatr (Paris) 1991; 38(9):630–2. 21. Alain JL et al. Laparoscopic pyloromyotomy for infantile hypertrophic stenosis. J Pediatr Surg 1996; 31(8):1197–8. 22. Downey EC, Jr. Laparoscopic pyloromyotomy. Semin Pediatr Surg 1998; 7(4):220–4. 23. Fujimoto T et al. Laparoscopic extramucosal pyloromyotomy versus open pyloromyotomy for infantile hypertrophic pyloric stenosis: which is better? J Pediatr Surg 1999; 34(2):370–2. 24. Georgeson KE, Fuenfer MM, Hardin WD. Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 1995; 30(7):1017–21; discussion 1021–2. 25. Georgeson KE et al. Primary laparoscopic-assisted endorectal colon pull-through for Hirschsprung’s disease: a new gold standard. Ann Surg 1999; 229(5):678–82; discussion 682–3. 26. Jona JZ et al. Laparoscopic pull-through procedure for Hirschsprung’s disease. Semin Pediatr Surg 1998; 7(4):228–31. 27. Georgeson KE, Inge TH, Albanese CT. Laparoscopically assisted anorectal pull-through for high imperforate anus – a new technique. J Pediatr Surg 2000; 35(6):927–30; discussion 930–1. 28. Davidoff AM et al. Laparoscopic oophorectomy in children. J Laparoendosc Surg 1996; 6 Suppl 1:S115–19. 29. Dolgin SE. Ovarian masses in the newborn. Semin Pediatr Surg 2000; 9(3):121–7. 30. Esposito C et al. Laparoscopic management of ovarian cysts in newborns. Surg Endosc 1998; 12(9):1152–4. 31. Mahomed A, Jibril A, Youngson G. Laparoscopic management of a large ovarian cyst in the neonate. Surg Endosc 1998; 12(10):1272–4. 32. Decker PA, Chammas J, Sato TT. Laparoscopic diagnosis and management of ovarian torsion in the newborn. Jsls 1999; 3(2):141–3. 33. Templeman CL et al. Laparoscopic management of neonatal ovarian cysts. J Am Assoc Gynecol Laparosc 2000; 7(3):401–4. 34. Bax NM, van der Zee DC. Laparoscopic clipping of the median sacral artery in huge sacrococcygeal teratomas. Surg Endosc 1998; 12(6):882–3.

17 Fetal surgery JYOJI YOSHIZAWA, LOURENÇO SBRAGIA AND MICHAEL R. HARRISON

INTRODUCTION In the past two decades, major advances in fetal imaging and diagnostic procedures have stripped the veil of mystery from the once secretive fetus and have dramatically changed our understanding and management of many prenatally diagnosed malformations. Early diagnosis and close follow-up of fetuses with congenital malformations have allowed us to deﬁne the disease’s natural history, determine the clinical features that affect clinical outcome, and plan management approaches to improve prognosis. Increasingly sophisticated ultrasonography can identify a growing number of disorders and structural defects at an early enough stage to be amenable to prenatal intervention. Selection criteria for in utero intervention were deﬁned, and anesthetic, tocolytic regimen, and surgical techniques for hysterotomy and fetal surgery were developed and reﬁned.1–5 As a result of this investment in basic and clinical research, the fetus has claimed a role as an independent patient.

MATERNAL–FETAL RISKS Fetal surgery is ﬁrst and foremost predicated on responsibility to the mother and her family since she, as well as her unborn child, is a patient in this setting. The risk-tobeneﬁt ratio favors the fetus with a lethal malformation since without intervention the mortality rate is 100% and with intervention survival is possible. It is not, however, that easily justiﬁed for the mother who is essentially an innocent bystander whose physical health is usually not jeopardized by her unborn baby’s condition. For this reason it was paramount to prove that any intervention through the mother could be done safely. This was tested in the most rigorous animal model, the non-human primate whose anatomy and physiology quite closely resemble that of the human pregnancy.6,7 The ﬁrst technical issue addressed was how to safely open and close the gravid uterus such that bleeding and membrane

separation were prevented and a water-tight closure attained. This was solved with an absorbable stapling device and special back-biting retractors for the uterine edges.8 Closing the uterus is performed in two layers with absorbable sutures, supplemented with ﬁbrin glue. Next, a means to monitor the fetus and uterine activity after the procedure was needed. This was solved by developing a relatively large radiotelemeter that is placed inside the fetus within a submuscular pocket.9 It monitors fetal heart rate, temperature, and uterine pressure (contractions). This is presently being miniaturized such that it can be passed down a trocar during fetoscopic procedures and it will just ﬂoat in the amniotic ﬂuid, sending out signals that are translated onto a real-time bedside computer (Harrison MR, personal communication). There has never been a maternal death during or after fetal intervention. Maternal morbidity is related to preterm labor and its treatment.10–13 The most common side effect of tocolytic therapy, pulmonary edema, occurs while the pregnant patient is receiving high doses. Although reversible, this complication emphasizes the need for close monitoring in an intensive care setting.14,15 It has been rarely seen after fetoscopic procedures since they incite less uterine irritability compared to open fetal surgery. During open fetal surgery, the hysterotomy is often not performed in the lower uterine segment due to fetal and placental position and because the lower uterine segment is not fully developed in the second trimester. Thus, delivery after fetal surgery and for all future deliveries must be by cesarean section to avoid the risk of uterine scar dehiscence during labor. This is not, however, necessary after fetoscopic procedures. Fortunately, the ability to carry and deliver subsequent pregnancies does not appear to be jeopardized by fetal surgery. In a recent survey of fetal surgical patients, 27 mothers have attempted pregnancy after fetal surgery, 25 conceived and delivered normal children. Two, both of whom had a strong preoperative history of infertility, failed to conceive.16

190 Fetal surgery

provides hemostasis and seals the membranes to the myometrium.8 The appropriate part of the fetus is then exposed. Warm lactated Ringer’s solution is continuously infused around the fetus and the open uterus to maintain fetal body temperature. For fetal monitoring in open fetal surgery, a sterile pulse oximeter is used and a radiotelemetric device that is implanted submuscularly (usually on the chest wall) records the fetal electrocardiogram, temperature and intrauterine amniotic pressure.9 After repair of the defect, the fetus is returned to the womb and amniotic ﬂuid is restored with warm saline containing an antibiotic such as nafcillin. The uterine incision is closed with two layers of absorbable sutures. Fibrin glue is used to help seal the uterine incision.

FETAL SURGICAL TECHNIQUES The development of both open and minimal-access fetal surgical techniques continues to evolve.12 Anesthesia of the mother and her baby is established with halogenated agents, which also provide profound uterine relaxation. Additionally, an epidural catheter is inserted to enhance postoperative pain control. In the operating room, the mother is positioned in the left-lateral decubitus position to avoid inferior vena caval compression by the gravid uterus. Maternal monitoring is accomplished with standard techniques including pulse oximetry, a radial arterial catheter, a blood pressure cuff, large-bore i.v. catheters, measurement of urine output, and an electrocardiogram. The two principal routes of access to the fetus will be discussed later.

Minimal-access fetal surgery – FETENDO Although fetoscopic techniques for direct optical visualization of the fetus are not new, recent modiﬁcations of existing postnatal endoscopic techniques and development of new fetoscopic instruments have resulted in minimal-access fetal surgery (FETENDO). The FETENDO strategy may preserve fetal homeostasis by protecting the intrauterine physiological milieu, and avoiding the morbidity of a uterine incision such as preterm labor and postoperative bleeding.17 The mother is placed in a modiﬁed lithotomy position. Anesthetic techniques, tocolytic therapy, and maternal monitoring are as described earlier. Pre- and intraoperative sonography maps the position of the placenta and the fetus and guides trocar placement. An anterior placenta usually requires a low transverse abdominal incision to expose the uterus; trocars are placed superiorly and posteriorly. Continuous irrigation using a pump irrigation system via the sheath of the hysteroscope is crucial to optimize visibility (Fig. 17.1). This system maintains a constant intrauterine ﬂuid

Open fetal surgery The timing of open fetal surgery is dependent on the malformation being treated and the pathophysiologic course encompassing that disorder. Commonly, accurate early diagnosis and the fragility of fetal tissue become limiting factors at less than 18 weeks’ gestation. After 30 weeks’ gestation, manipulations on the uterus are associated with a high risk of premature rupture of the membranes (PROM) and preterm labor. It is then more reasonable to deliver the fetus and treat the malformation with standard postnatal care. A low abdominal transverse incision is used to visualize the uterus. After identiﬁcation of the fetal position and placental location with intraoperative ultrasound, the fetus is given an intramuscularly administered narcotic and paralytic agent. Depending on the placental location, an anterior or posterior hysterotomy is performed using a specially developed absorbable uterine stapler device that

Irrigation telescope Heater In Out

Pressure Pump head

Temp

Out Increase fluid LR

Pu rge

In

HE

In Decrease fluid t

Ou

Waste

Figure 17.1 Warmed lactated Ringer’s solution is circulated through the inner sheath of the hysteroscope and exits at the lighted tip. Amniotic ﬂuid can be suctioned via the outer sheath. The irrigation/aspiration volume can be carefully regulated using the pump

Fetal malformation amenable to surgical correction 191

volume, avoids risk of air embolus with gas distention of the uterus, ensures a continuously washed operative ﬁeld, improves visibilitiy by exchanging the cloudy amniotic ﬂuid with lactated Ringer’s solution, and keeps the fetus warm. One of the difﬁcult obstacles of FETENDO is the manipulating of the fetus into the correct position and keeping it there for the duration of the procedure. This very often frustrating problem is best illustrated by the development of FETENDO tracheal occlusion to treat CDH, where a chin stitch (Fig. 17.2) is used to keep the fetal neck exposed by extending the head.17,18 At the end of the procedure, amniotic ﬂuid volume is assessed by sonography and optimized. Antibiotics are infused, the trocars are withdrawn and the puncture site is closed with an absorbable suture and ﬁbrin glue.

Sonogram

T-bar

Trocar

Chin suture

Tracheal screw

Figure 17.2 Under sonographic guidance, (1) the fetus’ neck is exposed and head stabilized by placing a transuterine chin suture, and (2) a T-bar is placed in the fetal trachea to aid in localizing the midline fetal neck. After anterior tracheal dissection, a tracheal ‘screw’ (inset) is placed in the tracheal wall and anterior traction applied, allowing safe posterolateral tracheal dissection. Subsequently, the trachea is occluded with a titanium clip

POSTOPERATIVE MANAGEMENT Daily fetal sonography and echocardiography are substitutes for direct fetal physical examination in the postoperative course. Continuous epidural analgesics ease maternal stress and aid tocolysis. The hospital stay ranges from 2–7 days, depending on the procedure and whether or not a maternal laparotomy was performed. Preterm labor, the Achilles’ heel of fetal intervention, remains the primary cause of maternal morbidity and fetal death. The pathophysiology of preterm labor after hysterotomy is incompletely understood. Currently, tocolytic regimen begins with administration of indomethacin to the mother prior to surgery and despite best

efforts, the development of appropriate postoperative tocolysis is a difﬁcult and frustrating clinical problem.10–12 Treatment with terbutaline, magnesium sulfate, indomethacin, or nifedipine has been relatively ineffective for preterm labor induced by a hysterotomy, in contrast to their value in spontaneous labor. Outpatient tocolysis is administrated with oral or s.c. (via a pump) terbutaline or oral nifedipine. Fetal sonograms are performed at least weekly. Cesarean delivery is performed when membranes rupture or labor cannot be controlled, usually before 36 weeks’ gestation.

FETAL MALFORMATION AMENABLE TO SURGICAL CORRECTION Prenatal diagnosis has deﬁned a ‘hidden’ mortality rate for some lesions, such as congenital diaphragmatic hernia (CDH), bilateral hydronephrosis, sacrococcygeal teratoma (SCT), and congenital cystic adenomatoid malformation (CCAM) of the lung. These lesions, when ﬁrst evaluated and treated postnatally, demonstrate a favorable selection bias because the most severely affected fetuses often die in utero or immediately after birth. Although most prenatally diagnosed malformations are best managed by appropriate medical and surgical therapy after maternal transport and planned delivery at a tertiary care center, an expanding number of simple anatomical abnormalities with predictable, lethal consequences have been successfully corrected before birth. The development of minimal-access fetal surgery techniques, along with improvements in the treatment and/or prevention of preterm labor may enable the transition from treating only life-threatening defects to treating non-life-threatening, but substantially morbid malformations, namely myelomeningocele.

Obstructive uropathy Obstructive uropathy occurs in 1 in 1000 live births.19 Unilateral urinary obstruction (e.g. ureteropelvic junction obstruction) has a good prognosis and usually does not require fetal intervention. Fetuses with bilateral obstruction, principally male fetuses with posterior urethral valves, are potential candidates for prenatal intervention based on the degree and duration of the obstruction.20 Newborns with partial bilateral obstruction may have only mild and reversible hydronephrosis. However, children born at term with a high-grade obstruction may already have advanced hydronephrosis and renal dysplasia that is incompatible with life. The outcome of patients with urinary tract obstruction is principally dependent on the development of oligohydramnios. Decreased fetal urine production leads to oligohydramnios, which can cause pulmonary hypoplasia

192 Fetal surgery

that, if long standing, may be fatal at birth (Potter sequence). The presence of oligohydramnios is a predictor for a mortality approaching that associated with urinary tract obstruction. Fetuses with oligohydramnios identiﬁed in the early second trimester have a mortality rate in excess of 90%.21,22 Prenatal ultrasound diagnosis is very accurate in the detection of fetal hydronephrosis and in determining the level of the urinary obstruction. When sonography demonstrates bilateral hydronephrosis, the initial assessment of fetal renal function is the determination of the quantity of amniotic ﬂuid. Because the majority of amniotic ﬂuid in middle and late pregnancy is the product of fetal urination, the presence of a normal amniotic ﬂuid implies the production and excretion of urine by at least one functioning kidney. Decreasing amniotic ﬂuid volume on serial ultrasound examinations in the setting of bilateral hydronephrosis is usually an indicator of deteriorating renal function. Renal function can then be assessed in two ways: by the appearance of the renal parenchyma on ultrasound, and by the laboratory analysis of urine via bladder aspiration. The presence of cortical cysts or increased echogenicity is highly predictive of renal dysplasia; the absence of these ﬁndings, however, does not preclude it.23 Direct sampling of fetal urine provides critical information about fetal renal function. Normal fetal urinary chemistry (Table 17.1) includes a urinary sodium less than 100 mEq/dL, chloride less than 90 mEq/dL, osmolarity less than 200 mOsm/L, and β2-microglobulin less than 4 mg/dL.20,21 Values greater than these indicate that the fetal kidney is unable to reabsorb these molecules and predicts poor postnatal renal function. Three successive bladder aspirations must be performed, each separated by at least 24 hours. The ﬁrst one empties stagnant bladder urine, the second empties the urine that was stagnant in the collecting system, and the third is most reﬂective of kidney function. The important dilemma in the management of fetuses with hydronephrosis is how to select fetuses with dilated urinary tracts that have a problem so severe that renal and pulmonary function may be compromised at birth, and yet renal function that is preserved enough to proﬁt from prenatal intervention. Only fetuses who present with (or develop) oligohydramnios with normal renal function (via urine electrolytes and protein), are less than 30 weeks’

gestation, and have no associated anomalies are considered for prenatal intervention. The aim of prenatal intervention is to bypass or directly treat the obstruction. If the urinary tract is adequately drained, restoration of amniotic ﬂuid will enhance fetal lung growth and abrogate any further renal function deterioration. Methods of urinary tract decompression include percutaneous vesico-amniotic shunt placement, fetoscopic vesicostomy, open vesicostomy, and fetoscopic fulguration of posterior urethral valves.19,24 Presently the most widely used and accepted means of treating bladder outlet obstruction is by percutaneous insertion of a double-J vesicoamniotic shunt.

Congenital diaphragmatic hernia (CDH) CDH is a simple anatomical defect, in which abdominal viscera herniate into the hemithorax, most often through a posterolateral defect in the diaphragm. Despite advances in prenatal care, maternal transport, neonatal resuscitation and the availability of extracorporeal membrane oxygenation (ECMO) the devastating physiological consequences due to pulmonary hypoplasia and hypertension are associated with a high neonatal mortality rate and appreciable long-term morbidity.1,2 It has been demonstrated in the fetal sheep model that compression of the lungs during the last trimester, either with an intrathoracic balloon or by creation of a diaphragmatic hernia, results in fatal pulmonary hypoplasia.25,26 Removal of the compression allowed progression of pulmonary growth and development, and increased the chances for survival. The prenatal diagnosis of CDH is established by sonographic demonstration of herniated abdominal contents such as loops of the bowel, stomach, or the left lobe of the liver. Unfortunately, while the function of certain fetal organs, such as fetal heart or fetal kidneys, can be assessed in utero, the fetal lungs do not exchange gas and thus cannot be directly assessed. Thus, several sonographically detectable predictors of the severity of a CDH have been proposed. The two most important parameters are the lung-to-head ratio (LHR)27 and the position of the left lobe of the liver.28 The LHR is the calculated volume of the contralateral lung (the ipsilateral lung cannot be identiﬁed with a CDH) indexed to

Table 17.1 Prognostic criteria* for the fetus with bilateral obstructive uropathy Predicted function Poor Good

Sodium (mEq/L)

Chloride (mEq/L)

Osmolarity (mOsm)

Output (ml/hour)

>100 <100

>90 <90

>210 <210

<2 >2

* Fetal urine composition and volume.

Fetal malformation amenable to surgical correction 193

head circumference to adjust for gestational age. Fetuses with an LHR of more than 1.4 have a favorable prognosis with tertiary postnatal care and are not candidates for fetal intervention. Fetuses with a major portion of the left lobe of the liver herniated into the hemithorax have an approximate 50% chance of survival, whereas those with liver in the normal abdominal position have a greater than 90% chance of survival.28 This determination is technically challenging, requiring color Doppler to visualize the position of the branches of the left portal vein. These prognostic indicators allow careful selection of severely affected fetuses who may beneﬁt from fetal intervention. The prenatal treatment strategy for CDH has undergone continuous development since the ﬁrst attempted CDH repair in 1986.29,30 Open fetal surgery, a procedure where a hysterotomy was performed and the diaphragm was directly repaired was associated with many technical problems. The reduction of a herniated lobe of the liver during repair resulted in a kinking of the intraabdominal umbilical vein, cutting off blood ﬂow from the placenta and led to fetal demise. Data from a National Institutes of Health- (NIH) funded prospective clinical trial demonstrated that repair of the diaphragm for those without liver herniation worked but was no better than standard postnatal care.31 For those with the more severe form (liver herniation), complete repair was not technically feasible. It was this technical problem that forced a redirection in thinking about how to treat fetuses with the most severe CDH. An accident of nature supplied us with a new paradigm for treating these fetuses. It has long been noted that fetuses with congenital high airway obstruction syndrome (CHAOS) due to laryngeal or tracheal atresia have large, hyperplastic lungs due to overdistention by lung ﬂuid.32 Laboratory studies not only conﬁrmed that this model is reproducible, but that the lungs that are physically larger are also functionally better. This concept is now being tested using fetoscopic techniques for temporary occlusion of the fetal trachea using titanium clips to accelerate fetal lung growth.33–37 The preliminary data have shown this technique to have great promise and has formed the basis for an ongoing NIHsponsored clinical trial comparing tracheal occlusion at 26 weeks’ gestation vs standard postnatal care for those fetuses with an LHR < 1.4 and liver herniation. The strategy for removal of the tracheal clips is called the EXIT (ex utero Intrapartum Treatment) procedure.38 During this procedure a hysterotomy is performed, the fetal head and shoulders are delivered, but the cord is not clamped (Fig. 17.3). During this period of placental support, the baby is bronchoscoped by one surgeon while the other removes the occluding clips and sutures the neck incision closed. The child is then intubated, surfactant is delivered and mechanical ventilation (by hand) begun. Once the oxygen saturation increases, the cord is cut and the infant delivered.

Bronchoscope

2.5 endotracheal tube Broviac catheter

Pulse oximeter

Cord blood access

Figure 17.3 Essential elements of the EXIT procedure

Congenital cystic adenomatoid malformation (CCAM) CCAM of the lung is the most common type of fetal thoracic mass that can be detected by prenatal ultrasound at as early as 16 weeks’ gestation, with the majority of cases being diagnosed before 22 weeks’ gestation.39 It is a hamartoma of the lung which is usually unilateral and lobar. The differential diagnosis includes pulmonary sequestration, congenital diaphragmatic hernia, other congenital cystic malformations (e.g. bronchogenic, enteric, neurogenic cyst), and CHAOS. CCAMs have a broad spectrum of clinical severity. They may enlarge signiﬁcantly, may remain the same size, or in fact, disappear prenatally.39,40 They lead to fetal demise in 100% when sufﬁcient cardiac and great vessel compression lead to hydrops. However, size and/or degree of mediastinal shift alone are not predictive of hydrops. Experimentally, the pathophysiogical consequences and the rationale for in utero treatment of CCAM have been elucidated.25,41,42 The abnormal physiology (hydrops) is reversible by removing the mass. Open fetal surgical resection of the massively enlarged pulmonary lobe (fetal lobectomy) at 21–29 weeks’ gestation in 13 hydrophic CCAM cases with 62% survivors.43 The rarer microcystic lesions can be decompressed percutaneously by needle aspiration or a thoracoamniotic shunt.44

194 Fetal surgery

Sacrococcygeal teratoma Sacrococcygeal teratoma (SCT) occurs in 1 of 40 000 livebirths.45 The natural history of prenatally diagnosed SCT is very different from neonatal SCT. The well-established prognostic indicators found for neonatal SCT do not apply when SCT is detected in the fetus.46 Malignant invasion, the primary cause of death in neonatal SCT, is rare in utero.47 The physiological consequences of fetal SCT are associated with the development of high-output cardiac failure due to a ‘vascular steal’ phenomenon through solid, highly vascular tumors.48 Only 10% of fetal SCT causes hydrops and, if untreated, results in 100% mortality.49 Furthermore, SCT may lead to a potentially devastating maternal complication called maternal mirror syndrome (Ballantine syndrome).50 In this syndrome, the mother experiences progressive symptoms suggestive of pre-eclampsia, including vomiting, hypertension, peripheral edema, proteinuria, and pulmonary edema due to the release of placental vasoactive factors or endothelial cell toxins from the edematous placenta. This syndrome is reversed only by delivering the child and the placenta, but not by removing the SCT prenatally. Prenatal sonographic diagnosis of SCT is based upon the demonstration of a characteristic caudal and/or intra-abdominal mass and has been reported as early as 14 weeks’ gestation.51 With widespread application of sophisticated obstetric sonography at midgestation, the majority of SCTs can be diagnosed in utero. Fetal SCTs can be either cystic, solid or mixed in appearance.52 The differential diagnosis includes myelomeningocele and obstructive uropathy. Color ﬂow Doppler ultrasound of large vascular tumors may demonstrate markedly increased distal aortic blood ﬂow and shunting of blood away from the placenta and to the tumor. There are two reported long-term survivors.53,54 In one series open fetal surgery was performed for ﬁve hydropic fetuses with large SCTs.53 Despite aggressive tocolytic therapy, preterm labor and delivery remained a severe problem in all ﬁve cases. Three of the neonates initially did very well. However, one died from an air embolism during resection of the residual tumor, and the second neonate died on the day of planned discharge from a central venous catheter complication. The remaining child is now developing normally at home. Currently, efforts are aimed at developing a minimally invasive approach that reverses the physiology via coagulation of the tumor’s major blood supply, not by tumor debulking.55 We have performed a ultrasoundguided percutaneous minimally invasive technique to coagulate the blood vessels in three fetuses.56

Twin-to-twin transfusion syndrome Twin-to-twin transfusion syndrome (TTTS) is the most common complication in monochorionic twin preg-

nancies, occurring in 5–35% of these pregnancies. Associated anomalies are extremely rare, but TTTS is associated with a high risk of miscarriage, brain damage, perinatal death and morbidity in survivors.57 Unequal sharing of the monochorionic placenta can usually be demonstrated sonographically; the smaller twin’s placental cord insertion is often marginal or velamentous, whereas the larger twin’s cord inserts into the placenta centrally.58 Vascular anastomoses on the placental surface exist between the two twins. If these are unbalanced, a net shunting of blood occurs due to arteriovenous anastomoses. Commonly, ultrasound can demonstrate severe oligohydramnios or anhydramnios in the pump twin’s sac (‘stuck twin’). The differential diagnosis for a ‘stuck twin’ includes uteroplacental dysfunction, discordant aneuploidy, structural urinary tract malformations, or congenital infection. The recipient develops polyhydramnios, pulmonary hypertension, and cardiomyopathy caused by chronic volume overload. Arteriovenous anastomoses can sometimes be demonstrated using Doppler sonography. The vessels in question are unpaired vessels with ﬂow from the donor to recipient. Spectral Doppler interrogation will demonstrate the characteristic pulsatile arterial blood ﬂow on the donor’s side, whereas the vessel will show a continuous venous ﬂow on the recipient’s side. The initial treatment is one or more amniocenteses of the recipient sac. For those nonresponders or those recipients who present with or develop hydrops, fetoscopic YAG-laser ablation of communicating anastomoses is performed. Some investigators elect to coagulate all vessels seen crossing the inter-twin septum,59 whereas others aim to coagulate only the unpaired inter-twin communicating vessels.60,61

Myelomeningocele Myelomeningocele (MMC), or spina biﬁda, is a midline defect resulting in exposure of the contents of the neural canal. Usually the defect is located in the dorsal portion of the lumbosacral vertebrae. Between 1500 and 2000 babies are born with MMC in the USA every year. More than 80% of children with MMC may be identiﬁed before birth with maternal serum alphafetoprotein screening.62 Direct sonographic visualization of the abnormal fetal spine can usually be accomplished by 16 weeks’ gestation. Other sonographic ﬁndings include frontal bone scalloping (lemon sign), abnormality of the cerebellum (banana sign), Chiari II malformation, hydrocephaly, microcephaly and encephalocele. The rationale for prenatal intervention is based on the observation that lower extremity function present in early pregnancy is progressively lost in later gestation. Several animal experiments have demonstrated that intrauterine repair of myelomeningocele may preserve

References 195

peripheral neurological function.63–68 Furthermore, experimental studies indicate that the Chiari II malformation, which is nearly always associated with myelomeningocele, may be prevented by prenatal repair.69 Recent clinical experience has demonstrated that open fetal surgery may improve neurological function and more dramatically resolve the hindbrain herniation associated with myelomeningocele.70–74 These early studies appear promising but the variable natural history, lack of accurate prenatal indicators of neurological function, absence of matched controls and long-term followup hampers the assessment of beneﬁts of prenatal intervention. An NIH-sponsored multicenter trial of fetal MMC repair is presently underway.

Congenital high airway obstruction CHAOS is usually caused by laryngeal or tracheal atresia, rarely by isolated tracheal stenosis, mucosal web or extrinsically by compression by a large cervical mass (e.g. teratoma, lymphangioma). Regardless of etiology, fetal upper airway obstruction prevents the normal egress of lung ﬂuid that is produced peripherally out of the airway, into the amniotic space. This ﬂuid is normally produced under a pressure that favors its movement out of the mouth, aided in part by fetal breathing movements. The resultant sonographic ﬁndings include large overdistended (ﬂuid-ﬁlled) echogenic lungs which compress the mediastinum, bilaterally ﬂattened or everted diaphragms, dilated large airways distal to the obstruction, and fetal ascites and/or hydrops due to heart and great vessel compression.75 If hydrops does not develop in utero, fetuses affected with CHAOS may be treated using the ex utero intrapartum treatment (EXIT) procedure, which maintains the baby on placental support while an airway is established by orotracheal intubation or tracheostomy.38 For fetuses who develop hydrops, early delivery or prenatal tracheostomy are options, depending on gestational age. There are three known survivors of prenatally diagnosed CHAOS.76–78

Amniotic band syndrome The incidence of amniotic band syndrome is 1 in 1200–15 000 live births. Early rupture of the amnion results in mesodermic bands which emanate from the chorionic side of the amnion and insert on the fetal body. These bands may lead to amputations, constrictions and postural deformities secondary to immobilization and have been replicated in an experimental model.79 The earlier the band occurs, the more severe the resulting lesion. Amniotic rupture in the ﬁrst weeks of pregnancy may result in cranio-facial and visceral defects, whereas during the second trimester, the fetal morbidity ranges from formation of syndactyly to limb

amputation. It may be fatal if umbilical cord constriction occurs.80 Mild forms of this syndrome do not warrant fetoscopic intervention at the moment given the potential fetal and maternal morbidity. There are two reported cases of fetoscopic lysis of amniotic bands.81

FUTURE OF FETAL SURGERY Increasingly sophisticated techniques for prenatal diagnosis have revolutionized the ﬁeld of fetal medicine. The fetus has come a long way from the biblical ‘seed’ and mystical ‘homunculus’, to an individual with medical problems that can be diagnosed and treated. The short but eventful history of fetal surgical intervention offers new hope for the fetus with an isolated congenital malformation. The great promise of fetal therapy is that for some diseases, the earliest possible intervention (i.e. before birth) will produce the best possible outcome, i.e. the best quality of life for the resources expended. However, the promise of cost-effective, preventive fetal therapy can be subverted by misguided clinical applications, e.g. a complex in utero procedure that ‘half-saves’ an otherwise doomed fetus for a life of intensive (and expensive) care. Enthusiasm for fetal intervention must be tempered by reverence for the interests of the mother and her family, by careful study of the disease in experimental fetal animals and untreated human fetuses, and by a willingness to abandon therapy that does not prove effective and cost-effective in properly controlled trials.

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References 197 42. Adzick NS, Hu LM, Davies P. Compensatory lung growth after pneumoectomy in fetal lambs: a morphometric study. Surgical Forum 1986; 37:309. 43. Adzick NS, Harrison MR, Crombleholme TM, Flake AW, Howell LJ. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179:884–9. 44. Blott M, Nicolaides KH, Greenough A. Postnatal respiratory function after chronic drainage of fetal pulmonary cyst. Am J Obstet Gynecol 1988; 159:858–9. 45. Bale PM. Sacrococcygeal developmental abnormalities and tumors in children. Perspect Pediatr Pathol 1984; 1:9–56. 46. Flake AW. Fetal sacrococcygeal teratoma. Semin Pediatr Surg 1993; 2:113–20. 47. Graf JL, Housley HAT, Albanese CT, Adzick NS, Harrison MR. A surprising histological evolution of preterm sacrococcygeal teratoma. J Pediatr Surg 1998; 33:177–9. 48. Bond SJ, Harrison MR, Schmidt KG et al. Death due to high-output cardiac failure in fetal sacrococcygeal teratoma. J Pediatr Surg 1990; 25:1287–91. 49. Langer JC, Harrison MR, Schnmidt KG et al. Fetal hydrops and death from sacrococcygeal teratoma: rationale for fetal surgery. Am J Obstet Gynecol 1989; 160:1145–50. 50. Kuhlmann RS, Warsof SL, Levy DL, Flake AW, Harrison MR. Fetal sacrococcygeal teratoma. J Pediatr Surg 1986; 21:563–6. 51. Holzgreve W, Mahony BS, Glick PL et al. Sonographic demonstration of fetal sacrococcygeal teratoma. Prenat Diag 1985; 5:245–57. 52. Westerburg B, Feldstein VA, Sandberg PL, Lopoo JB, Harrison MR, Albanese CT. Sonographic prognostic factors in fetuses with sacrococcygeal teratoma. J Pediatr Surg 2000; 35:322–6. 53. Graf JL, Albanese CT, Jennings RW, Farrell JA, Harrison MR. Successful fetal sacrococcygeal teratoma resection in a hydropic fetus. J Pediatr Surg 2000; 35:1489–91. 54. Adzick NS, Crombleholme TM, Morgan MA et al. A rapidly growing fetal teratoma. Lancet 1997; 349:538. 55. Westerburg BW, Chiba T, Gantert et al. Radiofrequency ablation of liver in the fetal sheep: A model for treatment of sacroccygeal teratoma in the fetus. Surg Forum 1998; 49:461–3. 56. Paek B, Jennings RW, Farmer DL et al. Radiofrequency ablation of human fetal sacroccocygeal teratoma. Am J Obstet Gynecol (in press). 57. Blickstein I. The twin–twin transfusion syndrome. Obstet Gynecol 1990; 76:714–22. 58. Fries MH, Goldstein RB, Kilpatrick SJ, Golbus MS, Callen PW, Filly RA. The role of velamentous cord insertion in the etiology of twin–twin transfusion syndrome. Obstet Gynecol 1993; 81:569–74. 59. Hecher K, Plath H, Bregenzer T, Hansmann M, Hackeloer BJ. Endoscopic laser surgery versus serial amniocentesis in the treatment of severe twin–twin transfusion syndrome (In Progress Citation). Am J Obstet Gynecol 1999; 180:717–24.

60. De Lia JE, Kuhlman RS, Harsted TW, Cruikshank DP. Fetoscopic laser ablation of placental vessels in severe previable twin–twin transfusion syndrome. Am J Obstet Gynecol 1995; 172:1202–8. 61. Feldstein VA, Machin GA, Albanese CT, Sandberg P, Farrell J, Farmer D, Harrison MR. Twin-twin transfusion syndrome: The SELECT procedure. Fetal Diagn Ther (in press). 62. Brock DJ, Sutcliffe RG. Alpha-fetoprotein in antenatal diagnosis of anencephaly and spina biﬁda. Lancet 1972; 2:197. 63. Heffez DS, Aryanpur J, Rotellini NAC et al. Intrauterine repair of experimental surgically created dysraphism. Neurosurg 1993; 32:1005–10. 64. Meuli M, Meuli-Simmen C, Hutchins GM et al. In utero surgery rescues neurologic function at birth in sheep with spina biﬁda. J Pediatr Surg 1995; 30:342–7. 65. Hutchins GM, Meuli M, Meuli-Simmen C, Jordan MA, Heffez DS, Blakemore KJ. Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr Path Lab Med 1996; 16:701–2. 66. Heffez DS, Aryanpur J, Hutchins GM et al. The paralysis associated with myelomeningocele: Experimental data implicating a preventable spinal cord injury. Neurosurg 1990; 26:987–92. 67. Meuli M, Meuli-Simmen C, Yingling CD, Hutchins GM, Seller MJ, Harrison MR, Adzick NS. Creation of myelomeningocele in utero: A model of functional damage from spinal cord exposure in fetal sheep. J Pediatr Surg 1995; 30:1028–32. 68. Michejda M. Intrauterine treatment of spina biﬁda: Primate model. Z Kinderchir 1984; 39:259–61. 69. Jennings RW, Wilkinson C, Westerberg B et al. Chari malformation develops in surgically created myelomeningocele, and is prevented by repair of the myelomeningocele in fetal lambs. Am J Obstet Gynecol (in press). 70. Bruner JP, Richard WO, Tulipan NB, Arney TL. Endoscopic coverage of fetal myelomeningocele in utero. Am J Obst Gynecol 1999; 180:153–8. 71. Ulipan N, Hernanz-Schulman M, Bruner JP. Reduced hindbrain herniation after intrauterine myelomeningocele repair: a report of four cases. Pediatr Neurosurg 1998; 29:274–8. 72. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina biﬁda. Lancet 1998; 352:1675–6. 73. Bruner JP, Tulipan N, Paschall RL et al. Fetal surgery for myelomeningocele and the incidence of shuntdependent hydrocephalus. JAMA 1999; 282:1819–25. 74. Sutton LN, Adzick NS, Bilaniuk LT et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999; 282:1826–31. 75. Martinez-Ferro M, Hedrick MH, Flake AW, Harrison MR, Adzick NS. Prenatal diagnosis of congenital high airway obstruction (CHAOS): potential for perinatal intervention. J Pediatr Surg 1994; 29:271–4.

198 Fetal surgery 76. Crombleholme TM, Sylvester K, Flake AW, Adzick NS. Salvage of a fetus with congenital high airway obstruction syndrome by ex utero intrapartum treatment (EXIT) procedure. Fetal Diagn Ther 2000; 15:280–2. 77. Paek B, Saito J, Callan P et al. CHAOS controlled: Successful fetal intervention for complete high airway obstruction syndrome. Fetal Diagn Ther (in press). 78. DeCou JM, Jones DC, Jacobs HD, Touloukian RJ. Successful ex utero intrapartum treatment (EXIT) procedure for congenital high airway obstruction syndrome (CHAOS) owing to laryngeal atresia. J Pediatr Surg 1998; 33:1563–5.

79. Crombleholme TM, Dirkes K, Whitney TM, Alman B, Garmel S, Conn RJ. Amniotic band syndrome in fetal lambs. I: Fetoscopic release and morphometric outcome. J Pediatr Surg 1995; 30:974–8. 80. Strauss A, Hasbargen U, Paek B, Bauerfeind I, Hepp H. Intrauterine fetal demise caused by amniotic band syndrome after standard amniocentesis. Fetal Diag Ther 2000; 15:4–7. 81. Quintero RA, Morales WJ, Phillips J, Kalter CS, Ngel JL. In utero lysis of amniotic bands. Ultrasound Obstet Gynecol 1997; 10:316–20.

2 Head and neck

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18 Choanal atresia in the newborn FRANCESCO COZZI AND DENIS A. COZZI INTRODUCTION Atresia of the choanae is a relatively rare congenital anomaly in which one or both choanae are obstructed by a membranous or bony plate, either partially or completely. The condition is variously reported as occurring one in 5000–10 000 births.1–3 Approximately 50% of cases are associated with other cranio-facial developmental anomalies such as Treacher Collins’ syndrome, anomalies of pharyngeal arches derivatives, CHARGE association. The latter association is an acronym of colobomata (retinal and/or iridial), heart disease, atresia choanae, retarded growth and development, genital anomalies in males and ear anomalies including deafness. An anomalous contribution of the cephalic neural crest cells to the embryogenesis of either the face or the autonomic nervous system, may explain why choanal atresia is nearly always associated with either minor facial anomalies or autonomic disorders.4 A disturbance of the mesodermal migration of the neural crest cells may also explain the frequent association with other major congenital anomalies.

PHYSIOPATHOLOGY In infants with complete nasal obstruction, it is widely accepted that the mechanism leading to asphyxia is the inability to open the mouth and start oral breathing.5–7 During inspiration, the lips and cheeks are drawn in and the tongue is sucked backwards and upwards to the hard palate, producing a sealing. During expiration, the soft palate is pushed against the base of the tongue, producing a complete obstruction as can be judged by a paradox dilatation of hypopharynx during expiration. This soft tissue sealing must be broken to avoid asphyxial death.6,7 The concept that the infant is an obligatory nasal breather has been recently challenged because nearly all normal infants are able to switch from nasal to oral respiration if nasal occlusion is not realized before the

infant starts to breathe through the mouth.8 Therefore, it is not the inability to mouth-breathe but the inability to sustain adequate mouth-breathing that may be the main cause of respiratory problems in infants with choanal atresia.8,9 During normal breathing, intrathoracic inspiratory depression does not result in collapse of musculomembranous pharyngeal walls because a neuromuscular mechanism acts, prior to inspiration, to stiffen the ﬂoppy structures of pharynx.10 The action of genioglossus plays a crucial role in maintaining the patency of the oropharyngeal airway because the tongue is a dynamic ﬂap valve which may easily obstruct the oropharyngeal airway when negative inspiratory pressure overcomes the genioglossus force.11 The autonomic control of forces acting on the upper airway muscles may present a developmental delay. The control may be also disturbed by factors that increase the negative intrathoracic pressure (respiratory tract infection, crying, exercise, etc.) and decrease the upper airway dilating muscle activity (sleeping, anesthetic, sedative, etc.). Infants present with a wide spectrum of neuromuscular activity of upper airway dilating muscles. Those at the lower end of the spectrum may experience respiratory difﬁculties even during a simple rhinitis. Conversely, infants at the upper end of the spectrum may remain asymptomatic even if affected by bilateral choanal atresia. In infancy, any type of nasal obstruction which results in a decreased inspiratory pressure overcoming the airway maintaining the genioglossus action causes recurrent episodes of functional upper airway obstruction during inspiration.12–14 Inspiratory dyspnea is the result of recurrent partial functional obstruction (glossoptosishypopnea). Apneic spells are the result of a complete functional obstruction due to a sealing of the tongue to the hard palate (vacuum-glossoptosis-apnea). Severe inspiratory dyspnea causes alveolar hypoventilation, which leads to hypoxemia, hypercapnia, and respiratory acidosis.13 Moderate inspiratory dyspnea causes a lower airway instability leading to miliary atelectasis (not detected by chest ﬁlms) with hypoxemia without hypercapnia.13

202 Choanal atresia in the newborn

The inspiratory dyspnea is often associated with an expiratory dyspnea, traditionally attributed to a passive functional obstruction due to approximation of the soft palate to the base of the tongue.6,7 The new concept is that the expiratory obstruction, at least in part, is due to an active braking of the expiratory ﬂow.14 Grunting expiration is a useful breathing strategy to avoid collapse of widespread areas of the lung and consequent right-toleft shunt. In infants with nasal obstruction and inspiratory dyspnea, active braking of the expiratory ﬂow may be particularly important since a large intrapulmonary shunt may play a role in the pathogenesis of apparent life-threatening episodes (ALTEs) with severe hypoxemia.15

CLINICAL FEATURES Babies with symptomatic choanal atresia or stenosis present clinical manifestations13,16,17 which are remarkably similar to those found in infants with other facial or thoracic malformations (congenital micrognathia, esophageal atresia, vascular ring, etc.). The common syndrome is due to a maturational dysautonomia affecting one or more autonomic functions. Nearly all infants with symptomatic choanal atresia or stenosis present with a disorder of autonomic control of respiration. The respiratory problems are characterized by recurrent episodes of partial or complete glossoptotic pharyngeal obstruction. The inspiratory dyspnea (polypnea, noisy inspirations, retractions, glossoptosis, retrognathia, opisthotonus, poor or absent air entry) is often associated with an expiratory dyspnea (paradox ballooning of soft tissues of the neck during expiration, barrel chest, hyperphonesis, wheezing and/or grunting). Lifethreatening episodes of complete airway obstruction due to glossoptosis are relieved by crying. The respiratory distress is very often associated with an abnormal autonomic control of sucking and/or swallowing, gastro-esophageal reﬂux and vomiting. About onethird of the patients present life-threatening cyanotic attacks which may occur during or soon after feeding, during crying or during suctioning of the pharynx. Infants with choanal obstruction may have additional autonomic disturbances such as life-threatening reﬂex bradycardia or tachycardia, life-threatening hyperthermia, hyperhydrosis, sialorrhea etc. Main complications include acute or chronic hypoxemia with or without hypercapnia, failure to thrive, pulmonary edema, cor pulmonale, asphyxic brain damage and sudden death.

DIAGNOSIS Relief of respiratory distress by keeping open the oropharyngeal airway excludes an obstruction at the

level of the larynx or trachea. Worsening of respiratory distress by pulling the tongue forward and concomitantly closing the mouth excludes a pharyngeal obstruction due to glossoptosis, and conﬁrms clinically the diagnosis of nasal obstruction. Complete or incomplete patency of the nasal cavity can be assessed by observing the movements of a thin wisp of cotton held in front of each side of the nares. A diagnosis of congenital choanal obstruction can be conﬁrmed by unsuccessful attempts to pass a No. 8 French catheter from the nose into the pharynx. When the catheter or metal sound is advanced along the ﬂoor of the nose next to the septum, it will encounter an obstruction at the level of the posterior choana. To discover whether the obstruction is complete or incomplete, a lateral skull X-ray can be taken while the patient is in the supine position and after injection of contrast medium. Computed tomography (CT) scanning gives excellent resolution of the anatomy of the nasal cavities.3 The information that CT scanning provides on the presence of a narrowing of the posterior part of the bony nasal cavity or on the thickness of the bony atretic plate, assists in the choice of technique for surgical correction in older patients. A deﬁnitive diagnosis of bilateral or unilateral choanal atresia or stenosis can be established by anterior and posterior rhinoscopy, using ﬂexible bronchoscopes or nasopharyngoscopes or nasopharyngeal mirrors. The differential diagnosis of nasopharyngeal abnormalities in infants with impaired nasopharyngeal airway includes traumatic birth lesions of the nose and nasal septum, rhinitis, turbinate hypertrophy, encephaloceles, polyps or tumors, and enlarged adenoids.18,19

PREOPERATIVE TREATMENT Both bilateral and unilateral symptomatic choanal atresia or stenosis require immediate treatment to avoid the risk of severe neonatal asphyxia. An oral airway with an obturator or McGovern nipple20 should be used as an emergency procedure to assure satisfactory ventilation. An orogastric tube can be used to maintain the airway open and to feed the infant. Orotracheal intubation is an option. A tracheostomy should always be avoided. Temporary use of an oral airway will allow the surgical correction of more urgent associated anomalies. Although the timing of deﬁnitive surgical repair has long been controversial, most recent writers1,2,13,21,22 have reemphasized that early establishment of a patent nasal airway minimizes the constant risk of fatal asphyxia. In addition, during the ﬁrst few months of life the soft bony atretic plate can be easily perforated, and early repair avoids a long hospital stay.

Technique of operation 203

TECHNIQUE OF OPERATION During the neonatal period the transnasal procedure is best because it is easily performed with minimal risk of facial growth disturbance. The most commonly used technique is endonasal perforation with blunt dilators followed by placement of tubes in the choanae. The tubes serve as a stent across the atretic area to prevent stenosis and as a nasopharyngeal airway.9 In the past, this technique fell into disuse because of a high frequency of recurrence of stenosis and difﬁculty in keeping the tubes clean. However, if nasal stenting is managed properly, a satisfactory and deﬁnitive repair can be made. Our surgical approach encompasses the following steps: 1 The infant is placed in the supine position on the operating table. Extension of head and neck is avoided. Anesthesia is given via an endotracheal tube passed through the mouth and ﬁxed to one side of the midline (Fig. 18.1). The surgeon sits or stands on the right side of the patient. The assistant sits or stands on the left side, keeps the mouth open and pulls the tongue forward using a laryngoscope; its light permits an excellent view of the pharyngeal cavity, which is kept clear with an angled sucker. 2 Pediatric urethral sounds are used to perforate the obstructing plate (Fig. 18.2). They have the ideal curvature to follow the sloping contour of the nasal ﬂoor and can prevent neurological injuries. 3 A No. 4 French sound is suitable for perforation of either membranous or bony atretic plate. The sound is passed along the ﬂoor of the nose (Fig. 18.3), staying against the septum to avoid penetrating the basisphenoid (a). When the obstruction plate is

Figure 18.1 Laryngoscope blade retracting the tongue forward, its light providing an excellent view of the pharyngeal cavity

Figure 18.2 Pediatric urethral sounds of various sizes

b

a

Figure 18.3 (a) The sound is passed along the ﬂoor of the nose, staying against the septum to avoid penetrating the basisphenoid. (b) When the obstruction plate is encountered, the sound is forced through it

encountered, the sound is forced through it (b). The direction of the sound can be followed by a ﬁnger introduced into the nasopharynx or by means of endoscopy. The perforation is then gradually dilated, avoiding spinal injuries by carefully following with dilators the gentle curve of the nasal ﬂoor. The limiting factor in the dilatation is the size of the anterior nares. 4 In bilateral cases two separate plastic No. 14 or 16 French feeding tubes with end-holes (Fig. 18.4) are fashioned long enough to allow a 1 cm protrusion into the nasopharynx (a). The proximal part of the connector is cut and discarded (b). The distal end of the tubes is sharpened with a pencil sharpener (c). 5 To facilitate placement, a No. 8 French gauge suction catheter is placed inside the tube and then passed from the nose into the pharynx. The tube is then railroaded onto it (Fig. 18.5). In bilateral choanal obstruction, two separate tubes are used.

204 Choanal atresia in the newborn

a

b

c

Figure 18.6 Anchoring of the tube to the forehead by an adhesive dressing Figure 18.4 (a) A No. 14 French plastic feeding tube. (b) The proximal part of the tube has been cut and discarded. (c) The distal end of the tube is sharpened with a pencil sharpener

become stenotic and if the nasopharyngeal airway is adequate, the stent is left out for an increasing number of hours until the infant can be weaned from the tubes day and night. Recurrent choanal stenosis is managed by repeated dilatations. In spite of widely patent choanae, some infants require use of the tubes for several months as a nasopharyngeal airway during sleep. Recently, transnasal repair of choanal atresia using a rod-lens telescope has been used with low morbidity.21,22

REFERENCES

Figure 18.5 The tube being railroaded from the nose into the pharynx

6 A silk suture is placed through the proximal part of the connector and taped to the central part of the forehead (Fig. 18.6). Pressure necrosis of the columella and alar rim should be avoided. This method of stenting has the advantage that the tube can easily be replaced. No antibiotics are used. Tube patency is maintained by instillation of 0.5 ml isotonic saline followed by suctioning. The tubes are removed once a day for thorough cleaning. Parents usually have no difﬁculty mastering the endonasal stent, so the infant can be sent home very soon with adequate medical and nursing supervision. Portable suction machines are used at home to facilitate parental care. After 2 months, the nasal tubes are removed and left out for 1 hour in the morning. If the choanae do not

1. Schwartz ML, Savetsky L. Choanal atresia: clinical features, surgical approach, and long term follow-up. Laryngoscope 1986; 96:1335–9. 2. Stahl RS, Jurkiewicz MJ. Congenital posterior choanal atresia. Pediatrics 1985; 76:429–36. 3. Shirkhoda A, Bigger WP. Choanal atresia. A case report illustrating the use of computed tomography. Radiology 1982; 142:93–4. 4. Cozzi F, Myers NA, Piacenti S et al. Maturational dysautonomia and facial anomalies associated with esophageal atresia: support for neural crest involvement. J Pediatr Surg 1993; 28:798–801. 5. Richardson CW. Congenital atresia of the post-nasal oriﬁce. Lancet 1914; 2:439–44. 6. Whitehouse WM, Holt JF. Paradoxical expiratory ballooning of the hypopharynx in siblings with bilateral choanal atresia. Radiology 1952; 59:216–20. 7. Hough JVD. The mechanism of asphyxia in bilateral choanal atresia: the technique of its surgical correction in the newborn. South Med J 1955; 48:588–94. 8. Rodenstein DO, Perlmutter N, Stanescu DC. Infants are not obligatory nasal breathers. Am Rev Respir Dis 1985; 131:343–7. 9. Cozzi F. Glossoptosis as a cause of apnoeic spells in infants with choanal atresia. Lancet 1977; 2:830–1.

References 205 10. Brouillette RT, Thach BT. A neuromuscular mechanism maintaining airway patency. J Appl Physiol 1979; 46:772–9. 11. Remmers JE, de Groot WJ, Sawerland EK et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931–8. 12. Cozzi F. Familial obstructive sleep apnea. N Engl J Med 1979; 300:506–7. 13. Cozzi F, Pierro A. Glossoptosis-apnea syndrome in infancy. Pediatrics 1985; 75:836–43. 14. Cozzi F, Bonanni M, Cozzi DA et al. Assessment of pulmonary mechanics and breathing patterns during posturally induced glossoptosis in infants. Arch Dis Childh 1996; 74:512–16. 15. Poets CF, Samuels MP, Southall DP. Potential role of intrapulmonary shunting in the genesis of hypoxemic episodes in infants and young children. Pediatrics 1992; 90:388–91.

16. Cozzi F, Stainer M, Rosati D et al. Clinical manifestations of choanal atresia. J Pediatr Surg 1988; 23:203–6. 17. Cozzi F, Myers NA, Madonna L et al. Esophageal atresia, choanal atresia, and dysautonomia. J Pediatr Surg 1991; 26:548–52. 18. Benjamin B. Evaluation of choanal atresia. Ann Otol Rhinol Laryngol 1985; 94:429–32. 19. Lantz HJ, Birck HG. Surgical correction of choanal atresia in the neonate. Laryngoscope 1981; 91:1629–34. 20. McGovern FH. Bilateral choanal atresia in the newborn: a new method of medical management. Laryngoscope 1961; 71:480–3. 21. Lazar RH, Younis RT. Transnasal repair of choanal atresia using telescope. Arch Otolaryngol 1995; 121:517–20. 22. Friedman NR, Mitchell RB, Bailey CM et al. Management and outcome of choanal atresia correction. Int J Pediat Otorhinolaryngol 2000; 52:45–51.

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19 Pierre Robin sequence EVELYN H. DYKES

INTRODUCTION The inclusion of a chapter on Pierre Robin sequence (or syndrome) in a textbook of operative surgery may be seen by some as outdated, since current management of this condition includes little in the way of surgical procedure. Nevertheless, as a time-honored ‘surgical’ cause of neonatal respiratory distress, the condition is worthy of mention, if only to draw attention to the changes which have taken place in the treatment of these infants.

HISTORY, INCIDENCE AND ETIOLOGY The combination of micrognathia and glossoptosis causing respiratory distress and failure to thrive during the neonatal period was recognized by Pierre Robin in 1926.1 It was 4 years later that Eley and Farber described four patients with these features, exacerbated by the presence of a cleft palate.2 They cited other reports, published as early as 1891, of similar conditions, and recognition of this cause of infantile respiratory distress was born. It is not clear why the eponym of Pierre Robin was applied to the condition and its description as a ‘syndrome’ is not strictly correct. A more accurate representation of the development of the features is gained by the term ‘sequence’ or ‘anomalad’,3,4 but the original eponym persists and is likely to do so for some time. The cardinal features of the Pierre Robin sequence (PRS) are micrognathia, glossoptosis and respiratory obstruction. The latter may be severe and persistent, stimulating immediate attention, or it may be intermittent, related to feeding or posture. Though not initially described by Robin himself, cleft palate is a frequent association2,5,6 – indeed some authors believe it to be a prerequisite of the diagnosis.7,8,9 This confusion has resulted in wide variations in the reported incidence of PRS, but long-term studies in the UK and Australia suggest that it may occur with a frequency of at least 1:8500 live births.7,10

The etiology of the structural defects in PRS is equally controversial. Mandibular hypoplasia is likely to be the primary lesion, resulting in posterior displacement of the tongue into the pharynx (glossoptosis) and frequently also upward displacement, causing cleft palate. Since relative mandibular hypoplasia with glossal displacement is a normal ﬁnding up to the seventh month of fetal life,11 it is presumed that the anomaly results from an insult to mandibular growth at this time. The nature of the insult is uncertain: mechanical compression (as in oligohydramnios), vascular accident, neuromuscular, metabolic and genetic abnormalities have all been proposed and substantiated either experimentally or clinically.12–14 A logical assumption is that a variety of factors may lead to persistent mandibular hypoplasia with the resulting postnatal manifestations.15,16 The severity and persistence of the clinical entity is probably related to the nature of the insult, as illustrated by the difference in outcome between ‘syndromic’ and ‘non-syndromic’ micrognathia.8,13,17

CLINICAL FEATURES AND MANAGEMENT More important than etiologic theorization is the early recognition of the features predisposing to glossoptotic upper airway obstruction. The infant with classical PRS presents a classic ‘bird-like’ facies (Fig. 19.1) with a small receding chin and a ﬂattened nasal base.18 The palate may be high and arched, or may have a complete or submucosal cleft. There may be associated abnormalities of other systems. Measurement of the jaw index has been used to deﬁne micrognathia; infants with PRS have an average jaw index over 3.6 times the normal values .19 With recent improvements in prenatal ultrasound, the diagnosis may be made prenatally.20–23 The presence of a family history of cleft lip or palate, or of PRS itself, should prompt careful examination of the fetal mandible. If fetal micrognathia is detected, a search for other abnormalities should ensue.

208 Pierre Robin sequence

Figure 19.2 (a) Receding chin of Pierre Robin facies; (b) glossoptosis in Pierre Robin anomalad obstructs breathing

Figure 19.1 Typical Pierre Robin facies with receding chin (Courtesy Mr P.A.M. Raine)

AIRWAY MANAGEMENT It should be noted that even minor degrees of micrognathia can result in glossoptosis. Airway obstruction can occur at or immediately after birth, but may take much longer (up to 3 weeks) to become apparent.24 The intermittence of the obstruction demands special vigilance, even in infants with apparently minimal defects. Since most of the complications of PRS are directly related to delayed or inadequate airway management, early diagnosis is mandatory if a favorable outcome is to be achieved.25–27 Airway obstruction in PRS is due to a narrowing or complete obstruction of the pharyngeal air passage by a posteriorly displaced tongue (Fig. 19.2). Upper airway obstruction is identiﬁed by increased respiratory effort, stridor, subcostal recession, and cyanotic or apneic spells. Choking attacks or cyanosis during feeds indicate inadequate airway protection or obstruction. In the apparently asymptomatic infant, repeated attacks of aspiration suggest an intermittent airway difﬁculty. Transcutaneous Po2 monitoring or continuous pulse oximetry may help to identify obstructive episodes.28 The infant displaying such signs should be nursed prone with the head to one side (Fig. 19.3). Level positioning is important – a head-up tilt may aggravate the tendency to glossoptosis, while head-down can stimulate gastro-esophageal reﬂux and aspiration.29 All nursing procedures such as bathing, changing and feeding can be performed with the baby in this position. If necessary, the child can be fed in the mother’s or nurse’s lap – again in the prone position. Ventral suspension of

Figure 19.3 Correct nursing position – prone with head level

the head by a stockinette cap may be of assistance (Fig. 19.4) but adds little to expert postural care. These measures are adequate for the majority of children with glossoptotic obstruction. However in some infants, persistence of respiratory difﬁculty necessitates further intervention. In such children a nasopharyngeal airway should be inserted without delay.30 It is not necessary to intubate the vocal cords, but merely to preserve the pharyngeal airway and, as such, a simple oral airway (Fig. 19.5a) may sufﬁce, at least as a temporary measure, until a formal nasopharyngeal (NP) airway can be obtained. An ordinary Portex endotracheal tube (Portex Inc., Wilmington, MA, USA) cut to the appropriate length, is inserted by the nasal route and securely strapped in place (Fig. 19.5b). Tunstall connectors (Penlon Inc., Cleveland, OH, USA) (Fig. 19.5c), if available, reduce the need for excessive facial trauma from adhesive tape30 but other types of connector, if secure, will serve equally well. The length of the NP airway is critical. The tip of the tube should be just above the epiglottis, thereby bypassing the tongue obstruction (Fig. 19.6) and the position should be conﬁrmed by lateral radiograph following insertion. Since the tube lies above the vocal cords, humidiﬁcation of inspired air is advantageous but not essential. A ‘Swedish nosepiece’ is too cumbersome for tiny infants and may result in dislodgement of the air-

Airway management 209

(a)

(b) Figure 19.4 Ventral suspension of head allowing jaw and tongue to fall forward, thus clearing airway (Courtesy Mr P.A.M. Raine)

way. Tube patency must be maintained, especially before feeds, and regular suctioning with prior installation of 0.5 ml normal saline is necessary. Recently, a modiﬁcation of the traditional NP tube has been described,31 which is claimed to reduce the dead space and airway resistance, and consequently may be better tolerated. If the NP airway is unsuccessful, more invasive measures may be required. Endotracheal intubation is a difﬁcult procedure in children with PRS and should be performed by someone skilled in intubating small infants. A selection of laryngoscope blades may be required,32,33 and occasionally ﬁberoptic techniques have been needed.34 An alternative to intubation is the laryngeal mask airway (LMA).35,36 This is a useful mechanism for short-term support during resuscitation or anesthesia, but is not appropriate for long-term maintenance. Once an endotracheal tube is inserted, humidiﬁcation of inspired gas is essential to prevent encrusting of the lumen with dried secretions. With proper nasotracheal tube care, it is possible to nurse the infant in this way for several weeks, until growth allows removal of the tube and a return to postural management. Previously described surgical procedures such as glossopexy or lip–tongue anastomosis offer no advantage over the NP airway other than to alleviate the need for assiduous nursing. As such they have little place in the present management of PRS, except in underdeveloped countries, where nurses are scarce and tracheostomy is undesirable. The reader in such situations is referred to

(c) Figure 19.5 (a) Infant oral airway; (b) nasopharyngeal airway; (c) Tunstall connector which allows ﬁxation of tube with minimal facial strapping

other sources for a description of the operative techniques.37,38 Tracheostomy carries a signiﬁcant morbidity rate in the small child39,40 and should be avoided if at all possible. Difﬁculty in maintaining the position of the NP airway, or rarely, persistent obstruction despite appropriate use of the NP airway, may result in a need for surgical management, in which event, tracheostomy is preferable to glossopexy.27 Since the glossoptosis of PRS is a temporary phenomenon which usually resolves with growth, endotracheal intubation will obviate the need

210 Pierre Robin sequence (a) (a)

(a)

(b)

Figure 19.6 (a) Narrowing of pharyngeal airway by posteriorly displaced tongue; (b) correct positioning of nasopharyngeal airway with tip of tube above epiglottis

for surgery, but a desire that the infant be orally fed or nursed more easily may take precedence. In this event, the procedure should be performed by a surgeon skilled in pediatric tracheostomy, since the operation differs in some detail from that used in adults (see Chapter 16).

(b)

Figure 19.7 (a) Standard nipple; (b) standard nipple with enlarged X-cut

ment to compensate for up to a tenfold increase in respiratory work.30 Indeed, failure to gain weight despite maximum nutritional intake should suggest the need for more aggressive airway management.43 The availability of total parenteral nutrition should prevent any instances of failure to thrive, but it is only rarely needed if other aspects are correctly managed.

MANAGEMENT OF ASSOCIATED ANOMALIES Nutritional management Failure to thrive was recognized by Pierre Robin and others as a frequent accompaniment of glossoptotic airway obstruction.1,2 Feeding difﬁculties are compounded if a cleft palate is present. Nevertheless, with skilled nursing, simple measures may sufﬁce to overcome these problems. As described earlier, maintenance of the airway is vital during feeding. To this end the infant may be bottle fed in the prone position, with forward placement of the jaw (and therefore also the tongue) encouraged by the thumb and second ﬁnger of the feeder. Care must be taken to avoid compromising the airway further by the injudicious placement of these ﬁngers! A lamb’s feeding teat has been favored by some, but others suggest that a standard nipple (Fig. 19.7a) with an enlarged x-cut (Fig. 19.7b) is better; the former produces a uniformly increased milk ﬂow, while the latter allows the infant to increase ﬂow on demand, with minimal effort.29 If oral feeding fails, gavage feeding may be required. In this event, the nasogastric tube should be withdrawn between feeds to reduce the likelihood of reﬂux and aspiration.29 A feeding gastrostomy relieves the need for repeated tube placement, and can be created via the percutaneous route, but the possibility of creating gastro-esophageal reﬂux should be considered.41,42 Adequate caloric intake is critical for PRS infants. Since the resolution of the airway problem is directly related to mandibular growth, it is important to achieve the maximum growth rate possible. Only recently has the increased work of breathing been appreciated in terms of calorie consumption; it may be necessary to provide these children with several times the normal caloric require-

Abnormalities of other systems are frequently seen with PRS18,44–46 and each infant should be carefully examined and investigated with this in mind.

Genetic syndromes Micrognathia and glossoptosis are components of numerous genetic syndromes.13 Identiﬁcation of inherited or inheritable defects is important, not only because of the need for parental counselling in such cases, but also because the outcome in children with ‘syndromal’ PRS is signiﬁcantly worse than in those in whom PRS is an isolated abnormality.8,10,13,46,47 The inheritance of PRS itself is unproven. While there are reports of familial PRS, most cases occur sporadically.10,44–46

Cleft palate Depending on the diagnostic criteria used, cleft of the soft or hard palate occurs in up to 80% of infants recognized to have PRS.6 Since the cleft is usually restricted to the palate and does not involve the lip, surgical reconstruction is not required during the neonatal period. The feeding maneuvers described will permit adequate nutrition in cleft babies; prostheses are not indicated in these children and may result in accidental airway obstruction. All infants with cleft palate may experience speech and hearing difﬁculties during development and PRS cases are no exception.45,46 The child with PRS and an associated cleft palate should be followed up carefully long after the respiratory difﬁculty has resolved, prefer-

Complications and outcome 211

ably in a center where a multidisciplinary ‘cleft clinic’ is readily available, since auditory assessment, speech therapy and orthodontic treatment are all required. This approach will minimize the educational and communication problems previously seen in so many of these children.

Skeletal anomalies Limb defects are seen in 11–21% of children with PRS.45,46 Common anomalies are talipes equinovarus, syndactyly, short or absent digits and hypoplastic long bones. Occipito-atlanto-axial instability has been described,47 emphasizing the need for experience in those who undertake the intubation of such patients. Orthopedic and radiological consultation should be sought in children with suspected skeletal problems. Rare neuromuscular defects can also occur, resulting in a tendency for glossoptosis to persist despite mandibular growth.13

Cardiovascular anomalies Intrinsic cardiac defects are found in up to 20% of infants with PRS.45,46,48 Septal defects are common but more complex lesions can occur. A thorough cardiovascular examination should be requested in PRS babies, particularly since the airway difﬁculties may aggravate the cardiac status.49

Ocular anomalies Retinal detachment and micrognathia occur as part of Stickler syndrome50 but 10% of infants with nonsyndromic PRS also have eye defects such as strabismus, ptosis and microphthalmia. More severe defects such as cataract and congenital glaucoma have also been reported, and ophthalmological consultation is recommended in all cases.45,46,51

will achieve normal or near-normal proportions, and the glossoptosis will resolve.8,18,54 One study has suggested that there is no signiﬁcant difference in proportional mandibular growth during the ﬁrst year of life between PRS infants and controls,55 but in the majority of affected infants, symptoms are relieved within a few months. Airway protection during this period is vital. The previously documented high incidence of mental retardation in PRS patients was almost certainly due to unrecognized episodes of hypoxia; with good airway management this complication is uncommon.45,46 Undiagnosed hypoxia may also lead to pulmonary vasoconstriction, with resultant pulmonary hypertension and cor pulmonale.49 Some instances of sudden death in PRS are likely to have been due to this problem; the presence of cardiomegaly on a chest X-ray (Fig. 19.8) should alert the physician to the possibility that hypoxic episodes have been overlooked, and appropriate steps should be taken immediately. Although airway patency improves with growth, there remains a potential for obstruction, particularly after invasive procedures such as intubation or cleft palate repair.33 In some children, obstruction may occur during sleep, causing occasional apnea with potentially hazardous consequences.53,56,57 A degree of mandibular hypoplasia may persist for several years, resulting in malocclusion and the need for dental treatment.6,10 The overall mortality rate in infants with PRS is approximately 25%. The majority of deaths (70%) occur in children with associated anomalies, particularly those with cardiac defects or an underlying syndrome.10,45,46 These facts must be considered when counselling parents of affected children. With good medical and nursing care, the prognosis for children with isolated PRS should be excellent.58

Nasal obstruction Choanal atresia is a rare accompaniment of PRS18,52 but may complicate the respiratory difﬁculties in small infants who do not mouth-breathe. It is important to ensure nasal patency, especially if one nostril is to be utilized for a nasogastric feeding tube. Choanal obstruction in itself can lead to glossoptosis, with consequences identical to those of PRS.53

COMPLICATIONS AND OUTCOME In isolated PRS, the long-term outcome is directly related to the quality of the management at the onset of symptoms. With adequate nutrition, mandibular growth

Figure 19.8 Chest X-ray in infant with Pierre Robin sequence showing cardiomegaly due to pulmonary hypertension (Courtesy Mr P.A.M. Raine)

212 Pierre Robin sequence

REFERENCES 1. Robin P. Glossoptosis due to atresia and hypotrophy of the mandible. Am J Dis Child 1934; 48:541–7. 2. Eley RC, Farber S. Hypoplasia of the mandible (micrognathy). Am J Dis Child 1930; 39:1167–75. 3. Lancet. Classiﬁcation and nomenclature of malformation. Lancet 1974; 1:798. 4. Lancet. Classiﬁcation and nomenclature of morphological defects. Lancet 1975; 1:513. 5. McCollum DW, Witkop CJ. The face and oral structures. In: Rubin A, editor. Handbook of Congenital Malformations. Philadelphia: WB Saunders, 1967: 145–6. 6. Millard DR. Mandibular Surgery. In: Cleft Craft. Vol 3. Alveolar and Palatal Deformities. Baltimore: Williams and Wilkins, 1980: 901–31. 7. Bush PG, Williams AJ. Incidence of the Robin anomalad (Pierre Robin syndrome). Br J Plast Surg 1983; 36:434–7. 8. Pashayan HM, Lewis MB. Clinical experience with the Robin sequence. Cleft Palate J 1984; 21:270–6. 9. Marques IL, Barbieri MA, Bettiol H. Etiopathogenesis of isolated Robin sequence. Cleft Palate Craniofac J 1998; 35:517–25. 10. Shefﬁeld LJ, Resiss JA, Strohm K et al. A genetic follow-up study of 64 patients with the Pierre Robin complex. Am J Med Genet 1987; 28:25–36. 11. Stark R. Development of the face. In: Hueston JT, editor. Transactions of the 5th International Congress of Plastic and Reconstructive Surgery. Sydney: Butterworths, 1971: 123–30. 12. Franklin AW. Special syndromes. In: Norman AP, editor. Congenital Abnormalities in Infancy. 2nd edn. Oxford: Blackwell, 1971: 350–91. 13. Carey JC, Fineman RM, Ziter FA. The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes. J Pediatr 1982; 101:858–64. 14. Edwards JRG, Newall DR. The Pierre Robin syndrome assessed in the light of recent research. Br J Plast Surg 1985; 38:339–42. 15. Cohen MM. The Robin anomalad: its non-speciﬁcity and associated syndromes. J Oral Surg 1976; 34:587–93. 16. Cohen MM Jr. Robin sequences and complexes: causal heterogeneity and pathogenetic/phenotypic variability. Am J Med Genet 1999; 84:311–15. 17. Shprintzen RJ. The implications of the diagnosis of Robin sequence. Cleft Palate Craniofac J 1992; 29:205–9. 18. Nyhan WL, Sakati NO. Pierre Robin syndrome. In: Genetic and Malformations syndromes in Clinical Medicine. Chicago: Year Book, 1976: 446–8. 19. Van der Haven I, Mulder JW, van der Wal KG et al. The jaw index: new guide deﬁning micrognathia in newborns. Cleft Palate Craniofac J 1997; 34:240–1. 20. Pilu G, Romero R, Reece EA et al. The prenatal diagnosis of the Robin anomalad. Am J Obstet Gynecol 1986; 154:630–2. 21. Malinger G, Rosen N, Archiron R et al. Pierre Robin sequence associated with amniotic band syndrome.

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Ultrasonographic diagnosis and pathogenesis. Prenat Diagn 1987; 7:455–9. Bromley B, Benacerraf BR. Fetal micrognathia: associated anomalies and outcome. J Ultrasound Med 1994; 13:529–33. Hsieh YY, Chang CC, Tsai HD et al. The prenatal diagnosis of Pierre Robin sequence. Prenat Diagn 1999; 19:567–9. Ogborn MR, Pemberton PJ. Late development of airway obstruction in the Robin anomalad (Pierre Robin syndrome) in the newborn. Aust Paediatr J 1985; 21:199–200. Sher AE. Mechanisms of airway obstruction in Robin sequence: implications for treatment. Cleft Palate Craniofac J 1992; 29:224–31. Myer CM III, Reed JM, Cotton RT, Willging JP, Shott SR. Airway management in Pierre Robin sequence. Otolaryngol Head Neck Surg 1998; 118:630–5. Bath AP, Bull PD. Management of upper airway obstruction in Pierre Robin sequence. J Laryngol Otol 1997; 111:1155–7. Freed G, Pearlman MA, Brown AS et al. Polysomnographic indications for surgical intervention in Pierre Robin sequence: acute airway management and follow-up studies after cleft palate repair and take-down of tonguelip adhesion. Cleft Palate J 1988; 25:151–5. Lewis MB, Pashayan HM. Management of infants with Robin anomaly. Clin Paediatr 1980; 19:519–28. Heaf DP, Helms PJ, Dinwiddie R et al. Nasopharyngeal airways in Pierre Robin syndrome. J Paediatr 1982; 100:698–703. Chang AB, Masters IB, Williams GR, Harris M, O’Neil MC. A modiﬁed nasopharyngeal tube to relieve high upper airway obstruction. Pediatr Pulmonol 2000; 29:299–306. Hatch DJ, Sumner E. Anaesthesia – basic pronciples. In: Neonatal Anaesthesia and Perioperative care. 2nd edn. London: Edward Arnold, 1986: 85–124. Hatch DJ. Anaesthesia for paediatric surgery. In: Summer E, Hatch DJ, editors. Textbook of Paediatric Anaesthesia Practice. Baillière Tindall, 1989: 275–304. Howardy-Hansen P, Berthelsen P. Fibreoptic bronchoscopic nasotracheal intubation of a neonate with Pierre Robin syndrome. Anaesthesia 1988; 43:121–2. Baraka A. Laryngeal mask airway for resuscitation of a newborn with Pierre Robin. Anaesthesiology 1995; 83:645–6. Osses H, Poblete M, Asenjo F. Laryngeal mask for difﬁcult intubation in children. Paediatr Anaesth 1999; 9:399–401. Routledge RT. The Pierre Robin Syndrome: a surgical emergency in the neonatal period. Br J Plast Surg 1960; 13:204–18. Parsons RW, Smith DJ. A modiﬁed lip-tongue adhesion for Pierre Robin anomalad. Cleft Palate J 1980; 17:144–7. Otherson HB. Trachea, lungs and pleural cavity. In: Welch KJ, editor. Complications of Paediatric Surgery: Prevention and Management. Philadelphia: WB Saunders, 1982: 184–98.

References 213 40. Dempster JH, Dykes EH, Brown WC et al. Tracheostomy in childhood. J Roy Coll Surg Edinb 1986; 31:359–63. 41. Spitz L, Kiely E, Brereton RJ. Esophageal atresia: ﬁve year experience with 148 cases. J Pediatr Surg 1987; 22:103–8. 42. Langer JC, Wesson DW, Ein SH et al. Feeding gastrostomy in neurologically impaired children: is an antireﬂux procedure necessary? J Pediatr Gastroenterol Nutr 1988; 7:837–41. 43. Parsons RW, Smith DJ. Rule of thumb criteria for tonguelip adhesion in Pierre Robin anomalad. Plast Reconstr Surg 1982; 70:210–12. 44. Warkany J. Some syndromes affecting the face. In: Congenital Malformations. Chicago: Year Book, 1971: 650–8. 45. Williams AJ, Williams MA, Walker CA et al. Robin anomalad (Pierre Robin syndrome) – a follow-up study. Arch Dis Childh 1981; 56:663–8. 46. Elliot M, Studen-Pavlovich D, Ranalli DN. Prevalence of selected pediatric conditions in children with Pierre Robin syndrome. Pediatr Dent 1995; 17:106–11. 47. Gamble JG, Rinsky LA. Combined occipito-atlanto-axial hypermobility with anterior and posterior arch defects of the atlas in Pierre Robin syndrome. J Pediatr Orthop 1985; 5:475–8. 48. Pearl W. Congenital heart disease in the Pierre Robin syndrome. Pediatr Cardiol 1982; 2:307–9. 49. Dykes EH, Raine PAM, Arthur DS et al. Pierre Robin

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syndrome and pulmonary hypertension. J Pediatr Surg 1985; 20:49–52. Opitz JM, France T, Herrman J et al. The Stickler syndrome. N Eng J Med 1972; 286:546–7. Smith JL, Stowe FR. The Pierre Robin syndrome (glossoptosis, micrognathia, cleft palate). Pediatrics 1961; 27:128–33. Borovik HR, Kveton JF. Pierre Robin Syndrome combined with unilateral choanal atresia. Otolaryngol Head Neck Surg 1987; 96:67–70. Cozzi F, Pierro A. Glossoptosis-apnoea syndrome in infancy. Pediatrics 1985; 75:836–43. Pruzansky S, Richmond JB. Growth of the mandible in infants with micrognathia: clinical implications. Am J Dis Child 1954; 88:29–42. Vegter F, Hage JJ, Mulder JW. Pierre Robin syndrome: mandibular growth during the ﬁrst year of life. Ann Plast Surg 1999; 42:154–7. Spier S, Rivlin J, Rowe RD et al. Sleep in Pierre Robin syndrome. Chest 1986; 90:711–15. Frohberg U, Lange RT. Surgical treatment of Robin sequence and sleep apnea syndrome; case report and review of the literature. J Oral Maxillofac Surg 1993; 51:1274–7. Bull MJ, Givan DC, Sadove AM et al. Improved outcome in Pierre Robin sequence: effect of multidisciplinary management. Pediatrics 1990; 86:294–301.

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20 Macroglossia GEORGE G. YOUNGSON

INTRODUCTION Tongue enlargement or macroglossia is one of the few disease processes to affect this structure and is deﬁned as a resting tongue which protrudes beyond the teeth, or in the case of the neonate, the alveolar ridge.1 Pseudomacroglossia arises when the tongue itself is normal, but relative protrusion occurs because of a small mandible, as seen in Down’s syndrome and Pierre Robin syndrome.2 When displaced because of adjacent pathology such as cystic hygroma, cysts into the lingual thyroglossal duct, neuroﬁbromatosis, or tumors such as rhabdomyosarcoma, the term ‘secondary macroglossia’ can be used. The causes of primary macroglossia include hypothyroidism and lymphangioma, hemangioma, idiopathic hyperplasia and chromosomal abnormalities. Macroglossia is one of the most constant features of the Beckwith–Wiedemann syndrome, which is characterized by an omphalocele, or umbilical hernia with associated visceromegaly, somatic gigantism or hemi-hypertrophy and hypoglycemia.3

(a)

PRESENTATION Lymphangioma is the commonest cause of macroglossia to present in the neonatal period and may be diagnosed by prenatal ultrasound when associated with Beckwith– Wiedemann syndrome.4 The clinical features of the condition include noisy breathing and drooling, and when difﬁculties in feeding occur, then failure to thrive and poor weight gain feature (Fig. 20.1 a,b). When lymphangioma is the cause, verrucous lesions may appear on the surface and these exude a serous discharge. Minor trauma to this tissue then results in intralesional hemorrhage and/or sepsis (usually cellulitic from group B hemolytic Streptococcus). In this event abrupt enlargement may compromise the airway and produce a life-threatening emergency (Fig. 20.2).

(b) Figure 20.1 a,b Lymphangioma of the tongue occluding the oral cavity in a 4-week-old neonate

216 Macroglossia

care requirements of the other features of this condition. Similarly surgical intervention is inappropriate if hypothyroidism is the primary diagnosis. However massive enlargement may precipitate the need for early intervention and the challenge of anesthesia and endotracheal intubation point towards the need for tracheostomy.

SURGERY

Figure 20.2 Intra-lesional hemorrhage into a lingual lymphangioma producing respiratory obstruction

If treatment is inappropriately delayed, protracted dental defects include prognathism, anterior open bite, and an increased angle between the ramus and body of the mandible.5 Speech defects occur and articulation is subsequently defective, especially expression of consonants which are precluded by inadequate tongue movement as a consequence of the increased bulk in a limited cavity. Regression of macroglossia is not a regular feature when it is due to lymphangioma and a conservative approach to the lesion has no merit.

EVALUATION Investigation, following thorough physical examination for secondary causes of macroglossia comprises thyroid function testing, echocardiography and karyotype analysis. Magnetic resonance imaging to detail the extent of tongue involvement is indicated if the volume of lingual tissue affected is not clinically apparent. If airway occlusion with associated respiratory distress exists, then pulse oximetry and side-stream capnography may help in the management of such critical cases. This is a rare circumstance. Biopsy is rarely indicated.

MANAGEMENT Multidisciplinary involvement is, as ever, helpful with speech therapists, dieticians and pediatric dentists valuable contributors to patient and parental management. When the tongue is particularly large, nursing the infant in the lateral or prone position assists in airway management and skin care, especially if drooling is a prominent feature. When part of the Beckwith– Wiedemann syndrome, the tongue is seldom grossly enlarged and treatment must be seen in context of the

Alternatives to reduction glossectomy include intravascular photocoagulation6 and embolism7 of vascular tongue anomalies and but early surgery (preferably before 7 months of age)8 confers optimal opportunity for rehabilitation of tongue movement and avoids complications such as glossitis, hemorrhage and secondary speech and maxillofacial abnormalities. Clearly postponing surgery in the newborn period is preferable for avoidance of unnecessary morbidity but the timing thereafter is a matter of individual clinical judgment. Steroid treatment confers temporary beneﬁt during management of the acute airway obstruction and penicillin-based antibiotic therapy is indicated for treatment of septic complications. These problems however are usually seen later in infancy and childhood rather than the neonatal period and result from inappropriate delay of surgery. Reduction glossectomy is the mainstay of treatment and options include central wedge resection, circumferential wedge resection or a combined transoral and transcervical approach for a massive inﬁltrative lymphangioma.9 The aims of reduction are to allow intra-oral position of the tongue in the ﬂoor of the mouth to restore normal tongue movement, and to permit speech and deglutition. Implicit in these objectives is the fact that surgery should be conservative and a repeat tapering procedure is preferable to removal of excess tissue.

TECHNIQUE V-shaped resection of the anterior tongue has been previously described.10 The principles involve careful hemostasis by use of a tourniquet effect as described later by Dr Upadhyaya or alternatively use of a Neodymium-YAG laser or harmonic scalpel.

OPERATION Nasal intubation or tracheostomy secures airway protection. The head is placed in a silicone ring and the neck extended. The peri-oral tissues are prepared with

References 217

0.5% chlorhexidine in aqueous solution and drapes applied. A traction suture (3/0 polydioxanone) is placed on the apex of the tongue and two hemostatic/traction sutures tied over silicone rubber dams at the base of the tongue (Fig. 20.3). 0 polydioxanone on a 30-mm round-bodied needle is used for this maneuver. Traction on these three sutures provides the necessary exposure and hemostasis sufﬁcient for central wedge resection. The resection should not usually extend into the posterior third, where the extrinsic muscles of the tongue are inserted. The lateral margins of the incision extend from the level of the anterior gum, with the tongue in a resting position, to the apex, and this incision is bevelled such that more ventral than dorsal tissue is removed. This re-creates the natural concavity of the central tongue (Fig. 20.4). A straight needle is a useful adjunct to creating this bevel.

Figure 20.5 The remaining lateral segments of the tongue approximated in the midline

A

L

The divided lingual arteries are ligated. Restoration of the tongue ﬂaps and the midline is performed with Vicryl incorporating mucosa and a few millimeters of muscle (Fig. 20.5). The opportunity to place a percutaneous gastrostomy should be taken if protracted delay in feeding is anticipated.

M

Figure 20.3 Traction sutures allow good exposure and good hemostasis during reduction glossectomy

PERIOPERATIVE CARE Antibiotics should be continued into the postoperative period to provide prophylaxis against sepsis in the ﬂoor of the mouth. Oral hygiene is maintained with chlorhexidine or saline oral toilet. The appropriate tracheostomy care, if required, is given and secondary orthodontic and speech therapy follow-up arranged.

REFERENCES

Figure 20.4 Wedge of tissue incorporating more of the dorsal than ventral aspect of the tongue is removed

1. Gupta OP. Congenital macroglossia. Arch Otolaryngol 1971; 94:381–82. 2. Murthy P, Laing M. Macroglossia. Br Med J 1994; 309:1386–87. 3. Vogel JE, Mulliken JB, Kaban LB. Macroglossia: a review of the condition and a new classiﬁcation. Plast Reconstr Surg 1986; 78:715–23. 4. Harker CP, Winter T, Mack L. Prenatal diagnosis of Beckwith–Wiedemann syndrome. Am J Roentgenol 1997; 168:520–2. 5. Rizer FM, Scheckter GL, Richardson MA. Macroglossia: aetiological considerations and management techniques. Int J Pediatr Otorhinolarygol 1985; 81:225–36. 6. Chang CJ, Fisher DM, Chen YR. Intralesional photocoagulation of vascular anomalies of the tongue. Br J Plast Surg 1999; 52:178–81.

218 Macroglossia 7. Slaba S, Herbreteau D, Jhaveri HS et al. Therapeutic approach to arterio-venous malformations of the tongue. Euro Radiol 1998; 8:280–5. 8. Shafer AD. Primary macroglossia. Clin Pediatr 1968; 7:357–65.

9. Dinerman WS, Myers EN. Lymphangiomatous Macroglossia. Laryngoscope 1976; 86:291–6. 10. Upadhyaya P, Upadhyaya P. Partial glossectomy for macroglossia. J Pediatr Surg 1986; 21:457.

21 Tracheostomy in infants THOM E. LOBE

INTRODUCTION Both the ﬁelds of neonatology and technology have made great advances over the last few decades. Because of the routine use of surfactant and steroids, it is now rare to see an infant dependent on a ventilator for lung disease alone, and it is neither unusual nor unsafe to leave an infant on a ventilator with an endotracheal tube in place for months on end. Most infants who need a tracheostomy do so because of an inadequate airway. These infants otherwise are ready to go home or to a facility for technologically dependent children, but still require ventilatory assistance. This chapter will discuss the indications for and techniques for insertion and maintenance of a tracheostomy in infants.

Patients with a congenitally stenotic airway or tracheal agenesis are special cases. In the case of agenesis, an emergency tracheostomy may be necessary where the trachea re-establishes distally. Usually, however, these patients can be ventilated best using a mask because the bronchi come off the esophagus and an esophageal tube can cause obstruction. There are several acquired conditions that require tracheostomy including infection, papillomatosis, neuromuscular failure, chronic aspiration and subglottic stenosis. Occasionally the management of a tumor such as a cervical teratoma or sarcoma in infancy will mandate a tracheostomy. More likely a hemangioma or lymphangioma will compromise the airway to the extent that a more stable airway is needed. Rarely, trauma will prompt the surgeon to perform a tracheostomy. This can be related to birth trauma, child abuse or accidents.

INDICATIONS FOR TRACHEOSTOMY The indications for tracheostomy in infants fall into ﬁve main categories: (1) airway immaturity, (2) obstructing congenital anomalies, (3) acquired obstructions, (4) tumors and (5) trauma. The immature airway manifests itself as laryngomalacia, tracheomalacia or a combination of the two conditions. These infants present with inspiratory stridor and some degree of nasal ﬂaring and chest retractions. Other related conditions are congenital vocal cord paralysis, which is usually due to a central nervous system deﬁcit, phrenic nerve injury, which may be associated with a difﬁcult delivery and recurrent laryngeal nerve injury, which may occur after ligation of a patent ductus arteriosus. Some patients with choanal atresia and Pierre Robin syndrome may be candidates for tracheostomy. Other cranio-facial deformities such as Freeman Sheldon syndrome, Cerebro-costo-mandibular syndrome, arthrogyposis multiplex congenita and others also may require a tracheostomy for airway maintenance.

PREOPERATIVE EVALUATION Most infants who need a tracheostomy already have an endotracheal tube in place. Infants suspected of laryngotracheomalacia may require direct laryngoscopy and/or bronchoscopy to assess the situation. The surgeon should make certain of the coagulation status, hemoglobin level and electrolytes as indicated by the patient’s condition. The nutritional status of the patient should also be taken into consideration. Poor nutrition will complicate nearly any condition in infancy and may weigh in favor of an earlier tracheostomy than would be indicated otherwise. When an infant is not intubated, but is under consideration for tracheostomy, the extent to which the child maintains oxygenation and demonstrates adequate ventilation as judged by the Pco2 measured by transcutaneous monitoring will determine the need for a more direct assessment before a decision for tracheostomy is made.

220 Tracheostomy in infants

Finally, patients with persistent aspiration, despite correction of any gastroesophageal reﬂux, may necessitate a tracheostomy to prevent severe pulmonary consequences.

TECHNIQUE The infant is placed supine on the operating table, sufﬁciently toward the foot of the table so that the surgeon can access the infant’s neck easily, but not so far down on the table that the anesthesiologist cannot reach the patient to manipulate the endotracheal tube when required. These cases should be done under a general anesthetic unless the infant is so ill as to be unable to tolerate the drugs. Even so, an anesthesiologist or anesthetist should maintain control of the airway while the surgeon is exposing and manipulating the trachea. The patient’s cardiorespiratory status should be monitored during the case. This should consist of a cardiac monitor for heart rate, a blood pressure monitor, and ideally a pulse oximeter to assess the infant’s oxygenation. If there is any question as to the status of the airway, bronchoscopy should be performed to assure that the tracheal lumen will accept a tracheostomy without difﬁculty. Special issues, such as a tracheostomy to stent an airway for severe tracheomalacia can be assessed by bronchoscopy to determine the proper length of the proposed cannula, which may have to be specially ordered. In some cases it may be necessary to use an ordinary endotracheal tube placed through the cervical incision and secured to the skin of the neck until this temporary tracheostomy cannula can be replaced with the specially ordered device. When positioning the infant on the operating table, the neck should be extended sufﬁciently to allow complete access to the neck. Sometimes, on chubby infants, it is still difﬁcult to see the entire neck, despite the best attempts. A roll should be placed under the infant’s shoulders to facilitate proper positioning (Fig. 21.1). The endotracheal tube should be secured so that the anesthesiologist can easily remove the tube at the appropriate time. This means that any tape should be loosened beforehand. If there is a feeding tube in place, it should be removed so that it does not interfere with endotracheal tube manipulation. When the infant is properly positioned and monitored, the entire neck from the lower lip to below the nipples should be prepped with a suitable surgical prep and draped. The superior most surgical drape should allow easy access to the patient by the anesthesiologist. Once prepped and draped, the surgeon should carefully palpate the infant’s neck to locate the trachea that

Figure 21.1 Position of infant for tracheostomy. The shoulders are elevated on a roll; the head is hyperextended on the neck and supported by a doughnut-form support

hopefully is in the midline. The surgeon must remember that the infant’s trachea is quite mobile and compressible, and may be difﬁcult to palpate. The anesthesiologist can jiggle the endotracheal tube from above to assist with its location. At our institution, we make our incision in the lower neck crease, about the width of one ﬁnger above the jugular notch. A transverse incision is preferable. If the incision is too low you will end up in the mediastinum and the cannula will be placed too low in the trachea. We ﬁrst score the skin with a scalpel, then use a needle-point electrocautery device to deepen the incision, taking care not to burn the skin. This incision is extended through the subcutaneous fascia and platysma muscle, which is quite thin in the small infant. It is helpful to insert two right-angled retractors in the corners of this incision to better expose the operative site. Next, we use two atraumatic forceps to grasp the cervical fascia on either side of the midline and open it vertically in the midline. We extend this incision inferiorly to the jugular notch and superiorly to the thyroid gland. The strap muscles, immediately beneath the anterior cervical fascia similarly are separated in the midline. Usually, there are few to no blood vessels in the dissection thus far. Occasionally, the surgeon will encounter a few small vessels that cross the midline. These should be cauterized and divided as they are encountered. Once these muscles are separated, we place the two retractors deep to the muscle edges and gently retract laterally to better expose the trachea below. Sometimes it is necessary to free the muscle edges sufﬁciently to allow room for the blade of the retractor to gain a secure purchase. The trachea should be visualized easily. If not, then palpation in the wound with manipulation of the endotracheal tube by the anesthesiologist will help locate the trachea. The proposed tracheostomy cannula should be selected, opened and its outer diameter visually checked

Technique 221

against the exposed trachea to judge the correctness of its size. If it seems that the initial selection was incorrect, then a tracheostomy cannula of a more appropriate size should be selected. The pre-tracheal fascia should be scored with the cautery to coagulate any tiny vessels on the surface of the trachea in the midline. Again, the blades of the retractors should be deep in the wound on either side of the trachea for optimal exposure. A suture of 4-0 Prolene or its equivalent should be placed on either side of the midline scored anterior trachea (Fig. 21.2). Each suture incorporates one or two tracheal rings. These sutures are not tied onto the tracheal wall, but can be tied at their ends and should be left 6–8 cm in length. At the end of the case, these sutures should be taped securely to the anterior chest wall and used to locate the tracheal incision in the event of a postoperative emergency in which the newly placed tracheostomy cannula dislodges. These sutures also can be used to hold open the edges of the tracheal incision for ease of placement of the tracheostomy cannula at operation. The surgeon should request that the endotracheal tube be loosened and prepared for removal. Using a No. 11 blade, a vertical incision is made through the tracheal wall along the score mark (Fig. 21.3). Two or three tracheal rings should be divided, usually rings 2, 3 and 4. Rarely, it is necessary to divide the isthmus of the thyroid gland for proper tracheostomy positioning. A transverse tracheal incision or removal of a tracheal ring is likely to result in a tracheal deformity and thus should be avoided. Suction should be available in case blood or secretions interfere with the surgeon’s view of the tracheal lumen.

Thyroid isthmus 2

3 Traction sutures placed

4

Figure 21.2 Traction sutures of ﬁne silk are placed around the 3rd tracheal ring to stabilize the trachea before incision. The sutures are tied in loose loops and later taped to the anterior chest wall. The sutures are left in place for 4 days as a precaution against accidental decannulation postoperatively

E.T. tube

Cartilages incised

Figure 21.3 The trachea should be opened through a midline vertical incision across 2–3 tracheal rings. The incision must be long enough to avoid excess tube pressure against the cartilages. A tight tube can result in pressure deformity and reabsorption of cartilage

The tip of the cannula to be inserted should be lubricated with a water-soluble surgical lubricant and positioned over the incision, poised for insertion when the endotracheal tube is withdrawn. The surgeon should then ask the anesthesiologist to withdraw the endotracheal tube sufﬁciently to clear the lumen so that the tracheostomy cannula can be inserted and directed caudally toward the carina. One way to avoid misplacement is to insert a suction catheter through the lumen, beyond the tip of the cannula (Fig. 21.4). The suction catheter then can be inserted into the tracheal lumen ﬁrst and serve as a guide over which the cannula can be passed. This technique also is useful should the cannula become dislodged after the procedure. If, for any reason, the tracheostomy cannula does not ﬁt easily into the trachea, it should be removed and the endotracheal tube advanced beyond the tracheal incision so that ventilation will not be compromised. This might occur if the diameter of the tracheal lumen has been over estimated and the previously selected tracheostomy is too large to ﬁt into the trachea. In the latter case, a smaller cannula should be selected. As soon as the cannula is in place, the obturator or suction catheter should be removed and the anesthesiologist should disconnect the ventilator hose from the endotracheal tube and connect it to the tracheostomy cannula. Once that is done, the anesthesiologist should administer several deep breaths to the patient to conﬁrm that the cannula is in the proper place and that the infant can be ventilated satisfactorily. If it appears that although the cannula width is appropriate, the cannula is too long

222 Tracheostomy in infants

E.T. tube

Trachea placed over catheter

Catheter introduced into trachea

Figure 21.4 Tube insertion into the trachea is accomplished by shifting the endotracheal tube up to the cephalad margin of the new stoma, inserting a tracheal suction catheter into the trachea through the newly established opening, and then advancing the tracheostomy tube over the catheter in the trachea. This is safer than using the tube obturator, the short tip of which sometimes slips out of the stoma and allows the tracheostomy tube to pass anterior to the trachea and into the mediastinum

Traction taped to chest

Figure 21.5 Prevention of accidental decannulation is the surgeon’s responsibility. The tube should be taped to the anterior chest for 4 days in case an unexpected tube change should become necessary

PERIOPERATIVE MANAGEMENT and its tip rests on the carina, then several pieces of gauze can be used to build up the gap between the neck and the tracheostomy collar, thus backing the tip of the cannula away from the carina. Once adequate ventilation is conﬁrmed, then the endotracheal tube can be removed completely. Once the cannula is connected to the ventilator, the cervical wings of the body of the cannula need to be secured to the patient. We don’t rely on a tie placed around the neck, but accomplish this with the aid of sutures. For each wing, a suture of 3-0 silk or its equivalent is passed through the skin of the neck, then through the upper edge of the wing of the cannula (midway between the midline and the end of the wing), through the lower edge of the wing, then again through the skin. When this suture is tied, the skin will be drawn over the wing and usually will cover it. After these sutures are placed, both wings will be securely ﬁxed to the skin of the neck. The two ties that were placed in the anterior tracheal wall should now be taped securely to the anterior chest wall in such a fashion that ensures that their ends are easily accessible in case they are needed in an emergency to reinsert the cannula (Fig. 21.5). Finally, the umbilical tape or tie that usually comes with the cannula is passed through the holes in the end of the wings and tied around the neck to further secure the cannula. This should be tied in back of the neck. A simple gauze dressing with antibiotic ointment applied is placed underneath the wings of the cannula over the cervical incision to complete the procedure. We send our infants to the intensive care unit after a fresh tracheostomy in case of emergency.

If the skin of the patient’s neck is infected with a bacterial or fungal infection, this should be cleared before any operation is undertaken unless emergency tracheostomy is required to save an infant’s life. In patients with short, fat necks, it may be necessary to place the infant in a position of neck extension to facilitate clearing any skin infection or breakdown that is due to chronic moisture. Simply exposing the infant’s neck to air for drying often is sufﬁcient to clear any problem. Immediately after the tracheostomy is secured, the roll under the patient’s neck should be removed and a radiograph of the chest should be reviewed before the patient is removed from the operating room. This is important to make certain that the tip of the cannula is sufﬁciently clear of the carina and will not become obstructed as the patient’s neck is manipulated. The fresh tracheostomy should be left in place for about 10 days before it is disturbed. At least once each day, the site should be cleaned with a cotton applicator soaked in a solution of hydrogen peroxide, and an antibiotic ointment should be applied to the incision site. The sutures securing the tracheostomy should be left untouched for the initial 10-day period, after which they can be cut. The sutures to the edges of the tracheal incision should be left until the tracheostomy is changed successfully for the ﬁrst time. If the patient is unusually agitated or the ventilator tubing is so heavy that dislodging the cannula is highly likely, then sedation or paralysis may be helpful until the wound has matured and reinsertion can be done more safely.

Complications 223

After the cannula is free and the umbilical tape is untied, the cannula can be removed and replaced. Ideally, the parents or ultimate caretakers should observe the exchange, particularly if the patient is close to discharge. If a temporary endotracheal tube is being replaced with a specially ordered tracheostomy cannula, the new cannula should be inserted as described earlier. Once it is obvious that the cannula can be changed with ease, is in its proper position and that the patient can be ventilated, it is safe to remove the sutures to the edges of tracheal incision. Suctioning of the newly placed tracheostomy should be done as often as necessary, particularly immediately after the procedure. Care must be taken, however, to restrict the passage of the suction catheter to no further than the tip of the cannula. Routine suctioning beyond the tip of the cannula promotes the development of granulation tissue that may obstruct the airway later on.

HOME INSTRUCTION AND CARE Patients should be discharged home with an extra tracheostomy cannula in case a problem occurs. The caretakers should be instructed and checked out on tracheotomy change and cardiopulmonary resuscitation (CPR). They should know how to suction the cannula and be sent home with a suction machine. They should know how to use an Ambu bag for ventilation in conjunction with suctioning. An air ﬁlter should be attached to the tracheostomy cannula if a ventilating device or some other moisturizing device is not otherwise connected. Of course, the family or caretakers must know how to use and trouble shoot in case of problems whilst using any of these devices. It is often helpful to arrange for home nursing visits until the family becomes familiar and comfortable with the new devices; this is especially true when it comes time for the ﬁrst scheduled tracheostomy change if it is to be done at home. The physician may choose to do the ﬁrst tracheostomy change in the ofﬁce and take the opportunity to further instruct and reassure the family or caretakers.

COMPLICATIONS Hemorrhage is an unusual complication that can occur at the time of operation or as a delayed event. When hemorrhage occurs at operation, it can be controlled easily with electrocautery or vessel ligation. Rarely, especially in the newborn, the thyroid gland is near the incision site on the anterior trachea and is inadvertently divided or lacerated. The resultant hemorrhage usually can be controlled with sutures or electrocautery.

Late hemorrhage often is more problematic and can be more serious. First, it must be ascertained whether the hemorrhage is from the tracheal lumen or from the incision. This can be accomplished by suctioning the cannula and inspecting the wound. Occasionally a small skin vessel will bleed briskly but can be easily seen and controlled with a simple suture or even with an injection of 1% Lidocaine containing 1:100 000 epinephrine. More problematic is the possibility of hemorrhage from one of the great vessels, such as the innominate vein or artery. This can occur from erosion of the vessels when the cannula ﬁts too snugly in the thoracic inlet and partially compresses the vessels against the manubrium or clavicle. This type of hemorrhage often presents with a so-called ‘herald bleed,’ which starts briskly but stops, and usually requires a trip to the operating room to repair the damaged vessel. Aside from hemorrhage, the cannula can become dislodged. We are compulsive about securing the cannula in place using the techniques described earlier in order to avoid this complication. Even so, despite our best efforts, a suture will pull loose or one of the plastic wings will tear, allowing the cannula to dislodge. Fortunately, we keep our infants in the intensive care unit during the immediate postoperative period. We anticipate that if the cannula becomes dislodged, it will be noticed immediately. Replacing the cannula in the immediate postoperative period can be a treacherous ordeal that under ideal circumstances should be done by someone familiar with cannula insertion. If a surgeon or intensivist is readily available, then one of them should replace the cannula and re-secure the device. The sutures to the tracheal incision should be taped in such a manner as to be easy to access, untape and retract to expose the tracheal lumen. Good lighting is essential to see well and either the obturator should be inserted into the cannula before reinsertion is attempted or a suction catheter should be used as a guide. It is very undesirable to force the cannula outside the trachea. Proper positioning is assured by administering a deep breath or two with an Ambu bag once the cannula is in place. If the chest does not rise immediately, chances are that the cannula is not in the proper place and should be replaced. A chest radiograph should be taken to assure proper cannula position. It is not usually necessary to use instruments to reinsert the cannula because the sutures attached to the edges of the tracheal incision should lead directly to the opening in the trachea. If difﬁculty arises, two small right-angled retractors should be sufﬁcient to complete the job. Infection is an unusual complication and should be treated with the appropriate antimicrobials according to culture results. Injury to the vagus nerves or, more likely, the recurrent laryngeal nerves can occur. In experienced hands with a surgeon well versed in the anatomy of the infant’s neck, this injury should be rare.

224 Tracheostomy in infants

While unlikely, it is possible to place the cannula into the esophagus. This can occur if the trachea is retracted out of the ﬁeld and the esophagus is entered in error. If this occurs, then the esophagus should be repaired primarily and a drain should be placed. The tracheostomy cannula then can be inserted properly. Endotracheal granulation tissue can result from the chronic irritation of the tip of the tracheostomy cannula against the tracheal wall or from the repeated suctioning of the trachea. It is common for granulation tissue to develop at the stoma. This can be exophytic at the level of the skin, or can be intralumenal. The exophytic granulation tissue at the skin should be cauterized with silver nitrate during an outpatient visit. This may need to be carried out every month or so if bothersome hemorrhage or chronic irritation with infection is present. If the granulation tissue develops immediately within the trachea at the stoma, it usually can be left alone until it is time for decannulation. Only if the granulation tissue is so bulky that it interferes with routine tracheostomy changes or causes signiﬁcant hemorrhage should it be removed before decannulation is contemplated. The development of granulation tissue at the tip of the cannula can present with obstruction, sometimes resulting in a ‘ball-valve’ effect, with trapped air and difﬁculty with ventilation. This can be diagnosed by slipping a ﬂexible bronchoscope through the cannula to visualize the tracheal lumen beyond the tip of the cannula. If the results of this diagnostic maneuver are unclear, rigid bronchoscopy may be necessary. We believe that this type of granulation tissue is best removed with laser. Our preference is for the KTP/532 laser or an equivalent wavelength that operates using a ﬂexible ﬁber. The technique for laser vaporization of granulation tissue is beyond the scope of this discussion.

SPECIAL SITUATIONS Occasionally, there exist special circumstances which require careful thought and planning. Such is the case with tracheal stenosis. Simple acquired subglottic stenosis can be easily managed with a tracheostomy inserted as described except for the size of the endotracheal tube. A small endotracheal tube may be difﬁcult to palpate, however, thus locating the trachea may be difﬁcult. With a particularly stenotic airway, mask ventilation may be the only way to maintain ventilation. The most difﬁcult part of the case is locating the trachea without an endotracheal tube. For patients with distal tracheal stenosis, tracheostomy insertion may be inappropriate. While beyond the scope of this discussion, the infant should be carefully studied if this diagnosis is suspected. Usually, plain radiographs of the chest may lead one to suspect the diagnosis.

Computerized tomography or bronchoscopy may be required for conﬁrmation. When the distal trachea is stenotic in an infant who is difﬁcult to ventilate, a conventional tracheostomy cannula is inappropriate and may interfere with tracheal reconstruction. Patients who are candidates for congenital heart surgery and in whom the ultimate need for a tracheostomy is anticipated, may be best managed by completing the cardiac surgery before tracheostomy is performed. Otherwise, the sternal incision is so close to the tracheostomy site that the risk of cardiac infection is greatly increased.

DECANNULATION Decannulation usually is anticipated well in advance. Its timing depends to a large degree on the indication for the tracheostomy. Patients with severe subglottic stenoses may have their tracheostomy removed at the time of their laryngoplasty. The timing of this procedure, then, depends on the surgeon and may occur any time between 4–6 months and 2 years, or later. In patients whose tracheostomy was placed because of tracheomalacia, it would be unusual to attempt decannulation before the infant is 1 year of age. The infant should undergo periodic bronchoscopic examination to assess the status of the malacia. Once it is certain that the airway is sufﬁciently mature as to be able to maintain its patency, decannulation can be attempted. The ﬁrst step is to make certain that the airway is mature and free of any potential obstructing lesions such as granulation tissue. This is best accomplished with rigid bronchoscopy. Any residual malacia or granulation tissue can be documented and dealt with as needed. At the time of attempted decannulation, we bring the patient to the operating room, positioned as described earlier for insertion of the cannula with the neck extended, and perform the bronchoscopy. In order to assess whether malacia is present, the patient should not be paralyzed and the anesthesia should be light. This is to determine whether the airway remains patent, with the patient breathing spontaneously. Once committed to decannulation, the bronchoscope and neck roll should be removed and the patient is observed for any difﬁculty such as severe chest retraction or deoxygenation that would suggest the continued need for the tracheostomy. If, on the other hand, the patient ventilates with ease, then the patient should be fully awakened and allowed to recover in a unit that permits careful observation. We usually keep these patients in the hospital overnight, or longer if there is any concern, to assure that the tracheostomy is no longer required. Once the cannula is removed, a snug dressing of plain or petroleum jelly-saturated gauze is secured over the

References 225

tracheostomy stoma to occlude it. The caretakers or parents should be instructed on how to change this dressing until the stoma closes completely. Occasionally, we encounter a stoma that does not close spontaneously. If, after several months, the stoma remains open and appears unlikely to close, and it is certain that the infant no longer is at risk for needing another tracheostomy, then operative closure of the stoma as an outpatient procedure can be performed. Usually, this is simply a matter of excising the stoma and placing a simple stitch or two in the anterior trachea. A larger persistent opening may require an anterior wedge excision for repair. This may necessitate admission to the hospital. If, after the patient leaves the operating room decannulated, the infant becomes fatigued or demonstrates other signs of respiratory distress, the dressing can be removed and another cannula should be reinserted. A smaller cannula size can be inserted if desired. This technique often is used to serially wean a patient to progressively smaller-sized cannulae until decannulation is certain to be successful. If, after decannulation, it is necessary to reinsert a tracheostomy, the procedure should be done in the operating room. While this is usually done with an endotracheal tube in place, there are some patients for whom it may be undesirable to insert an endotracheal tube. This avoids airway irritation and prevents re-stenosis. That being the case, the surgeon can inject a local anesthetic around the stoma, dilate the stoma with Hegar dilators (or possibly make a small incision with a No. 11 scalpel blade), and reinsert a cannula of an appropriate size. This maneuver should only be attempted if the anesthesiologist can maintain an adequate airway during the procedure.

REFERENCES 1. Aberdeen E, Downes JJ. Artiﬁcial airways in children. Surg Clin N Am 1974; 54:1155–70. 2. Aberdeen E. Tracheostomy and tracheostomy care in infants. Proc R Soc Med 1965; 58:900–4.

3. Jones JW, Reynolds M, Hewitt RL et al. Tracheoinnominate artery erosion: successful surgical management of a devastating complication. Ann Surg 1976; 184:194–204. 4. Ardran GM, Casut LJ. Delayed decannulation in children. J Laryngol 1963; 77:555–6. 5. Diamant H, Kinman J, Okmina L. Decannulation in children. Laryngoscope 1963; 71:404–14. 6. Smythe PM. The problem of detubating an infant with a tracheostomy. J Pediatr 1964; 65:446–53. 7. Montgomery EE. Tracheotomy in croup and diphtheria. Arch Pediatr 1885; 2:577–86. 8. Jackson C. High tracheostomy and other errors, the chief causes of chronic laryngeal stenosis. Surg Gynecol Obstet 1921; 32:392–8. 9. Foster S, Hoskins D. Home care of the child with a tracheotomy tube. Clin N Am 1981; 28:855–7. 10. Ruben RJ, Newton L, Jornsay D et al. Home care of the pediatric patient with a tracheotomy. Ann Otol Rhinol Laryngol 1982; 91:633–40. 11. Klotz DA, Hengerer AS. Safety of pediatric bedside tracheostomy in the intensive care unit. Arch Otolaryngol Head Neck Surg 2001; 127:950–5. 12. Walner DL, Loewen MS, Kumura RE. Neonatal subglottic stenosis – incidence and trends. Laryngoscope 2001; 111:48–51. 13. Crombleholme TM, Sylvester K, Flake AW, Adzick NS. Salvage of a fetus with congenital high airway obstruction syndrome by ex utero intrapartum treatment (EXIT) procedure. Fetal Diagn Therm 2000; 15:280–2. 14. Bui TH, Grunewald C, Frenchkner B, Kuylenstierna R, Dahlgren G, Edner A, Granstrom L, Sellden H. Successful EXIT (ex utero intrapartum treatment) procedure in a fetus diagnosed prenatally with congenital high-airway obstruction syndrome due to laryngeal atresia. Eur J Pediatr Surg 2000; 10:328–33. 15. Skelton VA, Goodwin A. Perinatal management of a neonate with airway obstruction caused by rhabdomyosarcoma of the tongue. Br J Anaesth 1999; 83:951–5. 16. Park JY, Suskind DL, Prater D, Muntz HR, Lusk RP. Maturation of the paediatric tracheostomy stoma: effect on complications. Ann Otol Rhinol Laryngol 1999; 108:1115–19.

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22 Miscellaneous conditions of the neck and oral cavity ANIES MAHOMED

CYSTS AND SINUSES OF THE NECK Congenital cysts and sinuses of the neck often result from persistence of remnants of embryological structures into postnatal life. These include cartilaginous structures of the cartilaginous skeleton, branchial cleft remnants and thyroglossal duct cysts. These anomalies rarely produce symptoms during the neonatal period. Sinuses and cartilaginous remnants are seen in infants, but cysts usually do not appear until later in childhood.

PREAURICULAR PITS, SINUSES AND ACCESSORY AURICLES Figure 22.1 Multiple accessory auricles in typical position

These lesions, which are familial and frequently bilateral, result from aberrant development of the auditory tubercles.1 Preauricular sinuses are common with an incidence of 15.5–43.7 per 10 000 births.2 These sinuses may present as an ectoderm lined sinus ‘pit’ containing tiny hairs, a skin tag, or a skin tag containing cartilage, called an ‘accessory tragus’. Preauricular sinuses most commonly present anterior to the tragus or in the ascending helical rim.3 Most of these lesions remain asymptomatic, but when problematic frequently present with drainage which may occur spontaneously or following infection. Infection should be treated in the ﬁrst instance with oral or i.v. antibiotics and following recovery, the sinus tract should be excised. Infected lesions may need to be incised and drained before deﬁnitive therapy, which in this context is complicated by a higher recurrence rate.4 Magnetic resonance imaging should be considered in all patients with a suspected ﬁrst branchial cleft anomaly. Accessory auricles are situated in the line of fusion between maxillary and mandibular processes of the ﬁrst branchial arch and are managed by complete excision (Fig. 22.1). Surgery can be safely postponed until after infancy.

BRANCHIAL CYSTS AND SINUSES Most branchial cyst and sinus remnants are derived from the ﬁrst and the second branchial clefts. First branchial anomalies are considered to be less common than those of the second cleft.5 However, those arising from the third branchial apparatus have seldom been reported.6,7

First branchial cleft anomaly These lesions are uncommon, but usually present as a cystic swelling below the lobule of the ear, associated with a sinus opening just behind the ramus of the mandible. Uncommonly, the ﬁrst cleft anomaly may manifest as a true ﬁstula originating about the site of the external auditory meatus and opening into the pharynx behind the posterior tonsillar fossa.8 The congenital tract has an unpredictable path in relation to the facial nerve.

228 Miscellaneous conditions of the neck and oral cavity

The diagnosis is established by careful cervical, parotid and auricular examination. Magnetic resonance imaging (MRI) allows assessment of the extent of the anomaly, especially in the parotid area, and high resolution computed tomographic (CT) imaging shows its exact relationship with the external auditory canal and the middle ear.9 Early resection should be considered as the planes of dissection are more likely to be intact, thereby facilitating facial nerve identiﬁcation and complete removal of the congenital tract.3 Repeated infections make subsequent surgery more difﬁcult by placing the facial nerve at greater risk. Wide exposure is therefore necessary and in most cases this involves a standard parotidectomy incision.

Second branchial cleft anomaly Branchial cyst and sinus remnants of the second branchial cleft present along the anterior border of the sternocleidomastoid muscle, usually in the middle or lower third of the neck. Sometimes the ﬁrst indication of a branchial cleft remnant may be evidence of infection. The treatment of choice is surgical excision of the cyst or sinus tract. The condition rarely presents in infancy and surgery can safely be postponed until the child is 2–3 years old.

Figure 22.2 MRI scan showing congenital lateral cervical cyst (arrow) in sagittal view with vertical extent from the hypopharynx to superior mediastinum

Thyroglossal duct cysts and sinuses Third branchial cleft anomaly The main presentation of a persistent third branchial cleft is as a congenital lateral cervical cyst. These cysts are rare, found exclusively on the left side of the neck and may have components arising from the fourth branchial apparatus. Typically, the cyst presents in the ﬁrst few days of life as a visibly enlarging lesion in the left side of the neck. Because of its size, pressure on the contiguous aerodigestive tract results in stridor with respiratory compromise and difﬁculty in feeding. Infection commonly induces a rapid increase in size but in instances where there is a large pharyngeal communication, it may also occur secondary to crying or feeding.6 Investigations include, cervical X-ray, which may demonstrate the presence of air sometimes with a ﬂuid level in the cyst, MRI which is useful in delineating the extent of the lesion (Fig. 22.2), and endoscopy for location and cannulation of the internal opening of the cyst.10,11 Management needs to be expeditious because of the potential for a sudden increase in the size of the cyst. Surgery involves complete cyst excision with ligation of the internal communication ﬂush with the pharyngeal wall. Histology of the cyst lining demonstrates both ecto- and endodermal components. In addition the presence of intramural thymic tissue as well as Hassal’s corpuscles and rarely thyroid tissue may be noted.6

These lesions result from persistence of the thyroglossal duct after the thyroid migrates from the foramen cecum to its ﬁnal location in the neck. It may rarely present at the base of the tongue in the newborn, where it may interfere with respiration.1 Classically, thyroglossal cysts present later than infancy and in the midline just below the hyoid bone. Treatment is by surgical excision and the excised specimen must include the central part of the hyoid bone and a core of soft tissue extending from the thyroglossal cyst to the foramen cecum.12

Congenital midline cervical clefts Congenital midline cervical clefts are rarely reported. The etiology of these clefts is obscure and it is not clear if it is of pharyngeal cleft origin with failure of fusion of the right and left arch ectodermis or the result of some intrauterine physical insult.8 The cleft consists of a mucosa-covered central depression with a skin tag superiorly.13 The adjacent skin is tethered by scar tissue and the trough ends in a blind pit inferiorly. Treatment consists of excision with z-plasty reconstruction.1 There are a number of other rare conditions which cause cystic neck masses in the neonate. These include persistent pharyngeal pouch derivatives, air-ﬁlled bronchogenic cysts, and laryngocele.

Lesions of the tongue and oral cavity 229

LESIONS OF THE TONGUE AND ORAL CAVITY There are a great variety of lesions of the tongue and oral cavity which may require surgical intervention in infancy. The differential diagnoses include tumors (malignant, teratoma, cystic hygroma, lymphangioma, hemangioma) epulis, dermoid cysts, thyroglossal duct cysts, duplication cysts, ranula, gastric and glial choristoma, hamartomas and lingual thyroid.

Tumors Malignant tumors of the tongue and oropharynx are extremely rare in the newborn. Approximately 5% of germ cell tumors arise in the extracranial head and neck region but malignancy at these sites is rare. The majority however are congenital and have been described in the pharynx, nasopharynx, paranasal sinuses and orbit. Obstruction of the pharynx antenatally may result in maternal polyhydramnios or fetal hydrops.14 Postnatally respiratory and esophageal obstruction may necessitate intubation and surgical decompression. Of head and neck rhabdomyosarcomas, 30% arise in intraoral and pharyngeal structures, but congenital involvement of the tongue has been documented in only a few cases. Presentation varies depending on the site; dysphagia, cough, and acute respiratory obstruction requiring tracheostomy have been described. Total excision of the lesion may sometimes be accomplished.15 Other rare tumors such as congenital malignant rhabdoid tumor and ﬁbrosarcomas have also been reported to occur in the oral cavity.16

Epignathus

multidisciplinary team comprising a neonatologist, anesthesiologist, pediatric surgeon and gynecologist. Delivery by cesarian section if the tumor is large, is recommended.20.21,23

CLINICAL PRESENTATION Epignathia are commonly recognized at birth or shortly thereafter because they are usually large in size, ﬁll the oral cavity, sometimes protrude from the mouth and cause respiratory distress (Fig. 22.3). These masses display varying degrees of maturity and may rarely have recognizable fetal parts.24 Inspiratory retractions of the chest wall, diminished breath sounds and cyanosis on room air, may occur shortly after birth and indicate worsening upper airway obstruction.25

PREOPERATIVE PREPARATION The preoperative management of newborns with epignathus should include early establishment of a reliable upper airway and exclusion of midline congenital central nervous system lesions. The airway should be secured immediately after delivery by endo- or nasotracheal intubation. In difﬁcult cases with large obstructing lesions, cricothyrotomy or tracheostomy may be undertaken as a life-saving procedure.18 X-ray examination of the skull may demonstrate areas of calciﬁcation compatible with a teratoma, occasional cranial asymmetry or other malformations such as cleft palate.26 CT scanning or MRI will deﬁne the extent of the lesion, determine the site of attachment, identify cysts and calciﬁcation as well as exclude CNS defects. It may be difﬁcult to demonstrate the precise origin of the tumors because they blend imperceptibly into normal tissues at sites where access is difﬁcult and where there are vital neural and vascular structures.

Epignathus is a rare congenital teratoid tumor protruding from the mouth and distorting orofacial anatomy. The tumor arises from the palate or pharynx in the region of the basisphenoid (Rathke’s pouch). They occur predominantly in girls. The etiology is unknown, but the more popular theory states that it may arise from pluripotential cells in the region of Rathke’s pouch that grow in a disorganized manner.17 Elements from all three germinal layers are represented. These tumors are benign in histology, but result in a high degree of morbidity and sometimes mortality by virtue of their size and location.18

(b)

ANTENATAL DIAGNOSIS Epignathus has been diagnosed antenatally.19–22 The typical sonographic appearance of epignathus are mixed echogenic lesions with areas of cystyic and solid tissue as well as associated calciﬁcation. Polyhydramnios is a common ﬁnding and may be due to the obstruction of the fetal oropharynx. Antenatal diagnosis is critical to a good outcome, as it allows for adequate assembly of a

(a) (c)

Figure 22.3 Epignathus. (a) A large tumor protruding from the mouth. (b) Arising from the palate. (c) Attached to the retropharyngeal region

230 Miscellaneous conditions of the neck and oral cavity

TREATMENT Surgical excision consists of an oral approach to excise the tumor at its base once encephalocele and intracranial tumor have been ruled out. Excision can be undertaken directly or assisted by endoscopy.18 If the base is of modest size, simple cautery can be employed and the defect so created can be covered with a ﬂap of mucosa elevated from the buccal sulcus, taking care to avoid damage to the point of entry of the parotid duct. Serial measurement of alphafetoprotein levels is essential to ensure complete excision and to monitor for recurrence.

PROGNOSIS The survival of these otherwise normal children was poor prior to the widespread use of prenatal ultrasonography but prenatal planning and proper postnatal specialist care has resulted in an excellent prognosis.22 Prolonged follow-up is necessary to correct speech impediments, facial deformities, dental irregularities and malocclusion of the jaw.

Cystic hygroma Cystic hygromas of the tongue are almost always associated with diffuse involvement of the ﬂoor of the mouth and neck. Antenatal ultrasonography has allowed for in utero diagnosis as well as facilitating adequate postnatal resuscitation. Presentation at birth is complicated by severe respiratory distress and marked salivation, indicating a difﬁculty in swallowing. These lesions have been treated successfully with OK432 (lyophilized mixture of Group A Streptococcus pyogenes).27 The best operative approach consists of staged resections for tongue, sublingual space and neck lesions.28 Good results have also been reported after laser surgery.29

Laser photocoagulation has been successfully employed in some patients to control tongue size but simple debulking does result in a high recurrence rate.32,33 These lesions may also appear in the lips (microchelitis), ﬂoor of mouth or the buccal mucosa.31,32

Hemangioma Large capillary hemangiomas of the tongue may cause difﬁculty in swallowing and breathing, which can be life threatening. Rarely, they may occur on the palate and present with feeding difﬁculty.34 Treatment with corticosteroids and interferon has resulted in a dramatic response in patients with rapidly enlarging capillary hemangiomas.34,35 Impressive results have also been obtained in recent years with laser application.36 Small hemangiomas which are asymptomatic are treated expectantly and usually regress spontaneously.

Congenital epulis Epulis, also referred to as congenital granular cell tumor of the gingiva, is a rare benign soft tissue tumor arising from the alveolar margin of the upper or lower jaw (Fig. 22.4). The tumor is present at birth and is mostly seen in females. It is sessile or partially pedunculated, encapsulated, bluish-red in colour and usually measures 2–5 cm in diameter; it is attached to the incisor or canine region of the mandibular or maxillary alveolus.37–39 The tumor consists principally of large eosinophilic granular cells arranged in solid nests that are separated by thin ﬁbrovascular areas. In addition, there are some spindleshaped cells and polygonal cells among the neoplastic granular cells.39 Rarely, the tumor may be large enough to produce feeding and respiratory difﬁculties.40 Spontaneous regression of this lesion has been described.31 However these are usually a cause of concern to parents

Lymphangioma Lymphangioma is the most common cause of macroglossia in infancy.30 The tumor may be conﬁned to a part of the tongue or there may be diffuse involvement. Typically, lymphangioma of the tongue is present as multiple small translucent cysts, giving a warty appearance. Deeper lesions may show no surface changes.31 Macroglossia secondary to lymphangioma can cause airway obstruction, swallowing difﬁculty, malocclusion and speech problems.32 Infection and trauma may result in recurrent tongue enlargement. Precise preoperative evaluation of extent with ultrasound, CT or MRI is mandatory. Surgical removal of the tumor is the treatment of choice. Satisfactory results are obtained by excising a sufﬁcient amount of tumor to enable re-shaping the contour of the tongue in order to enable proper speech and deglutition. Orthodontic problems are reduced and a reasonable cosmetic result is achieved.

Figure 22.4 Ranula of the sublingual duct displacing the tongue to the right

Lesions of the tongue and oral cavity 231

and for this reason surgical excision is recommended. Recurrences are extremely rare.

Dermoid cysts Dermoid cysts are congenital lesions derived from ectodermal differentiation of multipotential cells. About 30% of those occurring in the head and neck regions are located in the ﬂoor of the mouth. Lingual dermoids are rare entities. These cysts present clinically as swellings in the middle of the posterior aspect of the tongue, commonly on its dorsal aspect.41 Rarely these cysts may attain a massive size and interfere with feeding and breathing.42,43 Treatment consists of surgical excision of the cyst. Preoperative radiography with injection of contrast material to outline the anatomical extension of the cyst has been found to be useful during surgery.28 Malignant degeneration of dermoid cysts is possible but extremely rare.31

Figure 22.5 Newborn with a large epulis arising from the maxillary alveolar margin

Duplication cysts Intraoral duplication cysts are rare and only a few cases have been reported in the literature.44 The cysts are usually located at the base of the tongue. Diagnosis may be established antenatally, especially when the cyst is large and this allows for therapeutic aspiration, which improves access to the oropharynx for intubation at birth. Because of the potential for airway obstruction and respiratory difﬁculties at birth, it is important that preparations for tracheostomy are made in case oral intubation proves impossible. Surgical excision is the treatment of choice. Histology reveals a columnar lined mucosa consistent with enteric duplication cysts.45

(a)

Ranula Ranula is a term applied to a retention cyst of the sublingual gland. It results from partial obstruction of the sublingual salivary duct leading to dilatation of the more proximal duct. The cyst is round or oval in shape and located beneath the tongue (Fig. 22.5). It may occur congenitally and be evident on antenatal ultrasound scans.46,47 When large they interfere with respiration and feeding. Treatment of ranula consists of marsupialization of the cyst. The operative technique is demonstrated in Fig. 22.6.

Line of incision (b)

Lingual gastric choristoma Congenital rests of gastric epithelium may occur in a variety of head and neck locations. It has also been described to occur in association with intestinal epithelium as enterocytomas.48,49 These are rare lesions

Mucosa (c)

Figure 22.6 (a) Large ranula occupying the ﬂoor of the mouth. (b) Line of incision. (c) Continuous 4-0 Vicryl stitch to complete marsupialization

232 Miscellaneous conditions of the neck and oral cavity

with a predilection for affecting males. Presenting symptoms include: an asymptomatic cyst, bleeding ulcer, feeding difﬁculties and partial airway obstruction.50 Surgical excision is the preferred choice of treatment, however CO2 laser excision has been demonstrated to be a safe alternative.51

Lingual thyroid Lingual thyroid occurs when the thyroid gland fails to descend to its normal cervical location. Approximately one in 600 000 live births present in childhood or adolescence with a lingual thyroid.52 In a review of over 400 cases of undescended thyroid, 90% were found within the tongue and 10% in the anterior neck above the hyoid bone.53 The posterior part of the tongue around the foramen cecum is the most common site of the lingual thyroid. It is more common in females. Symptoms usually consist of dysphagia and dyspnea. Diagnosis is conﬁrmed by radioactive iodine scintigraphy. Of patients with lingual thyroids, 75% have no other functional thyroid tissue.31 Therefore, testing for location of thyroid tissue in addition to gland function is indicated. Treatment consists of complete excision of the lingual thyroid followed by life-long thyroid hormone therapy. Autotransplantation of the excised lingual gland or pedicle transfer, retaining a vascular pedicle and moving part of the thyroid into the neck, has been successful in several cases.54,55

Torticollis Torticollis in the neonate results from a ﬁbrous mass or tumor in the sternomastoid muscle (Fig. 22.7).

Although various theories have been proposed, the exact cause of the sternomastoid tumor is not clear. A widely accepted explanation is that birth trauma during a breech or difﬁcult delivery causes rupture of the sternomastoid muscle or its fascial sheath, resulting in ﬁbrous tissue which leads to shortening of the muscle. An alternative popular hypothesis is that the condition is the sequel of an intrauterine or perinatal compartment syndrome.56 The presence of torticollis is suspected from the infant’s abnormal posture, with the head tilted to the side of the lesion and rotation of the face to the opposite side. Plagiocephaly and facial asymmetry may be accompanying features. On palpation of the neck a 1–2 cm diameter, hard, immobile spindle-shaped mass can be felt in the mid-portion of the sternomastoid muscle. It usually develops 14–21 days after birth. Most (97%) present before the age of 3 months.57 Diagnosis of a sternocleidomastoid tumor can be conﬁrmed by ultrasonography. The echogenicity of the mass could be hyperechoic, isoechoic or hypoechoic relative to normal muscle. A hypoechoic rim is, however, frequently present.58 Treatment in the neonate involves active stretching exercises undertaken mainly by the parents but supervised by physiotherapists and pediatric surgeons. The involved muscle should be stretched to an over-corrected position by gentle, even and persistent motion with the infant lying in a supine position. The head is ﬂexed forward and away from the affected side and the chin is rotated toward the affected side. Most infants (80%) treated conservatively show complete recovery within 2–3 months. The poor outcome group and untreated cases that develop facial asymmetry, plagiocephaly and scoliosis,59 necessitate surgical release of the sternocleidomastoid muscle. Multiple surgical procedures for sternocleidomastoid tumors have been described and include, simple open myotomy, extensive release of the sternocleidomastoid muscle, myoplasties, bipolar release, or radical resections.57 The overall outcome is excellent.

Congenital goiter

Figure 22.7 Right sternomastoid tumor in a 3-week-old infant

The majority of neonatal goiters result from maternal ingestion of goitrogens. In the newborn infant, the most commonly implicated drugs are iodides and thiourea derivatives used for treatment of maternal thyrotoxicosis. Congenital goiter has also been described in a newborn with Prader-Willi syndrome.60 Most goiters in newborns are of the hyperplastic type and disappear a few weeks after birth. Ultrasonography is a useful noninvasive investigation in assessing the size of the goiter as well as the response to therapy.61 Rarely, goiters may be large enough to produce severe respiratory distress by tracheal compression. These patients may require division of the isthmus, or subtotal thyroidectomy to relieve tracheal compression. Follicular carcinoma has

References 233

been described in a neonatal dyshormogenetic hyperplastic goiter. Total thyroidectomy is necessary in this instance.62

Salivary gland tumors Fewer than 5% of all salivary gland tumors occur in children and are exceedingly rare in neonates. Histopathologically, Batsakis et al. categorized the perinatal salivary gland tumors into four groups.63,64 The ﬁrst group includes histologically benign tumors that have adult counterparts such as pleomorphic and monomorphic adenomas. The second group comprises the hamartomatous tumors. The third group includes epithelial enlarged-type tumors and are referred to either as sialoblastomas or embryomas. This group is the most common variety of perinatal salivary gland tumor and surgery without chemotherapy or irridiation is the treatment of choice. These lesions have a tendency for local recurrence.65 The last group, which are extremely rare, include the malignant salivary gland tumors of the newborn.66 Most congenital forms are carcinomatous in nature. MRI or CT is the method of choice for the radiological examination of masses in or around the salivary glands.65,67 These investigations provide exact anatomical detail, demonstrating the precise location of a mass within the parotid gland from which its probable impact on the position of the facial nerve may be inferred. Congenital malignant tumors of the parotid gland require conservative parotidectomy with preservation of the seventh nerve. The outlook after surgery for congenital malignant tumors of the parotid gland is excellent. Hemangioma and lymphangioma are the two most common benign neoplasms affecting the parotid gland in infants. These tumors are more common in female infants and are usually present at birth or appear during the ﬁrst month of life. They are usually conﬁned to the intracapsular portion of the gland, occasionally originate in adjacent tissues and extend into the gland. Capillary hemangioma is the most common vascular anomaly involving the parotid gland. These tumors demonstrate rapid growth in the ﬁrst few months of life with a tendency to complete regression by 4–5 years of age.8 The lack of distinctive clinical ﬁndings by which benign and malignant parotid tumors can be distinguished suggests the need for preliminary cautious biopsy. If the lesion is a non-threatening hemangioma with no component of lymphangioma, no treatment is indicated because satisfactory involution occurs within 3–4 years. High-dose corticosteroids, interferon therapy, transcutaneous arterial embolization and laser therapy have been successfully employed in life-threatening hemangiomas.68–71 Patients with intracapsular parotid lymphangioma or juxtaparotid lymphangioma require surgical removal of the tumor.

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234 Miscellaneous conditions of the neck and oral cavity 21. Loderio JG, Feinstein SJ, Molonea RA et al. Antenatal diagnosis of epignathus. A case report. J Reprod Med 1989; 34:997–9. 22. Jerella JT, Finberg FJ. Obstruction of the neonatal airway from teratomas. Surg Gynecol Obstet 1990; 170:126–31. 23. Todd DW, Votava HJ, Telander RL, Shoemaker CT. Giant epignatus, a case report. Minn Med 1991; 74:27–8. 24. Senyuz OF, Rizalar R, Celayir S et al. Fetus in fetu or giant epignatus protruding from the mouth. J Pediatr Surg 1992; 27:1493–5. 25. Sauter ER, Diaz JH, Arensman RM et al. The perioperative management of neonates with congenital oropharyngeal teratomas. J Pediatr Surg 1990; 25:925–8. 26. Valente A, Grant JO, Orr JD, Brereton RJ. Neonatal tonsillar teratoma. J Pediatr Surg 1988; 23:364–6. 27. Suzuki N, Tsuchida Y, Kuroiwa M, Ikeda H, Mohara J, Hatakeyama S, Koizumi T. Prenatally diagnosed cystic lymphangioma in infants. J Pediatr Surg 1998; 33:1599–1604. 28. Velak FT, Klotz DH, Hill CH et al. Tongue lesions in children. J Pediatr Surg 1975; 14:238–46. 29. Dixon JA, Davis RK, Gilbertson JJ. Laser photocoagulation of vascular malformations of the tongue. Laryngoscope 1986; 96:537–41. 30. Fonkalsrud EW. Malformations of the lymphatic system and hemangiomas. In: Holder TM, Ashworth KW, editors. Pediatric Surgery. Philadelphia, London: Saunders, 1980: 1054–60. 31. Dilley DC, Sieger MA, Budnick S. Diagnosis and treating common oral pathologies. Ped Clin N Am 1991; 5:1227–64. 32. Alqahtani A, Nguyen LT, Flageole H, Shaw K, Laberge JM. 25 Year experience with lymphangiomas in children. J Pediatr Surg 1999; 34:1164–8. 33. Balakrishnan A, Bailey CM. Lymphangioma of the tongue. A review of pathogenesis, treatment and the use of surface laser photocoagulation. J Laryngol Otol 1991; 105:924–9. 34. Lale AM, Jani P, Coleman M, Ellis PDM. A palatal haemangioma in a child. J Laryngol Otol 1998; 112:677–8. 35. Edgerton MJ. Treatment of hemangiomas with special reference to the role of steroid therapy. Ann Surg 1976; 183:517–32. 36. Irving IM. In: Lister J, Irving M, editors. Neonatal Surgery. London: Butterworths, 1990: 112–13. 37. Eppley BL, Sadove AM, Campbell A. Obstructive congenital epulis in a newborn. Ann Plastic Surg 1991; 27:152–5. 38. Chiba T, Okayama G. Congenital epulis of the newborn: report of a case with a review of the Japanese literature. Archiv fur Japanische Chirurgie 1990; 59:408–511. 39. Takahashi H, Fujita S, Satoh H, Okabe H. Immunohistochemical study of congenital gingival granular cell tumor (congenital epulis). J Oral Pathol Med 1990; 19:492–6.

40. Tokar B, Boneval C, Mirapoglu S, Tetikkurt S, Aksoyek S, Salman T. Congenital granulosa-cell tumor of the gingiva. Pediatr Surg Int 1998; 13(8):594–6. 41. Reddy VS, Radhakrishna K, Rao PLNG. Lingual dermoid. J Pediatr Surg 1991; 26:389–90. 42. Dahlman B, Livadatis A. Congenital cyst of the anterior half of the tongue. Z Kinderchir 1980; 29:244–7. 43. Tepas JJ, Deen HG, McArter R et al. Giant cystic chorista of the head and neck in a neonate. J Pediatr Surg 1988; 17:184–6. 44. Brown S, Kerr Willson R. Intra-oral duplication cyst. J Pediatr Surg 1978; 13:95–6. 45. Chen MK, Gross E, Lobe TE. Perinatal management of enteric duplication cysts of the tongue. Am J Perinatol 1997; 14:161–3. 46. Fernandez Moya JM, Cifuentes Sulzberger S, Diaz Racasens J, Ramos C, Sanz R, Perez Tejerizo G. Antenatal diagnosis and management of a ranula. Ultrasound in Obstet Gynecology 1998; 11:147–8. 47. Steelman R, Weisse M, Ramadan H. Congenital ranula. Clin Pediatr 1998; 37:205–6. 48. Grime PD. Giant enterocytoma within an infant’s tongue. J Laryngol Otol 1990; 104:814–18. 49. Said-Al-Naif N, Fantasia JE, Sciubba JJ, Ruggiero S, Sachs S. Heterotopic oral gastrointestinal cyst: report of 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 1999; 88:80–6. 50. Burton DM, Kearns DB, Seid AB, Pranksy SM, Billman G. Tongue gastric choristoma: failure to localise by technetium – 99m pertechnetate scan. Int J Pediatr Otorhino Laryngol 1992; 24:91–5. 51. Aydogan B, Kiroglu M, Soylu L, Aydin O, Satar M, Kiroglu F, Tunali N. Gastric cysts of the oral cavity. Int Journal Pediatr Otorhinolaryngol 1998; 45(3):255–8. 52. Gillis D, Brnjac L, Perlman K, Sochett EB, Daneman D. Frequency and characteristics of lingual thyroid not detected by screening. J Pediatr Endocrinol & Metab 1998; 11:229–33. 53. Wertz ML. Management of undescended lingual and subhyoid thyroid glands. Laryngoscope 1974; 84:507–21. 54. Steinwald OP, Muehrcke RC, Economou SG. Surgical correction of complete lingual ectopia of the thyroid gland. Surg Clin N Am 1970; 50:1177–86. 55. Davis RK. An alternative management of lingual thyroid: Excision implantation. J Ped Surg 1973; 8:869–70. 56. Lawrence WT, Azizkhan RG. Congenital muscular torticollis: A spectrum of pathology. Ann Plast Surg 1989; 23:523–30. 57. Cheng JCY, Tang SP, Chen TMK. Sternocleidomastoid pseudotumour and congenital muscular torticollis in infants: A prospective study of 510 cases. J Pediatr 1999; 134:712–16. 58. Chan YL, Cheng JC, Metrewelt C. Ultrasonography of congenital muscular torticollis. Pediatr Radiol 1992; 22:356–60.

References 235 59. Bredenkams JK, Hoover LA, Berke GS, Shaw A. Congenital muscular torticollis. A spectrum of disease. Arch Otolaryngol Head Neck Surg 1990; 116:212–16. 60. Insoft RM, Hurvitz J, Estrella E, Krishnamoorthy KS. Prader-Willi syndrome associated with fetal goitre: a case report. Am J Perinatol 1999; 16:29–31. 61. Bachrack LK, Daneman D, Daneman A et al. Use of ultrasound in childhood thyroid disorders. J Pediatr 1983; 103:547–52. 62. Medeiros-Neto G, Gil- Da- Costa MJ, Santos CL, Medina AM, Silva JC, Tsou RM, Sobrinho-Silmoes M. Metastic thyroid carcinoma arising from congenital goitre due to mutation in the thyroperoxidase gene. J Clin Endocrinol Metabol 1998; 83:4162–6. 63. Batsakis JG, Frankenthaler R. Embryoma (sialoblastoma) of salivary glands. Ann Otol Rhinol Laryngol 1992; 101:958–60. 64. Batsakis JG, Makay B, Ryka AF, Seifert RW. Perinatal salivary gland tumours (embryoma). J Laryngol Otol 1988; 102:1007–11. 65. Som PM, Brandwein M, Silvers AR, Rothschild MA.

66. 67. 68.

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Sialoblastoma (embryoma): MR ﬁndings of a rare pediatric salivary gland tumor. AJNR 1997; 18:847–50. Bianci A, Cudmore RE. Salivary gland tumours in children. J Pediatr Surg 1978; 13:519–21. Robinov K, Kell Jr T, Gordon PH. CT of the salivary glands. Radiol Clin N Am 1984; 22:145–59. Hosono S, Ohno T, Kimoto H et al. Successful transcutaneous arterial embolisation of a giant hemangioma associated with high output cardiac failure and Kassabach-Merrit syndrome in a neonate: A case report. J Perinat Med 1999; 27:399–403. Grienwald JH, Burke DK, Bonthius DJ, Bauman NM, Smith RJH. Arch Otolaryngol Head Neck Surg 1999; 125:21–7. Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: Histochemical and molecular changes. Pediatrics 2000; 105:117–21. Wacker FK, Cholewa D, Roggan A, Schilling A, Waldschmidt J, Wolf KJ. Vascular lesions in children: percutaneous MR imaging-guided interstitial Nd:YAG laser therapy – preliminary experience. Radiolog 1998; 208:789–94.

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3 Chest

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23 Congenital thoracic deformities ROBERT C. SHAMBERGER

INTRODUCTION Congenital thoracic deformities comprise a broad spectrum of abnormalities. They include the rare complete and incomplete sternal defects: thoracic ectopia cordis, thoraco-abdominal ectopia cordis (Cantrell’s pentalogy) and biﬁd sternum. More frequent are the deformities of the ribs including pectus excavatum, pectus carinatum and Poland’s syndrome, which are rarely repaired in infancy. Asphyxiating thoracic dystrophy (Juene’s syndrome) and spondylothoracic dysplasia (Jarcho-Levin syndrome) are seldom treated surgically and never with a long-term successful result.

ECTOPIA CORDIS The heart is in an extrathoracic position in ectopia cordis. Infants with this anomaly are classiﬁed by the precise location of the heart. Cervical ectopia cordis, in which the heart protrudes at the base of the neck, occurs in association with other severe deformities of the fetus and is the rarest form of ectopia cordis. There are no survivors with this lesion to date and many affected fetuses are stillborn. Thoracic ectopia cordis, the classic ‘naked heart’, includes infants with an entirely bare heart which is outside the thorax with cephalic orientation of the cardiac apex. It protrudes through a central sternal defect and lacks parietal pericardium and overlying skin. The condition may be associated with a separate epigastric omphalocele or upper abdominal wall defect. Thoracic ectopia cordis must be distinguished from cleft sternum, in which the heart is covered by normal skin in an orthotopic intrathoracic position and is anatomically normal. The heart is covered by skin or an omphalocele-like membrane in thoraco-abdominal ectopia cordis. A constellation of anomalies is often present in conjunction with thoraco-abdominal ectopia cordis, often called Cantrell pentalogy. These anomalies of the heart and

midline parietal wall include partial absence or cleft of the lower sternum, an anterior diaphragmatic defect (absence of the septum transversum), a pericardial defect corresponding to that of the diaphragm, and an upper abdominal defect ranging from an epigastric omphalocele or ventral hernia, to diastasis recti. The heart may be partially herniated into the abdominal cavity or a diverticulum of the ventricle may prolapse through the defect. In contrast with thoracic ectopia cordis, the heart is covered and lacks severe anterior displacement and cephalic orientation. The world literature on ectopia cordis has been extensively reviewed.1 Ectopia cordis can be readily deﬁned by prenatal ultrasound from the early stages of gestation, which facilitates perinatal planning and preparation.2,3 Intrinsic cardiac anomalies are often best demonstrated by in utero studies and other associated anomalies can be deﬁned as well to facilitate discussion with parents regarding prognosis.

Thoracic ectopia cordis The dramatic presentation of the heart, naked and beating upon the chest wall has stimulated many case reports. There are anecdotal reports of attempted repair, but few successes are described. Survival is limited by a generally lethal combination of associated intrinsic cardiac malformations and abnormal rotation of the heart with the apex pointing cephalad (Fig. 23.1).4 The ﬁrst successful repair of ectopia cordis was achieved by Koop in 1975, as reported by Saxena.5 An infant with a normal heart had skin ﬂap coverage at 5 hours of age, with inferior mobilization of the anterior attachments of the diaphragm. The sternal bands were 2 in (51 mm) apart and could not be approximated primarily without cardiac compression and compromise. At 7 months of age an acrylic resin of Dacron and Marlex mesh was inserted to widen the sternal cleft with primary skin closure. Necrosis of the skin ﬂaps complicated the postoperative course, with infection of the prosthetic material requiring its subsequent removal. This child still

240 Congenital thoracic deformities

Figure 23.1 Infant with thoracic ectopia cordis. Heart lies anterior to the thoracic cavity and apex is directed cephalad

survives at age 12 years and is reported to be entirely well.6 The success of this operation in three other patients is reported (Table 23.1).7–9 Dobell’s case is of note in that surgical correction was also performed in two stages.7 Skin ﬂap coverage was provided while the patient was a newborn. At 19 months of age, rib strut grafts were placed over the sternal defect and covered with pectoral muscle ﬂaps. The pericardium was divided from its anterior attachments to the chest wall, allowing the heart to fall back partially into the thoracic cavity. Lillehei (as reported by Hornberger) achieved successful repair of the only infant with an intrinsic cardiac anomaly, tetralogy of Fallot with pulmonary atresia.9 Skin ﬂaps were mobilized for coverage in the perinatal period with a Blalock-Taussig shunt at 4 days of age and a complete repair with aortic homograft at 2 years of age. The unifying theme of successfully managed cases is construction of a partial anterior chest cavity surrounding the heart and avoidance of attempts to return the heart to an orthotopic location. A combination of thoracic ectopia cordis and a separate omphalocele with an intervening bridge of normal skin is particularly difﬁcult to manage. In this group of patients, adequate skin and abdominal wall

components to cover both areas is lacking and no survivors exist. If a successful outcome is to be accomplished in infants with thoracic ectopia cordis, early deﬁnition of the associated cardiac malformation is necessary. Prenatal echocardiography will often deﬁne the cardiac lesion and is more successful than echocardiograms performed after birth with the ultrasound probe placed directly on the cardiac surface, which are complicated by cardiac motion and interference by air. Cardiac catheterization with angiography may be required in infants not diagnosed by antenatal studies. If the cardiac malformation is correctable, the infant should be taken directly to the operating room from the cardiac catheterization laboratory for cardiac repair. Some form of cardiac enclosure must then be provided. Use of prosthetic materials is associated with a high incidence of sepsis and death, especially when prosthetic materials have been used in cardiac repair.

Thoraco-abdominal ectopia cordis (Cantrell’s pentalogy) The required features of the pentalogy of Cantrell are a cleft lower sternum, a half-moon anterior diaphragmatic defect due to failure of development of the septum transversum, absence of the parietal pericardium, adjacent or completely separate omphalocele, ventral hernia or diastasis recti, and in most patients a major form of congenital heart disease, most commonly tetralogy of Fallot or diverticulum from the left ventricle (Fig. 23.2). A complete summary of all reported cardiac anomalies has been presented.1 This condition was precisely described by Wilson in 179810 with the ﬁrst repair attempted by Arndt in 189611 and the ﬁrst successful repair by Weiting in 1912.12 The anomaly was reviewed by Major in 195313 and later by Cantrell et al. in 1958.14 Immediate neonatal intervention is required in patients with a large upper omphalocele and lower sternal cleft. Skin closure must be achieved to avoid

Table 23.1 Successful repairs of ectopia cordis Author

Year

Cardiac lesion

Method of sternal closure

Koop (Saxena5) Dobell et al.7

1975

None

1982

None

Amato et al.8

1988

None

Lillehei (Hornberger et al 9)

1996

Tetralogy of Fallot

Skin ﬂap closure at 5 hours. Acrylic resin applied to sternal cleft at 7 months Perinatal skin closure in one stage. Second-stage repair with autologous rib grafts Skin ﬂaps mobilized, diaphragm moved inferiorly. Gortex membrane used to close defect with skin ﬂaps over it. Child survived but died of aspiration at 11 months of age Perinatal skin ﬂap closure Blalock-Taussig shunt at 4 days of life and complete repair at 2 years of age. No prosthetic tissue coverage

Biﬁd sternum 241

infection and mediastinitis. Approximation of the abdominal wall is of secondary importance and may require the use of Teﬂon mesh or other prosthetic material (Fig. 23.3a–c). Advances in pediatric cardiac surgery now allow correction of the intrinsic cardiac lesions which were previously fatal. An aggressive approach is required if salvage is to be improved. Patients with intact skin covering the defect, however, have lived years without surgical repair.

BIFID STERNUM Figure 23.2 Newborn male with Cantrell’s pentalogy. Flaring of the lower thoracic cavity is present with a large epigastric omphalocele. The septum transversum and the inferior portion of the pericardium were absent (From Welch,43 by permission of W.B. Saunders Co., Philadelphia)

Costal arch

Liver

Cleft sternum may be complete or incomplete and results from failure of ventral fusion of the sternal bars at or about the eighth week of gestation. In all such cases there is sternal separation and skin coverage of the midline defect, an intact pericardium, intact pleural

Freeing of diaphragmatic leaf

Pericardium closed

Diaphragm sutured to costal arch and to opposite leaf

Left leaf of diaphragm

(b)

(a)

Costal arch

Rectus muscle

Diaphragm

Relaxing incision of rectus sheath

(c)

Figure 23.3 Repair of pentalogy of Cantrell is depicted. (a) The pericardium is closed after appropriate lateral and inferior dissection to the vena cava. The right and left dorsal leaves of the diaphragm which are widely separated are identiﬁed. The liver is retracted inferiorly after division of the falciform ligament. (b) Pedicles of the diaphragm are developed from each side and transposed medially. They are sutured together and to each costal arch. (c) After diaphragmatic closure, the falciform ligament is reconstructed. Closure continues by advancement of the anterior sheath of the rectus muscle to the midline. Lateral relaxing incisions are often required. Parietal repair can be accomplished at the time of cardiac correction. Prosthetic material may be required to obtain closure of the abdominal component of the repair (From Welch,43 by permission of W.B. Saunders Co., Philadelphia)

242 Congenital thoracic deformities

envelopes, and a normal diaphragm. Omphalocele does not occur in association with this anomaly and the condition causes little difﬁculty other than dramatic increase in the deformity with crying or Valsalva maneuver (Fig. 23.4a,b). The sternal defect involved an upper cleft in 46 patients, an upper cleft to the xiphoid in 33 patients, and a complete cleft in 23 patients. The cleft involved the lower sternum in only ﬁve reported cases. A total of 69 repairs have been reported, 25 with primary closure.1 None had intrinsic congenital heart disease. Most authors now recommend surgical treatment in the newborn period when all such malformations can be dealt with by simple direct closure without the use of prosthetic materials.15,16 Cleft sternum has been associated with capillary hemangioma in a cervicofacial distribution and 15 such cases have been identifed.17 Two patients had major airway involvement and one multiple areas of involvement of the small bowel.17,18 All others lacked involvement of viscera. Operation in the perinatal period is recommended in all cases, since direct approximation and suture closure is

possible at that time without compression of the heart (Fig. 23.5a–d). No reports of recurrence or delayed healing have been encountered. Direct approximation and suture closure can be achieved, and partial transverse division of sternal bands is rarely necessary. Reconstruction of the anterior chest wall using multiple oblique sliding chondrotomies leaving the perichondrium intact was reported by Sabiston and subsequently by others.19 This technique is still useful in older infants with a less ﬂexible chest wall and wide defect. Closure employing composite cartilage grafts from the costal arch or prosthetic materials such as Marlex or Teﬂon mesh have also been reported, but these methods can be avoided with repair of the infants in a timely fashion. Recently, Shamberger and Welch1 reviewed their experience with sternal defects at the Children’s Hospital, Boston, MA, USA. A total of 16 patients with sternal defects were identiﬁed, ﬁve with thoracic ectopia cordis, eight with thoraco-abdominal ectopia cordis and

Clavicle

Pericardium and endothoracic fascia Midline incision

Sternal bar

1 2 3 4 5 6 7 (a)

Bifid sternum

(b) Tevdek or PDS sutures

Undermine

(a)

+ – wedge

(c)

(b) Figure 23.4 Newborn infant with a biﬁd sternum. (a) Vigorous crying produces retraction at the defect with inspiration (left) and protrusion with exhalation or Valsalva maneuver (right). (b) Following repair, normal conﬁguration of the sternum is present

(d)

Figure 23.5 (a) Repair of biﬁd sternum is best performed through a longitudinal incision extending the length of the defect. (b) Directly beneath the subcutaneous tissues the sternal bars are encountered with pectoral muscles present lateral to the bars. The endothoracic fascia and pericardium are just below these structures. (c) The endothoracic fascia is mobilized off the sternal bars posteriorly with blunt dissection to allow safe placement of the sutures. Approximation of the sternal bars may be facilitated by excising a wedge of cartilage inferiorly. Repair is best accomplished in the neonatal period because of the ﬂexibility of the chest wall. (d) Closure of the defect is achieved with 2-0 Tevdek or PDS sutures (From Shamberger and Welch,1 by permission of Springer-Verlag, Heidelberg, Germany)

Poland’s syndrome 243

three with cleft sternum.1 Thoracic ectopia cordis was uniformly fatal in our series; thoraco-abdominal ectopia cordis was fatal in ﬁve of eight cases and biﬁd sternum was successfully repaired in all three cases in infancy.

PECTUS EXCAVATUM Pectus excavatum (funnel chest or trichterbrust) is a depression of the sternum and lower costal cartilages. It is generally identiﬁed within the ﬁrst year of life (in 86% of patients) and in many infants it is noted at birth.20 The extent of sternal and cartilaginous deformity is quite variable, but generally consists of posterior displacement of the sternum below the insertion of the second costal cartilage. The ﬁrst and second costal cartilages are generally normal in contour, whereas the third to seventh are curved posteriorly to join the sternum. The ossiﬁed portion of the rib is normal in conﬁguration in infancy. In infants the extreme ﬂexibility of the costal cartilages results in remarkable changes in the deformity with vigorous respiration or crying. Self-limited deformities are either gone or vastly improved by 3 years of age. Hence, I avoid repair in all infants younger than 2 years of age, or later if they have continued sternal ﬂexibility. Pectus excavatum may occur as frequently as one in 300–400 live births.21 The etiology of pectus excavatum is unknown. A family history of some type of anterior thoracic deformity is present in 37% of patients.20 Scoliosis is identiﬁed in up to 15% of patients with pectus excavatum, usually in children with an asymmetric thoracic deformity, but it is generally not seen in infancy. Patients with Marfan’s syndrome have a high incidence of associated chest wall deformities, often in the most severe form and usually accompanied by scoliosis.

PECTUS CARINATUM Pectus carinatum is the anterior protrusion deformity of the chest. It is much less frequent than the depression deformity, comprising 16% of our combined series.22 A spectrum of protrusion deformities exists and these are often divided into four types. The most frequent type consists of anterior displacement of the sternum with symmetric concavity of the costal cartilages laterally. Asymmetric deformities with anterior displacement of the costal cartilages on one side and a normally positioned or oblique sternum and normal cartilages on the contralateral side are less common. ‘Mixed’ lesions have a carinate deformity on one side and a depression or excavatum deformity on the contralateral side, often with sternal obliquity. Most unusual are the upper ‘pouter pigeon’ deformities, with protrusion of the

manubrium and second and third costal cartilages and relative depression of the body of the sternum. The etiology of pectus carinatum is unknown. There is overgrowth of the costal cartilages, with forward buckling and anterior displacement of the sternum. As with pectus excavatum, there is a clear-cut increased family incidence, suggesting a genetic basis. In a recent review, 26% of patients had a family history of chest wall deformity and 12% had a family history of scoliosis.22 It is much more frequent in boys than girls, with a ratio of 4:1. Only the upper ‘pouter pigeon’ deformity is associated with congenital heart disease in 18% of cases.23 In contrast to pectus excavatum, patients with pectus carinatum have a much later appearance of the deformity. In a recent review, only one-sixth of the patients were noted to have a carinate deformity within the ﬁrst year of life and in almost half it was noted after the onset of the pubertal growth spurt at 11 years of age.22 The deformity, which may be mild at birth, often worsens rapidly during the growth period at puberty. Because of mild deformity at birth and ﬂexible costal cartilages, this deformity is rarely repaired during the ﬁrst 2 years of life and is probably best repaired in the early teenage years.

POLAND’S SYNDROME Poland in 1841 described congenital absence of the pectoralis major and minor muscles, associated with syndactyly.24 This entity is a spectrum, often involving chest wall and breast deformity as well as ipsilateral limb anomalies. The extent of thoracic involvement may range from hypoplasia of the sternal head of the pectoralis major and minor muscles with normal underlying ribs, to complete absence of the anterior portions of the second to fourth ribs and cartilages, often called the second to fourth rib syndrome. Breast involvement is signiﬁcant in females, ranging from varying degrees of breast hypoplasia to complete absence of the breast (amastia) and nipple (athelia). Hand deformities are frequent and occurred in the patient described by Poland. They may include hypoplasia (brachydactyly), fused ﬁngers (syndactyly) and mitten or claw deformity (ectromelia). This condition is present from birth and has an estimated incidence of 1 in 30 000 to 1 in 32 000.25 The etiology of this deformity is unknown, but it clearly affects the developing somatic tissue for the entire limb bud and chest wall. Abnormalities in the breast can be recognized at birth by the absence of the underlying breast bud and the hypoplastic, often superiorly displaced nipple. Chest wall deformities are identiﬁed at birth, including absence of ribs or posterior displacement of ribs on the involved side. The etiology of this deformity is unknown, but it clearly affects the develop-

244 Congenital thoracic deformities

ing somatic tissue for the entire limb bud and chest wall. In our experience, the deformity occurs equally in boys and girls. Chest wall correction was required in ten out of 41 cases but again never in infancy.26

THORACIC DEFORMITIES IN DIFFUSE SKELETAL DISORDERS Asphyxiating thoracic dystrophy (Jeune’s disease) Jeune in 1954 ﬁrst described a newborn with a narrow rigid chest and multiple cartilage anomalies.27 The patient died early in the perinatal period because of respiratory insufﬁciency. Subsequent authors have further characterized this form of osteochondrodystrophy which has variable skeletal involvement. It is inherited in an autosomal recessive pattern and is not associated with chromosome abnormalities.28 Its most prominent feature is a narrow ‘bell-shaped’ thorax and protuberant abdomen. The thorax is narrow in both the transverse and sagittal axis and has little respiratory motion due to the horizontal direction of the ribs (Fig. 23.6a–c). The ribs are short and wide and the splayed costochondral junctions barely reach the anterior axillary line. The costal cartilage is abundant and irregular like a rachitic rosary. Microscopic examination of the costochondral junction reveals disordered and poorly progressing endochondral ossiﬁcation, resulting in decreased rib length. Associated skeletal abnormalities which occur with this syndrome include short and stubby extremities with relatively short and wide bones. The clavicles are in a ﬁxed and elevated position, and the pelvis is small and hypoplastic with small, square iliac bones.

(b)

(c)

(a)

Figure 23.6 Infant with asphyxiating thoracic dystrophy (Jeune’s syndrome). (a) Clinical photograph demonstrates small size of thorax relative to infant. (b) Radiograph shows the short horizontal ribs and narrow thorax with limited lung volumes. (c) Lateral radiograph demonstrates the endings of the bony ribs at the mid-axillary line and the abnormal costochondral junctions (arrow)

References 245

The syndrome has variable expression and degrees of pulmonary impairment. While the initial cases reported resulted in neonatal deaths, subsequent reports have documented a wide range of survival of patients with this syndrome.29 The pathological ﬁndings in autopsy cases are variable as well showing a range of abnormal pulmonary development, although in most cases the bronchial development is normal and there is a variable decrease in alveolar divisions.30 Early surgical interventions were reported by Barnes and colleagues, Karjoo and co-workers , and Mustard.31–33 In 1971 Barnes and colleagues31 reported Waterson’s attempts at thoracic enlargement by splitting the sternum in a 4-month-old infant who had required ventilation since birth. The horizontally split sternum was held apart by the eighth rib, but it subsequently became dislodged, resulting in a ﬂail sternum. She needed continued ventilation, however, and at the age of 20 months she had two additional rib grafts added and a Dacron patch to stabilize her sternum. She was eventually weaned entirely from the ventilator. Karjoo and co-workers operated on a 10-month-old infant with failure to thrive and progressive tachypnea and repeated pulmonary infections.32 They also split the sternum and maintained its separation with a stainless steel wire strut and a sheet of Marlex mesh. Ventilation was reported to have improved after surgery. Mustard split the sternum of a 6-month-old child with progressive respiratory distress and cyanotic spells, and placed an iliac crest bone graft between the sternal halves, reinforced with a Vitallium plate.33 The child required long-term ventilation and died of progressive respiratory failure 1 year after surgery. Todd and associates have recently described a method of expanding the thoracic diameter by inserting a methylmethacrylate prosthesis between the sternum split longitudinally and spread 2.5 cm.34 This child was extubated following the surgery and was reported to have improved exercise tolerance. The report of Aronson describes early success of a tibial interposition graft placed between a longitudinally split sternum, but subsequent growth failure of the chest resulted in recurrent respiratory distress.35 Recent reports by Davis et al. describe ‘staggered’ divisions of the ribs laterally to expand the chest.36 Addition to this technique of distraction devices to lengthen the separation between rib segments may achieve some degree of continued growth of the thorax, but complete reports are anxiously awaited. The ultimate results of surgical attempts will depend on the degree of underlying pulmonary parenchymal impairment of the infants.

Spondylothoracic dysplasia (Jarcho-Levin syndrome) Spondylothoracic dysplasia is an autosomal recessive deformity in which there are multiple vertebral and rib

malformations. The ribs have a crab-like appearance. Death occurs in early infancy from respiratory failure and pneumonia.37 Patients have multiple alternating hemi-vertebrae which affect most if not all of the thoracic and lumbar spine. The ossiﬁcation centers rarely cross the midline. Multiple posterior fusions of the ribs as well as remarkable shortening of the thoracic spine result in a ‘crab-like’ radiographic appearance of the chest (Fig. 23.7). One-third of patients with this syndrome have associated malformations including congenital heart disease and renal anomalies. Its occurrence has been reported primarily in Puerto Rican families (15 out of 18 cases).38 Bone formation is normal in these patients. Successful prenatal diagnosis can be established by sonographic examination.39 Thoracic deformity in this entity is really secondary to the spinal anomaly which results in close posterior approximation of the origin of the ribs. Although most infants with this entity succumb before 15 months of age, no surgical efforts have been proposed or attempted.40 Some long-term survivors who did not receive intervention are reported.41,42

Figure 23.7 Radiograph of infant with spondylothoracic dysplasia (Jarcho-Levin syndrome). Severe abnormality of the spine is apparent with multiple hemivertebrae and the ‘crablike’ ribs with close approximation posteriorly and splaying out anteriorly

REFERENCES 1. Shamberger RC, Welch KJ. Sternal defects. Pediatr Surg Int 1990; 5:156–64. 2. Bagnani V, Quartuccio A, Quartuccio A. First-trimester sonographic diagnosis of Cantrell’s pentalogy with exencephaly. J Clin Ultrasound 1999; 27:276–8. 3. Tongson T, Wanapirak C, Sirivatanapa P et al. Prenatal sonographic diagnosis of ectopia cordis. J Clin Ultrasound 1999; 27:440–5. 4. Humpl T, Huggan P, Hornberger LK et al. Presentation and outcomes of ectopia cordis. Can J Cardiol 1999; 15:1353–7.

246 Congenital thoracic deformities 5. Saxena NC. Ectopia cordis child surviving; prosthesis fails. Pediatr News 1976; 10:3. 6. Van Praagh R, Weinberg PM, Smith SD et al. Malpositions of the heart. In: Adams FH, Emmanouilides GC, Riemenschneider TA, eds. Moss’s Heart Disease in Infants, Children, and Adolescents. 4th edn. Baltimore: Williams and Wilkins, 1989: 530–80. 7. Dobell ARC, Williams HB, Long RW. Staged repair of ectopia cordis. J Pediatr Surg 1982; 17:353–8. 8. Amato JJ, Zelen J, Talwalkar NG. Single-stage repair of thoracic ectopia cordis. Ann Thorac Surg 1995; 59:518–20. 9. Hornberger LK, Colan SD, Lock JE et al. Outcome of patients with ectopia cordis and signiﬁcant intracardiac defects. Circulation 1996; 94(Suppl II):32–7. 10. Wilson J. A description of a very unusual formation of the human heart. Phil Trans Roy Soc Lond. Part II, 1798, 346–56. 11. Arndt C. Nabelschnurbruch mit Herzhernie. Operation durch Laparotomie mit tödlichem Ausgang. Centralbl Gynakol 1896; 20:632–3. 12. Weiting K. Eine operative behandelte Hermissbildung. Dtsch Z Chir 1912; 114:293–5. 13. Major JW. Thoracoabdominal ectopia cordis. J Thorac Surg 1953; 26:309–17. 14. Cantrell JR, Haller, JA, Ravitch MM. A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surg Gynecol Obstet 1958; 10:602–14. 15. Daum R, Zachariou Z. Total and superior sternal clefts in newborns: A simple technique for surgical correction. J Pediatr Surg 1999; 34:408–11. 16. Dòmini M, Cupaioli M, Rossi F et al. Biﬁd sternum: Neonatal surgical treatment. Ann Thorac Surg 2000; 69:267–9. 17. Hersh JH, Waterﬁll D, Rutledge J et al. Sternal malformation/vascular dysplasia association. Am J Med Genet 1985; 21:177–86. 18. Ingelrans P, Debeugny P. Observation de biﬁdité du sternum associée à une angiomatose trachéale. Ann Chir Infantile 1965; 6:123–8. 19. Sabiston DC. The surgical management of congenital biﬁd sternum with partial ectopia cordis. J Thorac Surg 1958; 35:118–22. 20. Shamberger RC, Welch KJ. Surgical repair of pectus excavatum. J Pediatr Surg 1988; 23:615–22. 21. Ravitch MM. Pectus excavatum. In: Ravitch MM, ed. Congenital Deformities of the Chest Wall and their Operative Correction. Philadelphia: W.B. Saunders, 1977: 78–205. 22. Shamberger RC, Welch KJ. Surgical correction of pectus carinatum. J Pediatr Surg 1987; 22:48–53. 23. Lees RF, Caldicott WJH. Sternal anomalies and congenital heart disease. Am J Roentgenol 1975; 124:423–7. 24. Poland A. Deﬁciency of the pectoral muscles. Guy’s Hosp Rep 1841; 6:191–3. 25. McGillivray BC, Lowry RB. Poland syndrome in British

26.

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31. 32.

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38. 39.

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43.

Columbia: incidence and reproductive experience of affected persons. Am J Med Genet 1977; 1:65–74. Shamberger RC, Welch KJ, Upton J, III. Surgical treatment of thoracic deformity in Poland’s syndrome. J Pediatr Surg 1989; 24:760–6. Jeune M, Carron R, Beraud C et al. Polychondrodystrophie avec blocage thoracique d’evolution fatale. Pediatrie 1954; 9:390–2. Tahernia AC, Stamps P. ‘Jeune syndrome’ (asphyxiating thoracic dystrophy): report of a case, a review of the literature, and an editor’s commentary. Clin Pediatr 1977; 16:903–8. Kozlowski K, Masel J. Asphyxiating thoracic dystrophy without respiratory disease: report of two cases of the latent form. Pediatr Radiol 1976; 5:30–33. Williams AJ, Vawter G, Reid LM. Lung structure in asphyxiating thoracic dystrophy. Arch Pathol Lab Med 1984; 108:658–61. Barnes ND, Hull D, Milner AD et al. Chest reconstruction in thoracic dystrophy. Arch Dis Childh 1971; 46:833–7. Karjoo M, Koop CE, Cornfeld D et al. Pancreatic exocrine enzyme deﬁciency associated with asphyxiating thoracic dystrophy. Arch Dis Childh 1973; 48:143–6. Ravitch MM. Rib deformities in diffuse skeletal disorders. In: Ravitch MM, ed. Congenital Deformities of the Chest Wall and their Operative Correction. Philadelphia: W.B. Saunders, 1977: 272–84. Todd DW, Tinguely SJ, Norberg WJ. A thoracic expansion technique for Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 1986; 21:161–3. Aronson DC, VanNierop JC, Taminiau A et al. Homologous bone graft for expansion thoracoplasty in Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 1999; 34:500–3. Davis JT, Ruberg RL, Leppink DM et al. Lateral thoracic expansion for Jeune’s asphyxiating dystrophy: A new approach. Ann Thorac Surg 1995; 60:694–6. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 1938; 62:216–26. Heilbronner DM, Renshaw TS. Spondylothoracic dysplasia. J Bone Joint Surg 1984; 66A:302–3. Wong G, Levine D. Jarcho-Levin syndrome: Two consecutive pregnancies in a Puerto Rican couple. Ultrasound Obstet Gynecol 1998; 12:70–73. Roberts AP, Conner AN, Tolmie JL et al. Spondylothoracic and spondylocostal dysostosis: hereditary forms of spinal deformity. J Bone Joint Surg 1988; 70B:123–6. Lawson ME, Share J, Benacerraf B et al. Jarcho-Levin syndrome: Prenatal diagnosis, perinatal care, and followup of siblings. J Perinatology 1997; 17:407–9. Hayek S, Burke SW, Boachie-Adjei O et al. Jarcho-Levin syndrome: Report on a long-term follow-up of an untreated patient. J Pediatr Ortho Part B, 1999; 8:150–3. Welch KJ. Chest wall deformities. In: Holder TM, Ashcraft KW, eds. Pediatric Surgery. Philadelphia: W.B. Saunders, 1980: 162–82.

24 Mediastinal masses in the newborn STEVEN J. SHOCHAT

Mediastinal masses in the newborn represent a wide variety of congenital and neoplastic lesions which can present interesting diagnostic and therapeutic challenges. However, despite the heterogeneous make-up of this group of lesions, an accurate preoperative diagnosis can usually be established on the basis of the location of the mass. While the subject of this chapter deals with the treatment of masses in the newborn, it is helpful to discuss differences between various age groups when dealing with mediastinal masses in the childhood population.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of mediastinal masses in infants and children is simpliﬁed if the mediastinum is arbitrarily separated into three compartments (Fig. 24.1). For the purpose of this discussion the mediastinum will be partitioned as follows: the anterior mediastinum lies anterior to the heart and lung roots and contains the thymus, anterior mediastinal lymph nodes and rarely a substernal extension of the thyroid and parathyroid. The middle mediastinum contains the trachea, bronchi, mediastinal lymph nodes, heart and Posterior mediastinum Anterior mediastinum

Middle mediastinum

Figure 24.1 Compartments of the mediastinum

great vessels. The posterior mediastinum lies behind the heart and lung roots and contains the esophagus and intercostal sympathetic nerves. Anterior mediastinal masses include teratomas; thymic cysts, hyperplasia or tumors; cystic hygromas and lymphomas. Masses within the middle mediastinum include the lymphomas, bronchogenic cysts and granulomatous infections within the mediastinal lymph nodes. Posterior mediastinal lesions include the tumors of neurogenic origin, enterogenous cysts, and the undifferentiated sarcomas. The age of the patient at the time of diagnosis is extremely important, since certain masses have a predilection for younger infants and others are predominantly seen in older children and adolescents.1–4 In newborns and children under 2 years of age, the most common mediastinal mass is the neuroblastoma within the posterior mediastinum.4 In addition, thymic hyperplasia and bronchogenic cysts are seen predominantly in children less than 2 years of age. The various lymphomas are the most common mediastinal masses seen in children greater than 2 years. The mean age of children with mediastinal Hodgkin’s disease is approximately 13 years of age and the mean age of children who present with non-Hodgkin’s lymphoma is 11 years of age.3 The presenting signs and symptoms in infants and children with mediastinal masses vary depending upon age: • • • • • • • •

acute respiratory distress fever cough shortness of breath cervical adenopathy superior vena caval syndrome Horner’s syndrome asymptomatic

Infants under 2 years of age frequently present with signs of tracheal compression and acute respiratory distress. This is due to the smaller, softer, more pliable tracheobronchial tree in infants as well as the fact that they do not have a ﬁxed mediastinum so that large mediastinal

248 Mediastinal masses in the newborn

masses can cause a signiﬁcant shift of the mediastinum with compromise of the contralateral hemithorax. Older children will present with symptoms of fever, cough and shortness of breath. Approximately half the children with mediastinal lymphomas will present with cervical adenopathy. Superior vena caval obstruction is rare in children, but is occasionally seen. Horner’s syndrome may be the presenting ﬁnding in infants with neuroblastomas or neurogenic tumors of the posterior mediastinum. Asymptomatic mediastinal masses are seen in children of all ages and are frequently noted on a chest X-ray performed for a mild upper respiratory infection or are discovered incidentally following imaging studies for symptoms unrelated to the mediastinal mass.

mediastinal masses in order to detect intraspinous extension of tumor (dumb-bell tumors). Cervical lymph node biopsy should be considered in children with middle mediastinal lesions and suspected lymphoma. A bone marrow aspiration and biopsy should also be performed prior to other invasive studies in children suspected of having non-Hodgkin’s lymphoma. Skin testing and complement ﬁxation titers should be considered in infants with middle mediastinal masses to rule out granulomatous infections. Alpha fetoprotein determination and HCT titers should be performed in children with anterior mediastinal masses if malignant teratomas are suspected. Urinary catecholamine metabolites should be evaluated in infants with posterior mediastinal masses both for diagnosis and for postoperative follow-up in children with suspected neuroblastomas.

DIAGNOSIS ANTERIOR MEDIASTINUM A systematic approach to the diagnosis of a mediastinal mass in the newborn is imperative:5 • • • • • • • • •

posteroanterior–lateral chest X-ray barium swallow ultrasonography CT scan MRI bone marrow–lymph node biopsy skin test – complement ﬁxation serum markers – AFP, HCG urinary catecholamines

The most helpful diagnostic technique in this age group is still the chest X-ray in the posteroanterior and lateral projections, in order to localize the position of the mass. Vertebral anomalies associated with a mediastinal mass in an infant should raise the suspicion of the so-called neuroenteric variety of enterogenous cyst which communicates with the meninges. Calciﬁcation within a posterior mediastinal mass suggests the presence of a neuroblastoma and anterior mediastinal teratomas frequently contain calciﬁcation. In cases of suspected enterogenous and brochogenic cysts, the esophagogram may be of value. Ultrasonography of the chest can be quite helpful in deﬁning complicated mediastinal lesions and has been especially helpful in infants with suspected thymic hyperplasia. Echocardiography should be performed to delineate the heart and great vessels if lesions of these structures are suspected. A computed tomography scan should be reserved for difﬁcult diagnostic dilemmas and for delineating anatomic boundaries in preparation for tumor resection. Magnetic resonance imaging may be of help in differentiating masses of vascular origin from other mediastinal structures and may be helpful in infants with suspected thymic hyperplasia.6 In addition, magnetic resonance imaging should be considered in cases of posterior

Thymic hyperplasia is the most common anterior mediastinal mass seen in infants (Fig. 24.2). This diagnosis is usually not difﬁcult as there is frequently a characteristic ‘sail’ sign on routine chest X-ray. Recently, ultrasonography has been very helpful in differentiating thymic hyperplasia from other mediastinal masses and should be considered in difﬁcult cases. The use of steroids to help with the diagnosis of thymic hyperplasia in infants as listed below is rarely necessary and has not been required in our institution for some time. Benign teratoma is the most frequent anterior mediastinal neoplasm seen in children under 2 years of age (Fig. 24.3). These masses are usually well encapsulated and can be treated by total excision through a posterolateral thoracotomy. Cystic hygromas also are observed in infants, but usually have a cervical or axillary component which makes this diagnosis obvious. Thymic cysts are extremely rare in children and only 20 thymomas have been reported in childhood. Germ cell tumors of the anterior mediastinum are usually seen in older children

< 2 years Benign teratoma Thymic hyperplasia Cystic hygroma

Figure 24.2 Anterior mediastinum

> 2 years Malignant germ cell tumor Thymoma Lymphoma

Middle mediastinum 249

< 2 years Bronchogenic cyst

> 2 years Lymphoma Granuloma

Figure 24.4 Middle mediastinum

Figure 24.3 Cardiac teratoma with anterior mediastinal mass: (a) posteroanterior–lateral chest X-ray; (b) CT scan; (c) MRI scan

and adolescents and many have an endodermal sinus or yolk sac component with an elevated serum alpha fetoprotein.7 AFP and HCG levels should be performed in all older children with anterior mediastinal masses as these markers are helpful not only in diagnosis but in following response to therapy. These tumors are highly malignant lesions and total resection rarely is possible. Evaluation of these patients requires a multidisciplinary approach with consultation between surgeon, pediatric oncologist and radiation therapist. In the rare case where total excision is possible, this should be carried out and followed by multi-agent chemotherapy. However, radical resection is not indicated. When the tumor is non-resectable, a biopsy rather than partial resection is followed by chemotherapy and delayed primary excision. While isolated lymphomas of the thymus do occur, the majority of lymphomas of the anterior mediastinum will also have a major middle mediastinal component which makes diagnosis straightforward.

MIDDLE MEDIASTINUM Bronchogenic cysts may be seen in all age groups, but are the most frequent mass seen within the middle mediastinum in infants and children under 2 years of age (Fig. 24.4). Bronchogenic cysts are located in the subcarinal region and are frequently associated with a characteristic expiratory stridor due to accentuation of the obstruction of the lower trachea during expiration. Bronchogenic cysts are frequently difﬁcult to diagnose on routine chest X-ray, but there is usually a characteristic displacement of the esophagus on barium swallow (Fig. 24.5). Bronchogenic cysts occasionally are

Figure 24.5 Bronchogenic cyst showing displacement of esophagus. Normal appearing chest X-ray

250 Mediastinal masses in the newborn

intimately attached to the membranous trachea and if this is the case a small portion of the cyst should be left attached to the trachea. The most common mediastinal mass in individuals over 2 years of age is Hodgkin’s or non-Hodgkin’s lymphoma. Lymphomas are also the most frequent tumors involving the middle mediastinum. The initial diagnostic work-up in children with suspected lymphoma should include cervical or supraclavicular lymph node biopsy as well as bone marrow biopsy. Mediastinoscopy, anterior mediastinotomy or CT-guided needle biopsy are the procedures of choice to establish a tissue diagnosis in the absence of cervical adenopathy. A normal thoracotomy is rarely indicated for diagnosis or treatment in children with lymphoma. Children who present with a large middle mediastinal mass and respiratory distress and a suspected diagnosis of non-Hodgkin’s lymphoma may be treated initially with steroids prior to biopsy because of the dangers of acute respiratory decompensation on induction of anesthesia. However, every attempt should be made to safely establish a diagnosis prior to the use of steroids since even a brief course of therapy can make subsequent diagnosis difﬁcult.8 A multidisciplinary approach (surgeon, oncologist, radiotherapist) to the child with suspected mediastinal lymphoma is imperative and tissue obtained at the time of biopsy should be placed in saline so that immunologic surface marker studies can be performed. These studies are extremely important in the classiﬁcation and hence therapy of the various nonHodgkin’s lymphomas.9 Granulomatous infections of the paratracheal, subcarinal or hilar lymph nodes are occasionally seen and can usually be diagnosed by appropriate skin tests and complement ﬁxation titers. In the midwest of the USA and other endemic areas, histoplasmosis seems to have a predilection for the azygous node which is characteristically enlarged in children with this infection. Diagnosis is conﬁrmed by mediastinoscopy, mediastinotomy or rarely thoracotomy.

< 2 years Neuroblastoma Enterogenous cyst

> 2 years Ganglioneuroma Sarcoma

Figure 24.6 Posterior mediastinum

extension may present with neurologic symptoms due to spinal cord compression. While the treatment of mediastinal neuroblastomas in children is total excision if at all possible, this does not mean radical chest wall resection. In the rare case of a massive mediastinal neuroblastoma that cannot be resected without a radical operation, a biopsy to establish the diagnosis is followed by chemotherapy and delayed primary excision. While this clinical situation is unusual, we have found that a tissue diagnosis can usually be obtained by a percutaneous core needle biopsy, avoiding formal thoracotomy. In children with disseminated neuroblastoma, thoracotomy and resection should be carried out only after all metastatic sites are controlled with multi-agent chemotherapy. Despite impressive shrinking of tumor following chemotherapy and complete delayed primary excision, the prognosis continues to be discouraging. Children with posterior mediastinal neuroblastoma can also present with unusual symptoms. The case in Fig. 24.7 presented with a 3-month history of diarrhea. The mass turned out to be a large neuroblastoma that extended up

POSTERIOR MEDIASTINUM The most common mass of the posterior mediastinum and in fact the most common mass in newborns is a posterior mediastinal neuroblastoma (Fig. 24.6). Mediastinal neuroblastomas are interesting in that they seem to have a different biological behavior than intraabdominal tumors. The majority of mediastinal neuroblastomas are localized or low-stage disease and have a favorable outcome following resection.10 These tumors are more often occult and are diagnosed on X-ray examination for other complaints. Respiratory distress due to compression or deviation of trachea is a feature in some cases. Thoracic neuroblastomas with dumb-bell

Figure 24.7 Posterior mediastinal neuroblastoma treated by total excision. Note cervical extension (arrow)

References 251

into the cervical region. The tumor contained high concentrations of prostaglandin E which was the etiology of the diarrhea. Vasoactive intestinal polypeptide secreting neuroblastomas have also been described in children with profuse watery diarrhea. Recently, Ratner and Pelton reported an infant who presented with progressively worsening labored respirations and was found to have a neuroblastoma extending from the mediastinum, through the thoracic inlet, and into the neck.11 Enterogenous cysts, while rare, represent an interesting spectrum of lesions.12,13 They may be intimately associated with the esophagus and cause dysphagia or they can contain gastric mucosa which has been associated with peptic ulceration, perforation and bleeding. Large cysts can have abdominal extensions and communicate with an intestinal duplication. An interesting but rare variant is the so-called neurenteric cyst that communicates with the meninges through an intraspinous component. These infants present with a large mediastinal mass, respiratory distress and rarely neurologic symptoms. Characteristic deformities of the lower cervical and upper thoracic spine are always present on routine chest X-ray. During resection of these masses through a posterolateral thoracotomy, the communication between the thoracic and infraspinous component must be identiﬁed and ligated to prevent a spinal ﬂuid leak and meningitis. These patients should be evaluated by MRI scan, as the infraspinous cystic component may require laminectomy and excision.

The most important factor in preventing anesthetic complications in children with a mediastinal mass is a recognition of the above problems and the anticipation of a possible airway problem. A very thorough radiologic evaluation should be performed and CT examination to determine the tracheal cross sectional area may be extremely helpful.15 Pulmonary function studies may be of help as well. Once the preoperative evaluation is completed the anesthetic of choice can be determined depending upon the procedure that will be performed. Preoperative radiation therapy or chemotherapy may be required prior to primary excision or biopsy. Incisional biopsies can be performed under local anesthesia in older children and needle biopsy with local anesthesia can be performed in younger children and infants. In children with benign lesions one lung anesthesia with placement of the endotracheal tube beyond the obstruction has been found to be helpful and occasionally ventilation through a rigid bronchoscope is necessary. While cardiopulmonary bypass or ECMO may be required these techniques are usually not necessary in the majority of patients. A high index of suspicion, meticulous preoperative evaluation, and a multidisciplinary action plan decided upon by surgeons, anesthesiology, radiation therapist, hematology/oncologist, and pathologist can usually avert the potential catastrophe associated with general anesthesia in children with critical mediastinal masses.

OPERATIVE TECHNIQUE FOR REMOVAL OF MEDIASTINAL NEUROBLASTOMA ANESTHETIC MANAGEMENT OF INFANTS WITH A MEDIASTINAL MASS Respiratory compromise on induction of general anesthesia in children with large mediastinal masses is a well recognized complication that must be considered in the preoperative evaluation of any child with a mediastinal mass.14,15 Infants and small children have a small compressible airway, which is associated with a signiﬁcant increased airway resistance with even a modest degree of narrowing. In addition infants do not have a ﬁxed mediastinum and large masses can easily displace the mediastinal structures with compression of the tracheobronchial tree, superior vena cava or right ventricular outﬂow tract. Cardiac output may also be diminished due to pressure on the great vessels. Induction of anesthesia is associated with a decrease in the functional residual capacity, decrease lung capacity, and an increase in lung retractile force. The above alterations are extenuated with the addition of paralysis. Narrowing of the trachea will also become smaller when the patient changes from spontaneous to positive pressure ventilation. All of the above factors lead to the sometime critical condition that is associated with general anesthesia in these patients.

The tumor is usually approached through a standard posterolateral thoracotomy at the approximate level of the tumor. The lung is retracted medially to reveal tumor covered with pleura arising from the sympathetic trunk and an assessment made of it and obvious lymph node involvement in the vicinity. The pleura is incised around the tumor approximately 1 cm from it and the fascia and pleura mobilized towards the tumor. A plane of dissection can usually be developed superﬁcial to endothoracic fascia. The tumor is now mobilized from the ribs by sharp dissection and any intercostal vessels entering the tumor will need division. If the tumor extends far enough anteriorly, the azygos vein on the right side will need division between ties. Care is taken to avoid damage to the ﬁrst thoracic nerve passing laterally across the ﬁrst rib to join the brachial plexus. The superior intercostal artery normally descends between the ﬁrst nerve and the sympathetic trunk. Other intercostal nerves may be sacriﬁced if they are intimate with the tumor. Depending on how far the tumor has extended anteriorly, it will need to be dissected off the main structures in the superior mediastinum. This is most likely to be the esophagus and the closely applied vagus

252 Mediastinal masses in the newborn

nerve, but in a large tumor the trachea may be involved. It may prove useful to have a large size tube in the esophagus to aid dissection. On the left side, the thoracic duct, arch of aorta with subclavian and carotid branches along with the vagus will need protection. It should now prove possible to dissect the tumor off the bodies of the vertebra and any extension into the intravertebral foramen should be carefully dissected out. Titanium clips may prove useful to control hemorrhage in small vessels, and these will not interfere with subsequent CT scanning. They may also be used as markers if all tumor is not excised and radiation therapy is being considered. Any suspiciously involved lymph nodes locally should be taken for biopsy (staging). The chest is closed after leaving a chest drain.

REFERENCES 1. Azarow KS, Pearl RH, Zurcher R et al. Primary mediastinal masses. A comparison of adult and pediatric populations. J Thoracic Cardiovasc Surg 1993; 106:67–72. 2. Grosfeld JL, Skinner MA, Rescorla FJ et al. Mediastinal tumors in children: experience with 196 cases. Ann Surg Oncol 1994; 1:121–7. 3. Glick RD, LaQuaglia MP. Lymphomas of the anterior mediastinum. Sem Ped Surg 1999; 8:69–77. 4. Saenz NC. Posterior mediastinal neurogenic tumors in infants and children. Sem Ped Surg 1999; 8:78–84.

5. Esposito G. Diagnosis of mediastinal masses and principles of surgical tactics and technique for their treatment. Sem Ped Surg 1999; 8:54–60. 6. Siegel MJ, Nadel SN, Glazer HS et al. Lesions in children: comparison of CT and MRI. Radiology 1986; 160:241–4. 7. Billmire DF. Germ cell mesenchymal and thymic tumors of the mediastinum. Sem Ped Surg 1999; 8:85–91. 8. Borenstein SH, Gerstle T, Malkin D et al. The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Ped Surg 2000; 35:973–6. 9. Warnke RA, Link MP. Identiﬁcation and signiﬁcance of cell markers in leukemia and lymphoma. Am Rev Med 1983; 34:117–31. 10. Adams GA, Shochat SJ, Smith EI et al. Thoracic neuroblastoma: A Pediatric Oncology Group Study. J Pediatr Surg 1993; 28:372. 11. Ratner IA, Pelton JJ. Neuroblastoma of the thoracic inlet. J Pediatr Surg 1990; 25:547–9. 12. Snyder ME, Luck SR, Hernandez R et al. Diagnostic dilemmas of mediastinal cysts. J Pediatr Surg 1985; 20:810–15. 13. Superina RA, Ein SH, Humphreys RR. Cystic duplications of the esophagus and neurenteric cysts. J Pediatr Surg 1984; 19:527–30. 14. Vas L, Naregal F, Naik V. Anesthetic management of an infant with anterior mediastinal mass. Pediatric Anesthesia 1999; 9:439–43. 15. Shamberger RC. Pre-anesthetic evaluation of children with anterior mediastinal masses. Sem Ped Surg 1999; 8:61–8.

25 Subglottic stenosis FELIX SCHIER

INTRODUCTION Artiﬁcial ventilation via endotracheal intubation or tracheostomy represents a main feature of neonatal intensive care. Both techniques have their beneﬁts and complications. Post-intubational complications are mainly restricted to the subglottic area, with subglottic stenosis constituting a major proportion. In these cases, the remedy will generate a disease which outlasts the process which required intubation to begin with. As survival rates increase, more newborns with subsequent subglottic disease will be presented to the pediatric surgeon. From the various techniques on offer, we have formed a preference for three: endoscopic procedures, the anterior cricoid split and the interpositioning of cartilage grafts. In our opinion, they virtually obviate the need for tracheostomies.

DESCRIPTION The term ‘subglottic’ designates the area extending from below the vocal cords down to the pulmonary tree. However, it refers only to the area from immediately below the vocal cords to the most cranial segment of the trachea: the infraglottic cavity and especially the conus (Fig. 25.1). Subglottic, cricoidal and infraglottic are, for all practical purposes, synonyms. Nowhere else is the airway as narrow and as completely outﬂanked by cartilaginous structures as here. A predisposition to mechanical trauma is obvious. Any swelling of the interior soft tissue will have to extend centripetally at the expense of the airway. The normal tracheal diameter at birth is 5–5.55 mm and increases by 0.3 mm/year.1 The radius r enters as r4 into Hagen-Poiseuille’s law (for laminar airﬂow). It is more realistic to assume turbulent airﬂow. Therefore the radius r may well change in the formula to its ﬁfth power r5.2 Given a tracheal diameter of a mere 2.5 mm (i.e. of 50%) would cause a 32fold increase of resistance!

Figure 25.1 The subglottic space, shown by the hatched area

CONGENITAL SUBGLOTTIC STENOSIS Both cartilaginous and soft-tissue malformations are encountered. In roughly 10% of cases they are associated with other laryngotracheal anomalies: pathological ﬁndings outside the larynx or trachea concur in another 10%.3 The lesion can be circumferential or segmental. Surgical correction is seldom required.

ACQUIRED SUBGLOTTIC STENOSIS Intubation is the most common cause for traumatically acquired lesions to the subglottic area:4 it acts both mechanically and as an irritant to the mucosal layer. With delayed mucosal repair, infection will complete the clinical picture. Mucosal damage leads to accumulation of mucus. Bacterial contamination ensues and results in tracheitis. The pathohistological sequence is: mucosal edema, hemorrhage and ulceration, cartilaginous exposure, infection.5 In general, intubation can be considered as the insertion of a foreign body into an infected area, a situation which, according to general medical knowledge, will tend to maintain rather than diminish chronic

254 Subglottic stenosis

inﬂammation. Intermittent suction enhances the mechanical trauma. The healing process, which involves epithelial growth, formation of granulation tissue and thickening of the subepithelial connective tissue, will even persist beyond the period of primary mucosal repair.6 Thus a soft senosis (Fig. 25.2) may develop into a cicatricial ‘hard’ stenosis (Fig. 25.3). The hard stenosis is the one presented to the pediatric surgeon; it results from a concurrence of destructive and reparative processes.5 Apparently, the more immature the baby, the more pronounced the mesenchymal reactions to repeated trauma. There is no correlation

between the duration of the intubation and the later incidence of subglottic stenosis. Finally, although endotracheal intubation is undoubtedly the main cause for subglottic stenosis, a number of other potential causes exist: infections as well as various kinds of chemical, thermal and external physical trauma, and also angioma and cysts.

Clinical features Congenital subglottic stenosis presents itself with inspiratory stridor from birth onwards. The typical clinical picture depends on the severity of the stenosis; in the case of an angioma it may not develop before the fourth to sixth week: dyspnea, inspiratory stridor, sternal or intercostal retractions, a hoarse or bitonal cry, and coughing.6 Air hunger and tachypnea point to intrathoracic stenosis, while stridor and hoarseness are typical clinical symptoms of acquired subglottic stenosis. Apneic attacks may precede stridor, especially in preterm babies.7 Usually, any attempt to extubate will give rise to increasing stridor, hypoxemia, dyspnea on exertion, and mixed acidosis within hours or days. Angiomas, in our experience, develop slowly. On purely clinical grounds there is no speciﬁc difference between congenital and acquired stenosis, except that acquired stenosis is noted only after extubation.

Diagnosis

Figure 25.2 ‘Soft’ stenosis

The history and clinical presentation are indicative. Anteroposterior and lateral neck X-ray will visualize the stenosis. A computed tomography (CT) scan or nuclear magnetic resonance imaging (MRI) will reveal cartilaginous deformities and the extent of the lesion often demonstrates large extrinsic segments of angiomas and lymphangiomas. Finally, tracheoscopy will conﬁrm the diagnosis.

Indication

Figure 25.3 ‘Hard’ stenosis

The previous therapeutic policy was based on a principle adapted from adult surgery: initially bypass the stenosis by tracheostomy and then either wait or ‘launch an attack on the stenotic area’.4,5 However, tracheostomy in children was always a procedure associated with a high rate of morbidity, especially following long-term intubation.3,8 Today, children with localized stenoses, who seem able to tolerate general anesthesia and would otherwise undergo tracheostomy, may initially be submitted to endoscopic laser treatment.9,10 Tracheostomy can thus often be avoided. However, the planning of such interventions must take into account the possibility of redo

Acquired subglottic stenosis 255

procedures under emergency circumstances. The procedure should therefore only be performed in a setting which allows for these follow-up procedures.10,11 During one of these follow-up procedures, inspection of the bronchi is advisable in order to rule out other more distal alterations. Surgically and technically, a distinction needs to be made between congenital and acquired lesions.4

Therapeutic option

ENDOSCOPIC PROCEDURES (LASER, ELECTRORESECTION, CRYOTHERAPY) When technically feasible, endoscopic procedures are preferred. Both Nd: YAG and CO2 lasers are useful tools. However, there are no ﬂexible ﬁbers yet for the CO2 laser and control of bleeding is not as good as with the Hd: YAG laser. Laser treatment avoids some of the risks of open surgery, such as bleeding, scarring and wound infection. It can also obviate tracheostomy and can be repeated several times. In fact, laser therapy usually requires several sessions.10

WAIT AND SEE With ventilation terminated, subglottic stenosis may subside spontaneously. This is rare and can mainly be expected in angiomas and granulations. This was one of the main points made by advocates of tracheostomy: subglottic stenoses may almost disappear after a tracheostomy is performed in the more distal trachea, thus eliminating chronic trauma to the subglottic area.

CONSERVATIVE (STEROIDS, DILATATION, BOUGIENAGE) The recent literature provides no evidence of good results or curative effects with these modalities alone. Balloon dilatation with angioplasty catheters (under radiological control) has been used to treat postoperative restenoses.12 Bougienage may work in case of ﬁbrous and cartilaginous narrowing, but in cases of soft stenosis it may only accelerate the progression to hard stenosis.

STENTING This approach involved other complications and a prolonged duration of treatment. It includes a tracheostomy. We use open and closed stents, which are positioned subglotically.10 In combined stenosis including the larynx, stents are inserted in a glottic or transglottic position and exteriorized through the stoma with a T-like band. In subglottic stenosis, a short open stent is used and the children are supplied with a fenestrated tracheostomy tube for speech training.

ANTERIOR CRICOID SPLIT We prefer the anterior cricoid split in cases with cricoid hypoplasia. The technique is described later.

OPEN SURGERY Open surgery is indicated for more extensive and longdistance stenoses and in all cases of cartilaginous stenosis. We would not consider end-to-end resection in cases of subglottic stenosis. Our chosen techniques are primary tracheoplastic procedures with interposition of cartilage grafts.

TECHNIQUE Endoscopic procedure With the child in the supine position and the head in maximal dorsal ﬂexion, anesthesia is induced via a mask and followed by a short period of hyperoxygenation with 100% oxygen. A topical anesthetic is sprayed into the larynx and trachea. Also, although these instructions are referred to as ‘ventilating’ bronchoscopes (Storz), anesthesiologists would hardly dare to administer relaxants to a child being ventilated with the bronchoscope in place and thus narrowing the available airway.13 Sponges sufﬁce to protect the toothless baby from mechanical trauma. A bronchoscope at room temperature will quickly be blurred by condensation inside the airway. This can be prevented by applying either physiological saline with a few drops of normal household detergent or commercially available anti-clouding solutions to the tip of the bronchoscope. The larynx is exposed by insertion of a laryngoscope blade. With the child’s head extended to a slightly greater degree, the bronchoscope is passed from the corner of the mouth along the base of the tongue until the arytenoid cartilages are visible (Fig. 25.4). The tongue and epiglottis are pushed up, and the tip of the bronchoscope is advanced beyond the epiglottis. The vocal folds then become immediately visible (Fig. 25.5). With the child’s head extended even further, the tracheoscope is advanced through the vocal folds, and the subglottic area becomes fully exposed (Fig. 25.6). A typical postintubation subglottic stenosis will be identiﬁed at once (Fig. 25.7). Now the anesthetic T-piece is attached to the bronchoscope. The surgeon will occlude the child’s nose with his thumb and index ﬁnger. With a moist abdominal pad in the palm of the hand, the surgeon will then try to minimize the escape of anesthetic gases from the mouth. Since the small suction channel tends to become easily occluded by debris, it is advisable to keep physiological saline at hand to facilitate the clearance of the suction.

LASER CO2 laser ﬁbers small enough to be passed through pediatric ventilation bronchoscopes are not yet commercially available. Compared to Nd: YAG laser, they

256 Subglottic stenosis

Figure 25.7 Subglottic stenosis seen from above

Figure 25.4 Advancing of the bronchoscope from the corner of the mouth along the base of the tongue until the arytenoid cartilages are visible

Figure 25.5 The arytenoid cartilages and the vocal cords seen from above

would certainly be better suited for tracheal obstructions because of the limited thermal injury they cause. The ‘bare ﬁber’ of a Nd: YAG laser, however, can easily be passed through the instrument channel of Storz bronchoscopes (a special set is available for laser application in newborns and infants). The Nd: YAG laser has a good penetration and coagulation effect; it is preferable in cases where bleeding is anticipated. Using 15 W and exposure times of 0.2 seconds with intervals of 0.2 seconds, a depth-limited coagulation can be achieved through a contact method. Owing to the simultaneous shrinkage and Hagen-Poiseuille’s law, ventilation is immediately facilitated. Necrotic tissue will be removed with the ﬁber when it adheres to the tip or with suction or forceps. Extreme caution should be exercised as a number of tracheal burns, intratracheal combustions and even explosions have been reported in connection with laser application in airways ventilated with anesthetic gases.14 Ignition of plastic material (whether endotracheal tubes or gastric tubes) may even occur without direct contact to the laser beam. In an experimental setting, tubes burned in 100% O2, 100% N2O or any combination of the two. In air alone, the tubes did not burn. Combustion was weakly supported by 25% O2 and strongly by 30% O2. Additionally, red and latex rubber appeared to be more easily ignitable than plastic vinyl.3 Ignition can be prevented by avoiding the combination of ﬂammable material/anesthetic gases/ laser and by using special tubes.

OPEN SURGERY

Figure 25.6 Exposure of the subglottic area

Anterior cricoid split The anterior cricoid split4,15,16 (Fig. 25.8) consists of a horizontal skin incision and a vertical cartilage incision from just below the notch of the thyroid cartilage through the cricoid ring and the uppermost tracheal cartilage. The cricoid ring then bursts open. The endotracheal tube may become visible. The rationale is to relieve pressure on the cartilaginous ring and to lessen the pressure factors responsible for the subglottic lesion.16 Postoperatively, an endotracheal tube is placed as an internal stent for 10–14 days. An endoscopic

Acquired subglottic stenosis 257

Figure 25.8 The anterior cricoid split. Access is gained by a horizontal skin incision

procedure is not performed at this time. Good results have been reported.15

INTERPOSITIONING OF CARTILAGINOUS GRAFTS In this operation (Fig. 25.9), with the patient in the supine position and after endotracheal intubation, the trachea is exposed through a midline horizontal incision. Rarely, it may prove necessary to divide the cranial part of the sternum. The thymus is divided. The aortic arch and innominate vein are controlled by vessel loops. The trachea is opened by an incision from the cricoid to the third tracheal ring. The endotracheal tube is advanced by

the surgeon into the distal trachea. The posterior segment of the cricoid is dissected. The anterior sternal segment of the second rib is exposed, longitudinally split and slit at the antiperichondrial side in order to achieve greater ﬂexibility of the future interponate.17 The biconcavely shaped interponate is inserted with its perichondrial side to the inner side of the trachea. Interrupted monoﬁlamentous absorbable (PDS) sutures secure it to the cricoidal margins. Fibrin glue seals an occasional small disruption caused by an individual stitch. Postoperatively, our patients are kept intubated for 8–10 days, although others extubate them immediately after the procedure. Dexamethasone 1–1.5 mg/kg, applied intravenously, is believed to reduce postoperative tracheal edema, and high-humidity oxygen or ultrasonic nebulizers may help to reduce eschar formation.9

RESULTS A total of 92 patients with subglottic stenoses were treated, ranging from 680 g to 14 years of age (average 1.4 years; median 5 months). Three types and four stages were distinguished. Type A is a localized lesion: a membrane, or granulations. Type B extends down to the bifurcation, and type C includes the bifurcation and the more distal bronchial tree. According to a classiﬁcation by Cotton, 4, 16 stage I refers to a stenosis of less than 70%, stage II to a stenosis between 70% and 90%, stage III to a stenosis greater than 90%, and stage IV to a complete obstruction (Tables 25.1–3). A total of 62 children suffered from post-intubational scarring, 16 from granulations, 12 from angiomas, and one each from a papilloma and a cyst. The surgical techniques applied and the results obtained were as follows. All 92 children were primarily treated endoscopically with the laser, even when operated on later. As present, 12 children still have a stoma (13%), and two are intubated. All others are well and extubated. Cartilaginous grafts were performed in ten children; six are extubated, three have a stoma and Table 25.1 Types of subglottic stenosis Type

No. of patients

A B C

45 38 9

Table 25.2 Stages of subglottic stenosis Stage Figure 25.9 Cartilaginous graft from the second rib. The rib is split (only one-half is used and the inner side is grooved in order to achieve more ﬂexibility) and inserted into the stenotic tracheal segment. Ventilation is maintained by a tube inserted distally to the incision

I II III IV

No. of patients 6 27 50 9

258 Subglottic stenosis Table 25.3 Types and stages of subglottic stenosis Type

Stage

No. of patients

A

III III III IV

4 20 19 2

B

III III III IV

1 8 24 5

C

III III III IV

– – 7 2

one is still intubated. Anterior cricoid splits were undertaken in four children: they are all well and extubated. The only child with resection is extubated. Bougienage proved effective in 13 out of 14 children. Only two children, in whom stent were applied, are now extubated; ﬁve others either have a stoma or are intubated.

COMMENTARY The most frequent lesions are localized scars, membranes and granulomas. The more the narrowing extends beyond the subglottic region further down into the bronchial tree, the higher the degree of its narrowing effect. Usually, long-distance narrowings are severely stenotic. On average, laser application was necessary three times per patient. In more than 80% of the children, laser application alone was sufﬁcient to allow for subsequent extubation. In 20%, primary laser applications were followed by cricotomy, anterior split, and resection.

REFERENCES 1. Nixon C. Tracheal dimensions in childhood. Am J Roentgenol (letter) 1986; 147:1094–5.

2. Lambertsen CJ. The lung: physical aspects of respiration. In: Mountcastle VB, editor. Medical Physiology. 14th edn. St Louis: Mosby, 1980: 1677–90. 3. Holinger LD. Histopathology of congenital subglottic stenosis. Ann Rhinol Laryngol 1999; 108:101–11. 4. Walner DL, Loewen MS, Kimura RE. Neonatal subglottic stenosis – incidence and trends. Laryngoscope 2001; 111:48–51. 5. Duynstee ML, de Krijger RR, Monnier P, Verwoerd CD, Verwoerd-Verhoef HL. Subglottic stenosis after endolaryngeal intubation in infants and children: result of wound healing processes. Int J Pediatr Otorhinolaryngol 2002; 11:1–9. 6. Minningerode B, Richter HG. Pathophysiology of subglottic tracheal stenosis in childhood. In: Wurnig P, editor. Trachea and Lung Surgery in Childhood. Berlin: Springer-Verlag, 1987, 107. 7. Ratner I, Whitﬁeld J. Acquired subglottic stenosis in the very-low-birth-weight infant. Am J Dis Child 1983; 137:40–3. 8. Rodger BM, Rooks JJ, Talbert JL. Pediatric tracheostomy: long-term evaluation. J Pediatr Surg 1979; 14:258–63. 9. Hollinger PH, Kutnuck SL et al. Subglottic stenosis without tracheotomy. Ann Otol Rhinol Laryngol 1976; 91:407–12. 10. Triglia JM, Nocollas R, Romas S. Management of subglottic stenosis in infancy and childhood. Eur Arch Otorhinolaryngol 2000; 157:382–5. 11. Hollinger PH, Kitnick SL et al. Subglottic stenosis in infants and children. Ann Otol Rhinol Laryngol 1976; 85:591–9. 12. Philippart AI, Long JA, Greenholz K. Balloon dilation of postoperative tracheal stenosis. J Pediatr Surg 1988; 23:1178–9. 13. Hatch DJ, Sumner E. Neonatal anaesthesia and perioperative care. In: Hatch DJ, Sumner E eds. Current Topics in Anaesthesia. 2nd edn. London: Arnold, 1986. 14. Handa KK, Bhalla AP, Arora A. Fire during the use of NdYag laser. Int J Pediatr Otoorhinolaryngol 2001; 60:239–42. 15. Kaschke O, Olze H, Sandmann J. Use of cartilage grafts in treatment of laryngotracheal stenoses and defects in children. Eur J Pediatr Surg 2001; 11:147–53. 16. Silver FM, Myer CM III, Cotton RT. Anterior cricoid split. Update 1991. Am J Orolaryngol 1991; 12:343–6. 17. Kimura K, Mukohara N, Tsugawa C et al. Tracheoplasty for congenital stenosis of the entire trachea. J Pediatr Surg 1982; 17:669–871.

26 Tracheomalacia I. VINOGRAD AND R.M. FILLER

Perhaps more than any other single aspect of care in the acutely ill infant, the management of the airway is the most important determinant of survival or death. The newborn infant has several inherent disadvantages in respiratory mechanics. The diameter of the trachea and bronchi is small; thus the risk of major obstruction is increased. The musculature of the chest wall is relatively weak; thus coughing is less efﬁcient than in older subjects. On the favorable side, however, is the fact that hypoxia is relatively well tolerated. Exchange of gases between the alveolar air sacs and the environment requires an unobstructed tubular passageway, and sufﬁcient intrathoracic negative pressure to draw air into the lungs. Obstruction may occur at several levels and may be congenital or acquired. At the tracheal level, obstruction may result from changes of the tracheal internal lumen, from extrinsic pressure, and as a result of functional tracheal obstruction during the normal respiratory cycle. During normal respiration the diameter of the major airways is determined by the relationship between intrathoracic and intraluminal airway pressures (Fig. 26.1). Intrathoracic airways are narrowed by an increase in intrathoracic pressure during expiration and coughing because pleural pressure rises above the intraluminal airway pressure (atmospheric pressure). The linear movement of air exerts an increased pressure on the forward vector with a corresponding fall in the lateral vector (the Venturi principle). Airway collapse is prevented by the rigidity of the airway wall. With tracheomalacia, airway rigidity is decreased so that the physiologic narrowing that occurs during expiration and coughing can cause airway obstruction. In addition, external pressure from the aorta, innominate artery, or full esophagus, can also compress and narrow an abnormally soft air passage. There are two distinct forms of tracheomalacia – primary and secondary.1 Primary tracheomalacia is caused by a congenital deﬁciency or weakness of the cartilaginous and elastic supporting structure of the trachea. It occurs mainly as an isolated segmental defect,

often found in children born with esophageal atresia and tracheo-esophageal ﬁstula.2 Congenital tracheomalacia was also described in association with the Larsen syndrome3 and polychondritis.4 In primary tracheomalacia the reason for the collapse, weakness and instability of the tracheal wall appears to vary. It may be due to hypoplasia, dysplasia or absence of the normal cartilaginous framework. Histologic study of the trachea by Wailoo and Emery in children with esophageal atresia5 revealed several abnormalities. Cartilage rings were often incomplete, cartilage to muscle ratio was reduced, and there was an increase in the length of the membranous portion of the trachea which is the weakest part of the tracheal wall. The reasons for the association of tracheomalacia and esophageal atresia are

Inspiration (a)

Inspiration (b)

Expiration NORMAL

Expiration

Coughing

TRACHEOMALACIA

Figure 26.1 Physiologic relationship between intrathoracic airway pressure and the diameter of intrathoracic airways. (a) Normally, during expiration, intrathoracic airways are narrowed by the increased intrathoracic pressure. (b) With tracheomalacia, airway rigidity is decreased and the physiologic narrowing which occurs during expiration and coughing is greatly accentuated

260 Tracheomalacia

probably related to the abnormalities in the division of the primitive foregut as it forms the trachea and esophagus. In addition, Davies and Cywes postulated that the chronic compressive force by the dilated and hypertrophied proximal atresic esophageal pouch on the trachea plays a part in retarding the development of the trachea during fetal life.6 The distal tracheo-esophageal ﬁstula may aid in tracheal collapse since it allows a displacement of lung ﬂuid into the distal esophagus during swallowing and hence favors tracheal collapse. Secondary tracheomalacia may be acquired or possibly associated with another congenital anomaly which compresses the airway wall during its development or growth. Frequently the entire tracheobronchial tree is involved. In middle and late life it is most often associated with chronic lung disease, especially emphysema and bronchitis. In infants and children, secondary tracheomalacia may present during the treatment of acquired or congenital severe pulmonary disease such as bronchopulmonary dysplasia,7,8 recurrent bronchitis and cystic ﬁbrosis. A localized area of a soft tracheal cartilaginous wall which develops because of pressure from a vascular ring or a parabronchial tumor or cyst may cause symptoms after the primary lesion is diminished.9

CLINICAL FEATURES Clinical symptoms of tracheomalacia depend on the location, the length of the abnormal airway segment and the severity of the structural abnormality. In mild cases the deﬁciency in the cartilaginous tracheal components is usually small and short; it may interfere with the normal cough mechanism by allowing almost complete tracheal closure when intrapleural pressure increases. This is often clinically recognized as the ‘seal bark’ of the infant who has had repair of esophageal atresia. These infants often have noisy respirations, and may have more frequent episodes of respiratory infection associated with sputum retention than the normal child, especially in the ﬁrst year of life. Improvement occurs with growth. After 1 year of age, mild respiratory symptoms tend to resolve because of an increase in the rigidity of the trachea. In infants with severe tracheomalacia, symptoms may start immediately following birth. The infant may suffer from cyanosis, wheezing and expiratory stridor. Frequent respiratory infections and marked sputum retention are common, and attacks of cyanotic spells (‘dying spells’) may deteriorate to respiratory arrest. The apnoeic spells are usually the most prominent clinical features of the disease because of their life-threatening nature. Although some have suggested that these spells are due to a vagal reﬂex, transcutaneous Po2 measurements have clearly shown signiﬁcant arterial desaturation during feeding, in many cases suggesting that

progressive anoxia develops while eating, presumably because of compression of the soft trachea by the dilated esophagus.10 The affected infant continues to swallow despite the progressive hypoxia and bradycardia, cardiac arrest and respiratory arrest ensue. In some of the most severe cases, endotracheal intubation is necessary to maintain the airway and some of these infants will not be able to be extubated. The casual relationship between tracheomalacia and apnoeic spells can be elusive, especially in children following repair of esophageal atresia because neurologic, cardiac and esophageal problems can cause similar symptoms. Evaluation of all suspected cases should consider these other possible causes.

DIAGNOSIS In evaluating infants for the possibility of tracheomalacia, examination should start with lateral ﬂuoroscopic views of the trachea. This study is helpful to assess the caliber of the air-ﬁlled trachea at the different phases of respiration. A mild degree of airway narrowing during expiration is common in all children, but may be somewhat more notable in an infant who has had repair of esophageal atresia. However, severe narrowing or collapse is usually very signiﬁcant. Barium swallow will rule out recurrent tracheo-esophageal ﬁstula, anastomotic stricture or gastro-esophageal reﬂux, all of which could be present and responsible for symptoms. At the same time, the effect of swallow on the tracheal diameter can be estimated. Gastro-esophageal reﬂux is common in children following surgery after esophageal atresia.11 When found in association with tracheal collapse, it may be difﬁcult to determine which mechanism is responsible for the clinical symptoms. In fact, the reﬂux of gastric contents into the esophagus may in itself cause tracheal collapse if the upper esophagus enlarges during regurgitation. When gastro-esophageal reﬂux is present in association with tracheomalacia, the severity of tracheomalacia is best deﬁned by bronchoscopy. We rely on endoscopic ﬁndings to determine whether aortopexy or fundoplication should be performed in these cases. Bronchoscopy is the most accurate means to evaluate a patient with suspected tracheomalacia. During bronchoscopy, the infant must be breathing spontaneously so that the effect of respiratory phases and coughing can be properly assessed. Marked collapse of the trachea is seen only on forced expiration or during coughing. Endoscopy is best done using a small, rigid ventilating bronchoscope with a ﬁberoptic telescope. Currently available ﬂexible ﬁberoptic bronchoscopes may distort the dynamics of ventilation since much of the lumen of the small trachea is taken up by these solid instruments.

Treatment 261

Computed tomography (CT) and magnetic resonance imaging (MRI) techniques are new modalities which have an established role in the evaluation of ﬁxed airway obstruction. Yet, for dynamic lesions such as tracheomalacia, standard studies have not proved to be useful. Cine CT-ultrafast is a new method of imaging which was recently introduced by the Imatron L-100 scanner which can image up to eighth level in 0.224 seconds and repeat these scans at short time intervals.12,13 The potential for acquiring serial 0.05 s images of the trachea is unique to the ultrafast CT and facilitates the identiﬁcation of functional abnormalities of the trachea in infants and children.14 The experience with MRI for tracheal functional obstruction is more limited. Magnetic resonance images in sagittal and axial sections can clearly demonstrate tracheal compression due to vascular ring, but again do not appear to evaluate second-to-second changes in airway caliber.15

vascular compression of the trachea.20 The concept that this procedure could be used to alleviate the symptoms of tracheomalacia was, however, new. The aim of aortopexy is to change the cross-sectional proﬁle of the trachea from an elipse to a circle so that its walls will not appose during ventilation and coughing, and at the same time move the trachea away from the esophagus so that when full it cannot compress the airway. The suspension of the aorta vascular structure from the under-surface of the sternum is done without disrupting the fascia between it and the adjacent trachea which acts as a suspension ligament to change the conﬁguration of the trachea. The operative procedure of aortopexy now in use was adapted by Schwartz and Filler21 and from the technique originally described by Gross.

TREATMENT

After the initial bronchoscopy to conﬁrm the diagnosis, anesthesia is maintained through the ventilating bronchoscope. This allows continuous intraoperative monitoring of the corrective procedure. Thoracotomy is carried out through the left anterior third interspace. The left lobe of the thymus is resected and the anterior aspect of the aortic arch and great vessels is exposed. Interrupted non-absorbable sutures are placed through the adventitia and wall of the ascending aorta and the origin of the innominate vessel. The sutures are then passed through the sternum to a subcutaneous plane along the anterior surface of the sternum and tied in sequence (Fig. 26.2a). Traction is applied evenly to all sutures to bring the aorta to the sternum, while the degree of correction is assessed bronchoscopically (Fig. 26.2b). After the thoracotomy is closed and the child recovers from anesthesia, bronchoscopy should conﬁrm that aortopexy prevents tracheal collapse during spontaneous breathing and coughing (Fig. 26.2c). A chest drain is inserted in the left pleural cavity. An alternative method of aortopexy was described by Keily and colleagues.22 They sew a small patch of woven Dacron® to the proximal aortic arch with ﬁne suture material. The patch is then attached to the sternum with heavier sutures. This method would be most suitable for the smallest babies in whom the aorta was extremely thin.

Treatment of tracheomalacia depends in large part on the severity of the disease. In children with a minor degree of collapse and mild or moderate symptoms, surgery is not necessary. Usually by 1 year of age, mild respiratory symptoms will resolve because of an increase in the size and rigidity of the trachea. Medical management is directed to the treatment of respiratory infection. Respiratory physiotherapy, bronchodilators and in-hospital observation may be useful. A surgical approach is required for patients with severe tracheomalacia. In 21 infants and children treated by Filler for tracheomalacia and 4 for tracheobronchomalacia,10 life-threatening ‘dying spells’ was the most common surgical indication. Others were recurrent pneumonia, intermittent respiratory obstruction associated with cyanosis, and inability to extubate the airway (Table 26.1). Aortopexy has proved to be a safe, expedient method of treating tracheomalacia in most patients with severe tracheomalacia.10,16–18 In 1976 two articles in the surgical literature by Filler and colleagues19 and Cohen and colleagues2 alerted pediatric surgeons to the problems and treatment of tracheomalacia. The operation had been previously used by Gross and Neuhauser for

Surgical procedure of aortopexy

Table 26.1 Indications for aortopexy in 25 patients with tracheomalacia Indications for surgery

‘Drying spells’ Recurrent pneumonia Intermittent respiratory obstruction Inability to extubate airway

No. of patients Tracheomalacia

Tracheobronchomalacia

12 4 3 2

– – – 4

262 Tracheomalacia

iv v

(b) pa s p aa

(a)

(c)

Figure 26.2 Surgical procedure of aortopexy. (a) A thoracotomy is carried out through the third left anterior interspace. The left lobe of the thymus is removed and the pericardium is opened transversely just below its reﬂection on the arch of the aorta. Following the exposure of the aorta, sutures are placed through the adventitia and wall of the ascending aorta (aa) and the origin of the innominate vessel (iv). (b) The sutures are then passed through the sternum. (c) Traction is applied evenly to all sutures to bring the aorta to the sternum. The degree of correction is assessed bronchoscopically. In (b) and (c), photography of the tracheal lumen: (b) preoperative tracheal lumen appearance; (c) post-aortopexy tracheal lumen during expiration (p, pericardium; pa, pulmonary artery; s, sternum; v, vagus)

Aortic suspension has proved to be effective, safe and a relatively simple method of treatment of most patients with severe tracheomalacia. In patients with tracheobronchomalacia, aortopexy may also be effective by relieving the element of tracheal collapse and decreasing airway resistance during expiration. Lessened intrathoracic pressure during expiration in turn may tend to decrease the bronchial collapse.10 However, our experience has been limited in this group of infants. If bronchoscopy proves that aortopexy fails to improve tracheal collapse, an external splint may be applied on the trachea during the same anesthetic.

splint is determined by the site and extent of airway collapse. The prosthetic splint we use is fabricated from Marlex® mesh that is shaped into the desired semi-rigid form by cementing Silastic ribs or Silastic rings to its surface (Fig. 26.3). The prosthesis is cut and its shape modiﬁed to the same degree at the time of surgery to

Surgical technique of external tracheal stenting External stenting of the airway has been developed to treat tracheal and bronchomalacia which has not responded to aortopexy or in cases in which a long segment of trachea has collapsed and correction by aortopexy is unlikely.23 The surgical approach depends on the size and extent of airway collapse. A left or right main stem bronchus can be approached through a lateral thoracotomy incision. The intrathoracic trachea is exposed through a lower transverse neck incision and upper sternotomy or right posterolateral thoracotomy. The selection of the size and shape of the prosthetic

Figure 26.3 An airway splint made of Marlex® mesh. The splint is shaped into the desired semi-rigid form by cementing Silastic rings to its surface

Postoperative complications 263

conform to the airway to be splinted. The prosthesis is cut so that it overlaps and can be anchored to the normal airway at either end of its defective segment. The prosthesis is placed to encircle 75% of the circumference of the airway. It is sutured to its wall with interrupted non-absorbable sutures (Fig. 26.4). As with aortopexy, anesthesia for these operations is planned to permit intraoperative endoscopic examination of the affected portion of the airway and intraoperative assessment of the adequacy of repair. The use of prophylactic antibiotic therapy is recommended to minimize the possibility of infection associated with the implantation of a foreign body. The technique of implantation of an airway splint is relatively simple and we have had no postoperative complications from the procedure. Long-term follow-up study has revealed that airway growth was not affected and respiratory difﬁculties were effectively treated,24 although in 1 child the prosthesis was removed 1 year later because it had shifted. Other surgical techniques for external tracheal stenting have been described by Johnston and colleagues using a free rib autologous graft in 2 children,25 and by Vinograd and colleagues in an experimental model of tracheomalacia by application of autologous periosteal tibial graft, which becomes incorporated into weakened tracheal wall.26 Both operations have limited clinical experience, and further study is required to establish the effectiveness of these surgical techniques. In infants with diffuse tracheobronchomalacia associated with bronchopulmonary dysplasia, continuous positive airway pressure has been advocated as a successful mode of therapy.27 However, this method would apply to a limited group of patients with tracheomalacia, since signiﬁcant spontaneous improvement in tracheomalacia is unlikely to occur before 1 year of age.

RESULTS OF SURGICAL TREATMENT It is generally agreed that the chief objective in the surgical treatment of tracheomalacia is to relieve serious symptoms and to allow discontinuation of airway intubation in those who require it. As experience with the surgical treatment of tracheomalacia has accumulated, aortopexy has proved to be an effective and reliable method of treatment. In 15 infants of 19 with tracheomalacia treated by Filler,10 aortopexy alone eliminated airway collapse, relieving all symptoms of airway obstruction. In this group, airway decannulation was acquired in 5 patients who required either intermittent or continuous airway intubation. Among the four failures of aortopexy was an infant with unrecognized vascular ring. In the other three, intraoperative bronchoscopy at the completion of aortopexy showed that the tracheal collapse persisted. However, the application of prosthetic splints, as part of the same operation, was successful in eliminating airway collapse. A more recent study by Filler and colleagues reviews the experience of the surgical treatment of 32 children with severe tracheomalacia associated with esophageal atresia.28 Aortopexy was performed in 31 of 32 children, and a splint without aortopexy was used in 1 older girl. Splinting was also necessary in 2 of the 31 at the initial operation, when aortopexy failed to prevent tracheal collapse. There were 4 initial failures. Currently, 29 children are well (median follow-up, 6.6 years), 2 have a tracheostomy in place, and 1 died at home of unknown cause. In a smaller group of 7 patients treated by Rode and colleagues, substantial relief of symptoms was achieved following aortopexy over a period of 14–30 months follow-up.18 The infants were thriving, feeding normally, and only 1 child had residual problems with pneumonia. Postoperative ultrasound evaluation showed ﬁxation of the aortic arch to the under-surface of the sternum, with no evidence of widening or dislodgement.

POSTOPERATIVE COMPLICATIONS

Figure 26.4 Trachea with prosthetic airway splint. The splint is sutured around 75% of the circumference of the tracheomalacic airway

Postoperative complications are usually few and insigniﬁcant.10 Kiely and colleagues reported 8 infants with postoperative minor problems, in a group of 17 infants who had excellent results with immediate and permanent absence of symptoms.22 Thymic hematoma with chest infection appeared in 2 and hemothorax in 1 infant. In both, the left lobe of the thymus had been reﬂected and not excised. Two others developed minor postoperative chest infections and 1 infant showed signs of cardiac failure requiring short-term treatment. Chylopericardium has been reported as an unusual complication after aortopexy for tracheomalacia.29

264 Tracheomalacia Table 26.2 Surgical options in the treatment of functional airway obstruction

A. Tracheomalacia → B. Bronchomalacia →

Primary choice

Other options

Secondary choice

Aortopexy → Internal stent (Palmaz) →

Custom made Tracheostomy → Internal stenting (Palmaz) Segmental resection → External stenting

The indications and preferred operation procedure will vary with the functional status of the patient, the anamotic location and extent of the airway malacia, and the ability of the surgical team. Primary choice is the author’s preferred operative approach to a speciﬁc airway lesion. Secondary choice is recommended if the ﬁrst operation is unsuccessful.

Results of aortopexy in infants with tracheobronchomalacia are less promising. In a limited group of 4 infants reported by Blair and colleagues, 2 patients failed attempts at extubation and have since died.10 Another infant who failed postoperative extubation was treated by aortopexy and placement of a prosthetic splint on the left bronchus. Only 1 infant was extubated and is doing well 9 months following the aortopexy. In view of the experience with the surgical treatment of tracheomalacia, aortopexy has proved itself to be a safe, expedient way to relieve the problem of tracheomalacia in most infants. It may not be sufﬁcient to eliminate airway collapse when the entire length of intrathoracic trachea is involved or in patients with tracheobronchomalacia.

INTERNAL AIRWAY STENTING Stents inserted into the airway lumen have been found to be useful in the management of tracheo or bronchomalacia.30–31,32 The balloon expandable Palmaz stent has been designed and used for vascular stents. Its use in the airway is relatively new. The Palmaz stent is not self expanding but requires a balloon to expand it. Choice of length of stent and diameter of the balloon is critical. A balloon that is too small will not expand the stent to reach the wall of the trachea and will lead to stent displacement. A balloon diameter that is too large may expand the stent and apply excessive pressure on the wall of the airway and lead to ischemia and stricture, or, other complications like aortobronchial ﬁstula.33 The technique of stent insertion is straightforward. The stent is introduced through a rigid bronchoscope under ﬁberoptic control, after deﬁning the position for the stent, stent inﬂation by the balloon is controlled ﬂuroscopically. The position and expanded size of the stent should be conﬁrmed endoscopically. The disadvantage of the Palmaz stent is that once expanded the position of the stent cannot be adjusted and it is very difﬁcult to be removed. Other major problems associated with these devices is intraluminal overgranulation that can produce a severe airway obstruction. In a search to deﬁne the optional intraluminal stent, Loeff and associates34 proposed the following requirements –

1 2 3 4 5

simplicity of insertion, ﬁxation and removal biocompatibility no obstruction of airway tributaries improved clearance of secretion and accommodation to varying tracheal dimensions.

Until better stents can be developed, their use should be limited to patients with bronchial obstruction that cannot be treated safely with current surgical procedures (Table 26.2). Experimental and clinical use of a new intratracheal stent made from nitinol, an alloy with ‘shape memory effect’35,36 showed this new stent is a promising therapeutic adjustment in the management of children with dynamic airway collapse. It fulﬁlled the basic requirements of an optimal luminal airway stent. This stent would require further clinical trial before it could be considered as an optimal alternative to the Palmaz stent. Despite the acceptable short–medium term results of using the internal airway stent, it remains unclear how long such stents may safely remain in situ. The long term implication of the metallic stents in young children is unknown. Many of the patients would require dilatation of the stents with growth. The maximal internal diameter that can be achieved varies with the size of each stent. Overdilatation may affect the structural integrity required to support the lumen. If necessary another larger stent may be placed within and expanded to provide necessary support. Internal airway stenting plays a signiﬁcant adjunctive role in the treatment of selected cases or severe cases with tracheomalacia and mainly bronchomalacia. At present, their use should be restricted to patients in whom conventional treatment has failed or those who have a life threatening airway obstruction, where there is no other reasonable therapeutic option.

REFERENCES 1. Feist JH, Johnson TH, Wilson RJ. Acquired tracheomalacia; etiology and differential diagnosis. Chest 1975; 68:340–5. 2. Benjamin BB, Cohen D, Glasson M. Tracheomalacia in association with congenital tracheosophageal ﬁstula. Surgery 1976; 79:504–8.

References 265 3. Rock MJ, Grun CG, Pauli RM et al. Tracheomalacia and bronchomalacia associated with Larsen syndrome. Pediatr Pulmon 1988; 5:55–9. 4. Greenholz SK, Hall RJ, Lilly JR et al. Surgical implications of bronchopulmonary dysplasia. J Pediatr Surg 1987; 22:1132–6. 5. Wailoo MP, Emery JL. The trachea in children with tracheo-oesophageal ﬁstula. Histopathol 1979; 3:329–38. 6. Davies MRQ, Cywes S. The ﬂaccid trachea and tracheosophageal congenital anomalies. J Pediatr Surg 1978; 13:363–7. 7. Miller RW, Wood P, Kellman RK et al. Tracheobronchial abnormalities in infants with bronchopulmonary dysplasia. J Pediatr 1987; 111:779–82. 8. Denneny JC. Bronchomalacia in the neonate. Ann Otol Rhinol Laryngol 1985; 94:466–9. 9. Filston HC, Ferguson TB, Oldham HN. Airway obstruction by vascular anomalies. Ann Surg 1987; 205:541–9. 10. Blair GR, Filler RM, Cohen R. Treatment of tracheomalacia: 8 years experiences. J Pediatr Surg 1986; 21:781–5. 11. Christie DL. Pulmonary complications of esophageal disease. Pediatr Clin N Am 1984; 31:835–49. 12. Brash RC. Ultrafast computed tomography for infants and children. Radiol Clin N Am 1988; 26:277–86. 13. Kimura K, Sopu RT, Kao SCS et al. Aortosternopexy for tracheomalacia following repair of esophageal atresia: evaluation by cine-CT and technical reﬁnements. J Pediatr Surg 1990; 25:769–72. 14. Freey EE, Smith WL, Sato Y. Chronic airway obstruction in children: evaluation with cine-CT. Am J Roentgenol 1987; 148:347–52. 15. Fletcher B, Dearbon DF, Mulopulos CP. MR imaging in infants with airway obstruction; preliminary observations. Radiology 1986; 160:245–9. 16. Benjamin B. Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol 1984; 193:438–442. 17. Greenholz SK, Karrer FM, Lilly JR. Contemporary surgery of tracheomalacia. J Pediatr Surg 1986; 21:511–14. 18. Rode H, Miller AJW, Vega M et al. Oesophageal atresia – severe tracheomalacia and its correction by aortopexy. Kinderchir 1985; 40:282–6. 19. Filler RM, Rossello PJ, Lebowitz RL. Life-threatening anoxic spells caused by tracheal compression after repair of esophageal atresia; correction by surgery. J Pediatr Surg 1976; 11:739–48. 20. Gross RE, Neuhauser EBD. Compression of the trachea by an anomalous innominate artery; an operation for its relief. Am J Dis Child 1948; 75:570–74. 21. Schwartz MS, Filler RM. Tracheal compression as a cause

22. 23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

of apnea following repair of tracheooesophageal ﬁstula; treatment of aortopexy. J Pediatr Surg 1983; 15:842–8. Kiely EM, Spitz L, Brereton R. Management of tracheomalacia by aortopexy. Pediatr Surg Int 1987; 2:13–15. Filler RM, Buck JR, Bahric A et al. Treatment of segmental tracheomalacia and bronchomalacia by implantation of an airway splint. J Pediatr Surg 1983; 17:597–603. Vinograd I, Filler RM, Bahoric A. A long term functional result of prosthetic airway splint in tracheo and bronchomalacia. J Pediatr Surg 1987; 22:42–6. Johnston MR, Loeber N, Edmunds LH. External stent for repair of secondary tracheomalacia. Ann Thorac Surg 1980; 30:291–8. Vinograd I, Filler RM, England SJ et al. Tracheomalacia; an experimental animal model for a new surgical approach. J Surg Res 1987; 42:597–604. Wiseman NE, Duncan PG, Cameron CB. Management of tracheobronchomalacia with continuous positive airway pressure. J Pediatr Surg 1983; 20:489–93. Filler RM, Messineo A, Vinograd I. Severe tracheomalacia associated with esophageal atresia: results of surgical treatment. J Pediatr Surg 1992; 27:1136–41. Skarsgard ED, Filler RM, Superina RA. Postpericardiotomy syndrome and chylopericardium: two unusual complications after aortopexy for tracheomalacia. J Pediatr Surg 1994; 29:1534–6. Filler RM, Forte V, Chait P. Tracheobronchial stenting for the treatment of airway obstruction. J Pediatr Surg 1998; 33:304–11. Nicolai I, Huber RM, Mantil K et al. Metal airway stent implantation in children. Follow-up of seven children. Pediatr Pulmonal 2001; 31:289–96. Fueman RH, Backier CL, Hlinger LD. The use of balloonexpandable metallic stents in the treatment of pediatric tracheomalacia and bronchomalacia. Archiv Otolaryngol Head Neck Surg 1999; 125:203–7. Cook CH, Bhattachargya N, King DR. Aortobronchial ﬁstula after expandable metal stent insertion for pediatric bronchomalacia. J Pediatr Surg 1998; 33:1306–8. Loeff DS, Filler RM, Gorenstein A et al. A new tracheobronchial reconstruction, experimental and clinical studies. J Pediatr Surg 1988; 23:1113–17. Vinograd I, Klin B, Nevo R et al. A new intratracheal stent made from nitinol, an alloy with ‘shape memory effect’. J Thorac Cardiovasc Surg 1993; 107:1255–61. Tsugawa C, Nisghijima E, Asamo H et al. A shape memory airway stent for tracheobronchomalacia in children: An experimental and clinical study. J Pediatr Surg 1997; 32:50–53.

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27 Vascular rings EHUD DEVIRI AND MORRIS J. LEVY

INTRODUCTION Vascular rings (even when incomplete) are anomalies of the aorta and its branches, compressing the trachea, esophagus or both. Compression of the trachea and esophagus caused by anomalies of the pulmonary arteries will also be discussed in this chapter. Vascular rings were described for the ﬁrst time by Hommel in 1737.1 Bayford in 1789 described an aberrant right subclavian artery causing dysphagia.2 In 1939, Wolman reported the syndrome of esophageal and tracheal compression caused by a double aortic arch3 and a few years later, in 1945, Gross had successfully repaired this type of lesion, followed by the correction of many other forms of vascular rings.4,5 In 1946, Neuhauser introduced the radiographic basis for the diagnosis of vascular rings.6 The term ‘hypothetic double aortic arch’, which is the basis for the development of aortic arch anomalies, was introduced in 1948 by Edwards.7 This model consists of right and left aortic arches, two ductus arteriosus (in this chapter the term ‘ductus arteriosus’ relates either to patent ductus arteriosus or ligamentum arteriosum) and two upper descending aortas. The normal aortic arch is the result of regression of the right upper descending aorta and the right ductus arteriosus (Fig. 27.1). Most vascular rings are the result of either lack of regression of these segments or abnormal regression of other segments, or both. The seminal report of Stewart et al. classiﬁes these anomalies based on the development of the aortic arch.8 This is the basis for classiﬁcation of the vascular rings in the present chapter (Box 27.1).

(a)

Figure 27.1 (a) Embryological origin of aortic arch and its major branches. The normal aortic arch is the result of the regression of right upper descending aorta and right ductus arteriosis (shaded areas). (b) Normal aortic arch and its major branches

Box 27.1 Classiﬁcation of various types of vascular rings and related anomalies I II

III

MORPHOLOGY Double aortic arch Double aortic arch results from the failure of regression of any dorsal aortic root.8 There are two aortic arches,

(b)

IV V

Double aortic arch Left aortic arch Left upper descending aorta Anomalous innominate artery Anomalous left carotid artery Aberrant origin of the right subclavian artery Right-sided upper descending aorta Right-sided aortic arch Mirror-image branches and left ductus arteriosus connected to the aorta Aberrant origin of the left subclavian artery with a left ductus arteriosus connected to the aorta Aberrant left innominate artery Pulmonary sling Cervical aorta

After Stewart et al.8

268 Vascular rings

each giving rise to a carotid and subclavian artery (Fig. 27.2). The anterior arch is located in front of the trachea, and the posterior arch behind the esophagus. When the descending aorta is on the left side, the left arch is anterior and when the aorta descends on the right side, it is posterior. In 45–77% of cases, the aorta descends on the left side.9,10 In the majority of cases, the right arch is the larger. However, occasionally the left arch is the larger or both arches are of a similar size.7–10 Rarely, there is an atretic arch.7–10 In all reported cases, the ductus arteriosus has been found on the left side.10 Signs of compression of the trachea and the bronchus occur in the majority of cases. However, occasionally the patient may be asymptomatic.9 The degree of tracheal and esophageal compression depends on the size of the arches and that of the ductus arteriosus. When the ductus arteriosus is short, it pulls on the pulmonary artery, leads up to compression of the esophagus from the left and therefore contributes to the vascular ring. About 20% of cases may have associated cardiac anomalies such as tetralogy of Fallot, ventricular septal defect, coarctation of the aorta and transposition of the great arteries.8,10

(a)

(b)

Figure 27.2 Double aortic arch. (a) Most often the smaller arch is to the left or anterior to the main arch. (b) The anterior arch is divided between the left carotid and subclavian arteries

Left aortic arch with left upper descending aorta and anomalous innominate artery In this anomaly the innominate artery arises from the aorta more posteriorly than usual or the artery is too short. The trachea may be compressed from its anterior aspect and signs of compression may develop. The anatomy of the aorta and the other branches is normal. According to Mustard et al., 11 compression of the trachea by the innominate artery may be the commonest of all vascular anomalies.

trachea over the anterior surface. When there is sufﬁcient tension over the trachea, symptoms may develop.12

Left aortic arch with aberrant right subclavian artery Aberrant right subclavian artery is the most common anomaly of the aortic arch,7 appearing in 0.5–0.7% of autopsies.8–10 The right subclavian artery arises from the descending aorta and crosses to the right side, mostly behind the esophagus. This anomaly results in the regression of a segment of the ‘hypothetic double aortic arch’ between the right common carotid artery and the right subclavian artery (Fig. 27.3). In some exceptional cases the right subclavian artery may cross from the left to the right between the esophagus and the trachea, or even in front of the trachea.8 When the ductus arteriosus is on the left side, the vascular ring is incomplete and compression of the trachea and the esophagus is not the rule.7 In the few cases presenting with symptoms of stridor and dysphagia, reasons other than vascular compression should be ruled out.8 It was suggested that symptoms of obstruction may exist when the origins of the left and right carotid arteries are close to one another, so the esophagus may be compressed posteriorly by the aberrant right subclavian artery and anteriorly by the trachea and carotid arteries.13 In the rare cases where the ductus arteriosus is on the right side, the vascular ring is complete and signs of compression are more likely.8 A relatively high incidence (37%) of right ductus arteriosus has been found in children with Down syndrome suffering from congenital cardiac anomalies.14 Other associated anomalies are coarctation of the aorta8 and tetralogy of Fallot.10

Left aortic arch and right-sided upper descending aorta This rare anomaly results from regression of the segment between the right ductus arteriosus and the right subclavian artery, regression of the left ductus arteriosus and persistence of the right ductus arteriosus. The ascending aorta passes upwards, arches on the left of the trachea

Left aortic arch with left upper descending aorta and anomalous left carotid artery This anomaly is similar to the previous one. The aorta and its branches are in normal order. The origin of the left carotid artery is deviated to the right and crosses the

(a)

(b)

Figure 27.3 Aberrant right subclavian artery. (a) Anterior view. (b) After ligation and division

Morphology 269

then crosses to the right behind the esophagus, then descends on the right while a ductus arteriosus connects between the right pulmonary artery and the descending aorta.8,9 In cases where the site of the interruption of the hypothetic double aortic arch is between the right carotid and subclavian arteries, an aberrant right subclavian artery may result.7,10 In the majority of the cases there are associated intracardiac anomalies including tetralogy of Fallot, coarctation of the aorta, aortic valve stenosis and incompetence. In two reported cases the aorta crossed from the left to the right in front of the trachea rather than behind the esophagus.10 In a few cases, true vascular ring has been reported.7,8,10

Right aortic arch, mirror-image branches, left ductus arteriosus connected to the aorta Right aortic arch with mirror-image branching will result from regression of the left upper descending aorta. In cases with this anomaly, 95–98% are associated with congenital cardiac anomalies;15,16 90% have tetralogy of Fallot an the rest truncus arteriosus, and transposition of the great arteries.14 In most cases the left ductus arteriosus arises from the left subclavian artery or there is a right ductus arteriosus so there is no vascular ring. In rare cases where the ductus arteriosus connects the left pulmonary artery to the upper descending aorta (as the result of regression of the segment between the left subclavian artery and left ductus arteriosus), there is a complete vascular ring with signs of stridor and dysphagia.8,17–19

Right aortic arch, aberrant left subclavian artery with a left ductus arteriosus The basis of this anomaly is regression of the segment between the left common carotid artery and the left subclavian artery in the hypothetic double aortic arch. The left subclavian artery arises as the last branch and passes to the left behind the esophagus (Fig. 27.4). In the great majority of cases, the ductus arteriosus is left sided and connects the left pulmonary artery to the aberrant left subclavian artery or even to the descending aorta.

(a)

(b)

Figure 27.4 Right aortic arch with retro-esophageal left subclavian and left ligamentum arteriosum (posterior view). (a) Anterior view. (b) Posterior view

The upper descending aorta may cross to the left and descend on the left side, or may descend on the right side.8 There is a vascular ring in this anomaly. However, symptoms may be present in a minority of cases, and only rarely may patients with this anomaly require surgery.16 In contrast to patients with right aortic arch with mirror-image branches, additional intracardiac anomalies are rare in this instance and appear in 10–12% of cases.8,16,20 The associated anomalies may include tetralogy of Fallot,16 coarctation of the aorta and patent ductus arteriosus.18,20

Right aortic arch, aberrant left subclavian artery, atypical origin of the right subclavian artery, without left ductus arteriosus This is an extremely rare anomaly of which only one case has been reported.21 In this case even though the vascular ring was not complete the esophagus was compressed by the subclavian arteries, which were close to one another.

Aberrant left innominate artery This is a rare anomaly of which only a few cases have been reported;22 it results from regression of the left ascending aorta. The ﬁrst branch arising from the aorta is the right carotid artery, followed by the right subclavian artery; the last branch is the left innominate artery arising from the descending aorta. A vascular ring is formed by the right arch, retro-esophageal left innominate artery and the left ductus arteriosus connecting the innominate artery to the left pulmonary artery.

Cervical aortic arch Cervical aortic arch is a rare anomaly. There is an extension of the aortic arch above the clavicles. The embryonic basis may be an aortic arch derived from the second or third, rather than the fourth, brachial arch.23 There may be either left or right aortic arch in the case of cervical aorta. Frequently there are variations of the branching of the great arteries as absence of the innominate artery or aberrant subclavian artery.23 Symptoms of compression on the trachea or esophagus may appear in about half the cases.20 Associated cardiac anomalies, such as septal defect, double outlet right ventricle, tricuspid atresic patent ductus arteriosus, tetralogy of Fallot and multiple coarctations of the aorta have been reported.24

Pulmonary sling Pulmonary sling is an anomaly of the pulmonary artery where the anterior left sixth arch fails to develop. The left lung bud is supplied by a collateral artery branching from

270 Vascular rings

the pulmonary segment of the right sixth arch. Following separation of the lung bud, the artery elongates and takes the place of the left pulmonary artery. The result is a main pulmonary artery and ductus arteriosus in normal position and a left pulmonary artery crossing to the right in front of the trachea, encircling the trachea from the right and extending to the left lung in between the trachea and esophagus8,10 (Fig. 27.5). Signs of compression are common and limited to the respiratory stridor.8,10 Associated anomalies appear in about half the cases of pulmonary artery sling25,26and include left superior vena cava, patent ductus arteriosus, atrial septal defect, aortic arch anomalies, ventricular septal defect, tricuspid atresia, single ventricle and transposition of the great arteries.

cases there are episodes of apnea with cyanosis and unconsciousness. Recurrent respiratory infections aggravate the condition and are more frequent in vascular rings. In mild tracheal compression, symptoms may be present only at the time of respiratory infections. As a result of esophageal compression, the baby feeds poorly and its growth may be retarded. There is difﬁculty in swallowing liquids and solids. Regurgitation and choking, with aggravation of respiratory symptoms, are common in severe cases, whereas in mild cases of obstruction, dysphagia may be the only symptom.29 In case of cervical aortic arch, a pulsatile cervical mass with a thrill or murmur may be noticed.10,23

IMAGING

(a)

(b)

Figure 27.5 (a) Pulmonary artery sling (anterior view). (b) Completed operative repair

SIGNS AND SYMPTOMS About 75% of patients with vascular rings may be symptomatic.27 The four most important vascular rings of infancy and childhood are the double aortic arch, right aortic arch with an aberrant left subclavian artery, pulmonary artery sling, and anomalous origin of innominate artery. Symptoms and signs may appear in 75% of the patients with double aortic arch,10 90% of those with pulmonary artery sling,25,26 and 15% of those with right aortic arch with an aberrant left subclavian artery.16 In pulmonary artery sling and anomalous origin of the innominate artery, the symptoms and signs are related to tracheal obstruction. Usually, symptoms appear in the ﬁrst 6 months of life.23 Approximately half of the patients who are operated on for vascular rings were symptomatic at birth and 96% were symptomatic before 6 months of age.28 The existence and severity of symptoms are related to the tightness and completeness of the vascular ring.10 Respiratory signs include inspiratory stridor with or without an association with an expiratory wheeze and tachypnea. Various positions, such as lying on the back, may aggravate the stridor, while it may be relieved by extension of the neck. Other signs are noisy breathing, a hoarse cry and persistence of a barking cough. In severe

Radiography is a valuable tool in the diagnosis of vascular rings. X-ray presentations of vascular rings have been documented in the past by Neuhauser,6 Stewart et al.8,16 Klinkhamer13 and others. Plain chest X-ray and barium esophagogram may diagnose vascular rings precisely.8 In young children and infants, plain chest Xrays may be misleading when thymic tissue obscures the upper mediastinum. Although plain chest X-ray and barium meal may diagnose vascular rings, further investigations such as bronchoscopy, angiography, computed tomography (CT) scans, magnetic resonance imaging (MRI) and color Doppler echocardiography are necessary to identify the exact anatomy. It is frequently impossible to distinguish between double aortic arch and right aortic arch with aberrant left subclavian artery9 or a cervical aorta and aneurysm of the right carotid artery30 based on chest X-ray and barium esophagogram.

Chest X-ray A chest radiograph is mandatory in any symptomatic child. A normal chest radiograph is evidence against the presence of a vascular ring in symptomatic children.31 The plain X-ray shows prominence of the mediastinum to the right side in double aortic arch, right aortic arch with aberrant left subclavian artery, right aortic arch with mirror-image branching, and left ductus arteriosus and right aortic arch with aberrant left innominate artery. The aortic knob is on the left side in cases of left aortic arch with aberrant innominate or carotid artery, left aortic arch with aberrant right subclavian artery (in this case the aberrant vessel may be seen above the aortic knob) and in left aortic arch with right upper descending aorta (where there is absence of the descending aorta below the aortic knob). In cases of cervical aorta, there is non-speciﬁc widening of the upper mediastinum and absence of the aortic knob in its normal position.

Preoperative considerations 271

Uneven aeration of the lungs while the right lung shows either obstructive emphysema or atelectasis, low left hilus in a frontal X-ray and anterior bowing of the right bronchus in the lateral X-ray are the three radiographic signs typical of pulmonary artery sling.32

Barium esophagogram Barium esophagogram is the most useful method of investigation and is diagnostic in most cases.29, 33 Frontal barium esophagogram shows impression both on the right and left sides in cases of double aortic arch, right aortic arch with mirror-image branching and left ductus arteriosus. Oblique ﬁlling defect from the right, going upwards to the left, is seen in aberrant left subclavian artery with a right aortic arch, while a ﬁlling defect is in the opposite direction in left aortic arch with a right aberrant subclavian artery. In pulmonary artery sling, the esophagus may be deviated to the left. Lateral esophagogram shows posterior compression in cases of double aortic arch, aberrant left or right subclavian artery, aberrant left innominate artery with right aortic arch, left aortic arch with right-sided upper descending aorta, right aortic arch with mirror-image branching and left ductus arteriosus and cervical aortic arch. In pulmonary aortic sling, the esophagus is compressed from the front. In anomalous origin of right innominate or left carotid artery there is no compression on the esophagus. In cases of cervical aortic arch, the posterior pressure on the esophagus is seen at higher levels than in the other anomalies.

Aortography Aortography is an important and accurate method used to assess the anatomy of vascular rings. It may be considered to be the gold standard in the determination of the exact anatomy of vascular rings.8,25,27,34 Although it is an accurate method, angiography involves a signiﬁcant complication rate, especially in neonates.35 Since there are alternative accurate noninvasive imaging methods such as MRI, CT etc., angiograms should only be carried out in cases of rare anomalies where the noninvasive methods fail to obtain the exact anatomy.36

Magnetic resonance imaging MRI is a very accurate noninvasive method that does not necessitate injection of contrast material or radiation.37,38 MRI can demonstrate accurately both the anatomy of the blood vessels and the trachea. In rare cases MRI has compared favourably with angiogram.39 There is increasing evidence that MRI is the method of choice to evaluate the thoracic aorta, principal vessels, pulmonary arteries, and trachea.40–44

Other techniques The development of new CT imaging techniques, can give good imaging of vascular abnormalities.45,46 Ultrafast CT with three-dimensional volume reconstruction provides great anatomic detail of the vascular anomaly and may obviate the need for angiography.47 However CT necessitates injection of contrast material, which may be difﬁcult in the neonate. Bronchoscopy and esophagoscopy should not be used as a rule in the diagnosis of vascular ring, since there may be risk of aggravating the condition of newborns with respiratory distress.25 However, it is very important in the diagnosis of anomalous origin of the innominate artery10,48 and essential in the diagnosis of pulmonary artery sling, since associated tracheobronchial anomalies are common.49 Ultrasonography by using Doppler color ﬂow in suprasternal frontal sweep can display accurately the encirclement of air-ﬁlled trachea by the various types of vascular ring. However, atretic segments without ﬂow cannot be displayed by this method.50 Ultrasonography can diagnose accurately cardiac malformations and is important as a complementary imaging method when additional cardiac defects are suspected.29 In addition vaginal ultrasound can diagnose fetal vascular ring as early as 14–16 weeks’ gestation.51

Diagnosis The initial step in the diagnosis of vascular ring is a chest X-ray and contrast esophagogram. These are simple methods of investigation which may reveal in most cases accurately the anatomy of vascular ring. Once vascular ring has been diagnosed, possibilities other than vascular ring for the patient’s symptoms should be excluded, and a decision made as to whether the patient is symptomatic enough to warrant surgery. When surgery is considered, the anatomy of the vascular ring can be conﬁrmed either by MRI, or alternatively by CT scan.52 Echocardiography should also be performed in order to exclude associated cardiac anomalies and to complete the diagnosis. Aortography should be preserved only for exceptional cases when the results of MRI or CT are not satisfactory, or if there are associated cardiac lesions necessitating cardiac catheterization. In cases of pulmonary artery sling, anomalous origin of innominate artery or suspected tracheobronchial anomalies, bronchoscopy or bronchogram may be performed.

PREOPERATIVE CONSIDERATIONS Indications for surgery It has been shown by Ekstrom and Sanblom that unoperated neonates with severe symptoms of compression

272 Vascular rings

generally die within the ﬁrst 7 months of life.9 On the other hand children with mild symptoms tend to outgrow their symptoms in early childhood. Godtfredsen et al. found that of 11 children with vascular rings and mild symptoms, nine seemed to outgrow their symptoms within 2 years of diagnosis and before 4 years of age.53 Surgical treatment is indicated in neonates and infants with symptoms of stridor, cyanosis, apneic attacks, recurrent intractable respiratory infections and severe dysphagia. Even though in 96% of operated patients symptoms appeared before 6 months of age,28 some older children require surgical intervention due to recurrent respiratory infections54 and some adults were operated on because of dysphagia.48,55 In patients with anomalous innominate artery, bronchoscopy should reveal more than 50% stenosis before surgery is indicated.48

Preoperative management Once the diagnosis of vascular rings and the indication for surgery has been established, operation should not be delayed since there is a risk of sudden death.3,28,56 Patients with severe distress should be operated on without delay following intubation or tracheostomy.28,56 Thorough examination and echocardiogram are mandatory to exclude other tracheo-esophageal or cardiac anomalies. Since tracheobronchial anomalies are common in patients with pulmonary artery sling, preoperative bronchoscopy is recommended as concomitant tracheoplasty might be indicated.48 Neurological investigation, sleep studies and gastro-esophageal reﬂux should be performed to exclude other causes of apneic spells. When other cardiovascular or tracheo-esophageal anomalies are present, it must be determined whether they should be corrected simultaneously with the repair of the vascular ring or separately.48,56

TECHNIQUES OF OPERATION Double aortic arch The approach of choice is through a left thoracotomy in the fourth intercostal space. The technique of thoracotomy is shown in Chapter 25. The lung is retracted forwards and the mediastinal pleura is opened above the descending aorta upwards to the left subclavian artery. The descending aorta, ligamentum arteriosum and aortic arch are dissected completely, including the part of the right arch, which is behind the esophagus. Care is taken to dissect the components of the obstructing vessels away from the trachea and esophagus to relieve the obstruction as much as possible. During the dissection, the recurrent laryngeal phrenic nerves should be identiﬁed and protected.

When the two arches are of the same size, the right posterior arch should be divided between the subclavian artery and descending aorta to maintain normal anatomy. When the arches are of different sizes but both are patent, the smaller arch is to be divided between the subclavian artery and the descending aorta. When there is an atretic segment it should also be divided. Before division of the aortic arch, carotid and radial pulses should be monitored by the anesthetist after a vascular clamp is applied.28,48 The stumps of the aortic arches are sutured with two rows of 4-0 or 5-0 polypropylene stitches. Following division of the aortic arch, the ligamentum arteriosum is divided and ligated, or in the case of patent ductus arteriosus it should be sutured in two rows of 5-0 polypropylene stitches (Fig. 27.2b). To increase the space around the esophagus and trachea, the distal stump of the arch may be transﬁxed to the posterior chest wall by stitches through the adventitia.57 The pleural cavity is drained and the chest wall should be closed in layers. In the case of associated complex cardiac anomalies necessitating complete repair, a combined approach via mid-sternotomy, total circulatory arrest and hypothermia has been described.58 Another option in cases of cyanotic heart diseases in the neonate, or in cases which are not suitable for complete repair, a systemic pulmonary shunt with 4–5 mm polytetraﬂuoroethylene graft is done through a left thoracotomy. As a rule, esophageal atresia should be treated prior to vascular surgery. However, tracheo-esophageal ﬁstula may be treated simultaneously.56

VIDEO-ASSISTED THORACOSCOPIC SURGERY Video-assisted thoracoscopic surgery is an alternative to open thoracotomy with the advantage of minimal trauma to the chest wall structures (muscles and ribs). This technique is suitable for patients with an atretic aortic arch.59 Under general anesthesia with a single-lumen endotracheal tube the patient is placed in the right lateral decubitus position. Four 3 mm long incisions are made in the posterolateral chest wall to introduce grasping forceps, lung retractor, a 4 mm videoscope and a cautery probe. Exposure is achieved by retracting the left upper lobe of the lung inferomedially. The ring elements are dissected off the esophagus and surrounding tissues. Both the aortic attretic arch and ligamentum arteriosum are divided between vascular clips. Fibrous bands around the esophagus are divided, a 12F intercostal drain is inserted and the wounds are closed with STERYSTRIPS™.59 If a patent blood vessel requires division a limited thoracotomy may improve exposure. Proximal and distal control is achieved with vascular clamps and the vascular structure is divided between vascular clamps.59

Techniques of operation 273

Left aortic arch and anomalous innominate artery Anomalous origin of the innominate artery is usually treated by suspension of the proximal part of the artery and the aorta to the sternum. The innominate artery can be approached via mid-sternotomy,25 right anterior thoracotomy11,48 or left anterior thoracotomy.60

MEDIAN STERNOTOMY The sternum is split at the midline. The left lobe of the thymus is excised or retracted to the left. The pericardium is opened at the midline and retracted with stay stitches. The ascending aorta and the proximal 1 cm of the innominate artery are dissected. The artery should not be dissected above the trachea, so that the connective tissue acts as a suspension to the weak tracheal rings when it is retracted. The innominate vein is retracted upwards. Two or three pledged stitches of 2-0 or 1-0 polypropylene are supported with pledgets and are passed through the adventitia of the base of the innominate artery and adjacent aorta, and through the manubrium. Bronchoscopy is done at this stage to assess the relief of the obstruction.48,57 The pericardium is left open, the mediastinal cavity drained and the sternal incision closed.

LEFT THORACOTOMY With the patient lying with the left side elevated, extrapleural or transpleural left anterior thoracotomy is carried out through the second intercostal space. The thymus is retracted or its left lobe is excised. The pericardium is opened anteriorly to the phrenic nerve. The innominate artery is suspended to the manubrium as previously reported. The pericardium is loosely closed, the chest is closed in layers and the mediastinal or pleural cavity is drained.

RIGHT THORACOTOMY The patient is lying on his back and the right side is slightly elevated. Extra- or transpleural anterior thoracotomy is done through the right second intercostal space. The thymus is retracted to the left and the innominate vein retracted upwards. The pericardium is opened, and the superior vena cava retracted to the right. The innominate artery is suspended to the manubrium. Bronchoscopy is done, then the chest is drained and closed.

REIMPLANTATION OF THE INNOMINATE ARTERY Binet and Langlois routinely used division and reimplantation of the innominate artery to a generous annulus in the ascending aorta.56 This technique is not accepted as routine by many authors and may be used in exceptional cases.

Anomalous origin of the carotid artery This anomaly is rare and the surgical technique is identical to that for anomalous innominate artery.

Left aortic arch and aberrant right subclavian artery The approach is through a left thoracotomy. The distal aortic arch and the proximal aberrant right subclavian artery are dissected in the same way as for double aortic arch. The aberrant subclavian artery is divided and the stumps sutured with 5-0 polypropylene. The distal stump should be retracted to the right (Fig. 27.3b). In neonates and young children, the division of the subclavian artery does not cause major complications.61 In adults, the division of the aberrant right subclavian artery through a left thoracotomy and implantation of the right subclavian artery to the right carotid artery through a cervical approach has been described.62 A simpler approach for implantation of the aberrant subclavian artery and relief of the vascular ring is through the right thoracotomy. In case of concomitant coarctation of the aorta, a simultaneous operation for both lesions can be carried out.63

Left aortic arch and right-sided descending aorta The approach is from the right side through a posterolateral thoracotomy in the fourth intercostal space. The ductus arteriosus (or ligamentum arteriosum) is divided and the trachea and esophagus released from adhesive bands.

Right aortic arch with left ductus arteriosus The approach is the left posterolateral thoracotomy in the fourth intercostal space. The ductus arteriosus and ligamentum arteriosum are divided and the trachea and esophagus dissected from adhesive bands.48 The approach is the same, both for patients with mirrorimage branching and those with an aberrant left subclavian artery.48 In a case of compression caused by an aberrant left subclavian artery with an additional division of the ligamentum arteriosum, the left subclavian artery was divided and reimplanted to the left carotid artery.64 Reimplantation of the left subclavian artery is superior to its division without reimplantation. Steal phenomenon, which necessitated late reoperation for reimplantation of the divided aberrant subclavian artery, 44 years after the original operation has been reported.65 In cases of ligamentum arteriosum without compression caused by an aberrant left subclavian artery, division

274 Vascular rings

of the ligamentum arteriosum can be done by videoassisted thoracoscopic surgical techniques.59

POSTOPERATIVE CONSIDERATIONS Mortality

Cervical aorta In cervical aortic arch, relief of compression can be achieved by division of the ligamentum arteriosum.10,20

Pulmonary sling Repair of pulmonary artery sling can be done through a left thoracotomy66 or median sternotomy with cardiopulmonary bypass.

LEFT THORACOTOMY This is the main method used.25,67 A left posterolateral thoracotomy is done through the fourth intercostal space. The superior part of the pulmonary hilum is dissected to identify the left pulmonary artery. The left pulmonary artery is dissected as far as possible and freed from the adjacent structures while the ligamentum arteriosum is divided. The patient is given a heparin dose of 1.5 mg/kg. The pulmonary artery is divided between clamps and the proximal stump closed with a continuous 5-0 polypropylene stitch. Two incisions are made in the pericardium, one anterior to the phrenic nerve and the other posterior to the phrenic nerve. The distal stump is brought into the pericardial cavity in front of the trachea through the posterior incision. The left pulmonary artery is anastomosed to the main pulmonary artery and to the side by using a side-biting clamp. The posterior part is carried out with a single layer of running 5-0 polypropylene stitches and the anterior one by using interrupted sutures. The pericardium is left open and the chest closed.

MEDIAN STERNOTOMY Through a median sternotomy,25 cardiopulmonary bypass is used with a single venous drain. The temperature is lowered to 25°C. The pleural space is opened and the left main pulmonary artery dissected free. The pulmonary artery is resected and reimplanted anteriorly to the trachea on the main pulmonary artery.

RESECTION AND REANASTOMOSIS OF THE RIGHT BRONCHUS Other methods include tracheoplasty associated with reimplantation of the aberrant pulmonary artery on the main pulmonary artery.56 Another method used consists of transection of the right bronchus and reanastomosis posteriorly to the trachea. This method is not routinely used but is useful in cases of associated tracheal stenosis.26

Operative and early postoperative mortality rates vary between 0% and 5%.28,48,55,63,67 In the past 30 years the mortality rate has been approaching 0%.55,56,66,67 Patients undergoing operation for pulmonary artery sling may have a higher mortality rate (up to 50%).26 However, more recent reports show lower mortality rates.48,56,66 The late mortality rate is about 4%.48,55,67 The majority of deaths are caused by respiratory complications due to tracheomalacia and other tracheobronchial abnormalities.26,48,49,67 Following video-assisted thoracoscopy, the mortality rate is 0%.59,68

Postoperative care and operative results The postoperative care of these children may require special attention, including prolonged intubation, repeated tracheal aspiration toilet and bronchoscopies. Some patients may even need a tracheostomy. Tracheomalacia due to prolonged compression and the young age of patients may increase the rate of postoperative respiratory complications. Between 20% and 50% of patients may need prolonged ventilatory support28,62and 5% may need tracheostomy.28,48 Rates of respiratory complication are higher for patients operated on for pulmonary artery sling – 44% may require tracheostomy.48 Following the procedure, immediate relief of symptoms is expected in 43% of the patients,27 and later on 60–90% of the patients are asymptomatic.28,48 The rest of these patients may have various degrees of mild to moderate respiratory complications including cough, stridor, recurrent respiratory infection and recurrent hospitalizations.28,63,67 In the majority of these cases, the symptoms subside within 1 year.56 In these symptomatic patients, medical follow-up, including esophagogram and endoscopies, is required.69 Exceptional cases may require reoperation, including aortopexy, to relieve tracheal pressure.48 Although most cases show signiﬁcant symptomatic relief, respiratory studies show that there is residual elevated respiratory airway resistance up to 10 weeks following the operation.70 Long-term studies show that although most of the patients are asymptomatic following the operation, 41% show abnormal pulmonary function tests.67 Sade et al. showed that following repair of pulmonary artery sling, and good symptomatic relief, the left pulmonary artery was still frequently occluded.26 However, recent studies have shown that the left pulmonary artery was patent in 83% and left lung perfusion was present in all operated patients.66

References 275

REFERENCES 1. Hommel L. Commercium litterarium morimbergae, p.161. Cited by Ekstrom G, Sanblom P. Double aortic arch. Acta Chir Scand 1952; 102:183–202. 2. Bayford D. An account of a singular case of obstructed deglutition. Mem Med Soc Lond 1789; 2:275–86. 3. Wolman IJ. Syndrome of constricting double aortic arch in infancy. Report of a case. J Pediatr 1939; 14:527–33. 4. Gross RE. Surgical relief for tracheal obstruction from a vascular ring. N Engl J Med 1945; 233:586–90. 5. Gross RE. The surgical signiﬁcance of aortic arch anomalies. Surg Gynecol Obstet 1946; 83:435–48. 6. Neuhauser EBD. Roentgen diagnosis of double aortic arch and other anomalies of great vessels. Am J Roentgenol Rad Ther 1946; 56:1–12. 7. Edwards JE. Anomalies of the derivatives of the aortic arch system. Med Clin N Am 1948; (July):925–49. 8. Stewart JR, Kinkai OW, Edwards JE. An Atlas of Vascular Rings and Related Malformations of the Aortic Arch System. Springﬁeld, Illinois: Thomas, 1964. 9. Ekstrom G, Sanblom P. Double aortic arch. Acta Chir Scand 1951; 102:183–202. 10. Keith JD, Rowe RD, Vlad P. Heart Diseases in Infancy and Childhood, New York: Macmillan, 1978. 11. Mustard WT, Bayliss CE, Fearon B et al. Tracheal compression by the innominate artery in children. Ann Thorac Surg 1969; 81:312–19. 12. Gross RE, Neuhauser EBD. Compression of the trachea and oesophagus by vascular anomalies: surgical therapy in 40 cases. Pediatrics 1951; 7:69–88. 13. Klinkhamer AC. Aberrant right subclavian artery – clinical and roentgenological aspects. Am J Roentgenol Rad Ther Nucl Med 1966; 97:438–46. 14. Goldstein WB. Aberrant right subclavian artery in mongolism. Am J Roent Rad Ther Nucl Med 1965; 97:131–4. 15. Felson B, Palayew MJ. The two types of right aortic arch. Radiology 1963; 84:748–59. 16. Stewart JR, Kinkaid OW, Titus JL. Right aortic arch. Plain ﬁlm diagnosis and signiﬁcance. Am J Roentgenol Rad Ther Nucl Med 1966; 97:377–98. 17. Neuhauser EDB. Tracheoesophageal constriction produced by right aortic arch and left ligamentum arteriosum. Am J Roentgenol Rad Ther 1949; 62:493–9. 18. Otero-Cagide M, Moodie DS, Sterba R et al. Digital subtraction angiography in the diagnosis of vascular rings. Am Heart J 1986; 112:1304–8. 19. Slesinger AE, Mendeloff E, Sharkey AM, Spray TL. MR of right aortic arch with mirror branching and a left ligamentum arteriosum: an unusual case of a vascular ring. Pediatr Radiol 1995; 25:455–7. 20. D’Cruz IA, Cantez T, Neumin E et al. Right-sided aorta. Br Heart J 1966; 28:722–39. 21. Yap J, Hayward PE, Lincoln C. Right aortic arch with aberrant subclavian arteries: a cause of esophageal compression. Ann Thorac Surg 1999; 68:2331–2.

22. Grollman JH, Bedynek JL, Henderson HS et al. Right aortic arch with an aberrant retroesophageal innominate artery: angiographic diagnosis. Radiology 1968; 90:782–3. 23. Hyman RA, Stein HL. The cervical aortic arch anomaly. Angiology 1975; 26:749–58. 24. Kumas S, Mandalam KR, Unni M et al. Left cervical arch and associated abnormalities. Cardiovasc Intervent Radiol 1989; 12:88–91. 25. Kirklin JW, Barrat Boyes BG. Cardiac Surgery. New York: Wiley, 1986. 26. Sade RM, Rosenthal A, Fellows K et al. Pulmonary artery sling. J Thorac Cardiovasc Surg 1975; 69:333–46. 27. Bakker DA, Berger RM, Witsenburg M, Bogers AG. Vascular rings: a rare cause of common respiratory symptoms. Acta Paedatr 1999; 88:947–52. 28. Reosler M, de Leval M, Chrispin A et al. Surgical management of vascular ring. Ann Surg 1983; 197:139–46. 29. Lillehei CW, Colan S. Echocardiography in the preoperative evaluation of vascular rings. J Pediatr Surg 1992; 27:1118–20. 30. Beavan TEM, Fatti L. Ligature of aortic arch in neck. Br J Surg 1947; 34:414–16. 31. Pickhardt PJ, Siegel MJ, Gutierrez FR. Vascular rings in symptomatic children: frequency of chest ﬁndings. Radiology 1997; 203:423–6. 32. Capitanio MA, Ramos R, Kirkpatrick JA. Pulmonary sling – roentgen observations. Am J Roentgenol Rad Ther Nucl Med 1971; 112:28–34. 33. Ledwith MV, Duff DF. A review of vascular rings 1980–1992. Ir Med J 1994; 87:178–9. 34. Garti I, Aygen MM, Levy MJ. Double aortic arch anomalies: diagnosis by counter-current right brachial arteriography. Am J Roentgenol 1979; 133:251–6. 35. Stranger P, Heyman MA, Tarnoff H et al. Complications of catheterization of neonates, infants and children. Circulation 1974; 50:595–600. 36. Singh GK, Greenberg SB, Balsara RK. Diagnostic dilemma: left aortic arch with right descending aorta – a rare vascular ring. Pediatr Cardiol 1997; 18:45–8. 37. Coscina WF, Kressel HY, Gofter W et al. MR imaging of double aortic arch. J Comput Assist Tomog 1986; 10:673–5. 38. Kersting-Sommerhoff BA, Sechtem UP, Fisher MR et al. MR imaging of congenital anomalies of the aortic arch. Am J Roentgenol 1987; 149:9–13. 39. McLeary MS, Frye LL, Young LW. Magnetic resonance imaging of a left circumﬂex aortic arch and aberrant right subclavian artery: the other vascular ring. Pediatr Radiol 1998; 28:263–5. 40. Van Son JAM, Julsrud PR, Hagler DJ et al. Imaging strategies for vascular rings. Ann Thorac Surg 1994; 54:604–10. 41. Soer R, Rodriguez E, Requejo I, Fernandez R, Raposo I. Magnetic resonance imaging of congenital anomalies of the thoracic aorta. Eur Radiol 1998; 8:540–6.

276 Vascular rings 42. Beekman RP, Beek FJ, Hazekamp MG, Meijboom EJ. The value of MRI in diagnosis of vascular abnormalities causing stridor. Eur J Pediatr 1997; 156:516–20. 43. Van Son JA, Julsrud PR, Hagler DJ, Sim EK, Pairolero PC, Puga FJ, Danielson GK. Surgical treatment of vascular rings: the Mayo Clinic experience. Mayo Clin Proc 1993; 68:1056–63. 44. Azarow KS, Pearl RH, Hoffman MA, Zurker R, Edwards FH, Cohen AJ. Vascular ring: does magnetic resonance imaging replace angiography. Ann Thorac Surg 1992; 53:882–5. 45. Webb WR, Gamsu G, Speckman HM et al. CT demonstration of mediastinal aortic arch anomalies. J Comput Assist Tomog 1982; 6:445–51. 46. Baron RL, Gutierrez RF, Sagel SS et al. CT of anomalies at the mediastinal vessels. Am J Roentgenol 1981; 137:571–6. 47. Van Son JA, Starr A. Demonstration of vascular ring anatomy with ultrafast computed tomography. Torac Cardiovasc Surge 1995; 43:120–1. 48. Backer CL, Ibawi MN, Idriss FA et al. Vascular anomalies causing tracheoesophageal compression. J Thorac Cardiovasc Surg 1989; 97:725–31. 49. Campbell DN, Clarke DR, Lilly JR. Pulmonary artery sling (letter). Thorac Cardiovasc Surg 1990; 99:725–31. 50. Murdison KA, Andrews BAA, Chin AJ. Ultrasonographic display of complex vascular rings. J Am Coll Cardiol 1990; 15:1645–53. 51. Bronshtein M, Lorber A, Berant M, Auslander R, Zimmer EZ. Sonographic diagnosis of fetal vascular rings in early pregnancy. Am J Cardiol 1998; 81:101–3. 52. Katz M, Konen E, Rozeman J. Spiral CT and 3D image reconstruction of vascular rings and associated tracheobronchial anomalies. J Comp Assist Tomog 1995; 19:564–8. 53. Godtfredsen J, Wennevold A, Efsen F et al. Natural history of vascular ring with clinical manifestations – a follow-up study of eleven unoperated cases. Scand J Thorac Cardiovasc Surg 1977; 11:75–7. 54. Van Aalderen WMC, Hoekstra MO, Hess J et al. Respiratory infections and vascular rings. Acta Paediatr Scand 1990; 790:477–80. 55. Lam B, Kabbani S, Archiniegas E. Symptomatic anomalies of the aortic arch. Surg Gynecol Obstet 1978; 147:673–81.

56. Binet JP, Langlois J. Aortic arch anomalies in children and infants. J Thorac Cardiovasc Surg 1977; 73:248–52. 57. Filston HC, Ferguson TB, Oldham HN. Airway obstruction by vascular anomalies – importance of telescopic bronchoscopy. Ann Surg 1987; 205:541–9. 58. Virdi IS, Keeton BR, Shore DF et al. Surgical management in tetralogy of Fallot and vascular rings. Pediatr Cardiol 1987; 8:131–4. 59. Burke RP, Rosenfeld HM, Wernovsky G, Jonas RA. Videoassisted thoracoscopic vascular ring division in infants and children. J Am Coll Cardiol 1995; 25:943–7. 60. Stark J, de Leval M. Surgery for Congenital Heart Defects. London: Grune and Stratton, 1983, 227–34. 61. Todd DJ, Dangerﬁeld PH, Hamilton DJ et al. Late effects on left upper limb of subclavian ﬂap aortoplasty. J Thorac Cardiovasc Surg 1983; 85:678–83. 62. Syderys H. New operation for symptomatic aberrant right subclavian artery (dysphagia lusoria). J Thorac Cardiovasc Surg 1969; 57:269–76. 63. Richardson JV, Dety DB, Rossi NP et al. Operation for aortic arch anomalies. Ann Thorac Surg 1981; 31:426–32. 64. Chao LC. Repair of right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum. J Pediatr Surg 1990; 25:795–6. 65. Ciocca RG, Wilkerson DK, Madson DL, Andrew CT, Graham AM. Symptomatic subclavian steal syndrome four decades after operation for dyphagia lusoria. Ann Vasc Surg 1995; 9:204–8. 66. Dunn JM, Gordon I, Chrispin AR et al. Early and late results of surgical correction of pulmonary artery sling. Ann Thorac Surg 1979; 28:230–8. 67. Marmon LM, Bye MR, Haas JM et al. Vascular ring and slings – long term follow-up of pulmonary function. J Pediatr Surg 1984; 19:683–92. 68. Lavoie J, Burrows FE, Hansen DD. Video assisted thoracoscopic surgery for the treatment of congenital cardiac defects in the pediatric population. Anesth Analg 1996; 82:563–7. 69. Kraus DM, Hayes JD, Tucker HM. Vascular ring anomaly. Head Neck Surg 1989; 11:170–3. 70. Thompson AH, Beardsmore CS, Firmin R et al. Airway function in infants with vascular rings: preoperative and postoperative assessment. Arch Dis Childh 1990; 65:171–4.

28 Pulmonary air leaks PREM PURI

INTRODUCTION Pulmonary air leaks include urgent life-threatening neonatal emergencies like pulmonary interstitial emphysema, pneumomediastinum, pneumothorax or pneumopericardium.1 The incidence of pulmonary air leaks in the neonates has increased in recent years, possibly because an increasing number of sick infants with respiratory distress on assisted ventilation are now surviving to develop this complication.2 The sequence of events in the occurrence of pulmonary air leaks is similar regardless of whether it is caused by uneven alveolar ventilation, air trapping and high transpulmonary pressure swings. The rupture of terminal air sacs causes air to escape into the pulmonary interstitium, resulting in pulmonary interstitial emphysema. The air tracks along the sheaths of pulmonary blood vessels to the lung hilum and air may then rupture into mediastinum, pleura or pericardium.3 It has also been suggested that air directly enters the pleural cavity following a rupture of a subpleural bleb.4 Rarely systemic air embolism may be a terminal event of pulmonary air leaks.5,6

Presentation and diagnosis Pulmonary interstitial emphysema may be diffuse or localized. It is a radiological diagnosis found on the chest X-ray of an ill neonate. The radiological features consist of hyperinﬂation and multiple cyst-like lucencies that appear to radiate outward from the hilum of the lung (Fig. 28.1). Suspect neonates should be monitored by daily chest X-ray for an earlier diagnosis of PIE.

PULMONARY INTERSTITIAL EMPHYSEMA Pulmonary interstitial emphysema (PIE) is predominantly seen in preterm infants with respiratory distress syndrome (RDS) who are on assisted ventilation.1 Occasionally it follows vigorous resuscitative efforts. The lesion represents air that has dissected along perivascular sheath within pulmonary interstitium. The compression caused by interstitial ‘airconduits’ interferes with ventilation and reduces pulmonary perfusion leading to CO2 retention and hypoxemia. The incidence of PIE increases with low birth weight and prematurity. In one series, 20 out of 303 ventilated low birth weight (LBW) babies developed PIE,7 but signiﬁcantly high incidences of 32% and 42% have been reported in other series.8,9

Figure 28.1 Diffuse pulmonary interstitial emphysema in a baby weighing 1200 g and requiring prolonged positive pressure ventilation for hyaline membrane disease. The lungs are grossly hyperinﬂated with a diffuse cystic pattern in this ﬁlm at 7 days of life. Note narrow heart shadow due to tamponade effect of the distended lungs. A shallow pneumothorax is present in the left upper zone and a left chest drain has been inserted

278 Pulmonary air leaks

Treatment PIE, diffuse or localized, makes ventilatory management difﬁcult. Ventilatory pressures should be kept at a safe minimum while aiming for acceptable blood gas values of PaO2 > 6–7 kPa, pH > 7.25, and PaCO2 < 8 kPa.10 No speciﬁc treatment is indicated for diffuse PIE apart from various changes suggested in ventilation such as withdrawal of positive end-expiratory pressure (PEEP),11 increasing rates to 100–200/minute,12 and reintroduction of use of continuous negative pressure ventilations.13,14 An aggressive approach of decompressing the lungs and creation of artiﬁcial pneumothorax by scariﬁcation of the lung surface through the chest wall has been described.15 If the disease is unilateral or localized, selective partial or complete atelectasis of the desired segment can be achieved by selective bronchial intubation,16,17 or by placing the infant with his hyperinﬂated lung dependent in the lateral decubitus position at all times.18 Localized pulmonary interstitial emphysema cases have also been successfully treated by resection of the diseased lobes.19,20

retrosternal space (Fig. 28.2b). Ultrasound can be used to diagnose pneumomediastinum as an alternative to a decubitus ﬁlm.25 Retrocardiac pneumomediastinum has a strong association with other manifestations of extraalveolar air leaks such as PIE, pneumothorax, dissection of air into the soft tissues of the neck and pneumoperitoneum.26 Tension pneumomediastinum has also been described to cause isolated left ventricular inﬂow obstruction.27

Prognosis The mortality rate from diffuse PIE has been reported to be from 24% to as high as 60%.21,22 There have been no signiﬁcant differences in neonatal parameters between infants who died or survived. However, the survivors had a signiﬁcantly lower maximal peak inspiratory pressure and FiO2 on the ﬁrst day of ventilation.22 PIE is invariably fatal in the group of neonates with RDS who weigh < 1600 g at birth and who develop bilateral PIE within the ﬁrst 48 hours of life, needing FiO2 above 0.6 on the ﬁrst day. High positive inspiratory pressure on day 1 was found to be the most signiﬁcant parameter associated with fatal pulmonary interstitial emphysema. A cut-off level of 26 cmH2O was found to be discriminant.23 These criteria may be useful in selecting neonates who might beneﬁt best from the new modes of ventilation.

(a)

PNEUMOMEDIASTINUM Pneumomediastinum develops when interstitial air in PIE migrates to the mediastinum. If the collection of air is small, it remains asymptomatic. However, large collections of mediastinal air may produce respiratory distress. Heart sounds are mufﬂed and the sternum may appear bowed. The diagnosis is made on chest X-ray. The anteroposterior views may show the characteristic ‘angel-wing’ sign produced by air elevating the thymus gland (Fig. 28.2a). It has also been described as having a crescentic conﬁguration resembling a ‘spinnaker’ sail.24 Lateral X-ray of the chest shows marked hyperlucency in the superior

(b) Figure 28.2 Pneumomediastinum. (a) Anteroposterior view demonstrates the characteristic ‘angel wing’ sign produced by air elevating the thymus from the heart. (b) Lateral view conﬁrms air in the anterior mediastinum

Treatment 279

Symptomatic pneumomediastinum is managed by needle aspiration of the anterior mediastinal compartment. In asymptomatic cases, air is absorbed spontaneously and no treatment is indicated.

PNEUMOTHORAX Pneumothorax is far more frequent in the newborn period than in any other period of life – the incidence is 1% of all newborns.28–31 It is bilateral in about 15–20% of cases.10 Pneumothorax in the newborn predominantly occurs in patients with hyaline membrane disease, meconium aspiration syndrome, pulmonary hypoplasia, and infants requiring vigorous resuscitation at birth. The overall incidence of pneumothorax in the newborn with respiratory difﬁculties has been reported to be as high as 34% of those who are ventilated.32 Pneumothorax can also be caused by iatrogenic perforation of the bronchus33 and as a complication of deep endotracheal tube suction.34 A rare association of spontaneous tension pneumothorax with congenital cystic adenomatoid malformation35 and early spontaneous pneumothorax with common pulmonary vein atresia36 has been reported. The ‘surgical’ cases of pneumothorax and/or pneumomediastinum at the Liverpool Neonatal Surgical Centre included infants with gross renal anomalies, large exomphalos, a rare type of vascular sling, and spontaneous perforation of esophagus. In half of the cases the etiology was less obvious.37 Pneumothorax should be suspected in infants with respiratory distress who suddenly deteriorate. Tachypnea is a uniform ﬁnding and is often accompanied by grunting, chest retractions and cyanosis. Physical ﬁndings in unilateral pneumothorax include a shift of the cardiac impulse to the unaffected side, diminished or absent breath sounds, and a hyperresonant percussion note on the affected side. In tension pneumothorax, hypotension, apnea and bradycardia are usually the initial signs. A large pneumothorax can be diagnosed by transillumination using a high-intensity light with ﬁberoptic probe.38 The advantage of this method is the rapidity with which large life-threatening pneumothoraces can be diagnosed and treated. The gold standard for diagnosis is radiography of the chest. A large pneumothorax is easily recognizable in infants by identiﬁcation of the visceral pleural line, which is most readily seen over the apex and along the costal surface of the lung (Fig. 28.3). Other important observations in pneumothoraces are a mediastinal shift and absence of lung markings. Small volume pneumothoraces are more difﬁcult to identify and in these cases, lateral decubitus cross-table views are very helpful in showing the rise in pleural air to the lateral or medial side of the hemithorax (Fig. 28.4).

Figure 28.3 Right pneumothorax complicating interstitial emphysema in an infant with hyaline membrane disease. Note air lucency around right lung with absence of lung markings. The mediastinum is shifted to the left, indicating tension

Figure 28.4 Small-volume pneumothorax demonstrated in the lateral decubitus view with the right side raised

TREATMENT Most small pneumothoraces with no symptoms need only close observation and monitoring in a neonatal intensive care unit. The ventilatory management should aim to keep pressures at lower acceptable values, faster rates above 60/minute rather than 30–40/minute and use sedation or paralysis earlier.39–41 A pneumothorax should be drained in the following situations:

280 Pulmonary air leaks

• Tension pneumothorax • When it is symptomatic • In all babies on intermittent positive pressure ventilation (IPPV), even if asymptomatic. The infant should be temporarily disconnected from the ventilator during the introduction of a chest drain or aspiration of a pneumothorax to avoid the risk of lung damage.42 In a desperately ill neonate, a life-saving emergency needle aspiration of a tension pneumothorax can be done before formal insertion of a chest drain. A butterﬂy (18gauge) or i.v. cannula with a three-way tap and a 20 ml syringe can be used for decompression. Aspiration is performed through the second intercostal space in the mid-clavicular line. The insertion of the needle is oblique through the muscle plane to avoid entry of air once the needle is removed. Occasionally a single aspiration may be enough but all these babies must be closely observed and monitored clinically and radiologically as nearly all of them require a tube thoracostomy on follow-up. Tube thoracostomy is required in the majority of cases. A chest drain (10–14 French gauge) is inserted through the second intercostal space in the mid-clavicular line or the sixth space in the mid-axillary line under local anesthesia. A purse-string stitch in the skin around the site of the catheter insertion can be left to be tied later at the time of removal of the catheter.37 The tip of the chest tube should be placed anteriorly retrosternally for better drainage.43 After ﬁxing the catheter ﬁrmly, it is connected to an underwater seal drain with or without a low-grade suction of 5–10 cmH2O. Once the lung is expanded and stable, the tube can then be removed. A chest ﬁlm should be obtained after removal of the tube to ensure that a pneumothorax has not recurred. Use of conventional chest drains is not free from complication as they can cause lung perforation,42 and four cases of phrenic nerve paralysis have been reported related to abnormal location of the medial end of the chest tube.44 There are newly designed pigtail pleural drainage catheters available.45,46 but a properly sized ordinary chest drain should be adequate in the majority of cases, with an underwater seal or with a vacuum-control unit. The Heimlick ﬂutter valve, though useful clinically, adds to the resistance of the system, especially if ﬂuid accumulates in the valve.47

of grades 3 or 4 intraventricular hemorrhage in infants with pneumothoraces associated with hypotension is 89% as compared with neonates with pneumothoraces associated with normal blood pressure, which is only 10%.50 This can have a detrimental effect on the neurological outcome. Ventilatory parameters may be helpful in making a prognostic assessment. The survivor group respond well to a fraction of inspired oxygen of less than 70% and a PEEP of 6 cm or less. A CO2 retention associated with pneumopericardium and PIE is a bad sign.48

Pneumopericardium Pneumopericardium is the least frequent pulmonary air leak. However, recently it has been occurring with increasing frequency as a complication of ventilatory therapy. Pneumopericardium can also develop while the patients are on high-frequency ventilation respiratory support.51 Neonatal pneumopericardium has also been reported in a full-term neonate following a forceps delivery and mild asphyxia.52 The exact etiology of pneumopericardium is not known; it is probably interstitial pulmonary air, secondary to alveolar rupture, which dissects into the mediastinum and then enters the pericardial space at the reﬂection of the pericardium onto the great vessels. The pneumopericardium may be asymptomatic or symptomatic. Asymptomatic infants do well without any treatment. The clinical signs in symptomatic patients are those of cardiac tamponade, i.e. a sudden onset of bradycardia, mufﬂed heart sounds, cyanosis and hypotension. Changes in ECG axis and/or voltage may be observed. The classical radiological ﬁnding is a continuous radiolucent band of air that conforms to the cardiac outline and does not extend beyond the level of the great vessels (Fig. 28.5). Extra ventilatory air (PIE and pneumomediastinum) is present in over 90% of patients.

Prognosis Cases with pneumothoraces without underlying lung disease have a good prognosis. The mortality rate is 31% when it is associated with RDS.10 In one series of infants presenting with pneumothoraces within the ﬁrst 24 hours of life, the overall mortality rate was 52%.48 The mortality rate is inversely proportional to the infant’s birth weight: 53% in infants with birth weights < 1 kg.49 The incidence

Figure 28.5 Pneumopericardium in a 2-day-old full-term infant with complicating meconium aspiration. Note right pneumothorax also

References 281

Simple needle pericardiocentesis is the appropriate therapy for most cases with cardiac tamponade. However, a few babies with pneumopericardium uncontrolled by needle aspiration require placement of a pericardial catheter for continuous drainage of air. The mortality rate in infants with pneumopericardium is high.

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management of pulmonary interstitial emphysema: a preliminary study. J Perinatol 1989; 9(1):26–32. Milligan DWA, Issler H, Massam M, Reynolds EOR. Treatment of neonatal pulmonary interstitial emphysema by lung puncture. Lancet 1984; i:1010–11. Brooks JG, Bustamante SA, Koops BL. Selective bronchial intubation for the treatment of severe localised pulmonary interstitial emphysema in newborn infants. J Pediatr 1977; 91:648–52. Weintraub Z, Oliven A, Weissman D, Sonis Z. A new method for selective left main bronchus intubation in premature infants. J Pediatr Surg 1990; 25(6):604–6. Cohen RS, Smith DW, Stevenson DK, Moskowitz PS, Graham CB. Lateral decubitus position as therapy for persistent pulmonary interstitial emphysema in neonates: a preliminary report. J Pediatr 1984; 104:441–3. Fletcher DB, Outerbridge GE, Youssef S. Pulmonary interstitial emphysema in a newborn infant treated by lobectomy. Pediatrics 1974; 54:808–11. Bauer BR, Brennan MJ, Doyle C. Surgical resection for pulmonary interstitial emphysema in the newborn infant. J Pediatr 1978; 93:656–61. Greenough A, Dixon AD, Roberton NRC. Pulmonary interstitial emphysema. Arch Dis Childh 1984; 59:1046–51. Lerman-Sagie T, Davidson S, Wielunsky E. Pulmonary interstitial emphysema in low birth weight infants: characteristics of survivors. Acta Paediatrica Hungarica 1990; 30:383–9. Morisot C, Kacet N, Bouchez MC, Rouland V, Dobos JP, Gremillet C, Lequien P. Risk factors for fatal pulmonary interstitial emphysema in neonates. Eur J Pediatr 1990; 149(7):493–5. Moseley JE. Loculated pneumomediastinum in the newborn. A thymic ‘spinnaker’ sign. Radiology 1960; 75:788–90. Van Gelderen WF. Ultrasound diagnosis of an atypical pneumomediastinum. Paediatr Radiol 1992; 22(6):469. Rosenfeld DL, Cordell CE, Jadeja N. Retrocardiac pneumomediastinum: radiographic ﬁndings and clinical implication. Pediatrics 1990; 85(1):92–7. Case CL, Oslizlok P, Fyfe D, Gillette PC. Neonatal pneumomediastinum with isolated mitral obstruction. Arch Dis Childh 1990; 65:56–8. Steele RW, Metz JR, Bass JW, Dubois JJ. Pneumothorax and pneumomediastinum in the newborn. Radiology 1971; 98:629–32. Sahn SA, Heffner JE. Spontaneous pneumothorax. N Eng J Med 2000; 342(12):868–74. Wilcox DT, Glick PL, Karamanoukian HL et al. Spontaneous pneumothorax: a single-institution experience in patients under 16 years of age. J Pediatr Surg 1995; 30:1452–4. Alter SJ. Spontaneous pneumothorax in infants: a 10-year review. Pediatr Emerg Care 1997; 13:401–3.

282 Pulmonary air leaks 32. Madansky DL, Lawson EE, Chernick V, Taeusch HW. Pneumothorax and other forms of pulmonary air leaks in the newborn. American Review of Respiratory Disease 1979; 120:729–37. 33. Holcomb GW III, Templeton JM Jr. Iatrogenic perforation of the bronchus intermedius in a 1,100-g neonate. J Pediatr Surg 1989; 24(11):1132–4. 34. Jaw MC, Soong WJ, Chen SJ, Hwang B. Pneumothorax: a complication of deep endotracheal tube suction: report of 3 cases. Chin Med J 1991; 48(4):313–17. 35. Bentur L, Canny G, Thorner P, Superina R, Babyn P, Levison H. Spontaneous pneumothorax in cystic adenomatoid malformation. Unusual clinical and histologic features. Chest 1991; 99(5):1292–3. 36. Sharda JK, Kurlandsky LE, Lacina SJ, Radecki LL. Spontaneous pneumothorax in common pulmonary vein atresia. J Perinatol 1990; 10(1):70–4. 37. Irving IM. Neonatal Surgery. Malformations and acquired lesions of lungs, pleura and mediastinum. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990: 259–78. 38. Kulrus LR, Bednarek FJ, Wyman ML, Roloff DW, Borer RC. Diagnosis of pneumothorax or pneumomediastinum in the neonate by transillumination. Pediatrics 1975; 56:355–60. 39. Heicher DA, Kasting DS, Richards JR. Prospective clinical comparison of two methods of mechanical ventilation of neonates: rapid rate and short inspiratory time versus slow rate and long inspiratory time. J Pediatr 1981; 98:957–61. 40. Octave Study Group. Multicentre randomised controlled trial of high against low frequency positive pressure ventilation. Arch Dis Childh 1991; 66:770–8. 41. Cooke RWI, Rennie JM. Pancuronium and pneumothorax. Lancet 1984; i:286–7.

42. Moessinger AC, Driscoll JM Jr, Wigger HJ. High incidence of lung perforation by chest tube in neonatal pneumothorax. J Pediatr 1978; 92:635–7. 43. Allen RW, Jung AL, Lester PD. Effectiveness of chest tube evacuation of pneumothorax in neonates. J Pediatr 1981; 99:629–34. 44. Odita JC, Khan AS, Dincsoy M, Kayyali M, Masoud A, Ammari A. Neonatal phrenic nerve paralysis resulting from intercostal drainage of pneumothorax. Pediatr Radiol 1992; 22(5):379–81. 45. Lawless S, Orr R, Killian A, Egar M, Fuhrman B. New pigtail catheter for pleural drainage in pediatric patients. Crit Care Med 1989; 17(2):173–5. 46. Jung AL, Nelson J, Jenkins MB, Hodson WA. Clinical evaluation of a new chest tube used in neonates. Clin Pediatr 1991; 30(2):85–7. 47. Bakker JC, Liem M, Wijnands JB, Karsdon J, Berger HM. Neonatal pneumothorax drainage systems: in vitro evaluation. Eur J Pediatr 1989; 149(1):58–61. 48. Mandal AK, Yamini S, Bean X. Arterial blood gas and expiratory pressure monitoring in infants with pneumothorax: prognostic predictability. J Natl Med Assoc 1990; 82(1):33–7. 49. Greenough A, Robertson NRC. Morbidity and survival in neonates ventilated for respiratory distress syndrome. Br Med J 1985; 290:597–600. 50. Mehrabani D, Gowen CW Jr, Kopelman AE. Association of pneumothorax and hypotension with intraventricular haemorrhage. Arch Dis Childh 1991; 66(1 Spec No):48–51. 51. Neal RC, Beck DE, Smith VC, Null DM. Neonatal pneumopericardium with high frequency ventilation. Ann Thorac Surg 1989; 47(2):274–7. 52. Bjorklund L, Lindroth M, Malmgren N, Warner A. Spontaneous pneumopericardium in an otherwise healthy full term newborn. Acta Paediatr Scand 1990; 79(2):234–6.

29 Chylothorax and other pleural effusions in neonates RICHARD G. AZIZKHAN

INTRODUCTION Chylothorax results from the leakage of chyle from the thoracic duct into the pleural cavity. Although it is rare, it is a well-established clinical entity and is the most common cause of pleural effusion encountered in neonates.1–3 Whether congenital or acquired, chylothorax generally resolves with nonoperative measures aimed at optimizing ventilation and maintenance of nutrition. When these measures fail to bring about spontaneous healing, operative management becomes imperative. When resolution does not occur, persistent chylothorax can become a life-threatening disorder with profound respiratory, nutritional, and immunologic consequences.1,3–6 While early diagnosis, aggressive initiation of nonoperative management options, and a number of alternative surgical procedures have signiﬁcantly decreased the mortality rate from 50% before the 1950s7,8 to currently reported estimates ranging from 10–20%,2,9–13 signiﬁcant morbidity continues. In light of these facts, chylothorax will be the primary focus of this chapter. A basic description of the anatomy and embryology of the lymphatic system as well as the pathophysiology of chyle will provide the framework essential to an understanding of this disorder. Other pleural effusions, including empyema and hemothorax will also be brieﬂy discussed. Since malignant effusions rarely occur in neonates, they have been omitted from the discussion.

level of the ﬁfth thoracic vertebra, continues its ascent into the neck on the left of the esophagus, and opens into the venous system at the conﬂuence of the internal jugular and subclavian veins. In the thorax it receives lymph from the parietal pleura of both sides via several collecting trunks. Lymphatic branches from structures in the posterior mediastinum and from the left lung and its pleura join to form the left bronchomediastinal trunk; this trunk opens into the thoracic duct or directly into the great veins. There are also several potential lymphovenous communications that may function when the main duct is traumatized or blocked (Fig. 29.1). The lymphatic system, a diffuse network of endothelial channels, appears during the sixth week of

ANATOMY AND EMBRYOLOGY OF THE LYMPHATIC SYSTEM Lymph is collected in the cisterna chyli and reaches the venous system via the thoracic duct, which ascends in the posterior mediastinum between the azygos vein and the descending aorta. This duct crosses to the left at the

Figure 29.1 Anatomy of the lymphatic system

284 Chylothorax and other pleural effusions in neonates

development. The growth of this system is a phenomenon of consecutive centrifugal budding from original lymph sacs. In the early 1900s Sabin14 demonstrated that these sacs originated from the endothelium of the adjacent veins, establishing venous endothelium as the primordial structure of the lining of the lymphatic system. She further recognized that all lymphatic channels are developed as outgrowths of the venous endothelium in six original lymph spaces: two jugular lymph sacs, two iliac sacs, a single retroperitoneal sac, and the cisterna chyli.14 These sacs invade the tissues by continuous growth and branching. The lymphatic system arises by conﬂuence of perivenous mesenchymal spaces to form larger spaces. These in turn join to form continuous vessels that eventually drain into the venous system. While the thoracic duct is usually a singular structure, its embryology underscores the potential for anatomical variations and congenital anomalies.6,15 It may develop in different anatomical patterns with several lymphaticovenous anastomoses. Variation in lymphatic pathways and the presence of accessory lymphatic channels can account for chylous effusions resulting from surgical procedures that do not expose the main thoracic duct.16 Trauma to the duct in the posterior mediastinum can produce a unilateral or bilateral chylothorax. Increased intraductal tension leads to drainage of chyle into the thorax. A lesion to the thoracic duct below the level of the ﬁfth lumbar vertebra will result in a right-sided chylothorax; a left-sided chylothorax occurs with lesions above this level.

PATHOPHYSIOLOGY OF CHYLE At birth, chyle is clear and straw colored; soon after milk feeding begins, chylomicrons (emulsiﬁed fat globules) render it milky white. Depending on the amount of milk ingested, the fat content of the ﬂuid varies from 0.4–4.0 g/100 mL, with a triglyceride content of > 500 mg/100 mL.17 Although the protein and electrolyte contents of chyle are similar to those in plasma, chyle is rich in T-cell lymphocytes, with a lymphocyte count of 80–100%. The volume of chyle loss per day can exceed 1.7 times the patient’s blood volume, resulting in a serious state of depletion characterized by hyponatremia, hypoproteinemia, metabolic acidosis and lymphocytopenia.3 Untreated chylothorax is associated with severe respiratory compromise due to pulmonary parenchymal compression. The thoracic duct drains most of the body lymph, including the entire intestinal lymph (chyle) into the venous system in the neck. Basal ﬂow of the lymph from the duct averages 1.4 mL/kg/hour and varies with meals. Fatty meals may increase lymph ﬂow up to 10 times the basal rate, while lesser increases in the rate of ﬂow are

effected by the ingestion of proteins, carbohydrates, and even by oral intake of water.18

ETIOLOGY OF CHYLOTHORAX Congenital chylothorax Congenital chylothorax is a common cause of neonatal pleural effusion and is classically a disorder of infants at or near term. Males are affected twice as frequently as females and 60% of cases involve the right side of the chest.19 In view of existing knowledge of the anatomy and embryology of the thoracic duct, the occurrence of chylothorax in the absence of other demonstrable disease suggests the existence of congenital malformations involving the lymphatic system. Congenital atresia of the thoracic duct or congenital ﬁstulas due to failure of peripheral lymphatic channels to communicate with the major lymphatic network have moreover been assumed on the basis of diffuse chyle leakages seen during surgery.2 Congenital defects of the lymphatic system that may reveal themselves in chylothorax are well documented in the literature, presenting clinically as lymphangiomatosis20–26 or congenital pulmonary lymphangiectasis.27–29 Congenital chylothorax is also associated with hydrops fetalis30–34 and various syndromes such as trisomy 21,35–37 Turner syndrome, and Noonan syndrome.38,39 Over the past decade, its occurrence in combination with other uncommon disorders such as autosomal recessive lymphatic anomalies, mediastinal neuroblastoma in a newborn, and neonatal thyrotoxicosis has been documented as well.40–42

Acquired chylothorax Acquired chylothorax results primarily from surgical or traumatic insult to the thoracic duct, and virtually every intrathoracic surgical procedure has been associated with it. Iatrogenic injury can occur during surgery in the region of the aortic arch for conditions such as patent ductus arteriosus, coarctation of the aorta, vascular ring and other congenital cardiovascular anomalies, as well as during esophageal repair or repair of congenital diaphragmatic hernia.43–46 Acquired chylothorax also manifests as a complication of both subclavian and internal jugular venous cannulation and/or obstruction, superior vena caval obstruction secondary to central venous catheters or elevated central venous pressures,30,47–52 chest tube insertion53 and traumatic delivery.54 Additionally, in recent years there have been anecdotal reports of chylothorax resulting from a blunt blow to the abdomen due to child abuse.55 Chylothorax/chylopericardium is a rare complication, occurring primarily following surgery for congenital heart diseases.56

Management of chylothorax 285

CLINICAL FEATURES OF CHYLOTHORAX Presenting symptoms Tachypnea, dyspnea, retraction of chest and cyanosis mark the onset of chylothorax, with dullness and diminution of breath sounds on the affected side and displacement of the heart and mediastinum to the opposite side. In cases of congenital chylothorax, symptoms of respiratory distress may be noted shortly after birth or at any time up to 2 weeks of life. In contrast, the interval between surgery and the occurrence of acquired chylothorax can vary from 1–25 days. The time is shortest when there is a direct injury to the duct (5–7 days) and longest when there is high pressure or thrombosis of the vena cava (10–14 days). Chyle may accumulate in the mediastinum for several days before extravasating into the pleural space.

Consequence of continuous chylous ﬂow

Figure 29.2 Chest radiograph in a term neonate demonstrating bilateral chylothorax

The loss of large quantities of chyle over a period of time produces nutritional failure, sepsis, metabolic acidosis and renal failure. Considerable loss of protein and large numbers of lymphocytes may result in immunodeﬁciencies, including hypogammaglobulinemia and abnormal cell-mediated immune responses.

content of the chylothorax may be quite low and the ﬂuid does not have the characteristic milky appearance. The protein content is somewhat less than that of serum and the electrolytes approximate those of serum.

DIFFERENTIAL DIAGNOSIS

MANAGEMENT OF CHYLOTHORAX

Radiographs of the chest typically show opaciﬁcation of one or both hemithoraces, with compression of lung and displacement of mediastinal structures in unilateral chylothorax (Fig. 29.2). Radiographic diagnosis in premature infants may, however, be difﬁcult. Most of these infants already have signiﬁcant pulmonary disease, and chest radiographs may appear to have areas of increasing consolidation rather than the more typical layering of pleural ﬂuid seen in older children. Sonography is a reliable method of detecting chylothorax in these cases, and its increasing use in obstetric practice as the primary method of imaging the fetal chest has led to the increasing frequency with which fetal chylothorax is being diagnosed33, 57–61 (see section on fetal chylothorax). Diagnosis is conﬁrmed after analysis of the pleural ﬂuid drained by thoracentesis or chest tube placement. Initially, this ﬂuid is serous; it turns chylous only after milk feedings have begun. Chyle is characterized by elevated total protein and albumin levels, a speciﬁc gravity of > 1.012, the presence of white blood cells with a predominance of lymphocytes (80–100%) and elevated triglycerides, cholesterol, and total fat levels if the infant is milk fed.13 In the unfed neonate, the fat

Historical overview and current consensus Since chylothorax is associated with a wide array of disorders and accompanying clinical circumstances, the management of patients with this condition has varied considerably. Historically there has been a diversity of opinion regarding nonoperative and operative treatment approaches. The timing and type of operative intervention have been particularly controversial. Despite the differences, it is generally agreed that initial thoracentesis is diagnostic and may provide immediate relief of respiratory failure. If failure persists, mechanical ventilation may be required. A course of therapy that avoids the serious nutritional, metabolic and immunologic sequelae known to the disease should then be chosen.62 If the infant is able to tolerate enteral feeding, nonoperative management initially consists of enteral feeding with medium-chain triglycerides (MCT). In recalcitrant or severe cases, patients may require total parenteral nutrition (TPN) or a combination of both modalities.9–11,56,63,64 This protocol is generally successful. It was established in view of early studies indicating that the most serious complication of chylothorax was protein–calorie malnutrition.7,8 More than 60% of

286 Chylothorax and other pleural effusions in neonates

ingested fats travel to the bloodstream via the thoracic duct. MCTs, which have a 6- to 10-carbon backbone, are the only fats to be absorbed directly via the portal system, bypassing the lymphatics.65 There is general consensus that if lymphatic drainage does not resolve within a 2-week period with nonoperative management, or if a patient’s nutritional or metabolic status declines measurably during that time, surgical intervention should be undertaken.

General management principles The general principles of management for chylothorax include the following: • Thoracentesis is performed to provide immediate relief of respiratory failure and to conﬁrm the diagnosis through chemical analysis of a pleural ﬂuid specimen. • Supportive ventilation is instituted as required. • Thoracostomy tube drainage is carried out if pleural ﬂuid reaccumulates after one or two thoracenteses. (Repeating this procedure carries a risk of producing pneumothorax and introducing infection; chest tube drainage keeps the lungs fully expanded, which is necessary for sealing chyle leakage). • Nutritional losses are replaced through a high-protein diet, rich in MCTs that are absorbed directly into the portal venous system. • Parenteral feeding is instituted. (When superior vena caval thrombosis is present with chylothorax, TPN may need to be delivered via a peripheral vein).47,66 • The albumin, gammaglobulin and ﬁbrinogen that are contained in chyle, as well as fat-soluble vitamins, are adequately replaced. • Full expansion of the lungs is maintained by continuous chest tube drainage of chyle. (These tubes may become obstructed and require replacement as necessary). • Prophylactic antibiotics are given when chest tubes are in place, since many of these infants have an acquired immune deﬁciency caused by lymphocytopenia. Some infants may also need salt restriction, diuretics and digoxin. • Surgical intervention is warranted when these therapies fail to signiﬁcantly diminish chylous drainage for more than 14 days or if there is obvious deterioration in the patient prior to that period of time (Fig. 29.3).

Nonoperative management As cited earlier, an initial trial of nonoperative management relying on adequate drainage of chyle, coupled with nutritional supplementation via MCT-enriched

diets and/or TPN should be given in order to optimize the chance of recovery without surgery. Using this regimen, the majority of cases of congenital chylothorax and 50% of cases with traumatic chylothorax (postoperative) resolve spontaneously.63,64 Some investigators have observed no difference in MCT or TPN in regard to duration or amount of drainage.56,62,66 Others have found that for patients with superior vena caval obstruction and congenital lymphatic malformation, MCT alone is not as effective; thus they recommend the rapid administration of TPN.66 Positive reports on the use of somatostatin in a case of lymphorrhagia from a ruptured thoracic duct67 and the use of a somatostatin analog in the management of congenital chylous ascites68 lend optimism to the possibility of adding new therapies to the current nonoperative treatment armamentarium. Unpublished cases also indicate that moderately high doses of somatostatin have been successful in closing chylous ﬁstulas; this lends further credibility to the likelihood that this may offer another viable nonsurgical option.55 It is also noteworthy that a recently published case report described the use of nitric oxide for the successful management of refractory postoperative chylothorax in a neonate with pulmonary and central venous hypertension.69 This may offer yet another nonoperative therapeutic tool for this subset of the patient population.

Operative management The percentage of neonates requiring surgery and the timing of surgical intervention varies widely among reported series, and are dependent on the patient population studied and the clinical status of individual patients. Operative management has, however, been the mainstay of treatment for a number of clinical conditions that have a high failure rate with standard nonoperative management; these include postsurgical cases in which there is injury to the thoracic duct and massive lymph leakage, caval obstruction, or elevated central venous pressures.16,56,66,70,71 Congenital chylothorax associated with superior vena caval thrombosis in the premature neonate is also particularly refractory to standard nonoperative therapy.47 Since failure is associated with a high mortality rate, some investigators maintain that surgical intervention should be considered early in the management strategy of such cases.66,72–74 Several surgical options exist and they are often used in combination. They include pleuroperitoneal shunting, thoracic duct ligation (open thoracotomy or thoracoscopy), pleurodesis with different agents, pleurectomy, and intrapleural ﬁbrin glue.

PLEUROPERITONEAL SHUNTS The use of pleuroperitoneal shunts has become the ﬁrst line of surgical treatment at a number of major pediatric

Management of chylothorax 287 Chylorthorax

Progressive effusion Chest tube

Stable effusion

Improvement

Failure

Decreasing output

High output > 7 days

MCT-rich feedings 7–10 days Improvement

Failure

Surgical options

TPN 3 weeks

Failure Success

Failure

MCT-rich feedings 21 days

Success Effusion resolving

Postoperative chylothorax

Bilateral chylothorax, SVC obstruction, Congenital lymphangiectasia

Thoracoscopic Thoracic duct ligation + fibrin glue

Regular diet

Primary approach

Failure Pleuroperitoneal shunt Failure Pleurectomy Direct open ligation Lymphatic leaks

Success Shunt remains until effusions resolve (2–3 months)

Figure 29.3 Algorithm of management principles. SVC: superior vena cava; MCT: medium-chain triglycerides; TPN: total parenteral nutrition

centers across North America. First used by Azizkhan et al 75 in 1983 to treat ﬁve ventilator-dependent infants with persistent chylothorax, this procedure is considered safe, highly effective, and easy to perform. Moreover, it avoids the risks of a more complicated, open surgical procedure.74–77 The ideal shunt should have a pumping chamber that is capable of handling ﬂuid with an increased viscosity. It should contain a one-way valve system that opens at a very low pressure to allow transport of lymph from the pleural space, with a mean negative pressure, to the abdominal cavity, with a mean positive pressure. It should also have a reservoir that allows for percutaneous irrigation of the entire shunting system. At Cincinnati Children’s Hospital Medical Center, we use a pleuroperitoneal shunt system (Denver Biomaterials, Inc, Evergreen, CO) that is specially designed for pediatric

patients. The shunt has two polyester cuffs, a doublevalved pumping chamber, and fenestrated afferent and efferent catheter limbs; it is ﬂexible and can be trimmed to the appropriate length. The chamber has a pumping volume of 1.0–1.5 mL and is usually used for infants younger than 6 months. The valves open at a positive pressure of approximately 1.0 cm H2O and are designed to prevent retrograde movement of the chyle through the system. Manual pumping is used to transport ﬂuid from the pleural space into the peritoneal cavity. The shunting procedure is carried out under general anesthesia. The infant is kept in a supine position, with the affected hemithorax elevated by 25–30° on the operating table. A short transverse incision is made over the affected lower chest at the anterior axillary line, allowing access for the pleural catheter; this catheter is then tunneled 2–3 cm through the subcutaneous tissues

288 Chylothorax and other pleural effusions in neonates

(Fig. 29.4a, b). It is placed into the thorax at approximately the seventh or eighth intercostal space in the posterior axillary line, thereby allowing dependent drainage. A second small incision is made overlying the rectus muscle sheath in the upper abdomen midway between the costal margin and the level of the umbilicus. Prior to placement of the peritoneal catheter, the pumping chamber is compressed repeatedly to verify effective pumping action and proper transport of chyle from the thorax. The efferent catheter is tunneled 2–3 cm and placed into the peritoneal cavity through the rectus incision similar to a Tenckhoff catheter placement. A purse-string suture is used in the posterior rectus fascia to secure the catheter. A postoperative chest radiograph is obtained to make certain that the pleural catheter is properly placed. During the immediate postoperative period the pumping chamber is compressed 50–100 times per hour in order to completely clear the hemithorax of chyle. As the

infant’s clinical status improves, a gradual decrease in the frequency of shunt compression is begun. Non-invasive transcutaneous oxygen saturation monitoring, arterial blood gas determination, and serial chest radiographs are used to assess shunt efﬁcacy (Fig. 29.5). Manual compression of the shunt valve is discontinued when it is clear that chylothorax is resolved. This often occurs within 2–3 weeks. However, some infants require a more prolonged period of manual compression, lasting 6–8 weeks. A high-ﬂow external shunt designed to avoid some of the discomfort and positioning problems associated with a subcutaneous reservoir has recently become available.78 Once the chylous effusion clears, parents are taught the technique of pumping the chamber and the patient is discharged from the hospital. Over the ensuing 2–3 months, the frequency of pumping is further reduced. When the chylous effusion completely resolves, the catheter is removed. This approach offers less interruption of the sleep cycle and may facilitate a shorter hospital stay. It could, nevertheless, theoretically increase the likelihood of infection, but this has yet to be veriﬁed in clinical studies. While there has been some concern that elevated right atrial pressures transmitted to the venous and lymphatic bed of the peritoneal space may impair absorption of shunted pleural ﬂuid,73,79 a recent study has reported the successful use of pleuroperitoneal shunting with this patient population, even in the face of moderate elevations in right atrial pressure.73 Failure to resolve chylous effusions is associated with occlusion of the shunt catheter or signiﬁcant intra-abdominal chylous ascites. When the latter occurs, a pleuroperitoneal shunt

(a)

Reservoir Pumping chamber

(b) Figure 29.4 (a) Pleuroperitoneal shunt. (b) Schematic illustration showing placement of a pleuroperitoneal shunt

Figure 29.5 Chest radiograph showing resolution of a chylothorax after pleuroperitoneal shunt placement

Fetal chylothorax (hydrothorax) 289

and a peritoneovenous shunt combination has been successfully used in anecdotal cases. Encouraged by the success of pleuroperitoneal shunting in the management of refractory chylothorax, investigators have applied the same principle in the management of patients with chylopericardium. Case reports indicate that pericardial–peritoneal shunting provides an easy and effective alternative to prolonged pericardial drainage, thoracotomy, or thoracic duct ligation in patients with chylopericardium of various etiologies.80

OTHER SURGICAL ALTERNATIVES Although thoracic duct ligation has historically been the most common surgical therapy and has indeed been a successful approach in terms of resolving chylous leakage,5,81–83 it requires an already compromised, frail, and often premature neonate to undergo a major surgical procedure. Despite this drawback, it remains an option when pleuroperitoneal shunting fails to resolve the chylous leak or when chylothorax is due to penetrating trauma. The affected hemithorax is opened by a posterolateral thoracotomy through the sixth intercostal space. Giving cream through the nasogastric tube several hours before operation helps to identify the sites of leakage of the milky white ﬂuid. Major leaks from the thoracic ducts can be closed by direct suturing or ligating the duct above and below the leak. Chemical or talc pleurodesis84 and parietal pleurectomy85 have been used when there is generalized weeping of chyle from parietal pleura. However, these are also extensive surgical procedures that may increase the possibility of pulmonary lymphedema, ﬁbrosis, and further pulmonary demise.74 Fibrin glue applied to the leakage site after patent ductus arteriosus ligation has recently been reported to successfully manage chylothorax in both a 3.5-month-old infant,86 and a premature infant weighing 600 g.87 Video-assisted procedures are being used with increasing frequency. Video-assisted thoracoscopy offers the advantage of access to the entire hemithorax, with excellent visualization of the mediastinal structures. It allows application of clips to the thoracic duct at the hiatus or to the thoracic duct injuries or pleural defects. It also allows pleurodesis and application of ﬁbrin glue. However, despite its advantages, its use is limited by the infant’s size and pulmonary status. Also, it may be difﬁcult to correctly visualize leaks in the presence of a massive chylous effusion.

FETAL CHYLOTHORAX (HYDROTHORAX) Diagnosis and outcome Congenital chylothorax is the most common cause of fetal effusions. Moreover, with the growth in sonography

over the past 3 decades, it is being diagnosed with increasing frequency – as early as at 17 weeks’ gestation to an average of 30 weeks.34 For the most part, reviews indicate that congenital chylothorax has a much better prognosis when diagnosed after birth than when discovered in utero.1,12,13,60 In contrast to the relatively low mortality rate of newborns diagnosed at birth, only half of all diagnosed fetuses survive. Survival depends on multiple factors, including the presence of associated anomalies, and the gestational age at which diagnosis is ﬁrst made. The prognosis of small volume, unilateral, isolated fetal pleural effusion is usually good, with spontaneous resolution sometimes observed.60,88–90 Prognosis is poor when effusion is associated with chromosomal aberrations, multiple malformations and fetal hydrops. Since most large pleural effusions discovered in utero lead to hydrops and pulmonary hypoplasia, such effusions have a high mortality rate.60 Furthermore, retrospective studies have shown that the absence of hydrops predicts 100% survival; fetuses that initially presented without hydrops and subsequently developed it, had only a 38% survival.34 From a broad perspective, antenatal diagnosis is signiﬁcant not only in that it can often identify the need for potentially helpful intrauterine intervention and facilitate preparation of appropriate postnatal outcome, but also in that it has been found to be a reliable predictor of fatal outcome.91,92 As such, it facilitates the communication of a more accurate prognosis to parents. The presence of hydrops predicts poor perinatal outcome and indeed suggests a strong indication for therapeutic intervention.

Management The management of fetal chylothorax has been a matter of controversy and the optimal approach to its treatment remains unknown. Dissension is focused primarily on the following issues: (1) whether treatment should be attempted in utero or the infant should be delivered and treated after birth, (2) under what clinical circumstances antenatal intervention should be carried out, and (3) whether thoracentesis or pleuroamniotic shunting should be used for thoracic decompression. In an attempt to propose an overall prenatal management scheme, Weber and Philipson93 recently reviewed 124 cases from 38 reports in the medical literature on fetal pleural effusion. They concluded that the presence of three risk factors indicated the highest probability of poor outcome – delivery at less than 32 weeks’ gestation, presence of hydrops, and absence of antenatal intervention. While both thoracentesis and pleuroamniotic shunting have successfully managed prenatal chylothorax,31,32,60,61,94–98 the paucity of published data prevents generalized conclusions as to which approach is better. Both involve

290 Chylothorax and other pleural effusions in neonates

risks and potential complications. In a relatively recent (1995) case report, the authors suggest that in certain cases (nonimmune hydrops associated with a unilateral pleural effusion), single or serial thoracenteses may forego the need for intrathoracic shunt placement. If chylous effusions are not successfully reduced with two thoracenteses, they recommend the placement of a thoracic shunt. As they nevertheless maintain, in light of the scarcity of data, these recommendations are speculative at best.

OTHER PLEURAL EFFUSIONS Hemothorax Although massive hemothorax is very uncommon, accidental injury to the intercostal artery during thoracentesis or closed intercostal drainage can result in intrapleural bleeding.99 Hemothorax has been reported as a complication of a variety of congenital malformations (e.g. sequestration, patent ductus, and pulmonary arteriovenous malformation) and of subclavian vein catheters.100 It is also an occasional manifestation of intrathoracic neoplasms and blood dyscrasias, and bleeding diatheses.101 Additionally, it can occur spontaneously in neonates, sometimes in association with a pneumothorax. Symptoms reveal respiratory embarrassment similar to that seen in tension pneumothorax. However, the percussion note is dull and chest radiographs show opaciﬁcation. More importantly, the infant may show signs of hypovolemic shock. Blood transfusion and urgent tube thoracostomy generally provide adequate control of bleeding. To avoid sudden circulatory collapse, transfusion should precede intercostal drainage. If massive blood loss continues, urgent thoracotomy and identiﬁcation and securing of the bleeding site is required.99

Empyema Owing primarily to improved antibiotic treatment of chest infections, empyema (purulent effusion) has become a rare condition in infants. The most common cause of empyema is a pneumonia caused by organisms such as Staphylococcus areus, Pneumococcus and Hemophilus inﬂuenzae. It may, however, be incurred through the introduction of skin bacteria during thoracentesis or thoracotomy. Empyema may also be accompanied by anaerobic infection.102 Symptoms include indications of respiratory distress, in addition to abdominal distension, lethargy, and at times, a septicemic state. Diagnosis is suspected by chest radiograph in which the effusion and pneumonic process is identiﬁed. Ultrasonography during diagnostic thoracentesis is helpful in localizing the ﬂuid, if loculated. Prior to beginning a course of

antibiotic therapy, a ﬂuid specimen taken during thoracentesis is sent for a Gram stain and aerobic and anaerobic culture. While most cases resolve with effective intercostal tube drainage and a prolonged period of systemic administration of antibiotics, anaerobic infection tends to be multi-locular and may thus require debridement, and in rare instances, decortication.

REFERENCES 1. Vain NE, Swarner OW, Cha CC. Neonatal chylothorax. A report and discussion of nine consecutive cases. J Pediatr Surg 1980; 15:261–5. 2. Van Aerde J, Campbell AN, Smyth JA et al. Spontaneous chylothorax in newborns. Am J Dis Child 1984; 138:961–4. 3. Curci MR, Debbins AW. Bilateral chylothorax in a newborn. J Pediatr Surg 1980; 15:663–5. 4. Kosloske AM, Martin LW, Schubert WK. Management of chylothorax in children by thoracentesis and medium chain triglyceride feedings. J Pediatr Surg 1974; 9:365–71. 5. Bessone LN, Ferguson TB, Burford TH. Chylothorax: collective review. Ann Thorac Surg 1971; 12:527–50. 6. Randolph JG, Gross RE. Congenital chylothorax. Arch Surg 1957; 74:405–19. 7. Schackelford RT, Fisher AM. Traumatic chylothorax. South Med J 1938; 11:766–75. 8. Lampson RS. Traumatic chylothorax: a review of the literature and report of a case treated by mediastinal ligation of the thoracic duct. J Thorac Surg 1948; 17:778–91. 9. Higgins CB, Reinke RT. Postoperative chylothorax in children with congenital heart disease. Pediatr Radiol 1976; 119:409–13. 10. Verunelli F, Georgini V et al. Chylothorax following cardiac surgery in children. J Cardiovasc Surg 1983; 24:227–30. 11. Decancq HG. The treatment of chylothorax in children. Surg Gynecol Obstet 1965; 121:509–12. 12. Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr 1970; 76:624–32. 13. Brodman RF. Congenital chylothorax, recommendations for treatment. NY J Med 1975; 75:553–7. 14. Sabin FR. The origin and development of the lymphatic system. Johns Hopkins Hosp Rep 1916; 17:347–440. 15. McKendry JBJ, Lindsey WK, Gerstein MC. Congenital defects of the lymphatics in infancy. Pediatrics 1957; 19:21. 16. Bond SJ, Guzzetta PC, Snyder ML et al. Management of pediatric postoperative chylothorax. Ann Thorac Surg 1993; 56:469–73. 17. Strausser JL, Flye MW. Management of nontraumatic chylothorax. Ann Thorac Surg 1981; 31:520–6. 18. Harvey JG, Houlsby W, Sherman K et al. Congenital chylothorax: report of a unique case associated with ‘H’-type tracheo-oesophageal ﬁstula. Br J Surg 1979; 46:485–7.

References 291 19. Yancy WS, Spock A. Spontaneous neonatal pleural effusion. J Pediatr Surg 1967; 2:313–19. 20. Berberich FR, Bernstein ID, Ochs HD et al. J Pediatr 1975; 87:941–3. 21. Morphis IG, Arcinne EL, Krause JR. Generalized lymphangioma in infants with chylothorax. Pediatrics 1970; 46:566–75. 22. Takamato RM, Armstrong RG, Stanford W et al. Chylothorax with multiple lymphangiomatoses of the bone. Chest 1971; 59:681–2. 23. Dunkelman H, Sharief N, Berman L et al. Generalized lymphangiomatosis with chylothorax. Arch Dis Child 1989; 64:1058–60. 24. Moerman P, VanGeet C. Lymphangiomatosis of the body wall. Pediatr Pathol Lab Med 1997; 17:617–24. 25. Thomas HM, Shaw NJ, Weindling AM. Generalized lymphangiomatosis with chylothorax. Arch Dis Child 1990; 65:334. 26. Dutheil P, Leraillez J, Guillemette J et al. Generalized lymphangiomatosis with skin lymphangiomas in a neonate. Pediatr Dermatol 1998; 15:296–8. 27. Noonan J, Walter LR, Reeves JT. Congenital pulmonary lymphangiectasis. Am J Dis Child 1970; 120:314–19. 28. Moerman P, Vandenberghe K, Devlieger H et al. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am J Med Genet 1993; 47:54–8. 29. Hunter W, Becroft D. Congenital pulmonary lymphangiectasis associated with pleural effusions. Arch Dis Child 1984; 59:278–9. 30. Adiotomre PNA, Burns JE, McIntosh N. Hydrops foetalis and chylothorax associated with superior caval vein obstruction and resolution following balloon dilatation. Acta Paediatr 1994; 83:983–5. 31. Mussat P, Dommergues M, Parat S et al. Congenital chylothorax with hydrops: postnatal care and outcome following antenatal diagnosis. Acta Pediatr 1995; 84:749–55. 32. Aguirre OA, Finley BE, Ridgway LE III et al. Resolution of unilateral fetal hydrothorax with associated non-immune hydrops after intrauterine thoracentesis. Ultrasound Obstet Gynecol 1995; 5:346–8. 33. Ahmad FK, Sherman SJ, Hagglund KH et al. Isolated unilaterial fetal pleural effusion: the role of sonographic surveillance and in utero therapy. Fetal Diagn Ther 1996; 11:383–9. 34. Laberge JM, Crombleholme TM, Longaker MT. Fetal diseases and their management. In: Harrison MR, Golbus MS, Filly RA, editors. The Unborn Patient. 2nd edn. Philadelphia: W.B. Saunders Co., 1991: 314–19. 35. Yoss BS, Lipsitz PJ. Chylothorax in two mongoloid infants. Clin Genet 1977; 12:357–60. 36. Hamada H, Fujita K, Kubo T et al. Congenital chylothorax in a trisomy 21 newborn. Arch Gynecol Obstet 1992; 252:55–8. 37. Foote KD, Vickers DW. Congenital pleural effusion in Down’s syndrome. Br J Radiol 1986; 59:609.

38. Fisher E, Weiss EB, Michaels K et al. Spontaneous chylothorax in Noonan’s syndrome. Br J Pediatr 1982; 138:282–4. 39. Goens MB, Campbell D, Wiggins JW. Spontaneous chylothorax in Noonan syndrome. AJDC 1992; 146:1453–6. 40. Williams MS, Josephson KD. Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families. Am J Med Genet 1997; 73:286–9. 41. Easa D, Balaraman V, Ash K et al. Congenital chylothorax and mediastinal neuroblastoma. J Pediatr Surg 1991; 26:96–8. 42. Ibrahim H, Asamoah A, Krouskop RW et al. Congenital chylothorax in neonatal thyrotoxicosis. J Perintatol 1999; 19:68–71. 43. Cevese PG, Vecchioni R, D’Amico DF et al. Postoperative chylothorax. J Thorac Cardiovasc Surg 1975; 69:966–71. 44. Naik S, Greenough A, Zhang Y-X et al. Prediction of morbidity during infancy after repair of congenital diaphragmatic hernia. J Pediatr Surg 1996; 31:1651–4. 45. Claris O, Besnier S, Lapillonne A et al. Chylothorax following surgical repair of congenital diaphragmatic hernia in ﬁve neonates. Prenat Neonat Med 1996; 1:94–6. 46. Kavvadia V, Greenough A, Davenport M et al. Chylothorax after repair of congenital diaphragmatic hernia—risk factors and morbidity. J Pediatr Surg 1998; 33:500–2. 47. Dhande V, Kattwinkel J, Alford B. Recurrent bilateral pleural effusion secondary to superior vena cava obstruction as a complication of central venous catheterization. Pediatrics 1983; 72:109–13. 48. Ruggieto RP, Caruso G. Chylothorax – a complication of subclavian vein catheterization. J Parenter Enter Nutr 1985; 9:750–3. 49. Seguin JH. Right-sided hydrothorax and central venous catheters in extremely low birthweight infants. Am J Perinatol 1992; 9:154–8. 50. Kramer SS, Taylor GA, Garﬁnkel DJ et al. Lethal chylothoraces due to superior vena caval thrombosis in infants. AJR 1981; 137:559–63. 51. Blalock A, Cunningham RS, Robinson CS. Experimental production of chylothorax by occlusion of the superior vena cava. Ann Surg 1936; 104:359–63. 52. Liote H, Hamy I, Piganeau N et al. Neonatal bilateral chylothoraces secondary to obstruction of the superior vena cava (as complication of inadvertent placement of an umbilical vein catheter). Radiographics 1990; 10:152–6. 53. Kumar SP, Belik J. Chylothorax—a complication of chest tube placement in a neonate. Crit. Care Med 1984; 12:411–12. 54. Wilson-Storey D, MacKinlay GA. Thoraco-abdominal birth injury—presentation, diagnosis and management in an unusual case. Scot Med J 1987; 32:89–90. 55. Rodgers BM. Verbal communication, 2000. 56. Nguyen DM, Shum-Tim D, Dobell ARC et al. The management of chylothorax/chylopericardium following pediatric cardiac surgery: a 10-year experience. J Card Surg 1995; 10:302–8.

292 Chylothorax and other pleural effusions in neonates 57. May DA, Barth RA, Yeager S et al. Perinatal and postnatal chest sonography. Radiol., Clin North Am 1993; 31:499–516. 58. Petres RE, Redwine FO, Cruikshank DP. Congenital bilateral chylothorax: antepartum diagnosis and successful intrauterine surgical management. JAMA 1982; 28:1360–1. 59. Jaffa AJ, Barak S, Kaysar N et al. Antenatal diagnosis of bilateral congenital chylothorax with pericardial effusion. Acta Obstet Gynecol Scand 1985; 64:455. 60. Longaker MT, Laberge JM, Dansereau J et al. Primary fetal hydrothorax: natural history and management. J Pediatr Surg 1989; 24:573–6. 61. Rodeck CH, Fisk NM, Fraser DI et al. Long-term in-utero drainage of fetal hydrothorax. N Engl J Med 1988; 319:1135–8. 62. Allen EM, VanHeeckeren DW, Spector ML et al. Management of nutritional and infectious complications of postoperative chylothorax in children. J Pediatr Surg 1991; 26:1169–74. 63. Robinson C. The management of chylothorax. Ann Thor Surg 1985; 39:90–5. 64. Rubin JW, Moore HV, Ellison RG. Chylothorax: therapeutic alternatives. Am Surg 1977; 43:292–7. 65. Hashim S, Roholt HB, Babayan VK et al. Treatment of chyluria and chylothorax with medium-chain triglyceride. N Engl J Med 1964; 270:756–61. 66. Le Coultre C, Oberhansli I, Mossaz A et al. Postoperative chylothorax in children: differences between vascular and traumatic origin. J Pediatr Surg 1991; 26:519–23. 67. Ullibarri JI, Saqnz Y, Fuentes C et al. Reduction of lymphorrhagia from ruptured thoracic duct by somatostin. Lancet 1990; 336 (8709):258. 68. Caty MG, Hilﬁker ML, Azizkhan RG et al. Successful treatment of congenital chylous ascites with a somatostatin analogue. Pediatr Surg Int 1996; 11:396–7. 69. Berkenbosh JW, Withington DE. Management of postoperative chylothorax with nitric oxide: a case report. Crit Care Med 1999; 27:1022–4. 70. Higgins CB, Mulder DG. J Thorac Cardiovasc Surg 1971; 61:411–18. 71. Puntis JWL, Roberts KD, Handy D. How should chylothorax be managed? Arch Dis Child 1987; 62:593–6. 72. Stringel G, Mercer S, Bass J. Surgical management of persistent postoperative chylothorax in children. Can J Surg 1984; 27:543–6. 73. Rheuban KS, Kron IL, Carpenter MA et al. Pleuroperitoneal shunt for refractory chylothorax after operation for congenital heart disease. Ann Thorac Surg 1992; 53:85–7. 74. Engum SA, Rescorla FJ, West KW et al. The use of pleuroperitoneal shunts in the management of persistent chylothorax in infants. J Pediatr Surg 1999; 34:286–90. 75. Azizkhan RG, Canﬁeld J, Alford BA et al. Pleuroperitoneal shunts in the management of neonatal chylothorax. J Pediatr Surg 1983; 18:842–8.

76. Murphy MC, Newman BM, Rodgers BM. Pleuroperitoneal shunts in the management of persistent chylothorax. Ann Thorac Surg 1989; 48:195–200. 77. Milsom JW, Kron IL, Rheuban KS et al. Chylothorax: an assessment of current surgical management. J Thorac Cardiovasc Surg 1985; 89:221–7. 78. Cummings SP, Wyatt DA, Baker JW et al. Successful treatment of postoperative chylothorax using an external pleuroperitoneal shunt. Ann Thorac Surg 1992; 54:276–8. 79. Sade RM, Wiles HB. Pleuroperitoneal shunt for persistent pleural drainage after Fontan procedure. J Thorac Cardiovasc Surg 1990; 100:621–3. 80. Chan BBK, Murphy MC, Rodgers BM. Management of chylopericardium. J Pediatr Surg 1990; 25:1185–9. 81. Selle JG, Snyder WH, Schreiber JT. Chylothorax: indications for surgery. Ann Surg 1973; 177:245–9. 82. Patterson GA, Todd TRJ, Delarue NC et al. Supradiaphragmatic ligation of the thoracic duct in intractable chylous ﬁstula. Ann Thorac Surg 1981; 32:44–9. 83. Goorwitch J. Traumatic chylothorax and thoracic duct ligation. Case report and review of the literature. J Thorac Surg 1955; 29:467–79. 84. Adler RH, Levinsky L. Persistent chylothorax: treatment by talc pleurodesis. J Thorac Cardiovasc Surg 1978; 76:859–64. 85. Barret DS, Large SK, Rees GM. Pleurectomy for chylothorax associated with intestinal lymphangiectasia. Thorax 1987; 42:557–8. 86. Stenzl W, Rigler B, Tscheliessnigg KH et al. Thoracic Cardiovasc Surg 1983; 31:35–6. 87. Nguyen D, Tchervenkov CI. Successful management of postoperative chylothorax with ﬁbrin glue in a premature neonate. Can J Surg 1994; 37:158–60. 88. Kerr-Wilson RHJ, Duncan A, Hume R et al. Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn 1985; 5:73–6. 89. Jaffe R, Di Segni E, Altaras M et al. Chylothorax spontanie neontatale. Arch Fr Pediatr 1986; 43:752. 90. Lien JM, Colmorgen GHC, Gehret JF et al. Spontaneous resolution of fetal pleural effusion diagnosed during the second trimester. J Clin Ultrasound 1990; 18:54–6. 91. Thompson PJ, Greenough A, Brooker R et al. Antenatal diagnosis and outcome in hydrops fetalis. J Perinat Med 1993; 21:63–7. 92. Echeverria LJ, Benito A, Arena AJ et al. Congenital chylothorax. An Esp Pediatr 1998; 49:161–4. 93. Weber AM, Philipson EH. Fetal pleural effusion: a review and meta-analysis for prognostic indicators. Obstet Gynecol 1992; 79:281–5. 94. Schmidt W, Harms E, Wolf D. Successful prenatal treatment of non-immune hydrops fetalis due to congenital chylothorax: case report. Br J Obstet Gynecol 1985; 92:685–7. 95. Seeds J, Bowes W. Results of treatment of severe fetal hydrothorax with bilateral pleuroamniotic catheters. Obstet Gynecol 1986; 68:577–80.

References 293 96. Roberts A, Clarkson P, Pattison N et al. Fetal hydrothorax in the second trimester of pregnancy: successful intrauterine treatment at 24 weeks gestation. Fetal Ther 1986; 1:203–6. 97. Blott M, Nicolaides KH, Greenough A. Pleuroamniotic shunting for decompression of fetal pleural effusions. Obstet Gynecol 1988; 71:798–800. 98. Mandelbrot L, Dommergues M, Aubry MC et al. Reversal of fetal distress by emergency in utero decompression of hydrothorax. Am J Obstet Gynecol 1992; 167:1278–83. 99. Haller JA. Thoracic injuries. In: Welch KJ, Randolph JG,

Ravich MM, editors. Pediatric Surgery. 4th edn. Chicago: Year Book Medical Publishers, 1986: 143–54. 100. Feliciano D, Mattox K, Graham J et al. Major complications of percutaneous subclavian vein catheters. Am J Surg 1979; 138:869. 101. Stern RC. Diseases of the pleura. In: Beherman RE, Baughan VC, Nelson WE, editors. Philadelphia: W.B. Saunders, 1987: 936–40. 102. Upadhyaya P. Management of empyema thoracis. In: Spitz L, Nixon H, editors. Rob and Smith’s Operative Surgery (Paediatric Surgery). 4th edn. London: Butterworths, 1988: 166–79.

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30 Congenital malformations of the lung HORACE P. LO AND KEITH T. OLDHAM

INTRODUCTION Congenital lung abnormalities are uncommon and diverse in their presentation. However, all those who care for infants and children must have an appreciation for the diagnosis and treatment of these anomalies because the potential consequences can be life threatening. In order to understand the pathophysiology of these malformations, a basic understanding of the embryology of lung development as well as respiratory physiology and anatomy is required and these are brieﬂy presented later. Classical lesions including congenital lung cysts, cystic adenomatous malformation, pulmonary sequestration and lobar emphysema will be considered in some detail later, as well as a number of the less common anomalies.

EMBRYOLOGY During the third week of gestation, the human embryo develops a diverticulum of the ventral foregut, which forms the primordium of the respiratory system. This is mainly of endodermal origin; however, cartilaginous and muscular elements will be derived from the splanchnic mesoderm that surrounds the primitive foregut. As the respiratory diverticulum grows caudad, it becomes separated from the foregut by the lateral esophagotracheal ridges, which fuse to form a septum at the end of the fourth gestational week. Thus, the dorsal esophagus and the more ventral trachea and lung buds are deﬁned. The larynx, which is formed from the fourth and sixth branchial arches, maintains communication between the pharynx and the trachea. The lung buds penetrate the coelomic cavity by caudal growth, resulting in the formation of pleuroperitoneal canals on either side of the foregut. The expanding lung buds eventually come to nearly ﬁll these canals, with the small residual spaces becoming the primitive pleural cavities. The right lung bud divides into three lobes whereas the left divides into two by the mid-portion of

the embryo’s sixth week. The bronchi continue successive dichotomous division, and by the end of the sixth month of gestation, 17 generations of subdivisions have formed. This period is also the time at which terminal bronchioles and alveoli are forming. An additional six divisions of the terminal airways will occur during early postnatal life, however, lung development probably does not cease until about 8 years of age.1 Thus development of conductive airways is essentially complete by the end of the second trimester, while terminal airways and alveoli, which are the site of gas exchange, continue to develop in late fetal life and indeed during infancy and early childhood. As one considers the various clinical lesions and their therapeutic options this perspective is critical.2,3 The pulmonary vasculature begins to develop in the mesoderm around the primitive lung buds at 7–8 weeks of gestation. By the seventh gestational month, pulmonary blood ﬂow has matured to the point where gas exchange is possible.

ANATOMY A brief discussion of clinically relevant anatomy is appropriate; several excellent references are available for a more detailed review.4,5 As seen in early gestational development of the lungs, the mature right lung is composed of three lobes in contrast to the two lobes of the left. The carina is positioned at the level of the fourth thoracic vertebral body in the term infant. The mainstem bronchus of the right lung follows a straighter, more caudad course and is usually shorter and larger in diameter than that of the left. This accounts for the preference of aspirated material to enter the right lower lobe or the posterior segment of the right upper lobe as well as for right mainstem bronchus intubation during endotracheal tube placement. The vascular supply of the trachea, bronchi, and lung parenchyma is systemic in origin and separate from the pulmonary arterial circulation, which is dedicated to gas

296 Congenital malformations of the lung

exchange. The trachea is supplied by branches of the paired inferior thyroid arteries, which anastomose with the bronchial blood supply derived from the aorta on the left, and the third intercostal artery on the right. Venous drainage is via the azygous and hemiazygous systems. This systemic arterial supply and its accompanying venous drainage generally follow the segmental architecture of the lung and bronchi.4–6

CONGENITAL LOBAR OVERINFLATION OR CONGENITAL LOBAR EMPHYSEMA Congenital lobar overinﬂation (CLO), otherwise known as congenital lobar emphysema, is among the most common of the congenital lung anomalies. It is characterized by air trapping and overdistention of one or more lobes which are otherwise anatomically normal. This distention causes compression of adjacent normal lung parenchyma and can result in mediastinal shift and cardiorespiratory compromise (Fig. 30.1). Although a speciﬁc etiology of this disorder cannot be demonstrated in up to half of reported cases,7 it is believed to result most commonly from structural deﬁciency or absence of supportive cartilage in the affected lobar bronchus, thereby causing expiratory collapse of the conducting airway with impedance to expiratory ﬂow.8 Other reported etiologies include extrinsic compression from anomalous or enlarged blood vessels, congenital heart disease, mediastinal lymphadenopathy, bronchogenic and enteric cysts, and tumors.9 Partial obstruction from a reversible endobronchial source such as mucous plugging, inﬂammation, or aspirated materials is a possible cause and should be ruled out by rapid and judicious bronchoscopic evaluation in order to avoid unnecessary lung resection.

Figure 30.1 Congenital lobar emphysema. Chest radiograph in a 3-day-old infant who presented with respiratory distress, showing marked hyperinﬂation of right upper lobe

Polyalveolar morphology mimics lobar emphysema in its clinical presentation. This is a descriptive histologic term that refers to unusual and abnormal anatomic ﬁndings characterized by an increase in the number of alveoli in a particular lobe, resulting in expiratory air trapping and lobar overdistension with respiratory compromise. This is in contrast to lobar emphysema where alveolar histopathology is normal except for overdistention. The diagnosis and treatment of polyalveolar morphology are not different than for congenital lobar emphysema. Congenital lobar emphysema is most often seen in the Caucasian population with a 2:1 or 3:1 male preponderance. It is most common in the left upper lobe (40–50%), with other sites affected less frequently: right middle lobe (30–40%), right upper lobe (20%), and lower lobes (1%).10,11 In 15% of infants, lobar emphysema is associated with congenital heart disease or abnormalities of the great vessels;12,13 therefore, routine echocardiography is recommended in the screening evaluation of these patients.

Presentation and diagnosis Contrary to its moniker, patients with congenital lobar emphysema do not demonstrate respiratory problems immediately at birth, rather they develop symptoms as lobar distention progresses over time with expiratory air trapping in the course of postnatal air breathing. Severity is usually related to age of presentation; the most threatening presentations typically occur in newborns. Approximately half of patients develop respiratory distress within the newborn period while the remainder present up to 4–6 months of age7 or later. Presenting signs are those of respiratory embarrassment, including dyspnea, tachypnea, agitation, and wheezing. Depending upon the severity of adjacent lung compression, cyanosis and respiratory failure can result. Therefore, the surgeon must be available for emergent decompressive thoracotomy, particularly when positivepressure ventilation is employed at procedures such as anesthesia induction or bronchoscopy. A few older children may present with milder symptoms such as recurrent respiratory infections or cough. On exam, the patient with congenital lobar emphysema will demonstrate signs consistent with a hyperinﬂated lobe, including thoracic and respiratory asymmetry, decreased breath sounds and percussive hyperresonance of the ipsilateral chest. Findings of mediastinal shift such as tracheal deviation, and displacement of the cardiac apical impulse are relatively late clinical signs. Chest roentgenography is the initial diagnostic maneuver of choice (Fig. 30.1). There is increased lucency over the affected side, with accompanying atelectasis of adjacent compressed parenchyma and a ﬂattened ipsi-

Congenital cystic adenomatoid malformations 297

lateral hemidiaphragm. Mediastinal displacement to the contralateral side may also be apparent. The chest radiograph should be inspected closely in order to differentiate between congenital lobar emphysema and tension pneumothorax, which may have similar presentation and appearance, but vastly different management. The latter problem, tension pneumothorax, has no peripheral lung markings visible while lobar emphysema does with careful inspection of the ﬁlms. In the ﬁrst hours after birth, the affected lobe may still be ﬁlled with fetal lung ﬂuid and therefore have the appearance of a ﬂuid-density mass lesion. Some authors advocate ventilation-perfusion radioisotope scanning as a useful adjunct to the chest radiograph.14 Others advise the use of computed tomography (CT) and magnetic resonance imaging (MRI). However, these studies are reserved generally for situations in which the diagnosis is in doubt.15

Treatment If a correctable source of endobronchial obstruction cannot be found and successfully reversed, then the often-progressive nature of this lesion, as well as the risk of respiratory failure, dictate thoracotomy with lobectomy of the affected lobe in infants. For the older child without symptoms, this approach can be reasonably tempered. Reconstructive procedures such as bronchoplasty or segmental bronchial resection are generally not appropriate as the bronchial defects may not be focal or readily localized. In addition, lobectomy in the infant population is very well tolerated16,17 and bronchial reconstruction in the newborn is fraught with technical limitations.

CONGENITAL CYSTIC ADENOMATOID MALFORMATIONS Congenital cystic adenomatoid malformations (CCAMs) are a rare group of cystic lobar hamartomatous lesions, but represent up to 50–70% of the bronchopulmonary foregut malformations in some reports.18,19 The lesions are generally large, ﬁrm, multicystic masses that are composed of terminal respiratory structures, usually bronchiolar in origin. CCAMs are thought to result from developmental arrest in terminal bronchiole maturation, resulting in marked overgrowth of these structures in relation to alveoli. This lesion is characterized by a mass of interconnected and disorganized cysts on gross inspection. Because of the histopathology and associated disorders of organogenesis, it has been proposed that the pathogenic event occurs between 3–7 weeks’ gestation, although the precise pathogenesis is unknown.20 Involvement is usually unilobar, with a slight predilection for the lower lobes; right and left sides are affected equally. Histology demonstrates ciliated cuboidal or columnar cells lining the cysts,

with a lack of organized architecture; usually no cartilage is present (Fig. 30.2). These malformations typically communicate with the normal bronchial tree and have a normal vascular supply, although aberrant systemic vasculature, sometimes derived from the aorta, has been described.21 Stocker et al. classiﬁed CCAM into three distinct pathologic types (Table 30.1),22 which carry both descriptive and prognostic signiﬁcance. Type I CCAM accounts for about 50% of cases. These consist of one or more large (> 2 cm) cysts. Patients usually have a good prognosis. Type II lesions have multiple smaller cysts (< 2 cm), and are frequently associated with other congenital anomalies. Type III lesions are more solid than cystic in nature. Both Types II and III lesions have a poor clinical outcome, presumably because they tend to be relatively large and noncompressible, thus limiting normal maturation and development of unaffected but adjacent lung. Physiologic consequences of CCAM can be seen antepartum and occur secondary to mediastinal shift and compression of normal lung tissue. Large masses, especially those involving Types II or III lesions can result in hydrops fetalis and fetal demise. Postpartum complications result from pulmonary hypoplasia of the remaining lung in newborns or secondary infection in older infants and children. Although the presenting symptoms of respiratory failure may be dramatic, only about one-third of patients present in this fashion.23 Most lesions not discovered prenatally will be discovered because of recurrent pneumonia or lung abscess resulting from inability to effectively clear secretions from the abnormal lobe. Gestational polyhydramnios is common with CCAM and may contribute to prematurity, which does affect outcome as well. Malignant degeneration can occur in all congenital cystic lung lesions including CCAM. Although this is rare, it is clearly a long-term risk to be considered as management decisions are made.24

Figure 30.2 Cystic adenomatoid malformation of lung. Histology specimen of lung showing mucinogenic cells, papillary epithelium and disorganized, irregular alveoli

298 Congenital malformations of the lung Table 30.1 Classiﬁcation of congenital cystic adenomatoid malformation Characteristic

Type 1

Type II

Type III

Distribution Associated anomalies Respiratory distress

19 cases Rare (5%) Day 1 to 4 weeks of life

16 cases Common (56%) Day 1 of life plus symptoms of other congenital anomalies

3 cases None reported Within hours after birth

Gestational age Premature Term Not stated Stillborn

32% 52% 16% 16%

75% 25% – 32%

67% 33% – 33%

Gross and microscopic features Cysts Cystic wall cartilage Smooth muscle and elastic tissue Mucus-producing cells Striated muscle outside the cysts Between the cysts

Prognosis

Single or multiple large (>2 cm) Multiple, small (<2 cm) Absent Absent Prominent bands present Absent

Large non-cystic Absent Absent

Present in 30% Absent

Absent Absent

Absent Occasionally present

Alveolar-like structures 1–10 Distended respiratory No cysts, just masses of times the size of normal alveoli bronchioles and dilated alveoli alveolus-seized structures separating bronchiole-like structures Good

Poor

Poor

From Stocker et al.22 and Shamji et al.,25 by permission.

Presentation and diagnosis Since the advent of routine ultrasound in obstetric practice, the majority of cystic lung lesions are now discovered prenatally in many institutions in the USA. The location of the stomach aids in differentiation between CCAM and congenital diaphragmatic hernia (CDH), although prenatal MRI may be needed for deﬁnitive diagnosis in difﬁcult cases.26 Serial ultrasonographic examinations may demonstrate shrinkage or even spontaneous resolution in up to 40% of fetal CCAMs.19,27 More severe lesions may be associated with polyhydramnios or hydrops in the fetus as noted earlier. Polyhydramnios is thought to result from esophageal compression, preventing fetal swallowing of amniotic ﬂuid; hydrops results from mediastinal shift from the mass effect, diminishing cardiac output by vena caval obstruction.19 Either of these ﬁndings during pregnancy is associated with a poor outcome. After birth, some neonates demonstrate tachypnea, dyspnea, cyanosis, or impending respiratory failure. Of the remainder, most will present within the ﬁrst years of life with recurrent or persistent respiratory infections, pulmonary abscesses, reactive airway disease or failure to thrive. As for all bronchopulmonary foregut malformations, the plain chest radiograph is the best initial diagnostic test in the neonate (Fig. 30.3). Nasogastric tube position

Figure 30.3 Cystic adenomatoid malformation of the left lung with gross expansion of the lung, marked mediastinal shift to the right and downward displacement of the diaphragm. Note surgical emphysema of left axilla and chest wall, indicating rupture of a cyst

Congenital cystic adenomatoid malformations 299

is often helpful to distinguish CCAM from CDH, as an intrathoracic stomach is quite common with left CDH. The radiographic ﬁndings are variable; radiographs taken early in the neonatal period may demonstrate ﬂuid within the lesion, whereas later ﬁlms may show air-ﬁlled cysts. Mediastinal shift, an ipsilateral ﬂattened diaphragm and compressed adjacent normal lung may also be present, depending on the severity of disease. It is advisable to obtain an axial imaging study, either a chest CT scan with i.v. contrast or MRI in all patients with cystic lesions of the chest in order to establish a diagnosis as well as delineate anatomic relationships prior to elective resection (Fig. 30.4). Even those who have had spontaneous intrauterine involution of an apparent CCAM demonstrated by serial prenatal ultrasound should be evaluated with CT imaging following birth, as residual parenchymal abnormalities may be present28 and they may still be at risk for pulmonary infections or malignancy.

Treatment The treatment objective in patients with CCAM is to resect the abnormal tissue. Usually this requires postnatal thoracotomy with lobectomy. Patients with multilobular disease may beneﬁt from segmental resection if possible, and total pneumonectomy may be required occasionally.29 Prenatal diagnosis of CCAM should prompt referral to a tertiary care center, where critical care support and emergent pediatric surgical care is available. Like infants with congenital lobar emphysema, the switch to breathing air or positive pressure ventilation may rapidly precipitate a crisis in these patients if there is progressive distention of the affected lobe. Older children who present with pulmonary infection may be managed acutely with antibiotics; however, long-term expectant medical management is not appropriate due to the frequency and severity of infectious complications and the risk of malignant degeneration. As noted earlier, there are a number of reports of spontaneous shrinkage and/or resolution of fetal CCAMs, therefore serial ultrasounds in the fetus are recommended to document ﬁndings. Although it is a point of some controversy, these infants should undergo axial imaging following delivery with elective resection of residual anomalous parenchyma. Recent reports describe some success with fetal intervention for CCAM. The approaches have included thoracoamniotic shunting in lesions with a single predominant cyst, and resection in those with more complicated Types II and III CCAM. It appears that the learning curve for this approach is extremely steep and the risk of maternal–fetal complications is relatively high. The issue of appropriate prenatal patient selection is also critical since many of these fetuses do well without intervention and a number of the lesions resolve

(a)

(b) Figure 30.4 (a) Plain chest radiograph of a 9-year-old child who presented with fever, pleuritic chest pain, and cough. The lesion is an infected cystic adenomatoid malformation of the right lower lobe. (b) The lesion in a is shown on chest CT scan after treatment with antibiotics and before surgical resection of the right lower lobe (With permission from Coran AG, Oldham KT. The pediatric thorax. In: Greenﬁeld LJ, Mulholland MW, Oldham KT et al. editors. Surgery: Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott, 1993:944)

entirely. However, CCAM associated with fetal hydrops or polyhydramnios carries a high mortality rate and fetal intervention at specialized centers may be an option in some of these cases. The subject remains controversial.30,31

300 Congenital malformations of the lung

PULMONARY SEQUESTRATION Pulmonary sequestrations make up 10–30% of the cystic bronchopulmonary foregut malformations.29,32 They are classiﬁed by whether the sequestration resides within the visceral pleura of the normal lung (intralobar sequestration) or is invested by its own visceral pleura (extralobar sequestration). In both types of pulmonary sequestration however, there is no bronchial communication between the sequestrum and the normal tracheobronchial tree. In addition, the malformation receives its blood supply from aberrant systemic arterial vessels (Table 30.2). Intralobar sequestrations make up about 50–70% of the pulmonary sequestrations and most commonly involve the posterior and basal segments of the left lower lobe.33,34 As mentioned, these intralobar lesions are surrounded by normal lung parenchyma and pleura. The arterial supply is usually derived from aberrant branches of the descending thoracic aorta, although occasionally intercostal, brachiocephalic, or abdominal aortic aberrant vessels are encountered. Venous drainage is usually via the associated pulmonary vein. Although sequestrations are by deﬁnition nonfunctional and sequestered from the respiratory tree via functional bronchioles, intralobar sequestrations may communicate with neighboring alveoli in normal lung via abnormal air spaces, allowing some ventilation and airtrapping within the intralobar lesions. Extralobar sequestrations are completely separated from the normal lung, are invested by an individual pleura and are completely separate from the functional

airways. They are found in the left lower chest most commonly, but may occur anywhere; rarely, subdiaphragmatic locations are reported.34,35 A 3:1 male predominance is reported in most series for extralobar sequestrations. These sequestrations also derive arterial blood supply from the descending aorta, with up to 20% having an aberrant vessel traversing the diaphragm (Figs 30.5 & 30.6).36 Drainage into systemic veins, such as the azygous, hemiazygous, or the portal system is typical for extralobar sequestrations. There is an association of extralobar pulmonary sequestrations with CCAM and CDH37 as well as a variety of other congenital defects.6,29,37 Aberrant air space connections are not present, rather extralobar sequestrations are prone to hemorrhage or arterial-venous shunting and the patients may present with high-output congestive heart failure. The embryologic origin of pulmonary sequestrations is unclear, but they are thought to result from either abnormal budding of the tracheobronchial tree or accessory budding of the foregut, or a combination of the two. The stimulus is not known. Extralobar sequestrations are clearly congenital in origin. This conclusion is drawn by the frequent association with other congenital anomalies, their presence in neonatal autopsies, and the now routine discovery of these lesions on prenatal ultrasound.

Presentation and diagnosis Patients with intralobar sequestration will typically present with pulmonary infections due to abnormal airspace connections with inadequate drainage, or from

Table 30.2 Characteristics of pulmonary sequestrations Characteristic

Intralobar

Extralobar

Incidence Incidence ratio Sex Side Location Age at presentation and symptoms Associated anomalies

Uncommon 3 Equal 60% left Usually in the posterior basal segment Adolescent to young adults, 50% >20 years, recurrent pulmonary infections Uncommon

Rare 1 Male 80% 90% left Above the diaphragm, rarely below Neonate 60%, <1 year, respiratory distress

Diagnosis at neonatal autopsy Arterial supply Venous drainage

None Systemic – from aorta, large vessels, often a single Pulmonary – inferior pulmonary vein

Anatomical relations

Not separate, within and part of normal lobe

Connection with foregut Bronchial communication

Very rare Present, small

From Shamji et al.,25 by permission.

Frequent (>50%), e.g. congenital diaphragmatic hernia (30%) Frequent Systemic – from pulmonary or aorta, usually small vessels Systemic – azygos or hemiazygos vein; rarely portal vein Separate, has its own investment – visceral pleura More common None

Pulmonary sequestration 301

(a)

ultrasound has Doppler capability. If the mass is large, shift of mediastinal structures, fetal hydrops, and fetal demise can occur. Due to the frequency of associated anomalies, extralobar sequestrations are often diagnosed early in infancy during evaluation for these other problems. Plain radiographs of the chest will usually demonstrate an intralobar sequestration as a non-aerated, atelectatic mass, or as a cyst with an air-ﬂuid level (Fig. 30.5). Extralobar sequestrations typically appear as a left posterior mediastinal mass or triangular retrocardiac density on chest radiographs. In most infants and children with pulmonary sequestration, additional imaging beyond the initial radiographs is recommended. Ultrasound with Doppler, CT with contrast, or MRI provide good anatomic detail and demonstrate relationships to neighboring structures. Importantly, all delineate the aberrant arterial vessels for purposes of both diagnosis and preoperative planning. Preoperative upper gastrointestinal contrast study may assist in identifying the 10% of patients who have anomalous foregut communication with their sequestration, but some experienced pediatric surgeons do not do this routinely. Angiography, although considered routine in the past, is no longer necessary given the evolution of other less invasive imaging modalities detailed earlier.

Treatment

(b) Figure 30.5 Pulmonary sequestration. (a) Chest radiograph demonstrates a well-deﬁned mass at base of right lung. (b) Prenatal Doppler ultrasound demonstrating two aberrant arterial vessels to extralobar sequestration (arrow)

compressive atelectasis of adjacent parenchyma. Because of this, infants are rarely diagnosed with this lesion, rather presentation occurs later in childhood or adulthood with complaints of recurrent or refractory pneumonias, lung abscesses, or hemoptysis. Extralobar sequestrations, on the other hand, are frequently seen on prenatal ultrasound. The infants are often asymptomatic at birth, however, as noted, these lesions can be associated with arterial-venous shunting and congestive heart failure. The pathognomonic aberrant blood supply may be identiﬁed prenatally if the

Treatment for pulmonary sequestrations consists of excision of the abnormal tissue. Although extralobar sequestrations may be asymptomatic, the cumulative risks of hemorrhage, infection, arteriovenous shunting and late malignancy have generally been considered indication for resection when diagnosed. In patients with extralobar sequestration, this is a relatively straightforward procedure performed via thoracotomy, or more recently by thoracoscopy in some instances. Intralobar sequestration is treated with thoracotomy and lobectomy, although in selected cases, segmentectomy may be appropriate.38 Segmentectomy may be more feasible in situations where prenatal discovery offers opportunity for resection prior to the onset of infectious complications. An essential requirement for all procedures involving resection of a pulmonary sequestration is the identiﬁcation and control of the anomalous systemic arterial blood supply. Reports of unrecognized or uncontrolled hemorrhage from accidental division of the aberrant arteries emphasize this point;39 this is especially true of vessels with a subdiaphragmatic origin that course through the inferior pulmonary ligament and are prone to retraction into the abdomen when severed or avulsed. With modern imaging and knowledge of this risk however, this problem should be managed routinely in contemporary practice.

302 Congenital malformations of the lung

Other important technical points are that particular care must be taken to identify the phrenic nerve, which may travel adjacent and lateral to an extralobar sequestration. Abnormal foregut communications, whether diagnosed preoperatively or not, must be carefully sought and controlled appropriately intraoperatively. Although controversial, fetal interventions such as thoracoamniotic shunting and drainage may be helpful in certain cases of tension hydrothorax and hydrops fetalis. In contemporary pediatric surgical practice the outcome for affected infants and children should be excellent.40,41

CONGENITAL BRONCHOGENIC LUNG CYSTS Congenital lung cysts comprise up to one-third of bronchopulmonary foregut malformations in some reports.42,43 The most common of these lesions are bronchogenic cysts. Bronchogenic cysts are typically thick-walled, unilocular lesions which are comprised of smooth muscle, cartilage and mucous glands lined by pseudostratiﬁed ciliated columnar epithelium. It is believed that they become separated from the tracheobronchial tree during development but remain adjacent, which is where they are found clinically. Congenital lung cysts may develop at any time between the third and 16th weeks of gestation as the lung buds begin their initial segmental divisions and subsegmental dichotomous divisions progress. Bronchogenic cysts arise from the trachea, bronchus or other conducting airways but have usually lost their connection with the parent structure (Fig. 30.6). They are usually simple, and contain mucus, however, air-ﬂuid levels and infection may be seen if there is continuity with the tracheobronchial tree. Because these lesions result from abnormal development of bronchi, they may contain any of the cellular elements of the respiratory tract. In contrast to sequestrations, bronchogenic cysts have a normal bronchial blood supply. Although bronchogenic cysts may reside anywhere in the respiratory tract, including paravertebral, paraesophageal, subcarinal, and cervical areas, the majority are found in the lung parenchyma or mediastinum.8,29,44,45 More rare than bronchogenic cysts are parenchymal lung cysts, which are thought to arise from abnormal budding of distal airways and other respiratory structures. Some consider these among the spectrum of bronchogenic cysts, however most consider them separate because of a more peripheral location and their origin from pulmonary parenchymal structures rather than a conducting airway. Regardless, the histology is variable but resembles that of the structure of origin. The general features of presentation and principles of management for peripheral lung cysts are similar to those of bronchogenic cysts, unless the anomalous

(a)

(b) Figure 30.6 (a) Chest radiograph showing a large cyst occupying lower half right thorax. (b) Lateral view localized the cyst to lower lobe

structure is lymphatic in origin. In these latter cases, pulmonary lymphangiectasis may be present; this is manifested by diffuse bilateral cystic lung involvement and a poor clinical prognosis.6

Presentation and diagnosis Some patients with bronchogenic cysts are asymptomatic. Of those with symptoms, the most common presentations are wheezing, tachypnea or dyspnea, all related to compression of the adjacent conducting airway

Congenital bronchogenic lung cysts 303

with partial obstruction. If there is a patent connection between the tracheobronchial tree and a bronchogenic cyst, patients may develop infection and present with productive cough, fever, chills, and hemoptysis. Rarely, the cyst may enlarge to the point where the mass effect leads to mediastinal displacement, compression of normal lung, and cardiorespiratory failure. Plain chest radiographs typically demonstrate a smooth, spherical, paratracheal or hilar solid mass without calciﬁcations. If airway communication or infection is present, an air–ﬂuid level may be seen. Displacement of adjacent airway structures is commonly observed. More often than not, these cysts are unilocular, however, a honeycomb appearance is seen with some forms of this lesion. As with other congenital cystic lesions, CT or MRI imaging will allow anatomic relationships to be identiﬁed. Other studies to delineate important relationships include contrast esophogram to identify foregut communications or extrinsic compression, and bronchoscopy for similar reasons.

(a)

Treatment Acute respiratory decompensation from a large tense bronchogenic or lung cyst may necessitate needle or chest tube thoracostomy as a temporizing measure. Preexisting pneumonias should be treated with preoperative antibiotics. Thereafter, or in patients with stable cysts, simple cystectomy should be performed with oversewing of any anomalous bronchial communications (Fig. 30.7). If a bronchogenic cyst cannot be removed in its entirety, remaining portions of cyst wall may be destroyed with electrocautery in this situation. For a parenchymal cyst, lobectomy, segmental or wedge resection may be necessary if simple cystectomy is judged to be inadequate. The principle in this circumstance is to preserve as much normal lung parenchyma as possible. Generally, lateral thoracotomy is employed for management of these lesions, although median sternotomy may be appropriate for certain central lesions. Thoracoscopic resection has been used in selected patients with recent success as well.

(b)

(c)

Figure 30.7 Operative technique of lung cystectomy. (a) Cyst wall exposed after incising lung tissue just above the cyst. (b) Dissection in the plane between the cyst and lung tissue. (c) Showing a small bronchus opening into the cyst – the opening is closed by oversewing it

304 Congenital malformations of the lung

PULMONARY HYPOPLASIA, APLASIA, AND AGENESIS Pulmonary hypoplasia refers to the abnormal development of an entire lung or both lungs, resulting in a diminutive and potentially dysfunctional gas exchange organ. This occurs most commonly as a consequence of extrinsic compression during gestational development, although primary hypoplasia does occur. A number of intrathoracic mass lesions may be responsible, however the most common are congenital diaphragmatic hernia and CCAM. Pulmonary aplasia results from developmental arrest during organogenesis sometime after the sixth gestational week, resulting in a reduction in the number of alveoli; this may be marked. The physiologic consequences of both derangements can be severe and include pulmonary hypertension, persistent fetal circulation and respiratory failure. Extraordinary measures of clinical support are frequently required32,46 including high-frequency oscillation, extracorporeal membrane oxygenation, and the use of inhaled nitric oxide. Pulmonary agenesis is the complete absence of one or both lungs. The speciﬁc cause of this accident of embryogenesis is unknown, however there is apparent failure of organogenesis at about the time the trachea divides into the two lung buds, early in the fourth week of gestation. Bilateral pulmonary agenesis is exceedingly rare and is inevitably incompatible with life. Unilateral pulmonary agenesis may be asymptomatic, however symptomatic patients may pose difﬁcult neonatal management issues, not only from the standpoint of respiratory insufﬁciency, but also because of a high incidence of associated anomalies.47–49 Older children may be asymptomatic or demonstrate nonspeciﬁc respiratory symptoms including a history of failure to thrive, exercise intolerance, recurrent respiratory infections, and chest asymmetry or scoliosis. A shift in the location of heart tones and absent ipsilateral breath sounds are demonstratable on physical examination. Chest roentgenograms will demonstrate hyperinﬂation of the contralateral lung or possibly a ﬂuid-ﬁlled ipsilateral thorax. Either is usually associated with marked displacement of the mediastinum. Absence of the ipsilateral mainstem bronchus or the pulmonary artery are deﬁnitive diagnostic ﬁndings and this can be established by endoscopy, angiography, ECHO or axial imaging techniques.

LUNG SURGERY IN NEWBORNS Although a full discussion of thoracic surgery in children is beyond the scope of this chapter, a brief description of surgical technique in neonates is relevant. A number of comprehensive texts are available.50,51 Lung surgery in neonates is generally similar to that in adults except that

the diminutive size, the associated lesions, and the unique pathologic entities require certain special considerations. Of course, the smaller the child, the more care must be taken in order to avoid technical injury. As with all lung surgery, technical problems may result in serious and irreversible consequences. Collaboration with pediatric anesthesiologists familiar with the unique circumstances of pediatric chest surgery is essential.

Lobectomy The patient is positioned in the lateral decubitus position, with the upper arm extended and placed over the head (Fig. 30.8). Rolled towels and other positioning devices may be placed in order to optimize stabilization and exposure of the operative ﬁeld. As always in pediatric surgery, heat loss is a concern, and coverings should be placed over exposed areas without interference to the surgical site. Convective and radiant warmers should also be employed. Optimal exposure is gained by transverse or oblique incision over the fourth or ﬁfth intercostal space, below and lateral to the nipple to avoid cosmetic and functional damage to the breast tissue. There should be some space between the tip of the scapula and the posterior extent of the incision. This becomes important during closure of the muscle layers, especially if the incision must be extended posterolaterally. Underlying muscle and subcutaneous tissue is divided along the line of incision (Fig. 30.8b) by electrocautery. To limit postoperative morbidity, it is desirable and usually possible to employ a muscle-sparing approach; this affords adequate exposure yet avoids division of the serratus anterior and chest wall musculature other than the latissimus dorsi. The scapula is elevated off the chest wall by retractor to gain exposure, and palpation is used to count the ribs to the correct interspace. In most situations in infants, the highest palpable rib is the second. Generally, the fourth interspace is used for a lobectomy although the ﬁfth can be used effectively as well. The incision is then continued with electrocautery just superior to the lower rib of the selected intercostal space to avoid damage to the neurovascular bundle that runs along the inferior border of each rib (Fig. 30.8c). Care must be taken when entering the pleura to avoid injury to the lung parenchyma beneath. A rib spreader is then placed to facilitate retraction (Fig. 30.8d). The incision may then be continued anteriorly or posteriorly from inside the chest if further exposure is needed. The following technique and illustrations are described for left upper lobectomy, however the principles are the same for any lobe resection. Gentle lateral and inferior traction on the lobe exposes the hilum. The visceral pleura is carefully incised circumferentially, exposing the hilar structures (Fig. 30.9). Meticulous dissection reveals the left main pulmonary

Lung surgery in newborns 305

(a)

(b)

(c)

(d)

Figure 30.8 Operative technique of thoracotomy: (a) Transverse lateral incision. (b) Division of external intercostal muscles. (c) Division of intercostal muscles along the upper border of the lower rib. (d) Retraction of ribs to expose the lung

Aorta

Left main pulmonary artery Left upper lobe bronchus

Left lung

Artery branches of the left upper lobe

Carina Aorta

Left pulmonary artery

Left vein branches of left upper lobe

Left upper lobe bronchus Left lower lobe bronchus

Figure 30.10 The main segmental pulmonary artery branches to the left upper lobe

Figure 30.9 Normal anatomy of the left lung hilum containing the pulmonary artery, veins and bronchus

artery as it courses under the aortic arch (Fig. 30.10) and crosses the left upper lobe bronchus. Nearby structures to be noted are the left phrenic nerve anteriomedially along the mediastinum, and the recurrent laryngeal nerve branching from the vagus under the aortic arch. A review of segmental anatomy of the lung describes four main arterial branches supplying the left upper lobe,

however this can be variable. These are individually encircled, ligated and divided. This is typically done with heavy silk and using double proximal ligatures. The bronchial blood supply traveling with the left upper lobe bronchus is likewise identiﬁed and ligated. Attention is then directed to the left upper lobe venous drainage. Again, individual branches are circumferentially dissected and ligated using the same approach as for the

306 Congenital malformations of the lung

arterial circulation (Fig. 30.11). The bronchus is then clamped or otherwise controlled, and divided. Closure of the bronchial stump with commercial surgical stapling devices is appropriate in older children; however, size and other technical limitations make this undesirable in infants, where a simple sewn closure is best (Fig. 30.12). Air leaks may be identiﬁed for suture repair by ﬁlling the chest with warm saline coincident with inﬂation of the residual lobe by the anesthesiologist. The inferior pulmonary ligament should be divided at this time to facilitate expansion of the left lower lobe, or it may be done early in the dissection to facilitate exposure. A chest tube is placed within the pleura for drainage, and the wound is closed in anatomical layers using absorbable sutures. Postoperatively, drains can be removed early, provided no air leak is demonstrable. Wedge resections and lobectomies are remarkably well tolerated in the pediatric population, although age at resection is a factor. Older children demonstrate less compensatory growth than infants. Even so, most children will have little or no functional deﬁcit after these procedures.16,17,52 The need for pneumonectomy is much more limited in infants and children but functional outcomes are still

Left upper pulmonary vein

Left vein branches of left upper lobe

Left main bronchus Left upper pulmonary vein

Figure 30.11 The segmental vein branches of the left superior pulmonary Stump of the upper lobe bronchus

Left lower lobe bronchus

Figure 30.12 Vascular clamp placed across the left upper bronchus and the bronchus oversewn

generally good. Several techniques have been described to manage the potential problem of marked mediastinal shift in the postoperative period.

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congenital cystic adenomatoid malformation: a followup study. Scand J Thorac Cardiovasc Surg 1982; 16:293–8. Wolf SA, Hertzler JH, Philippart AI. Cystic adenomatoid dysplasia of the lung. J Pediatric Surg 1980; 15:925. Adzick NS, Harrison MR, Crombleholme TM et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179(4):884–9. Miller RK, Sieber WK, Yunis EJ. Congenital adenomatoid malformation of the lung: a report of 17 cases and review of the literature. Pathol Annu 1980; 15:387–407. Rashad F, Grisoni E, Gaglione S. Aberrant arterial supply in congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 1988; 23:1007–8. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Hum Pathol 1985; 20:483. Wang NS, Chen MF, Chen FF. The glandular component in congenital cystic adenomatoid malformation of the lung. Respirology 1999; 4(2):147–53. Granata C, Gambini C, Balducci T et al. Bronchioalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review on malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol 1998; 26(3):230–1. Shamji FM, Sachs HJ, Perkins DG. Cystic disease of the lungs. Surg Clin N Am 1988; 68:581–620. Hubbard AM, Adzick NS, Crombleholme TM et al. Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiol 1999; 212(1):43–8. vanLeeuwen K, Teitelbaum DH, Hirschl RB et al. Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal presentation, surgical indications, and natural history. J Pediatr Surg 1999; 34(5):794–8. Winters WD, Effmann EL, Ngheim HV et al. Disappearing fetal lung masses: importance of postnatal imaging studies. Pediatr Radiol 1997; 27:535–9. Ryckman FC, Rosenkrantz JG. Thoracic surgical problems in infancy and childhood. Surg Clin North Am 1985; 65:1423. Kitano Y, Adzick NS. New developments in fetal lung surgery. Curr Opin Pediatr 1999; 11(3):193–9. Dommergues M, Louis-Sylvestre C, Mandelbrot L, Aubry MC et al. Congenital adenomatoid malformation of the lung: When is active fetal therapy indicated? Am J Obstet Gynecol 1997; 177(4):953–8. Schwartz MZ, Ramachandran P. Congenital malformations of the lung and mediastinum – a quarter century of experience from a single institution. J Pediatr Surg 1997; 32(1):44–7. Cilley RE. The pediatric chest. In: Greenﬁeld LJ, Mulholland M, Oldham KT et al. editors. Surgery: Scientiﬁc Principles and Practice. 3rd edn. Philadelphia: Lippincott, Williams and Wilkins, 2001. Frazier AA, Rosado de Christenson ML, Stocker JT et al. Intralobar sequestration: radiologic pathologic correlation. Radiographics 1997; 7(3):725–45.

35. Gross E, Chen MK, Lobe TE et al. Infradiaphragmatic extralobar pulmonary sequestration masquerading as an intraabdominal, suprarenal mass. Pediatr Surg Int 1997; 12(7):529–31. 36. Sade RM, Clouse M, Ellis FH Jr. The spectrum of pulmonary sequestration. Ann Thorac Surg 1974; 18:644. 37. Conran RM, Stocker JT. Extralobar sequestration with frequently associated congenital cystic adenomatoid malformation, type 2: report of 50 cases. Pediatr Dev Pathol 1999; 2(5):454–63. 38. Takeda S, Miyoshi S, Inoue M et al. Clinical spectrum of congenital cystic disease of the lung in children. Eur J Cardio-Thor Surg 1999; 15(1):11–17. 39. Savic B, Birtel FJ, Tholen W et al. Lung sequestration: report of seven cases and a review of 540 published cases. Thorax 1979; 34:96–101. 40. Halkic N, Cuenoud PF, Corthesy ME et al. Pulmonary sequestration: a review of 26 cases. Eur J Cardio-Thor Surg 1998; 14(2):127–33. 41. Lopoo JB, Goldstein RB, Lipshutz GS et al. Fetal pulmonary sequestration: a favorable congenital lung lesion. Obstet Gynecol 1999; 94(4):567–71. 42. Evrard V, Ceulemans J, Coosemans W et al. Congenital parenchymatous malformations of the lung. World J Surg 1999; 23(11):1123–32. 43. Wesley JR, Hiedelberger KP, DiPetro MA et al. Diagnosis and management of congenital cystic disease of the lung in children. J Pediatr Surg 1986; 21:202. 44. Ramenofsky ML, Leape LL, McCauley RGK. Bronchogenic cyst. J Pediatr Surg 1979; 14:219–24. 45. DiLorenzo M, Collin PP, Vaillancourt R et al. Bronchogenic cysts. J Pediatr Surg 1989; 24:988–91. 46. Wasak P, Claris O, Lapillonne A et al. Cystic adenomatoid malformations of the lung: neonatal management of 21 cases. Pediatr Surg Int 1999; 15(5–6):326–31. 47. Booth JB, Berry CL. Unilateral pulmonary agenesis. Arch Dis Child 1967; 42:361. 48. Osborne J, Masel J, McCredie J. A spectrum of skeletal anomalies associated with pulmonary agenesis: possible neural crest injuries. Pediatr Radiol 1989; 19:425. 49. Hoffman MA, Superina R, Wesson DE. Unilateral pulmonary agenesis with esophageal atresia and distal tracheoesophageal ﬁstula: report of two cases. J Pediatr Surg 1989; 10:1084. 50. Ferguson MK. Surgical approach to the chest wall and mediastinum: incision, excisions, and repair of defects. In: Nyhus LM, Baker LJ, Fischer JE, eds. Mastery of Surgery. 3rd edn. Boston: Little, Brown, and Co., 1997: 613. 51. Sugarbaker DJ, DeCamp MM Jr, Liptay MJ. Pulmonary resection. In: Nyhus LM, Baker LJ, Fischer JE, editors. Mastery of Surgery. 3rd edn. Boston: Little, Brown, and Co., 1997: 613. 52. Szots I, Toth T. Long-term results of the surgical treatment for pulmonary malformations and disorders. Prog Pediatr Surg 1977; 10:277.

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31 Congenital diaphragmatic hernia TINA GRANHOLM, CRAIG T. ALBANESE AND MICHAEL R. HARRISON

INTRODUCTION Congenital diaphragmatic hernia (CDH) is a malformation characterized by a defect in the posterolateral diaphragm, the foramen of Bochdalek, through which the abdominal viscera migrate into the chest during fetal life. It is a fairly common malformation, occurring at a reported frequency of 1 in 3500–5000 births in recent population-based studies.1 Approximately 20% are right sided, 1–4% are bilateral, and close to 80% are left sided.1,2 In spite of recent advances in neonatal intensive care, the mortality rate remains high – in some series as high as 60%3 – and the infant with CDH thus presents a challenge to every pediatric surgeon. The mortality and morbidity are usually caused by concomitant pulmonary hypoplasia.

Some evidence now suggests that the pathogenesis of CDH may be more complicated than previously proposed. Iritani suggested that hypoplasia of the lung may precede the diaphragmatic defect,9 and Kluth et al. could show that the pleuroperitoneal canals in rats are too small to result in the diaphragmatic defect seen in CDH.10 Several groups have shown an aberrant expression of different growth factors in experimental models as well as in infants with CDH.11,12 Furthermore, the lungs in experimental models of CDH exhibit a response to growth factors differing from normal lungs.13 CDH has been extensively studied in animal models. Surgically created CDH in fetal lambs has proven a useful model for fetal intervention, as well as providing insight into respiratory and cardiovascular physiology.14,15 The teratogen-induced model of exposing pregnant mouse or rat dams to the herbicide Nitrofen has provided further knowledge in the pathogenesis and the role of different growth factors.9

EMBRYOGENESIS The etiology of CDH is unknown. Most cases occur sporadically, but there are reports of familial cases, including known chromosomal aberrations, as well as autosomal recessive inheritance of unknown chromosomal origin.4,5 The embryogenesis of CDH is usually described as a failure of the pleuroperitoneal canals in the posterolateral aspect of the diaphragm to fuse during gestational week 8. The resulting defect allows the gut as well as the liver and spleen to migrate into the chest when the gut returns into the intraperitoneal cavity during gestational week 10.6 The presence of gut, stomach and in particular the left liver lobe in the chest is thought to cause pulmonary hypoplasia by compression of the growing lungs. The pulmonary hypoplasia extends to all aspects of the lung, resulting in fewer bronchial divisions, a decreased number of alveoli and a hypoplastic and abnormal vascular tree.7,8 The morphology of the CDH lung furthermore has an immature appearance. The ipsilateral lung is the most severely affected, but the changes usually extend to the contralateral lung, as well.

PATHOPHYSIOLOGY Live-born infants with CDH usually present with severe respiratory distress. Although the major cause of this is pulmonary hypoplasia, the resulting hypoxia and hypercarbia will result in pulmonary vasoconstriction and pulmonary hypertension. This in turn will cause reversal to right-to-left shunting through the ductus arteriosus and the foramen ovale, and the infant enters a vicious, self-perpetuating cycle, as described in Figure 31.1. There are several additional factors contributing to the severe pulmonary hypertension in CDH. The pulmonary vascular bed is abnormal, with increased muscularization of arterioles in a manner similar to infants with idiopathic persistent pulmonary hypertension of the newborn (PPHN).8 Increased thickness of the media as well as the adventitia of arteries of all sizes has also been demonstrated.16 Furthermore, vasoactive substances such as endothelin-1 seem to be increased in infants with CDH. Kobayashi and Puri found increased blood levels of

310 Congenital diaphragmatic hernia

degree of pulmonary hypoplasia. Currently, intrauterine lung measurement by MRI is being investigated as a means of estimating lung size.24 Postnatally, CDH should be suspected in infants with severe respiratory distress at birth or within the ﬁrst few hours of life. With left-sided CDH, the heart sounds are shifted to the right, and the breathing sounds are decreased bilaterally. The abdomen may be scaphoid, and the thorax enlarged. The deﬁnitive diagnosis is made by chest radiograph, showing bowel loops in the chest, and mediastinal shift to the contralateral side (Fig. 31.1).

TREATMENT

Figure 31.1 Chest radiograph of a left CDH with viscera visible in the left chest, pulmonary hypoplasia, and signiﬁcant mediastinal shift to the right

endothelin, as well as increased expression of endothelin1 in endothelial cells in the pulmonary vasculature.17 Endothelin-1 causes pulmonary vasoconstriction by binding to the endothelin A (ETA) receptor. The ETA receptor is ubiquitously present in the smooth muscle cells of the pulmonary vasculature,18 and the increased endothelin-1 levels may thus adversely affect pulmonary vasoconstriction. Hypoxia and hypercarbia may be further aggravated by a reported immaturity of the surfactant system in experimental animals and infants with CDH.19 Others could, however, not conﬁrm this deﬁciency,20 and recent studies suggest that the apparent surfactant deﬁciency may in fact be secondary to respiratory failure, rather than to a primary deﬁciency.21

On presentation, the infant with CDH should be intubated, paralyzed and have a nasogastric tube placed to prevent distension of the stomach and bowel. CDH was previously considered a surgical emergency, where prompt surgery with reduction of the abdominal viscera, thereby allowing the lungs to expand, was thought to be the only way to save infants in severe respiratory distress. The increased knowledge of the pathophysiology of CDH has led to a different approach, where prolonged preoperative stabilization has proven useful. Most centers now prefer delayed surgery, with a delay of sometimes several days, waiting for the stabilization of the pulmonary circulation before surgery.25 The treatment should be aimed at the different aspects of the vicious cycle (Fig. 31.2), i.e. hypoxia/hypercarbia, pulmonary vasoconstriction and pulmonary hypertension. To this purpose, aggressive hyperventilation and hypocarbia was previously widely used. However, a different approach, using gentle ventilation and permissive hypercarbia, has proven more useful in decreasing the mortality rate.26,27 Without this approach, a high mortality rate from barotrauma can be expected.28,29 Several centers have shown improved survival as compared to historical controls, using a combination of Pulmonary hypoplasia

DIAGNOSIS CDH can predictably be diagnosed prenatally by ultrasonography at approximately 20 weeks’ gestation. At the time of prenatal diagnosis, it is of vital importance to exclude the presence of other anomalies, including neural tube defects, cardiac malformations and chromosomal aberrations, e.g. trisomy 18 and 21. Furthermore, the degree of pulmonary hypoplasia should be assessed. The presence of liver in the chest in left-sided CDH indicates severe pulmonary hypoplasia.22 The lung-to-head ratio (LHR – the area of the right lung at the level of the four-chamber view divided by the head circumference)23 has been shown to be a predictable estimation of the

Hypoxia hypercarbia

Poor gas exchange Right to left shunting

Pulmonary vasoconstriction

Pulmonary hypertension

Figure 31.2 Pathophysiology of the deterioration seen following the ‘honeymoon period’ in infants with CDH

Operative repair 311

gentle ventilation and delayed surgery.27,30 Highfrequency oscillatory ventilation (HFOV) is a valuable tool in the treatment of infants with respiratory distress, since it provides effective ventilation while decreasing barotrauma. However, in CDH, HFOV has not been shown to alter the mortality or morbidity rates.28,31 Appropriate ﬂuid management, as well as the use of inotropic agents, are crucial in the treatment of CDH. Adequate sedation and pain management should be used, but the use of paralysis is controversial. Surgery should be performed when the infant is stable with minimal ventilator settings, is diuresing well, and the chest radiograph is improving. Since the role of pulmonary vasoconstriction and right-to-left shunting was recognized in the late 1970s, a battery of pharmacological agents has been used in an attempt to decrease pulmonary vascular resistance. None of these have a proven effect on CDH. Initially, inhaled nitric oxide (iNO), which provides selective pulmonary vasodilatation, seemed to be a promising therapy,32 but more recent conclusions seem to be that although selected infants may respond well to iNO, this response seems to be variable or temporary.33,34 In consequence, iNO is usually used as an adjunct to conventional mechanical ventilation and HFOV while preparing for extracorporeal membrane oxygenation (ECMO) cannulation. ECMO is used in the treatment of CDH when conventional mechanical ventilation fails. The evidence supporting the use of ECMO is conﬂicting,28,31,35 although some evidence seems to support the use of ECMO in selected cases.27,30,36 ECMO provides a period of lung rest, while allowing the infant to adapt, and the pulmonary vascular resistance to decrease. The problem, however, is the difﬁculty in assessing the amount of pulmonary hypoplasia before starting ECMO treatment in patients with pulmonary hypoplasia incompatible with life. To that extent, several centers advocate the use of ECMO only in patients with evidence of a ‘honeymoon period’, i.e. patients with adequate gas exchange for a period preceding the deterioration in respiratory status. Others use preductal blood gases, where only patients with a period of normal preductal pO2 and pCO2 will be considered for ECMO.27 Some centers, however, claim that no criteria as yet exist to adequately select the patients who will beneﬁt from ECMO. Since some studies suggest surfactant deﬁciency in CDH infants, surfactant replacement has been tried as an adjunct to conventional mechanical ventilation or ECMO. No beneﬁcial effect has as yet been proven.37 Several novel therapies of ventilation are in evolution, several of which have been tried in CDH infants. Partial liquid ventilation has been beneﬁcial in some cases,38 and some preliminary promising results have been obtained by the use of intratracheal pulmonary ventilation (ITPV).39 Both of these methods provide efﬁcient ventilation, while apparently protecting the lung against baro-

trauma. However, none of these methods can improve the fundamental problem with the CDH lung, i.e. hypoplasia, and therefore share the shortcomings of ECMO treatment.

OPERATIVE REPAIR Repair of the defect is usually the most straightforward part of the management of CDH. Preoperative antibiotics are usually used, and although not generally necessary, blood should be available. The defect is exposed through a left subcostal abdominal incision, and the viscera are reduced from the chest (Fig. 31.3). There is usually a layer of peritoneum running from the retroperitoneum over the lower edge of the defect. Division of this tissue usually allows visualization of the posterior edge of the diaphragm. If a large portion of the liver is herniated into the chest, reduction of this organ is facilitated by division of the umbilical vein and falciform ligament. The diaphragm is then closed using interrupted nonabsorbable sutures. In some cases, the defect is too large for primary closure, and prosthetic material is used. An alternative to this approach is a muscle ﬂap taken from the transversus abdominus, leaving the outer abdominal muscle layers intact. This technique should not be performed on

Figure 31.3 Operative repair of CDH. The herniated viscera are reduced, the diaphragmatic defect is inspected, and the peritoneal layer over the retroperitoneum is divided to enhance visualization of the lower diaphragmatic edge

312 Congenital diaphragmatic hernia

patients on ECMO, or at risk of ECMO treatment, because of the risk of hemorrhagic complications. Prior to closure, the abdomen is manually stretched to make room for the herniated viscera. It is controversial whether a chest tube should be inserted prior to closure. If a chest tube is used, suction should not be applied, since it can too rapidly shift the mediastinum and may increase the transpulmonary pressure gradient, and predispose to pneumothorax. Postoperative care should be performed in the same manner as preoperatively, with a close watch on ﬂuid management, ventilatory support and hemodynamic monitoring. Feeding is begun when bowel function is evident.

PRENATAL TREATMENT In spite of the recent advances in neonatal intensive care, a certain proportion of these babies will die from pulmonary hypoplasia, either pre-, peri- or postnatally. This group should be eligible to prenatal treatment. Fetal surgery, with primary repair of the defect, was shown to be promising as a way of mitigating pulmonary hypoplasia in experimental and initial clinical studies.40 However, the herniated liver proved to be a difﬁcult obstacle. In spite of innovative techniques,41 fetal surgery of ‘liver-up’ CDH proved to be impossible, since reducing the liver caused kinking of the umbilical vein, cutting off blood ﬂow from the placenta and causing fetal demise.42 Although open fetal surgery was felt to be physiologically sound and technically feasible, it should thus be reserved for fetuses without liver herniation. However, the survival rate in these fetuses remains high whether treated pre- or postnatally, and they should thus not be eligible for prenatal intervention.43 An experiment of nature led to the evolution of a novel technique of prenatal intervention. Infants with laryngeal atresia were found to have enlarged lungs at autopsy. Furthermore, laryngeal atresia reversed the profound pulmonary hypoplasia in patients with renal agenesis.44 This led to experimental studies, where pulmonary hypoplasia in fetal lambs caused by fetal nephrectomy as well as surgically created CDH, was alleviated by tracheal ligation.45–48 A fetoscopic technique of temporary tracheal occlusion by placing clips on the human trachea was then developed.49,50 This method has undergone further evolution, and currently a technique using one port, and the endoscopic placement of a tracheal balloon, is used. Fetal tracheal occlusion as a means of improving survival in CDH is currently being investigated in a prospective randomized trial, sponsored by the National Institute of Health (http://commons.cit.nih.gov/crisp/crisp_lib.query) and conducted at the Fetal Treatment Center, University of California, San Francisco.

In order to deliver infants with fetal tracheal occlusion, a special method of delivery had to be developed, the ex utero intrapartum treatment procedure (EXIT). Cesarean section is performed with maximal uterine relaxation, and while keeping the infant on placental support, the upper airway can be instrumented. This method is useful as a means of delivering infants with other conditions affecting the upper airway as well, e.g. cystic hygroma of the neck or laryngeal atresia.51 Although tracheal occlusion is very promising, several complications have been reported. Prolonged tracheal occlusion may lead to hydrops and fetal demise,52 and several reports have shown a decrease in type II pneumocytes and deﬁcient surfactant production after tracheal ligation.53–55 Some results seem to favor late gestation occlusion, demonstrating less effect on surfactant production.56 The effect on lung growth by tracheal occlusion and retention of pulmonary ﬂuid seems to be exerted by pulmonary stretch itself, which in turn causes upregulation of different growth factors. Vascular endothelial growth factor (VEGF) has been shown to be upregulated by pulmonary stretch, and may contribute to pulmonary growth by increasing angiogenesis.57 Insulin-like growth factor-I (IGF-I) gene expression is reduced in the lung parenchyma of lambs with surgically created CDH. IGF-I is, however, restored to normal or increased levels after tracheal ligation or postnatal lung distension.58 A similar method of pulmonary stretch has been tried as a means of inducing postnatal lung growth in CDH infants. The lungs are then continuously distended with perﬂuorocarbon during ECMO treatment. Experimental as well as initial clinical results are promising.59 Prenatal non-invasive treatment is thoroughly being investigated as well. Promising results on outcome and pulmonary maturity have been obtained by prenatal treatment with dexamethasone in experimental models on rats and sheep.60 Prenatal us of dexamethasone is currently being investigated in the clinical setting in a prospective randomized trial. Vitamin E has been shown to induce lung growth in experimentally induced CDH, and may in the future be tried clinically, as well.61

PROGNOSIS Although several centers have reported an increased survival rate using novel therapies, including ECMO,27,30 the fact remains that the hidden mortality rate is very high.62 Since most centers are only aware of the cases that reach their center alive, pre- and perinatal mortality is usually not included. In spite of optimal postnatal care, the mortality in isolated CDH diagnosed before 24 weeks’ gestation and followed prospectively, was as high as 58% in a recent study.3 All of those cases fulﬁlled the criteria for prenatal intervention.

References 313

It is of vital importance to recognize variables that predict pre- and perinatal mortality, since they will inﬂuence the information given to the family, as well as deciding eligibility to prenatal intervention. Firstly, other lethal malformations, as well as chromosomal aberrations, should be excluded. In isolated left-sided CDH, herniation of the liver into the chest has been shown to be a predictor of high mortality, whereas survival is highly likely if the liver is not herniated into the thorax.22,63 Furthermore, the LHR has been shown to adequately predict outcome in left-sided, ‘liver-up’ CDH. In a prospective series, an LHR <1.0 was associated with 100% mortality, whereas all patients with an LHR >1.4 survived.23 Currently, fetal MRI as a means of measuring lung volume and thereby predicting pulmonary hypoplasia, is investigated.24 Postnatal prediction of pulmonary hypoplasia and survival has proven more difﬁcult to ascertain. Bohn et al. correlated preoperative Paco2 with an index of ventilation (VI; mean airway pressure × respiratory rate), and could divide the infants into four groups, where the group with a Paco2 <40 mmHg and a VI <1000 had the best survival rate.64 ECMO was not used in this study, however. Several centers use preductal Pao2 as a predictor of survival.27 Recently, a study of computer-assisted analysis of the postoperative chest radiograph has been shown to predict pulmonary hypoplasia.65 However, accurate preoperative predictors are needed in order to avoid placing patients with lethal pulmonary hypoplasia on ECMO.

LONG-TERM OUTCOME Although long-term outcome, regarding respiratory function, has been shown to be excellent, these series usually do not take into account the more recent therapies, including ECMO, where it can be predicted that patients with marginal lung function may survive. Some evidence supports the fact that a signiﬁcant number of survivors may be impaired by long-term pulmonary hypertension.66 Developmental delay, as well as hearing loss, has been reported in patients with CDH.67,68 These complications are most likely to be due to prolonged hypoxia. A signiﬁcant number of survivors report gastrointestinal symptoms, including gastroesophageal reﬂux, which may be symptomatic and incapacitating well beyond the neonatal period.69,70 Furthermore, recurrence of the hernia may lead to rapid deterioration in respiratory function, as well as gastrointestinal symptoms.70, 71 Recurrence is more common in patients repaired with a prosthetic patch. In conclusion, most survivors beyond the neonatal period are able to lead a normal life, but children with CDH should be followed up and assessed for respiratory status until normal lung function can be ascertained.

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hernia complicated by pulmonary hypertension. J Pediatr Surg 1998; 33:382–7. Kobayashi H, Puri P. Plasma endothelin levels in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1258–61. Nobuhara KK, Wilson JM. Pathophysiology of congenital diaphragmatic hernia. Semin Pediatr Surg 1996; 5:234–42. Glick PL, Stannard VA, Leach CL et al. Pathophysiology of congenital diaphragmatic hernia II: The fetal lamb CDH model is surfactant deﬁcient. J Pediatr Surg 1992; 27:382–8. Sullivan KM, Hawgood S, Flake AW et al. Amniotic ﬂuid phospholipid analysis in the fetus with congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1020–4. IJsselstijn H, Zimmermann LJ, Bunt JE et al. Prospective evaluation of surfactant composition in bronchoalveolar lavage ﬂuid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med 1998; 26:573–80. Metkus AP, Filly RA, Stringer MD et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996; 31:148–52. Lipshutz GS, Albanese CT, Feldstein VA et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:1634–6. Coakley FV, Lopoo JB, Lu Y et al. Normal and hypoplastic fetal lungs: volumetric assessment with prenatal singleshot rapid acquisition with relaxation enhancement mr imaging. Radiology 2000; 216:107–11. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia: Is emergency operation necessary? J Pediatr Surg 1988; 23:731–4. Wung JT, James LS, Kilchevsky E et al. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76:488–94. Wung JT, Sahni R, Mofﬁtt ST et al. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30:406–9. Wilson JM, Lund DP, Lillehei CW et al. Congenital diaphragmatic hernia – a tale of two cities: the Boston experience. J Pediatr Surg 1997; 32:401–5. Sakurai Y, Azarow K, Cutz E et al. Pulmonary barotrauma in congenital diaphragmatic hernia: a clinicopathological correlation. J Pediatr Surg 1999; 34:1813–17. Frenckner B, Ehrén H, Granholm T et al. Improved results in patients who have congenital diaphragmatic hernia using preoperative stabilization, extracorporeal membrane oxygenation, and delayed surgery. J Pediatr Surg 1997; 32:1185–9. Azarow K, Messineo A, Pearl R et al. Congenital diaphragmatic hernia – a tale of two cities: the Toronto experience. J Pediatr Surg 1997; 32:395–400.

32. Frostell CG, Lonnqvist PA, Sonesson SE et al. Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia. Successful use of inhaled nitric oxide. Anaesthesia 1993; 48:679–83. 33. Shah N, Jacob T, Exler R et al. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1010–15. 34. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99:838–45. 35. UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75–82. 36. Congenital Diaphragmatic Hernia Study Group. Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia? J Pediatr Surg 1999; 34:720–5. 37. Lotze A, Knight GR, Anderson KD et al. Surfactant (beractant) therapy for infants with congenital diaphragmatic hernia on ECMO: evidence of persistent surfactant deﬁciency. J Pediatr Surg 1994; 29:407–12. 38. Wilcox DT, Glick PL, Karamanoukian HL et al. Partial liquid ventilation and nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:1211–15. 39. Schnitzer JJ, Thompson JE, Hedrick HL. A new ventilator improves CO2 removal in newborn lambs with congenital diaphragmatic hernia. Crit Care Med 1999; 27:109–12. 40. Harrison MR, Bressack MA, Churg AM et al. Correction of congenital diaphragmatic hernia in utero. II. Simulated correction permits fetal lung growth with survival at birth. Surgery 1980; 88:260–8. 41. Harrison MR, Adzick NS, Flake AW et al. The CDH two-step: A dance of necessity. J Pediatr Surg 1993; 28:813–16. 42. Harrison MR, Adzick NS, Flake AW et al. Correction of congenital diaphragmatic hernia in utero: VI. Hardearned lessons. J Pediatr Surg 1993; 28:1411–18. 43. Harrison MR, Adzick NS, Bullard KM et al. Correction of congenital diaphragmatic hernia in utero VII: A prospective trial. J Pediatr Surg 1997; 32:1637–42. 44. Wigglesworth JS, Desai R, Hislop AA. Fetal lung growth in congenital laryngeal atresia. Pediatr Pathol 1987; 7:515–25. 45. Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993; 28:1433–40. 46. DiFiore JW, Fauza DO, Slavin R et al. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:248–57. 47. Hedrick MH, Estes JM, Sullivan KM et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 1994; 29:612–17.

References 315 48. Luks FI, Gilchrist BF, Jackson BT et al. Endoscopic tracheal obstruction with an expanding device in a fetal lamb model: preliminary considerations. Fetal Diagn Ther 1996; 11:67–71. 49. VanderWall KJ, Skarsgard ED, Filly RA et al. Fetendo-clip: a fetal endoscopic tracheal clip procedure in a human fetus. J Pediatr Surg 1997; 32:970–72. 50. Harrison MR, Mychaliska GB, Albanese CT et al. Correction of congenital diaphragmatic hernia in utero IX: Fetuses with poor prognosis (liver herniation and low lung-tohead ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998; 33:1017–23. 51. Mychaliska GB, Bealer JF, Graf JL et al. Operating on placental support: The ex utero intrapartum treatment procedure. J Pediatr Surg 1997; 32:227–31. 52. Graf JL, Gibbs DL, Adzick NS et al. Fetal hydrops after in utero tracheal occlusion. J Pediatr Surg 1997; 32:214–16. 53. O’Toole SJ, Sharma A, Karamanoukian HL et al. Tracheal ligation does not correct the surfactant deﬁciency associated with congenital diaphragmatic hernia. J Pediatr Surg 1996; 31:546–50. 54. O’Toole SJ, Karamanoukian HL, Irish MS et al. Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment. J Pediatr Surg 1997; 32:407–10. 55. Bullard KM, Sonne J, Hawgood S et al. Tracheal ligation increases cell proliferation but decreases surfactant protein in fetal murine lungs in vitro. J Pediatr Surg 1997; 32:207–13. 56. Liao SL, Luks FI, Piasecki GJ et al. Late-gestation tracheal occlusion in the fetal lamb causes rapid lung growth with type ii cell preservation. J Surg Res 2000; 92:64–70. 57. Muratore CS, Nguyen HT, Ziegler MM et al. Stretchinduced upregulation of vegf gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg 2000; 35:906–12. 58. Nobuhara KK, DiFiore JW, Ibla JC et al. Insulin-like growth factor-I gene expression in three models of accelerated lung growth. J Pediatr Surg 1998; 33:1057–61. 59. Nobuhara KK, Fauza DO, DiFiore JW et al. Continuous intrapulmonary distension with perﬂuorocarbon accelerates neonatal (but not adult) lung growth. J Pediatr Surg 1998; 33:292–8. 60. Hedrick HL, Kaban JM, Pacheco BA et al. Prenatal

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glucocorticoids improve pulmonary morphometrics in fetal sheep with congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:217–22. Islam S, Narra V, Cote GM et al. Prenatal vitamin E treatment improves lung growth in fetal rats with congenital diaphragmatic hernia. J Pediatr Surg 1999; 34:172–7. Harrison MR, Bjordal RI, Langmark F et al. Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 1978; 13:227–30. Albanese CT, Lopoo J, Goldstein RB et al. Fetal liver position and perinatal outcome for congenital diaphragmatic hernia. Prenat Diagn 1998; 18:1138–42. Bohn D, Tamura M, Perrin D et al. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, conﬁrmed by morphological assessment. J Pediatr 1987; 111:423–31. Dimitriou G, Greenough A, Davenport M et al. Prediction of outcome by computer-assisted analysis of lung area on the chest radiograph of infants with congenital diaphragmatic hernia. J Pediatr Surg 2000; 35:489–93. Schwartz IP, Bernbaum JC, Rychik J et al. Pulmonary hypertension in children following extracorporeal membrane oxygenation therapy and repair of congenital diaphragmatic hernia. J Perinatol 1999; 19:220–6. Ahmad A, Gangitano E, Odell RM et al. Survival, intracranial lesions, and neurodevelopmental outcome in infants with congenital diaphragmatic hernia treated with extracorporeal membrane oxygenation. J Perinatol 1999; 19:436–40. Bouman NH, Koot HM, Tibboel D et al. Children with congenital diaphragmatic hernia are at risk for lower levels of cognitive functioning and increased emotional and behavioral problems. Eur J Pediatr Surg 2000; 10:3–7. Nagaya M, Akatsuka H, Kato J. Gastroesophageal reﬂux occurring after repair of congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1447–51. Van Meurs KP, Robbins ST, Reed VL et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122:893–9. Nobuhara KK, Lund DP, Mitchell J et al. Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol 1996; 23:873–87.

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32 Extracorporeal membrane oxygenation for neonatal respiratory failure EUGENE S. KIM AND CHARLES J. H. STOLAR

INTRODUCTION Extracorporeal membrane oxygenation (ECMO) was ﬁrst used in newborns in 1974. Since then, the Extracorporeal Life Support Organization (ELSO) has recorded approximately 15 000 newborns who have been treated with ECMO for a variety of cardiorespiratory disorders. The most common disorders in the newborn treated with ECMO are meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the neonate (PPHN), congenital diaphragmatic hernia (CDH), sepsis and cardiac support. Depending on the indication for ECMO, the outcome has varied, but overall, a survival rate of 76% has been reported for newborns treated in this high (> 80%) mortality group.1 This chapter will discuss the selection criteria for ECMO in neonates and the management of these babies while on ECMO. It will then discuss ECMO for use in difﬁcult, clinical scenarios, such as CDH and preterm infants, and ﬁnally review outcome and follow-up of neonates treated with ECMO.

SELECTION CRITERIA FOR NEONATAL ECMO The selection criteria for newborns are based on historic experience from multiple institutions, patient safety and mechanical limitations related to the equipment.

Gestational age The gestational age should be at least 34 weeks. In the early experience with ECMO, premature infants (<34 weeks’ gestation) who were offered ECMO developed signiﬁcant morbidity and mortality related to intracranial hemorrhage.2 Despite reﬁnement of ECMO techniques in the 1980s, premature infants continue to be at risk for intracranial hemorrhage. This may be due to the

fact that ependymal cells within the brain may not be fully developed in preterm infants, thus making them susceptible to intracranial bleeding. In addition, the systemic heparinization necessary to maintain a thrombus-free ECMO circuit also increases the risk of bleeding complications.

Birth weight The birth weight should be nearly 2000 g. The principle of this criteria is limited to the size of the baby and the limitation of cannula size. The smallest single-lumen ECMO cannula is 8 French (Fr.) gauge. Flow through the tube is related to the radius of the tube by a power of 4. If the vein is small, then the cannula will be small, resulting in ﬂow that will be reduced by a 4th power. From historic experience, if the baby weighs less than 2 kg, then the difﬁculty of the placement of the cannula in conjunction with the inadequate ﬂow from small catheters make ECMO in these small babies challenging.

Bleeding complications The baby should have no active bleeding or major coagulopathy. Patients with uncorrectable coagulopathy, ongoing uncontrollable bleeding, or sepsis and its associated coagulopathy are at high risk of bleeding complications while on ECMO. The need for continuous systemic heparin therapy while on ECMO adds to this risk of bleeding.3 Therefore, prior to initiating ECMO, bleeding should be controlled.

Intracranial hemorrhage The infant should not have an intracranial hemorrhage. ECMO candidates with a pre-existing intracranial hemorrhage may exacerbate the problem secondary to

318 Extracorporeal membrane oxygenation for neonatal respiratory failure

the use of heparin and altered cerebral blood ﬂow while on ECMO. Infants with small interventricular hemorrhages (grade I–II) may be considered for ECMO on an individual case basis, but these cases should be closely monitored for worsening bleeding. Patients with previous intracranial bleeds, cerebral infarcts and other risk factors (prematurity, coagulopathy, ischemic central nervous system injury, or sepsis) are particularly at high risk for intracranial hemorrhage.2,4

Reversible disease process The baby should have a reversible lung disease and be supported by aggressive mechanical ventilation for no longer than 10–14 days prior to ECMO. Babies who have had prolonged exposure to high-concentration oxygen and positive-pressure ventilation develop bronchopulmonary dysplasia (BPD).5 Recovery of this type of irreversible lung injury may take from weeks–months to occur, if at all. ECMO therapy can be a good treatment for reversible lung disease over a relatively short period of time (2–3 weeks). However, even a lengthy ECMO course would not be sufﬁcient to permit recovery of the irreversible ﬁbrotic changes that occur to the lung following sustained barotrauma and/or oxygen toxicity. In addition, with a longer ECMO run, the chance of infection, bleeding complications, thromboembolic events, and mechanical failure increase. In a retrospective case–control study which reviewed the records of ECMO patients over 66 months, patients with oxygen dependency at 1 month of age and radiographic evidence of BPD were compared to patients without these ﬁndings.6 Patients with BPD were placed on ECMO at an older mean age than non-BPD patients (135- vs 50-hours-old). The BPD group had longer mean ECMO courses as well (203 vs 122 hours). The authors suggest that risk of BPD from high levels of ventilatory support occur with as little as 4 days of assisted ventilation.

Coexisting anomalies The baby should have no lethal congenital anomalies. Every effort should be made to establish a clear diagnosis before the initiation of ECMO. If that is not possible, then the diagnosis should be established during the course of ECMO. ECMO is not intended to delay an inevitable death. Many lethal pulmonary conditions, though, may present like reversible diseases such as congenital alveolar proteinosis, alveolar capillary dysplasia and overwhelming pulmonary hypoplasia. Other treatable conditions, such as total anomalous pulmonary venous return and transposition of the great vessels, may initially manifest with respiratory failure. If possible, an echocardiogram should be rapidly obtained to determine the need for ECMO or cardiac surgery.

Failure of medical management The baby must have ﬁrst failed optimal medical management. This is often the most difﬁcult criteria to elucidate. Different institutions have varying specialties, capabilities, and expertise. ‘Optimal’ medical management is a subjective term which may vary widely. Current optimal medical management may include pharmacologic support with vasodilator or vasoconstrictive agents, inotropic agents, sedatives and analgesics. Ventilatory support usually begins with conventional strategies, but may change to include exogenous surfactant administration, achievement of respiratory alkalosis, hyperoxia, high postexpiratory end pressure (PEEP), inverse I:E ratios, or high frequency ventilation. Early use of steroids in the management of respiratory distress syndrome (RDS) has been proposed to decrease pulmonary inﬂammation, and achievement of metabolic alkalosis may be preferred to respiratory alkalosis.7 The merits and demerits of all these treatment strategies are beyond the scope of this paper. Innovations in medical management have been developed, which have prevented ECMO in patients who meet the criteria for ECMO. These innovations in management include high-frequency oscillatory ventilation, permissive hypercapnea with spontaneous ventilation and nitric oxide. In 1985, Wung et al. used a non-traditional approach to the management of patients with persistent pulmonary hypertension.8 Hyperventilation and hyperoxia were not emphasized, and muscle relaxants were not used. Permissive hypercapnea in conjunction with spontaneous ventilation was employed. By tolerating a Paco2 of 50–80 mmHg and a PaO2 of 40 mmHg and by using low-pressure ventilator settings to provide adequate chest wall excursion, the series of 15 patients, who met institutional criteria for ECMO, survived with this medical approach alone. Other, more objective criteria have been established to quantify respiratory failure and aid in determining which infants should be placed on ECMO. High-pressure ventilator settings (PIP > 40 cm H2O, PEEP > 7 cm H2O, IMV > 100 and FiO2 of 1.0) have correlated with mortality. In addition, studies have examined arterial oxygen pressure (Pao2 < 40 mmHg), alveolar-arterial oxygen gradient (A − ado2 > 600 mmHg × 4 hours) and oxygenation index (OI > 40) as predictors of mortality as well.9–12 However, some have argued that the alveolar-arterial oxygenation gradient and oxygenation index should not be heavily weighted because these factors can be manipulated by ventilator settings.

CLINICAL MANAGEMENT OF NEONATES ON ECMO Veno-venous vs veno-arterial ECMO A decision is ﬁrst made whether the infant would best be

Clinical management of neonates on ECMO 319

served with veno-venous (VV) or veno-arterial (VA) support. VV support delivers oxygen for respiratory indications. VV ECMO can be performed through a double-lumen catheter which is placed in the right internal jugular vein. The double-lumen catheter both drains deoxygenated blood and returns oxygenated blood to the right atrium. Double-lumen catheters of 12–14 Fr. gauge are commonly used in the newborn. As opposed to VV ECMO, VA ECMO not only delivers oxygen for respiratory failure but also provides circulatory support in the event of cardiac failure, difﬁculty weaning from cardiopulmonary bypass or occasionally CDH anatomy. In these cases, VA support is provided by venous drainage of the right atrium through a cannula inserted in the internal jugular vein (Fig. 32.1). Oxygenated blood is returned through a cannula in the carotid artery. Patients who present with profound lactic acidosis and hypoxic ischemia often have a component of cardiovascular collapse and may also require the circulatory support of VA as opposed to VV ECMO.

Superior thyroid vein

Carotid sheath

Internal jugular vein

Common carotid artery

(a) Venous cannula

Vessel

Cannula

Cannula management The preferred site for cannula placement is in the vessels of the right neck. The internal jugular vein is accessed via an open procedure. During the open procedure, muscle relaxants are given to prevent the inadvertent aspiration of air into the vein. In the event of VA ECMO, the carotid artery is dissected and identiﬁed for catheter placement. After placement of the catheters and initiation of ECMO ﬂow, the catheters are carefully secured with sutures to the blood vessel and skin (Fig. 32.2a–c). Heat exchanger

O2 Fluids Membrane oxygenator

Heparin

Pump

Figure 32.1 Schematic of completed veno-arterial ECMO circuit. Extrathoracic cannulation of the right atrium and acending aorta allows venous drainage to a servo-controlled valley pump and arterial return directly to the heart and brain. Oxygenation and CO2 removal is provided by a nonporous silicone membrane oxygenator. The blood is rewarmed before returning to the infant. All parenterally administered substances such as heparin, ﬂuids, blood products and drugs are given directly into the circuit

Silastic bumper

Arterial cannula (b)

(c)

Figure 32.2 Details of the cannulation procedure. (a) The carotid sheath is opened with the sternomastoid muscle retracted laterally. This exposes the common carotid artery and internal jugular vein. (b) The infant is anticoagulated after the vessels are dissected and then ligated cephalad. A 10 Fr. arterial cannula is passed into the ascending aorta by an arteriotomy. A 12–14 Fr. venous cannula is passed into the right atrium by the venotomy. (c) The cannulas are ﬁxed in position by ligation over a Silastic bumper to facilitate removal. The two ligatures on each vessel are then tied together. After the incision is closed, the cannulas are also sutured to the mastoid process and connected to the ECMO circuit

The position of the catheter is conﬁrmed in two ways. First, a chest radiograph is performed, which can grossly demonstrate catheter position. The tip of the venous cannula should be located within the right atrium, while the tip of the arterial cannula should be located in the ascending aorta. The second mode of conﬁrming cannula placement is cardiac echocardiography. The double-lumen catheter should be visualized within the right atrium, venting the return oxygenated blood through the tricuspid valve to minimize recirculation. Another mode of determining catheter position is also two-dimensional duplex doppler. If there is persistent difﬁculty maintaining ﬂow due to poor venous withdrawal, the possibility of a catheter problem must be entertained and further imaging should be performed to conﬁrm proper position.

320 Extracorporeal membrane oxygenation for neonatal respiratory failure

Prime management The tubing of the ECMO circuit is initially circulated with carbon dioxide gas. This is followed by the addition of crystalloid and 5% albumin solution. The albumin coats the tubing to decrease its reactivity to circulating blood. The carbon dioxide gas dissolves into the ﬂuid. Approximately 2 units of packed red blood cells are required for initial priming of the pump, which displaces the crystalloid and colloid in the circuit. The initial pH, oxygen content and carbon dioxide content of the circuit are then measured and adjusted to physiologic parameters. If the prime blood is acidotic, this may exacerbate the infant’s condition; or if the primed circuit has a low carbon dioxide content, this may cause metabolic problems for the neonate. Additionally, a heat exchanger warms the prime to normal body temperature. In sum, the primed circuit must be physiologically compatible with life prior to initiating ECMO to maximize support and prevent initial worsening of the child’s condition.

Pump management The goal of ECMO is to maintain adequate pump ﬂow, which will result in good oxygen delivery to the tissues and organs. Oxygen delivery to the infant is dependent on the speed or rotations per minute (r.p.m.) of the roller pump as it non-occlusively propels the volume of blood in the ‘raceway’ (tubing within the roller pump housing). With VA ECMO, adequate perfusion and oxygen delivery can be monitored by the pH and Po2 of a ‘mixed venous’ blood sample (pre-oxygenator blood sample). The ﬂow of the roller pump should be adjusted to maintain a mixed venous Po2 of 37–40 mmHg and saturation of 65–70%. With VV ECMO, the ‘mixed venous’ sample may not be a reliable indicator of perfusion as recirculation may produce a falsely elevated Po2. Therefore, other indicators of poor perfusion should be followed: persistent metabolic acidosis, oliguria, seizures, elevated liver function tests and hypotension. If oxygen delivery is found to be inadequate, then the r.p.m. of the pump may need to be increased to improve perfusion. Roller pumps roll against the tubing to propel the blood towards the oxygenator. This area of contact is at risk for tubing rupture over time. To reduce the risk of rupture, the ‘raceway’ is advanced regularly after temporarily stopping the pump ﬂow. Tubing rupture is a rare event thanks to modern materials such as Supertygon (Norton Performance Plastics Corp., Akron, OH, USA), a chemically altered polyvinyl chloride (PVC).

Oxygenator management The silicone membrane (envelope) oxygenator (Avecor, Inc., Minneapolis, MN, USA) is critical to the success of

ECMO and long-term bypass. The mechanism of gas exchange occurs when blood in the tubing enters a manifold region and is distributed around the envelope of a silicone membrane lung. Oxygen, which is mixed with a small amount of carbon dioxide to prevent hypocapnea (Carbogen 95% O2 + 5% Co2), ﬂows through the inside of the membrane envelope in a countercurrent direction to the ﬂow of blood. Oxygen diffuses across the silicone membrane into the blood as carbon dioxide is eliminated. The oxygenated blood drains into a manifold and is returned to the infant via a heat exchanger. A thrombus may form in the oxygenator over time. As a thrombus extends, the membrane surface area is decreased, resulting in decreased oxygen and carbon dioxide transfer. This can lead to increased resistance to blood ﬂow. The gaseous portion of the oxygenator may also develop obstructions, which may lead to air emboli. Long-term use may wear the silicone membrane, resulting in blood and water in the gas phase. Therefore, the oxygenator should be replaced when the post-oxygenator Po2 decreases to < 200 mmHg or pre-oxygenator circuit pressures increase to > 400 mmHg at ﬂow rates required to support the patient. In addition, a larger oxygenator may also be required if the gas and blood ﬂow rating of the old oxygenator are exceeded in order to maintain adequate perfusion.

Volume management While on ECMO, maintenance ﬂuids for a term newborn under a radiant warmer are estimated to be 100 cc/kg/day. Water loss through the oxygenator may approach 2 cc/m2/hour. For a baby weighing 3 kg, this would be about 13 cc/kg/day. Fluid losses from urine, stool, chest tubes, nasogastric tubes, ostomies, mechanical ventilation, radiant ﬂuid loss and blood draws should be carefully recorded and repleted. Fluid management may become difﬁcult in the baby on ECMO as ﬂuid extravasates into the soft tissues during the early ECMO course. Therefore, meticulous recordings of the net ﬂuid balance on ECMO should be maintained. Classically, the weight increases in the ﬁrst 1–3 days as the patient becomes increasingly edematous. Starting the third day on ECMO, diuresis of the excess edema ﬂuid begins, and can be facilitated with the use of furosemide. This diuretic phase is often the harbinger of recovery. In the event of renal failure on ECMO, hemoﬁltration or hemodialysis can be added to the ECMO circuit for removal of excess ﬂuid and electrolyte correction.

Respiratory management on ECMO Once the desired ﬂow is attained, the ventilator should be promptly weaned to avoid further oxygen toxicity and barotrauma. Such ‘rest settings’ have been studied and debated.13 At the current authors’ institution, the FiO2 is

Clinical management of neonates on ECMO 321

decreased to 0.4, PEEP to 5 cm H2O, PIP to 20–25 cm H2O, a rate of 12 breaths/minute and inspiratory time of 0.5 seconds if the infant’s arterial and venous oxygenation are adequate. If the baby remains hypoxic despite maximal pump ﬂow, then higher ventilator settings may be temporarily required. Alternatively, hypoxic neonates on VV ECMO may need to be converted to VA ECMO for full cardiorespiratory support. On occasion, the chest X-ray will worsen in the ﬁrst 24 hours independent of ventilator settings and improve after diuresis. As the patient improves on ECMO and the pump ﬂow is weaned, ventilator settings are then modestly increased to support the baby off ECMO. In neonates, if the oxygen saturation is greater than 93%, the current authors consider an FiO2 of 0.4, PIP < 28, PEEP of 5, and a rate < 30 as adequate settings for a trial off of ECMO. In addition, during the course of ECMO, pulmonary toilet is essential to respiratory improvement and includes gentle chest percussion and postural drainage. Special attention should be made to the ECMO catheters and keeping the head and body aligned. Endotracheal suctioning is also recommended every 4 hours and as needed based on the amount of pulmonary secretions present.

Medical management After the initiation of ECMO, vasoactive medications should be quickly weaned down if the blood pressure remains stable. In the event of seizures, phenobarbital is usually given and maintained to prevent further seizures. In addition, gastrointestinal prophylaxis with an H2blocker, such as ranitidine, is instituted. Fentanyl and midazolam are usually administered for mild sedation, however the use of paralytics should be avoided. The baby’s muscle activity is not only important for ﬂuid mobilization of edema but also for monitoring neurological activity. Infectious prophylaxis is provided by the use of ampicillin and gentamicin, which covers most common perinatal bacterial infections. With the use of gentamicin, attention should be directed to renal function. For this reason, cefotaxime may be used for Gram-negative coverage instead of gentamicin. Due to the cannula and manipulation of the circuit at stopcocks, the risk of infection is a constant concern; therefore, strict observance to aseptic technique when handling the ECMO circuit should be maintained. Routine blood, urine, and tracheal cultures should be obtained to monitor for infection. The caloric intake on ECMO should be maximized using standard hyperalimentation. For a newborn, total parenteral nutrition (TPN) should be started at 100 kcal/kg/day. Normally, this should be supplied as 60% carbohydrates (14.6 g/kg/day) and 40% fat (4.3 g/kg/day). Intralipid infusions may be used as a

fat source, although there is some controversy with its use in the setting of severe lung disease. As a result, the percentage of fat in the hyperalimentation may be lowered. Amino acids may be added but must be considered in the setting of poor renal function and increasing BUN levels. With normal renal function, approximately 2.5 g protein/kg/day should be provided in the TPN mixture. Electrolytes should be closely monitored with potassium, calcium and magnesium repleted as necessary. Sodium and phosphorus are usually not repleted as they are often provided in blood products and volume expanders.

Coagulation management While on ECMO, the baby’s hemoglobin is maintained at 15 g/dL to maximize the oxygen-carrying capacity of the blood. Platelet destruction during ECMO is anticipated and is secondary to the ﬂow through the oxygenator. The platelet consumption should not exceed one-half to three units/day in neonates. In order to reduce the risk of bleeding during ECMO, the platelet count should be kept above 100 000/mm.14 The current authors recommend using ‘hyperspun’ platelets to avoid the excess administration of ﬂuid, and thus preventing further problems with volume overload and edema. Heparin is initially administered as a bolus (50– 100 mg/kg) followed by a constant heparin infusion (30–60 mg/kg/hour) to maintain a thrombus-free circuit. The level of anticoagulation is monitored by the activated clotting time (ACT). The heparin infusion is adjusted to maintain an ACT of 180–220 seconds. After decannulating, the heparin infusion is stopped and not reversed with protamine sulfate.

Complications on ECMO MECHANICAL COMPLICATIONS While hypovolemia is an important cause for poor venous return to the circuit and subsequent poor pump ﬂow, other causes must be eliminated prior to volume infusion. These may include small venous catheter diameter, excessive catheter length, catheter kinks, improper catheter position, insufﬁcient hydrostatic column length (i.e. patient height), and improper calibration or set-up of the venous control module system. After these causes have been excluded, small amounts of volume (5–20 cc/kg) may then be introduced into the circuit to support higher pump ﬂow rate. However, a large amount of volume infusion in conjunction with long-term muscle relaxants and venodilators can lead to anasarca, which in turn, can lead to poor chest wall compliance, compromised gas exchange and oxygen delivery. In some conditions such as sepsis,

322 Extracorporeal membrane oxygenation for neonatal respiratory failure

there may be endothelial damage and capillary leakage, in which case anasarca may be unavoidable.

NEUROLOGIC COMPLICATIONS The most serious complications of the ECMO patient have been neurologic (e.g. learning disorders, motor dysfunction, cerebral palsy) and appear to be due to hypoxia and acidosis prior to ECMO. During the ECMO course, frequent neurological examinations should be performed, and paralytic agents should be avoided. The exam consists of evaluation of alertness and interaction, fullness of the fontanels, reﬂexes, tone, spontaneous movements, eye ﬁndings, and presence of seizures. Intracranial hemorrhage (ICH) is the most devastating complication on ECMO. Therefore, careful attention must be made to the rate of ECMO ﬂow, rate of exchange of Pco2, ﬂuctuations in the ACT and platelet count. Cranial ultrasounds should be performed at least every other day to monitor ICH and after any major event, such as equipment malfunction, sudden worsening in oxygenation status, and pneumothorax. Electroencephalography (EEG) may also be helpful in the neurologic evaluation of the neonate.

RENAL COMPLICATIONS Infants on ECMO may sustain acute tubular necrosis (ATN) marked by oliguria and increasing BUN and creatinine levels. ATN may extend into the ﬁrst 24–48 hours of ECMO before improvement in urine output is seen. If the renal condition does not improve, poor tissue perfusion should be considered. A combination of inadequate ECMO ﬂow rate, low cardiac output and intravascular volume depletion from diuresis may lead to decreased renal function. If the infant remains in complete anuric renal failure and requires dialysis, a hemoﬁltration module can be added in series to the ECMO circuit to remove excess ﬂuid and stabilize electrolyte abnormalities.

Weaning from ECMO As the patient improves during the ECMO course, the ﬂow of the circuit is weaned, based on improving postductal arterial and venous oxygenation. From starting ﬂows as high as 150 cc/kg/minute, the ﬂow is decreased to 30–50 cc/kg/minute while maintaining adequate perfusion. The ACT should be maintained at a higher level due to the lower ﬂows to prevent thrombosis. If the baby tolerates the low ﬂow, then the ECMO cannula (VV) or cannulas (VA) may be clamped while the ECMO circuit recirculates. The current authors prefer to wean patients on to moderate conventional ventilator settings, i.e. IMV 20, FiO2 0.4, PIP 25, and PEEP 5. Higher ventilator settings, though, may be tolerated if the risks of continuing ECMO outweigh those of discontinuing ECMO. If the recirculation is tolerated, then decannulation is

performed. As with the insertion, decannulation should be performed as a sterile surgical procedure. The patient should be placed in the Trendelenburg position and muscle relaxants should be administered to prevent air aspiration into the vein. Prior to decannulation, vasoactive medication and hyperalimentation should be switched from the ECMO circuit to other vascular access. Once the catheter is removed, the vein is ligated and not repaired. This is also true for the artery in the case of VA ECMO.

ECMO in infants with congenital diaphragmatic hernia Neonates with CDH have abdominal viscera in the thoracic cavity, most commonly on the left side. This often leads to signiﬁcant pulmonary hypoplasia and pulmonary hypertension. Pulmonary insufﬁciency can ensue, leading to hypoxemia, hypercarbia, and acidosis soon after birth; this can then lead to a vicious cycle of pulmonary vasospasm, pulmonary hypertension, right-to-left shunting of blood and worsening hypoxemia, hypercarbia and acidosis. This cycle must be broken, if not medically, then with the assistance of ECMO. Medical management has improved greatly with the use of pulmonary vasodilators such as tolazoline and inhaled nitric oxide. If a fetus is antenatally diagnosed with a CDH, plans should be made for delivery in a medical center with ECMO capabilities in case of potential rescue therapy. There is no surgical indication or beneﬁt to early delivery of cesarian section. In the delivery room, intubation should be performed immediately after birth. The baby should then be transferred to a neonatal intensive care unit and started on mechanical ventilation to stabilize oxygenation and hemodynamics. In the past, newborns with CDH have undergone repair as a surgical emergency. However respiratory mechanics frequently worsen postoperatively, perhaps as a result of early repair.15 In the 1980s, however, surgeons reported improved results with delayed surgery after postnatal medical stabilization.16–21 A strategy of delayed repair in CDH patients after stabilization of respiratory and hemodynamic parameters with or without ECMO is the current standard of care.

OUTCOME AND FOLLOW-UP OF NEONATES TREATED WITH ECMO Mortality Mortality statistics for ECMO-treated patients have remained stable over the past decade according to the ELSO registry. Severe respiratory failure has been a major cause for return hospitalization and late deaths, but mortality has remained speciﬁc to the primary diagnosis prior to ECMO.1 For example, ECMO patients with

Outcome and follow-up of neonates treated with ECMO 323

the diagnosis of CDH or total anomalous pulmonary venous return (TAPVR) have about a 50% mortality rate while the diagnosis of meconium aspiration syndrome has a mortality rate of about 5%.1,22 For all diagnoses, the mortality rate for newborns placed on ECMO is about 20% according to the ELSO registry.1 Of the infants who die on ECMO, about half die from severe bleeding complications. Another risk factor for mortality is a birth weight of < 2 kg. A retrospective study reviewed 300 newborns treated with ECMO, and the infants who weighed < 2.5 kg, although meeting the criteria of 2 kg, had a relative mortality risk of 3.45% compared to ECMO neonates with birth weights > 2.5 kg.23

Feeding and growth sequelae After decannulation from ECMO, an important factor affecting NICU discharge is initiation of successful enteral feeding. Feeding problems have been reported in as many as one-third of ECMO-treated infants and varies in presentation.24–26 These problems are due to a variety of possible causes which include interference from tachypnea, generalized CNS depression, poor hunger drive, soreness in the neck from the surgical procedure, sore throat from intubation, poor oral–motor coordination, and manipulation or compression of the vagus nerve during the cannulation procedure.26,27 Feeding problems also differ according to pre-ECMO diagnosis. For example, infants with CDH have a higher incidence of feeding difﬁculty than infants with MAS and RDS.27–29 The CDH infants often have foregut dysmotility which leads to signiﬁcant reﬂux, delayed gastric emptying and feeding difﬁculties. Respiratory compromise and severe chronic lung disease also interfere with feeding. These babies may require prolonged nasogastric feeding or even a gastrostomy, fundoplication and pyloroplasty to maintain adequate growth. However, ECMO infants generally do not have major long-term feeding complications. Although normal somatic growth is most commonly reported, ECMO-treated children are more likely to experience problems with growth than normal controls. Head circumference below the 5th percentile occurs at a higher rate (10%) in post-ECMO children. Furthermore, poor head growth is associated with a major handicapping condition with a risk greater than 75% at 5 years of age.30 Although controversial, there have also been reports of macrocephaly, which follows a pattern of venous obstruction secondary to internal jugular vein ligation observed on neonatal neuro-imaging.30,31 Growth problems are most commonly associated with ECMO children who had CDH or residual lung disease.28

Respiratory sequelae Signiﬁcant respiratory problems are reported in ECMO survivors during the ﬁrst 2 years of life, with

a high rate of re-hospitalizations for pulmonary conditions.32,33 Approximately 15% of infants treated with ECMO require oxygen at 28 days. By the age of 5 years, ECMO children were twice as likely to have a reported case of pneumonia than control children (25% vs 13%). Approximately half of the ECMO children with pneumonia were hospitalized compared to none of the control cases. Half of the cases of pneumonias in ECMO children occurred before 1 year of life compared to none in the control group. In addition, more than half of the ECMO re-hospitalizations for pneumonia occurred within the ﬁrst 6 months of life. Of the ECMO-treated neonates, the primary diagnosis of CDH, in particular, has been found to be associated with chronic lung disease, deﬁned by the need for bronchodilators, diuretics, or supplemental oxygen for the management of pulmonary symptoms. Speciﬁcally, the use of supplemental oxygen at discharge from the hospital has been reported in 22–80% of CDH patients.29,34–36 This is most likely due to aggressive ventilator management and lung injury prior to initiating ECMO. The age at the time of ECMO, correlating with the amount of time on mechanical ventilation prior to ECMO, is another factor associated with oxygen need past 28 days.6 Neonates with severe respiratory failure had an 11.5-fold increased risk of bronchopulmonary dysplasia if ECMO was initiated at later than 96 hours of age. In addition, ECMO infants with birth weights of 2–2.5 kg have a greater risk for chronic lung disease than larger ECMO infants.23

Neurodevelopmental sequelae Perhaps the most serious of post-ECMO morbidities is sensorineural handicap. Reports of neurodevelopmental outcome after 1 year of age have been published from multiple institutions. Among 540 ECMO survivors from 12 institutions, the total rate of sensorineural handicap (cerebral palsy, blindness, hearing impairment) is 6% on average, ranging from 2–18%.30,37–49 Signiﬁcant developmental delay among ECMO survivors is 9% on average, ranging from 0–21%. This is comparable to other critically ill neonates. For example, newborns with extremely low birth weights (< 750 g) have a 15% rate of having major sensorineural handicap with 21% testing in the mentally retarded range.50 Additionally, newborns with PPHN not treated with ECMO have an average sensorineural handicap rate of 23% (0–37% range) among 162 survivors from eight institutions.51–58 Auditory deﬁcits are reported in more than 25% of ECMO neonates at the time of discharge.59 The majority consists of mild–moderate deﬁcit by brainstem auditory evoked response (BAER) testing which generally resolve over time. These auditory deﬁcits may also be partly iatrogenic due to alkalosis secondary to furosemide

324 Extracorporeal membrane oxygenation for neonatal respiratory failure

administration or gentamicin ototoxicity. As a result, hearing screening is recommended at the time of neonatal intensive care unit (NICU) discharge. Examining data for 313 ECMO children from ﬁve centers shows an overall rate of 9% (range 4–21%).30,42,44,46 This rate is not higher than that reported for non-ECMO PPHN children (23%, range 0–37%).51–54 Visual deﬁcits in ECMO neonates are usually due to the immature retina in premature patients. This is uncommon in ECMO neonates weighing more than 2 kg. Concern about retinopathy of prematurity due to the hyperoxic condition of ECMO has not been borne out. Hanley reported ocular ﬁndings in 16 of 85 ECMO neonates. These ﬁndings included vascular immaturity, vitreous and retinal hemorrhage, and optic nerve atrophy.60 However, not all infants were examined in this study and there may have been additional complications. Long-term sequelae were not reported, and non-ECMO controls were not tested. Seizures, both clinical and electroencephalographic, are widely reported among ECMO neonates, ranging widely from 20–70%.61–64 The timing and type of seizure activity are not consistent. However, in a group of 5-year-olds ECMO children, only 2% had a diagnosis of epilepsy. Seizures in the neonate are associated with neurologic disease and poorer long-term outcome, including cerebral palsy and epilepsy.65 According to one study, the handicap rate following neonatal seizures is 8%.66 A predictive association between abnormal EEG and developmental status has been found, with only 18% of infants having normal EEGs with developmental delays; this is compared to 35% of infants with one abnormal EEG and 58% of ECMO infants with two or more abnormal EEGs.62 Neuromotor deﬁcits range from a continuum of reports of mild hypotonia, gross motor delay, and asymmetry to isolated cases of spastic quadraparesis. Although moderate hypotonia is not uncommon at discharge, it generally improves over the next 4–6 months. However, these neuromotor ﬁndings are also seen in normal control children.33 The incidence of severe non-ambulatory cerebral palsy is less than 5%.30,37,42 These cases are generally accompanied by mental retardation, demonstrating a global insult to the brain. More commonly seen is a mild case of cerebral palsy in up to 20% of ECMO children. ECMO-treated neonates as a group most commonly function within the normal range.30,37,39,42–49 The rate of major handicap appears to be stable across studies with an average of 11%, range 2–18%. By the time of discharge, at approximately 1 month of life, ECMO infants still exhibit signs of general CNS depression, including lethargy, hypotonia and weak primitive reﬂexes, an indication of moderate hypoxic– ischemic encephalopathy. By 4 months of age, ECMO infants typically function in the normal range deﬁned by Bayley mental and motor scales. Residual hypotonia or

mild asymmetry persists in about 25%. Mild motor delay usually accompanies the hypotonia. Signiﬁcant neurological abnormalities and motor deﬁcits (more than two standard deviations below norm) are found in approximately 10–15% of affected individuals. By 3 years of age, the rate of handicap appears to be stable, but more subtle handicaps manifest at this age such as learning disabilities, particularly with language and perceptual functioning.26,67–69 By 5 years of age, a diagnosis of mental retardation (IQ < 70, delay in social adaptive functioning) becomes more certain. In one 5-years old, 11% of individuals studied were diagnosed as mentally retarded, most in the mild range with IQs of 50–70. For ECMO children who had carotid artery cannulation and ligation, controversy remains over reconstruction of the artery. Baumgart et al. reported experience of 84 ECMO children who had carotid ligation and 41 who had right common carotid artery reconstruction.70,71 Failure of the reanastomosis, deﬁned by > 50% occlusion or no ﬂow, occurred in 25% of procedures. No signiﬁcant differences were reported for occurrence of grade 3 and 4 hemorrhages, but 60% of the group reanastomosed had moderate to severe abnormalities on EEG, compared to 35% of the non-reconstructed group. Despite this, no differences were reported in the proportion of signiﬁcant neurodevelopmental delays.

SUMMARY Since the ﬁrst use of ECMO in neonates in 1974, much has been learned about the treatment of infants with cardiac and respiratory disease. New, less invasive medication and techniques have been developed which have kept numerous babies from ECMO cannulation. Over the years, much has also been learned about ECMO; indications have been expanded and selection criteria honed. Currently, the successful treatment of a variety of neonatal respiratory diseases such as meconium aspiration syndrome, persistent pulmonary hypertension of the neonate and severe pneumonia can be achieved. ECMO may also be helpful in neonates with cardiac lesions and difﬁculty weaning from bypass. Difﬁcult clinical scenarios such as congenital diaphragmatic hernia and sepsis have also met with success through the use of ECMO. The criteria for ECMO candidates have been slowly ﬁne-tuned to maximize survival rates and avoid unnecessary ECMO in infants with irreversible disease. Such criteria include early gestational age, low birth weight, coagulopathy, intracranial hemorrhage, lethal anomalies and irreversible lung disease. In summary, any hypoxic infant who has a reversible pulmonary or cardiac condition, who is physically large enough for ECMO, and who has failed maximal medical therapy should be considered for

References 325

ECMO. Meticulous attention and thorough documentation of each ECMO patient have improved knowledge about ECMO through the ELSO Registry. With ECMO as a safety net, new therapies can be developed for this poor surviving group of newborns such that the ultimate success of ECMO, will be its discontinuation.

REFERENCES 1. Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. 1999: July. 2. Cilley RE, Zwischenberger JB, Andrews AF, Bowerman RA, Roloff DW, Bartlett RH. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics 1986; 78(4):699–704. 3. Sell LL, Cullen ML, Whittlesey GC, Yedlin ST, Philipart AI, Bedard MP, Klein MD. Hemorrhage complications during extracorporeal membrane oxygenation: Prevention and treatment. J Pediatr Surg 1986; 21(12):1087–91. 4. Allmen D, Babcock D, Matsumoto J, Flake A, Warner BW, Stevenson RJ, Ryckman FC. The predictive value of head ultrasound in the ECMO candidate. J Pediatr Surg 1992; 27(1):36–9. 5. Northway WH, Rosan RC, Porter DY. Pulmonary disease following respiratory therapy of hyaline-membrane disease. N Engl J Med 1967; 276(7):357–8. 6. Kornhauser MS, Cullen JA, Baumgart S, McKee LJ, Gross GW, Spitzer AR. Risk factors for bronchopulmonary dysplasia after extracorporeal membrane oxygenation. Arch Ped Adolesc Med 1994; 148:820–5. 7. Sanders RJ, Cox C, Phelps DL, Sinkin RA. Two doses of early intravenous dexamethasone for the prevention of bronchopulmonary dysplasia in babies with respiratory distress syndrome. Pediatr Res 1994; 36(1):122–8. 8. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76(4):488–94. 9. Krummel TM, Greenﬁeld LJ, Kirkpatrick BV, Mueller DG, Kerkering KW, Ormazabal M, Napolitano A, Salzberg AM. Alveolar-arterial oxygen gradients versus the neonatal pulmonary insufﬁciency index for prediction of mortality in ECMO candidates. J Pediatr Surg 1984; 19(4):380–4. 10. Beck R, Anderson KD, Pearson GD, Cronin J, Miller MK, Short BL. Criteria for extracorporeal membrane oxygenation in a population of infants with persistent pulmonary hypertension of the newborn. J Pediatr Surg 1986; 21(4):297–302. 11. Marsh TD, Wilkerson SA, Cook LN. Extracorporeal membrane oxygenation selection criteria: Partial pressure of arterial oxygen versus alveolar-arterial oxygen gradient. Pediatrics 1988; 82(2):162–6.

12. Ortiz RM, Cilley RE, Bartlett RH. Extracorporeal membrane oxygenation in pediatric respiratory failure. Pediatr Clin N Am 1987; 34(1):39–46. 13. Keszler M, Subramanian KN, Smith YA et al. Pulmonary management during extracorporeal membrane oxygenation. Crit Care Med 1989; 17:495–500. 14. Raithel SC, Pennington DG, Boegner E, Fiore A, Weber TR. Extracorporeal membrane oxygenation in children after cardiac surgery. Circulation 1992; 86:II305–10. 15. Sakai H, Tamura M, Hosokawa Y, Bryan AC, Barker GA, Bohn DJ. Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 1987; 111:432–8. 16. Cartlidge PHT, Mann NP, Kapila L. Preoperative stabilization in congenital diaphragmatic hernia. Arch Dis Child 1986; 61:1226–8. 17. Breaux CW Jr, Rouse TM, Cain WS, Georgeson KE. Improvement in survival of patients with congenital diaphragmatic hernia utilizing a strategy of delayed repair after medical and/or extracorporeal membrane oxygenation stabilization. J Pediatr Surg 1991; 26:333–8. 18. West KW, Bengston K, Rescorla FJ, Engel WA, Grosfeld JL. Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg 1992; 216:454–62. 19. Nakayama DK, Motoyama EK, Tagge EM. Effect of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia. J Pediatr 1991; 118:793–9. 20. Wung JT, Sahni R, Mofﬁtt ST, Lipsitz E, Stolar CJ. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30(3):406–9. 21. Lally KP, Paranka MS, Roden J et al. Congenital diaphragmatic hernia: Stabilization and repair on ECMO. Ann Surg 1992; 216:569–73. 22. Stewart D, Mendoza J, Winston S, Cook L. Extracorporeal life support (ECLS) in infants with total anomalous pulmonary venous drainage (TAPVD): a review of the ELSO registry. 1992, CNMC ECMO Symposium 81. 23. Revenis M, Glass P, Short BL. Mortality and morbidity rates among lower birth weight infants (2000–2500 grams) treated with extracorporeal membrane oxygenation. J Pediatr 1992; 121:452–8. 24. Grimm P. Feeding difﬁculties in infants treated with ECMO. CNMC ECMO Symposium 1993: 25. 25. Nield T, Hallaway M, Fodera C et al. Outcome in problem feeders post ECMO. 1990, CNMC ECMO Symposium 79. 26. Glass P. Patient neurodevelopmental outcomes after neonatal ECMO. In: Arensman R, Cornish J, editors. Extracorporeal life support. Boston, MA: Blackwell Scientiﬁc Publications, 1993. 27. Tarby T, Waggoner J. Are the common neurologic problems following ECMO related to jugular bulb thrombosis? 1994, ENMC ECMO Symposium 100.

326 Extracorporeal membrane oxygenation for neonatal respiratory failure 28. Van Meurs K, Robbins S, Reed V, Glass P, O’Brien A, Short BL. Congenital diaphragmatic hernia: long-term outcome of neonates treated with ECMO. 1991, CNMC ECMO Symposium 25. 29. Rajasingham S, Reed V, Glass P, Wagner A, Civitello L, Coffman C, Short BL. Congenital diaphragmatic hernia – outcome post-ECMO at 5 years. 1994, CNMC ECMO Symposium 35. 30. Glass P, Wagner A, Papero P et al. Neurodevelopmental status at age ﬁve years of neonates treated with extracorporeal membrane oxygenation. J Pediatr 1995; 127:447–57. 31. Walsh-Sukys M, Bauer R, Cornell D, Friedman H, Stork E, Hack M. Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes. J Pediatr 1994; 125:104–10. 32. Gershan L, Gershan W, Day S. Airway anomalies after ECMO: bronchoscopic ﬁndings. 1992, CNMC ECMO Symposium 65. 33. Wagner A, Glass P, Papero P, Coffman C, Kjaer M, Short BL. Neuropsychological outcome of neonatal ECMO survivors at age 5. 1994, CNMC ECMO Symposium 31. 34. D’Agostino J, Bernbaum J, Gerdes M et al. Outcome for infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: the ﬁrst year. J Pediatr Surg 1995; 30:10–15. 35. Van Meurs K, Robbins S, Reed V et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122:893–9. 36. Atkinson J, Poon M. ECMO and the management of congenital diaphragmatic hernia with large diaphragmatic defects requiring a prosthetic patch. J Pediatr Surg 1992; 27:754–6. 37. Adolph V, Ekelund C, Smith C, Starrett A, Falterman K, Arensman R. Developmental outcome of neonates treated with ECMO. J Pediatr Surg 1990; 25:43–6. 38. Andrews A, Nixon C, Cilley R, Roloff D, Bartlett R. One-tothree year outcome for 14 neonatal survivors of extracorporeal membrane oxygenation. Pediatrics 1986; 78:692–8. 39. Flusser H, Dodge N, Engle W, Garg B, West K. Neurodevelopmental outcome and respiratory morbidity for ECMO survivors at 1 year of age. J Perinatol 1993; 13:266–71. 40. Glass P, Miller M, Short BL. Morbidity for survivors of extracorporeal membrane oxygenation: neurodevelopmental outcome at 12 years of age. Pediatrics 1989; 83:72–8. 41. Grifﬁn M, Minifee P, Landry S, Allison P, Swischuk L, Zwischenberger J. Neurodevelopmental outcome in neonates after ECMO: cranial magnetic resonance imaging and ultrasonography correlation. J Pediatr Surg 1992; 27:33–5. 42. Hofkosh D, Thompson A, Nozza R, Kemp S, Bowen A, Feldman H. Ten years of ECMO: neurodevelopmental outcome. Pediatrics 1991; 87:549–55.

43. Krummel T, Greenﬁeld L, Kirkpatrick B et al. The early evaluation of survivors after ECMO for neonatal pulmonary failure. J Pediatr Surg 1984; 19:585–90. 44. Schumacher R, Palmer T, Roloff D, LaClaire P, Bartlett R. Follow-up of infants treated with ECMO for newborn respiratory failure. Pediatrics 1991; 87:451–7. 45. Towne B, Lott I, Hicks D, Healey T. Long-term follow-up of infants and children treated with ECMO: a preliminary report. J Pediatr Surg 1985; 20:410–14. 46. Wildin S, Landry S, Zwischenberger J. Prospective, controlled study of developmental outcome in survivors of ECMO: the ﬁrst 24 months. Pediatrics 1994; 93:404–8. 47. Stolar CJ, Crisaﬁ MA, Driscoll YT. Neurocognitive outcome for neonates treated with extracorporeal membrane oxygenation: Are infants with congenital diaphragmatic hernia different? J Pediatr Surg 1995; 30:366–72. 48. Davis D, Wilkerson S, Stewart D. Neurodevelopmental follow-up of ECMO survivors at 7 years. 1995 CNMC ECMO Symposium 34. 49. Stanley C, Brodsky K, McKee L, Gringlas M, Graziani L. Developmental proﬁle of ECMO survivors at early school age and relationship to neonatal EEG status. 1995 CNMC ECMO Symposium 33. 50. Hack M, Taylor H, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. School-age outcomes in children with birthweights under 750 g. N Engl J Med 1994; 331:753–9. 51. Walton J, Hendricks-Munoz K. Proﬁle and stability of sensorineural hearing loss in persistent pulmonary hypertension of the newborn. J Speech Hear Res 1991; 34:1362–70. 52. Naulty C, Weiss I, Herer G. Progressive sensorineural hearing loss in survivors of persistent fetal circulation. Ear Hear 1986; 7:74–7. 53. Leavitt A, Watchko J, Bennett F, Folson R. Neurodevelopmental outcome following persistent pulmonary hypertension of the neonate. J Perinatol 1987; 7:88–291. 54. Sell E, Gaines J, Gluckman C, Williams E. Persistent fetal circulation: neurodevelopmental outcome. Am J Dis Child 1985; 139:25–8. 55. Marron M, Crisaﬁ M, Driscoll J, Wung J, Driscoll Y, Fay T, James L. Hearing and neurodevelopmental outcome in survivors of persistent pulmonary hypertension of the newborn. Pediatrics 1992; 90:392–6. 56. Bifano E, Pfannenstiel A. Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 1988; 81:657–61. 57. Ferrara B, Johnson D, Chang P, Thompson T. Efﬁcacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy. Pediatrics 1984; 105:457–61. 58. Bernbaum J, Russell P, Sheridan P, Gewitz M, Fox W, Peckham G. Long-term follow-up of newborns with persistent pulmonary hypertension. Crit Care Med 1984; 12:579–83.

References 327 59. Desai S, Stanley C, Graziani L, McKee L, Baumgart S. Brainstem auditory evoked potential screening (BAEP) unreliable for detecting sensorineural hearing loss in ECMO survivors: a comparison of neonatal BAEP and follow-up behavioral audiometry. 1994, CNMC ECMO Symposium 62. 60. Haney B, Thibeault D, Sward-Comunelli S, Grin T, StassIsern M, Grist G. Ocular ﬁndings in infants treated with ECMO. 1994, CNMC ECMO Symposium 63. 61. Hahn J, Baucher Y, Bejar R, Coen R. Electroencephalographic and neuroimaging ﬁndings in neonates undergoing extracorporeal membrane oxygenation. Neuropediatrics 1993; 24:19–24. 62. Graziani L, Streletz L, Baumgart S, Cullen J, McKee L. Predictive value of neonatal electroencephalograms before and during extracorporeal membrane oxygenation. J Pediatr 1994; 125:969–75. 63. Campbell L, Bunyapen C, Gangarosa M, Cohen M, Kanto W. The signiﬁcance of seizures associated with ECMO. 1991, CNMC ECMO Symposium 26. 64. Kumar P, Bedard M, Delaney-Black V, Shankaran S. Post-ECMO electroencephalogram (EEG) as a predictor of neurological outcome. 1994, CNMC ECMO Symposium 65. 65. Scher M, Kosaburo A, Beggerly M, Hamid M, Steppe D,

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Painter M. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993; 91:128–34. Ittman P, Schumacher R, Vanderkerhove J. Outcome in newborns following pre-ECMO CPR. 1993, CNMC ECMO Symposium 30. Stewart D, Davis D, Reese A, Wilkerson S. Neurodevelopmental outcome of extracorporeal life support (ECLS) patients using the Stanford Binet IV. 1993, CNMC ECMO Symposium 24. Mendoza J, Wilkerson S, Reese A, Vogel R. Outcome of neonates treated with ECMO: longitudinal follow-up from 1 to 3 years of age. 1991, CNMC ECMO Symposium 29. Wilkerson S, Stewart D, Cook L. Developmental outcome of ECMO patients over a four year span. 1990, CNMC ECMO Symposium 23. Baumgart S, Graziani L, Streletz L et al. Right common carotid artery reconstruction following ECMO: structural and vascular imaging electrocephalography and neurodevelopmental correlates to recovery. 1993, CNMC ECMO Symposium 27. Stanley C, Merton D, Desai S et al. Four year follow-up doppler ultrasound studies in children who received right common carotid artery (RCCA) reconstruction following neonatal ECMO. 1995, CNMC ECMO Symposium 104.

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33 Bronchoscopy in the newborn JOHN D. RUSSELL

INTRODUCTION Bronchoscopy in the newborn is an important and diagnostic and therapeutic tool.1 Congenital laryngotracheal malformations and airway complications due to prolonged intubation are two of the main indications for pediatric bronchoscopy.2 Bronchoscopy in children was ﬁrst performed by Killian in 1895.3 It was however associated with a high rate of complication because of poor visibility through small-diameter bronchoscopes and poor lighting. Maintaining ventilation was the main problem. Modern Hopkins lens systems and intense yet ‘cold’ light sources together with modern anesthetic techniques have facilitated safer examination of the airway in the neonate.4 In fact continued advances in instrumentation, anesthesia, endoscopic techniques and pharmacology have facilitated the ongoing evolution in the technique of bronchoscopy of the neonatal airway.5 Pediatric ﬂexible bronchoscopy was initiated in the mid 1970s. Since then newer and smaller instruments with suction channels have enabled pediatricians to visualize the airway of premature infants and neonates without the need for general anesthesia. This enables the pediatrician to examine the airway without signiﬁcantly distorting the anatomy or the normal physiology.6

INSTRUMENTATION Good instrumentation is essential for pediatric bronchoscopy. The systematic assessment of the newborn airway involves laryngoscopy, tracheoscopy and bronchoscopy. One therefore needs a full range of laryngoscopes, bronchoscopes, telescopes and telescopic forceps. The author’s preference is for those obtainable from Karl Storz. The Lindholm–Benjamin laryngoscope is one of the best scopes for examining the neonatal larynx. Suspension of the laryngoscope on a Mayo stand is essential (Fig. 33.1). The modern ventilating bronchoscopes have revolutionized the assessment of the airway,

Figure 33.1 Benjamin–Lindholm laryngoscope attached to a Mayo table. Infant is receiving halothane/oxygen via a nasopharyngeal tube

even in the low birth weight (LBW) premature infant. The components of a modern bronchoscope are (Fig. 33.2): 1 A closed gas system allowing connection to an anesthetic circuit 2 A rigid Hopkins rod telescope to allow distal illumination and vision. 3 A side channel for the passage of suction catheters or ﬂexible forceps. The bronchoscopes range in size from 2.5 (outside diameter 4.0 mm) to 6.0 (outside diameter 8.2 mm). Sizes 2.5–3.0 are the most appropriate for neonates (Table 33.1).

INDICATIONS FOR RIGID BRONCHOSCOPY The list in Box 33.1 is not exhaustive but does provide the main indications. The commonest causes of stridor and airway obstruction in a neonate are: (1) laryngomalacia (2) subglottic stenosis, congenital and acquired, and (3)

330 Bronchoscopy in the newborn

Figure 33.2 Equipment for rigid laryngobronchoscopy 0° telescope (top). 2.5 mm ventilating bronchoscope (middle). Benjamin–Lindholm laryngoscope (bottom)

vocal cord paralysis, unilateral and bilateral. Rarer causes include laryngeal clefts, hemangiomas and papillomas. Rigid bronchoscopy is the diagnostic procedure of choice in the management of airway obstruction. Neonates with stridor can be subdivided into three main groups. In the ﬁrst group is the neonate with severe stridor and signiﬁcant airway obstruction, who will require urgent bronchoscopy and airway support. Secondly a neonate with worsening airway obstruction is another indication for bronchoscopy. Thirdly mild or moderate stridor with poor weight gain or difﬁculty in feeding, apnea or cyanosis would also be an indication for endoscopy. Radiological investigations often raise the suspicion of a diagnosis, e.g. a vascular ring on barium swallow. Endoscopy is needed to conﬁrm this diagnosis. In neonates with recurrent aspiration rigid bronchoscopy is necessary to rule out a laryngotracheal cleft. A complete systematic assessment is necessary as about 70% of bronchoscoped neonates have more than one pathology.4 The presence of stridor and respiratory distress is the most common indication for endoscopy in the neonate and congenital abnormalities are the most common problems encountered.7

TECHNIQUE OF RIGID LARYNGOBRONCHOSCOPY Table 33.1 Diameter of rigid Storz bronchoscopes for newborns Length (cm)

Nominal size (mm)

Internal diameter (mm)

External diameter (mm)

20 20 26 20 26 30

2.5 3.0 3.0 3.5 3.5 3.4

3.2 4.2 4.2 4.9 4.2 4.9

4.0 5.0 5.0 5.7 5.0 5.7

Box 33.1 Small Storz Hopkins telescope diameter, 2.8 mm. Standard Storz Hopkins telescope diameter, 4 mm. Management of severe upper airway obstruction To establish a temporary airway in an emergency Management of massive hemorrhage and blood clots To maintain airway and control bleeding Laser bronchoscopy To remove benign tumors (recurrent respiratory papillomatosis) Endoscopic management of strictures, webs, granulation tissue Open airway surgery Foreign body extraction Evaluation of tracheal pathology, e.g. tracheomalacia, laryngotracheal cleft and subglottis. Re-expansion of consolidated/atelectatic pulmonary lobes

All these examinations are performed under general anesthesia. Modern techniques are versatile, controlled and safe. They allow unhurried, precise and complete examination without stress to the patient, anesthesiologist, the surgeon and the staff.8 A full range of neonatal and pediatric laryngoscopes, bronchoscopes and telescopes are essential. Modern 1 chip and 3 chip cameras allow magniﬁcation and excellent resolution of the image on screen of these tiny airways. A spontaneous respiration technique is the anesthetic method of choice. Halothane is in most anesthesiologists’ opinions, the anesthetic of choice. It allows a deep plane of anesthesia without causing respiratory arrest. The following is an orderly sequence of airway assessment in a neonate that is systematic and complete.

Airway assessment The neonate is anesthetized with a mixture of halothane and oxygen via a face mask. The larynx is then visualized and sprayed with topical lignocaine. An appropriately sized nasopharyngeal airway is inserted and the anesthetic agent is then provided via this route. The baby is also given atropine to prevent bradycardia and to dry up the secretions during the assessment. The topical lignocaine prevents laryngospasm. A baby Lindholm laryngoscope is then inserted, exposing the whole larynx. The scope is suspended on a Mayo table to avoid com-

Indications for ﬂexible bronchoscopy 331

pression of the baby’s chest. The larynx is now examined with the aid of a Zeiss operating microscope. Pathological conditions looked for are: (1) laryngeal cleft, (2) webs, (3) cysts, (4) glottic stenosis, and (5) hemangiomas. The mobility of the arytenoids are then checked. Once the larynx is fully examined a 4 mm 0° telescope is introduced into the subglottis and trachea. This allows a complete atraumatic inspection of the subglottis and trachea. In order to examine the bronchi in detail one has to remove the laryngoscope and introduce an appropriately sized bronchoscope (Fig. 33.3). Turning the baby’s head to the left allows entry through the right main bronchus and turning the head to the right allows entry into the left mainstem bronchus. The ﬁnal part of the assessment is to look at the trachea and vocal cords as the baby is lightening up from the anesthetic. This is the only time when tracheobronchomalacia and vocal cord paralysis can be diagnosed.

Vocal cords Epiglottis Laryngoscopic blade Glottis

Figure 33.3 Under direct visualization of the larynx, the bronchoscope is introduced into the trachea

ADVANTAGES OF RIGID BRONCHOSCOPY The major advantage of rigid instruments is the excellent control of ventilation they provide, which is so important in the neonate. They also excel as therapeutic instruments through which surgery can be performed. General anesthesia allows a magniﬁcent unhurried leisurely view of the larynx and lower airways. Rigid bronchoscopy allows the lower airways to be inspected safely and in great detail while maintaining complete and safe control over ventilation. Flexible bronchoscopy does not allow such control and in a small neonate or infant will cause signiﬁcant, if not total airway obstruction. The image quality obtained by the rigid telescope is also superior to that obtained with the ﬂexible ﬁberoptic bundles.

COMPLICATIONS OF RIGID LARYNGOBRONCHOSCOPY The safety of rigid laryngobronchoscopy depends on the anesthetic technique, monitoring of the patient, the procedures performed during the endoscopy, having adequate equipment, the expertise of the staff, and the

condition of the patient.5 The complication rate of rigid laryngobronchoscopy ranges from 2–4%. The types of complications are: laryngospasm, torn vocal cords, subglottic edema, pneumothorax, pneumonia, hoarseness, hemorrhage, cardiac arrhythmia, and death. In Hoeve et al.’s series in 1993,9 tetralogy of Fallot, biopsy or drainage, foreign body extraction and tracheal stenosis were the main risk factors for complications. Interestingly, fewer complications occurred in the age group < 3 months.

FLEXIBLE BRONCHOSCOPY This technique was initiated in the mid 1970s and since then newer and smaller scopes have enabled pediatricians to visualize the airway of premature infants and neonates without the need for general anesthesia. The advantages of the procedure are: (1) it can be performed on an outpatient basis, and (2) it requires little preparation except for no oral intake 4–6 hours preoperatively. Infants up to 18 months old usually tolerate ﬂexible bronchoscopy utilizing only lignocaine jelly in the nose. The average procedure lasts about 30 seconds. The pediatrician however needs to be able to monitor the baby with pulse oximetry, electrocardiographic and respiratory monitors. A resuscitation cart and a video system are also necessary. All personnel should be trained in resuscitation and i.v. access. Provided ﬂexible bronchoscopy is performed by an experienced operator in a controlled setting, the procedure is very safe. Vauthy6 has performed over 10 000 bronchoscopies with no mortality.

INDICATIONS FOR FLEXIBLE BRONCHOSCOPY Flexible bronchoscopy in neonates is particularly useful in the diagnosis of unexplained mild stridor, unexplained wheezing, hemoptysis, or unexplained cough (Box 33.2). Persistent atelectasis and recurrent or persistent Box 33.2 Diagnostic – Unexplained stridor – Unexplained wheezing – Hemoptysis – Unexplained cough – Persistent atelectasis – Recurrent or persistent pulmonary inﬁltrates To aid intubation Therapeutic bronchoalveolar lavage Brush biopsies Removal of airway secretions Diagnose and monitor after lung transplantation Transbronchial biopsy

332 Bronchoscopy in the newborn

pulmonary inﬁltrates are also indications for its use. Flexible bronchoscopy is also extremely useful in the management of the neonate in the intensive care unit (ICU).10 The advantages are severalfold. Firstly the patients can be assessed in the ICU and no longer need to be transferred to the theater. Secondly the procedure can be performed via a tracheostomy or via the endotracheal tube. This assures maintenance of a safe airway. Sudden episodes of deterioration in a neonate’s respiratory status in the ICU can be due to severe mucous plugging, atelectasis, granuloma formation, tracheitis or tracheobronchomalacia. The technique permits the diagnosis of disease and allows careful direction of suction catheters to improve pulmonary toilet. Full-term infants tolerate ﬂexible bronchoscopy with a 3.4 mm instrument which has suction channels for insufﬂation of oxygen, suction and bronchial brushings or bronchoalveolar lavage. Bronchoalveolar lavage has become a very useful tool for the diagnosis of infection, gastro-esophageal reﬂux and the removal of mucous plugs. The avoidance of a general anesthetic, intubation and mechanical ventilation reduces the cost and possible complications of these interventions.

TECHNIQUE OF FLEXIBLE BRONCHOSCOPY Infants up to 18 months old can easily tolerate ﬂexible bronchoscopy using only lignocaine jelly in the nose. It is important to restate that when the information to be gained is not going to alter the patient’s management, or be of substantial beneﬁt to the patient, then ﬂexible bronchoscopy is probably not indicated. The neonate is placed on the table with the assistant providing oxygen via mask or nasal cannula. The average diagnostic procedure lasts approximately 30 seconds. Post-procedure management includes examination after the procedure and 1.5 hours’ observation. The patient is allowed to feed under supervision after this period.

COMMON PITFALLS FOR THE UNWARY FLEXIBLE BRONCHOSCOPIST

most cases. Wood et al. in 1990 encountered only three patients in whom the transnasal passage of the ﬂexible bronchoscope was not possible.11

Pharyngeal hypotonia Patients with tracheostomies or who have reduced muscle tone because of neurologic disease often have pharyngeal hypotonia. Finding the larynx may be very difﬁcult in these cases.

COMPLICATIONS OF FLEXIBLE BRONCHOSCOPY Obstruction of a large proportion of the airway can lead to hypoxemia. It is also difﬁcult to remove foreign bodies with a ﬂexible scope. The contraindications to ﬂexible bronchoscopy are: (1) hypoxemia, (2) respiratory distress, (3) hemorrhagic diathesis, (4) cardiac arrhythmia, and (5) a foreign body. All these problems increase the risk of complications with ﬂexible bronchoscopy. The complication rate ranges from 2.2–8.0%.12 The nature of complications of ﬂexible endoscopy are laryngospasm, pneumothorax, epistaxis, bradycardia and/or hemorrhage. Generally high-risk patients are more likely to undergo rigid bronchoscopy.

CONCLUSION Modern rigid and ﬂexible bronchoscopy in the newborn carried out by trained personnel is a safe, relatively atraumatic procedure with a very low complication rate. This is due to the advances in anesthesia, pharmacology and instrumentation, camera and video techniques. Rigid and ﬂexible bronchoscopy should be viewed as complimentary and not competing mutually exclusive techniques. Both procedures should be in the armamentarium of the pediatric airway surgeon. There are advantages and disadvantages to each technique. It is to the neonate’s advantage to have both types of endoscopes available so the procedure with the highest beneﬁt-torisk ratio can be employed.

Concurrent lesions Children frequently have multiple airway abnormalities and these can often be missed due to the speed of the ﬂexible assessment.

Difﬁcult nasal passage Nasal septal deviations or turbinate hypertrophy can lead to difﬁculty passing the ﬂexible scopes. The use of a topical vasoconstrictor enables the nose to be entered in

REFERENCES 1. Lockhart CH, Elliot JL. Potential hazards of pediatric rigid bronchoscopy. J Pediatr Surg 1989; 19:239. 2. Lindhall H, Rintala R, Malinen L et al. Bronchoscopy during the ﬁrst month of life. J Pediatr Surg 1992; 27:548–50. 3. Clerf LH. Historical aspects of foreign bodies in the air and food passages. Ann Otol Rhinol Laryngol 1952; 1:5–17.

References 333 4. Ungkanont K, Friedman M, Sulek M. A retrospective analysis of airway endoscopy in patients less than 1 month old. Laryngoscope 1998; 108:1724–8. 5. Holinger LD. Diagnostic endoscopy of the pediatric airway. How I do it. Laryngoscope 1989; 99:346–8. 6. Vauthy P. Evaluation of the pediatric airway by ﬂexible endoscopy in practical pediatric otolaryngology. Lippincott-Raven Ch. 29.B. Philadelphia: New York, 1999, 491–6. 7. Holinger LD. Etiology of stridor in the neonate, infant and child. Ann Otol Rhinol Laryngol 1980; 89:397. 8. Benjamin B. Technique of laryngoscopy. Int J Pediatr Otorhinolaryngol 1987; 13:299–313.

9. Hoeve LJ, Rombout J, Meursing AE. Complications of rigid laryngobronchoscopy in children. Int J Pediatr Otorhinolaryngol 1993; 26:47–56. 10. Myer CM, Thompson RF. Flexible ﬁbreoptic bronchoscopy in the neonatal intensive care unit. Int J Pediatr Otorhinolaryngol 1987; 15:143–7. 11. Wood RE. Pitfalls in the use of the ﬂexible bronchoscope in pediatric patients. Chest 1990; 97:1:199–203. 12. Fan LL, Flynn JW. Laryngoscopy in neonates and infants: experience with the ﬂexible ﬁbreoptic bronchoscope. Laryngoscope 1981; 91:451–6.

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4 Esophagus

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34 Esophageal atresia and tracheo-esophageal ﬁstula PAUL D. LOSTY AND COLIN T. BAILLIE

INTRODUCTION

Box 34.1 Landmarks in the history of esophageal atresia and TEF Durston (1670)

Esophageal atresia (EA) and tracheo-esophageal ﬁstula (TEF) remain a signiﬁcant challenge to modern pediatric surgery. There are many unanswered questions in the clinical and basic science arenas. Improved survival has resulted in a greater emphasis on the complications of EA and TEF, with continuing debate over the management of pure long-gap atresia, gastroesophageal reﬂux (GER), anastomotic stricture, and tracheomalacia. A relatively new body of literature is available concerning long-term outcome and quality of life. The ﬁelds of applied embryology and genetics continue to yield fascinating insights into the etiology of EA and TEF, with signiﬁcant contributions arising out of the development of animal models. The control mechanisms for the fundamental embryological processes that are defective in EA and TEF are now being unravelled at the molecular level.

HISTORY The history of EA and TEF is well described in the literature.1 Some of the important landmarks are highlighted in Box 34.1. The period up to 1935 represents the pre-survival era. As survival improved, prognostic variables became a major focus of attention. In 1962, Waterston’s landmark paper demonstrated that survival was likely in EA and TEF, unless neonates belonged to speciﬁc ‘high-risk’ groups as deﬁned by low birth weight, pneumonia and the presence of associated congenital anomalies.2 Improvements in neonatal intensive care and anesthesia have since contributed to the salvage of many of these ‘high-risk’ infants with EA.

Described isolated EA in one of a pair of conjoined twins3 Gibson (1697) Described the common form of EA and distal TEF4 Lamb (1873) Described H-type TEF5 Hoffman (1899) Attempted cervical repair of EA and TEF, performed ﬁrst gastrostomy6 Richter (1913) Attempted ﬁstula ligation, esophagostomy and gastrostomy7 Donovan (1935) First survivor of isolated EA. Initially neonatal gastrostomy. Esophageal continuity established 16 years later by Humphries1 Lanman (1936) First attempted extra-pleural repair. However, by 1940 no survivors in 30 infants8 Imperatori (1938) First successful repair H-type TEF9 Ladd/Leven First survivors EA and distal TEF using (1939) staged gastrostomy, ligation of ﬁstula and esophagostomy, delayed staged formation of ante-thoracic subcutaneous skin-lined neoesophagus10,11 Haight and First successful primary anastomosis12 Towsley (1943) Waterston et al. ‘At risk groups’ based on weight, (1962) pneumonia and congenital anomaly2 Waterston (1964) Popularized colonic interposition in long-gap EA13 Livaditis (1969) Described circular myotomy in long-gap EA14 Cohen et al. Reversed gastric tube interposition in (1974) long-gap EA15 Gough (1980) Popularized anterior ﬂap in long-gap EA16 Spitz (1984) Popularized gastric interposition in long-gap EA17 Spitz et al. (1994) Revised at-risk groups for the 1990s18

338 Esophageal atresia and tracheo-esophageal ﬁstula

CLASSIFICATION In 1929, Vogt proposed the ﬁrst anatomical classiﬁcation of EA and TEF, based on radiological and post-mortem ﬁndings.19 A variety of surgical classiﬁcations were suggested, as operative treatment became successful, the most frequently employed being that of Gross.20 The most detailed classiﬁcation, however, is attributed to Kluth, and incorporates all described anatomical variations of EA and TEF.21 A working classiﬁcation based on the frequency of each anomaly is of the greatest practical value to the neonatal surgeon (Fig. 34.1).

with signiﬁcant morbidity,25 and probably increased mortality (although statistical conﬁrmation is difﬁcult because of the relative rarity of long-gap EA). Table 34.1 Spitz classiﬁcation system Group

Features

Survival

I

Birth weight >1500 g, no major cardiac disease Birth weight <1500 g, or major cardiac disease Birth weight <1500 g, and major cardiac disease

97%

II III

59% 22%

EPIDEMIOLOGY

82.8%

8.4%

3.4%

3.3%

2.1%

Figure 34.1 Classiﬁcation and frequency of esophageal atresia and tracheo-esophageal ﬁstula. EA and distal TEF – 85%; Isolated EA – 7%; H-type TEF – 4%; EA with proximal and distal ﬁstulas – 3%; EA and proximal ﬁstula –1%

PROGNOSIS Waterston’s seminal paper describing the inﬂuence of pulmonary disease, birth weight and associated congenital anomalies on outcome of infants treated for EA,2 provided a historical basis for comparison of subsequent outcome-based classiﬁcation systems. Advances in medical care have now rendered the Waterston classiﬁcation outdated. Spitz et al. have described a simpliﬁed classiﬁcation system for the modern era (Table 34.1), based on birth weight and the presence or absence of major congenital heart disease.18 A Montreal classiﬁcation system places greater emphasis on preoperative ventilator dependence and associated major anomalies as survival determinants.22 Other studies continue to emphasize the negative inﬂuence of respiratory distress syndrome (RDS) and pneumonia on outcome,23 and the contribution of aspiration episodes and other respiratory morbidity to late death following repair of EA.24 The inﬂuence on outcome of factors directly related to the atresia has received little attention. In this category, ‘long-gap’ EA is associated

In the Liverpool region the incidence of EA and TEF is 1 in 3300 live births.26 The reported range varies from 1 in 2440 in Finland,27 to 1 in 4500 both in Australia28 and the USA.29 The sex ratio has been reported as equal by many authors, but others quote a slight male preponderance.30 EA and TEF are more common in twin pregnancies.30 Exposure to teratogenic drugs during pregnancy has been implicated, including thalidomide, progesterone and estrogen.31

GENETICS The sporadic reports of vertical and transverse familial cases of EA and TEF suggest a polygenic hereditary etiology. The best estimate of risk of recurrence for parents of a single affected child is 0.5–2.0%, rising to 20% if another sibling is born with EA. The vertical transmission risk is 3–4%.32 A 10% incidence of non-speciﬁc chromosomal abnormalities (translocations, deletions and duplications) has been noted. However, only trisomies 18 and 21 show any deﬁnite association with EA and TEF. Recognition of a syndrome suggestive of a major chromosomal abnormality in EA and TEF should prompt the urgent involvement of a clinical geneticist before corrective surgery is undertaken. EA and TEF have been described in association with various syndromes including Holt–Oram syndrome, and DiGeorge sequence, polysplenia, and Pierre Robin sequences.32 Chromosome studies in cases of EA and TEF have occasionally shown deletions or translocations, suggesting possible locations for candidate genes. The most likely of these belongs to the clustered homeobox gene family, HOX. HOXD is implicated in embryonic patterning of the axial skeleton, limbs, and genital and digestive tracts. This fundamental involvement in embryological development may explain the frequent association of vertebral, limb and anorectal anomalies with EA and TEF.

Associated anomalies 339

ANIMAL MODELS Signiﬁcant contributions to our understanding of the embryology and genetic control of foregut development are likely to result from basic laboratory research involving animal models of EA and TEF. The adriamycin rat model in which timed pregnant rats are administered i.p. adriamycin on gestational days 8 and 9, yields EA with distal TEF in two-thirds of fetuses.33,34 These pups also demonstrate associated anomalies belonging to the VACTERL spectrum (denoting vertebral, anorectal, cardiac, tracheo-esophageal, radial/renal and limb anomalies). Recently, a murine model of the VACTERL association has been developed in strains with targeted deletions of the transcription factors Gli-2 and Gli-3 for the Sonic hedgehog (Shh) gene, which is involved in axial organogenesis. Gli-2–/–;Gli-3–/– double mutants demonstrate the full phenotypic spectrum of VACTERL suggesting a pivotal role for Shh in the genetic control of foregut development.35,36 These experimental models may yield insights into the molecular pathogenesis of EA and VACTERL in human infants.

EMBRYOLOGY There is no unifying embryological theory which successfully explains all the anatomical variants of EA and TEF. The complete pathology has been demonstrated in the 5-week-old human embryo; therefore the causative factors must operate before this. In the developing embryo, the ventral aspect of the primitive foregut is destined to become the tracheobronchial tree. A median laryngotracheal groove develops in the ventral aspect of the foregut of the 23-day-old embryo. As the groove elongates with the esophagus, it is postulated that lateral epithelial ridges fuse to bring about septation. Whilst explaining tracheo-esophageal cleft and H-type ﬁstula, caudo-cranial separation of the ventral trachea from the dorsal esophagus by a mesenchymal tracheo-esophageal septum, clearly cannot adequately explain all variants of EA and TEF. The ﬁnding of both an increased number of tracheal rings and a longer trachea in the adriamycin model of EA and TEF, suggests localized abnormal proliferation and elongation of the ventral respiratory component of the common foregut tube. The preferential incorporation of tissue into the trachea may result in esophageal discontinuity.37 The association of 13 pairs of ribs with long-gap TEF has also been used to strengthen the argument that abnormal forces, in this case hypersomatization, result in a relative deﬁciency of tissue which is preferentially absorbed into tracheal development at the expense of the esophagus.38

There is evidence from the adriamycin model that the notochord is implicated in signaling activity to determine the fate of neighboring cell populations. Shh protein, which is expressed in notochordal tissue, is postulated to be pivotal in this signaling process.39 Shh stimulates cell proliferation and inhibits apoptosis, probably via intermediary HOX gene expression. Shh binds to the cell surface protein ‘Patched’ (Ptc), which is upregulated by Shh, and thus limits the inductive capabilities of Shh. Ventral misplacement of the notochord may result in an abnormal diffusion gradient for Shh and a localized imbalance of proliferation and apoptosis in the primitive foregut.

ASSOCIATED ANOMALIES Associated anomalies are seen in over half of all newborns presenting with EA and TEF. Although some of these are relatively insigniﬁcant, a high proportion are life threatening and signiﬁcantly contribute to the morbidity and mortality of this condition. The early management of babies with EA and TEF may have to be tailored to accommodate social, ethical and surgical issues relating to these anomalies. The incidence of associated anomalies appears to be highest in pure EA compared with other variants of EA and TEF.31 Infants with EA and TEF have a higher incidence of prematurity than is seen in the normal population. Congenital heart disease (27%) is the commonest comorbid condition and has the greatest impact upon survival. Recently aortic arch anomalies have been shown to occur frequently in association with long-gap EA and TEF.40 Other common associated abnormalities include urogenital (18%), skeletal (12%), anorectal (12%), and other gastrointestinal conditions (9%), most notably duodenal atresia. The spectrum of associated anomalies encountered in EA patients at Alder Hey Children’s Hospital, over 4 decades is shown in Table 34.2. Several phenotypic variants have been reported in association with EA and TEF. The ﬁrst to be described was the VATER association,42 which is now encompassed by the

Table 34.2 Abnormalities associated with esophageal atresia and TOF (Liverpool series 1953–97) 26,41 Type

1953–97 (581 cases)

Cardiac Urogenital Skeletal Vertebral Anorectal Gastrointestinal Palate/laryngotracheal

154 (27%) 105 (18%) 71 (12%) 64 (11%) 67 (12%) 53 (9%) 44 (8%)

VACTERL41

25 (19%)

340 Esophageal atresia and tracheo-esophageal ﬁstula

VACTERL acronym. The presence of three or more of the features is essential to deﬁne the association.43 In a recent Liverpool series, the incidence of the VACTERL association was 19%.41 The CHARGE association (coloboma, heart disease, atresia choanae, retarded development, genital hypoplasia, and ear deformities with deafness), is another constellation of phenotypes associated with EA and TEF.44,45 EA and TEF are also recognized in the SCHISIS association (exomphalos, neural tube defects, cleft lip and palate, and genital hypoplasia).46 Infants with EA and TEF have a higher than expected incidence of pyloric stenosis.47 The almost universal association of gastro-esophageal reﬂux with EA may lead to delays in diagnosis if gastric outlet obstruction is not considered. A degree of tracheomalacia is invariably present in these infants, but the full spectrum of associated tracheobronchial and pulmonary abnormalities deserves closer scrutiny. Excluding tracheomalacia, signiﬁcant anatomical tracheobronchial anomalies can be seen in 47% of infants undergoing bronchoscopy.48 Pulmonary agenesis, foregut duplication cysts, congenital cystic adenomatoid malformations, and sequestered lobe have all been described in association with EA and TEF. Other rare foregut pathologies such as laryngotracheo-esophageal cleft and congenital esophageal stenosis may coexist with EA and TEF.

ANTENATAL PRESENTATION Fetal diagnosis is now possible in cases of EA and TEF.49 This may be advantageous, as delivery can be planned at or near a specialist center with full neonatal surgical capability. Counselling is essential in these cases, and a careful search for associated chromosomal or cardiac anomalies is important. The identiﬁcation of a chromosomal abnormality may have implications for termination of pregnancy. Antenatal diagnosis of EA should theoretically reduce the likelihood of inadvertent feeding and aspiration pneumonitis. Despite the potential advantages of antenatal diagnosis, it is plausible that fetal ultrasonography selects a group of infants with a worse prognosis. The perinatal mortality (excluding terminations) in a series from Newcastle, UK was 21%.50 The classical ultrasonographic features of EA and TEF in the fetus are absence of the stomach bubble and associated hydramnios.51 However, prenatal detection rates remain low (9–24%), and there is a high false-positive rate, with over half of all cases proven not to have EA after birth.50

CLINICAL PRESENTATION AND DIAGNOSIS A newborn with EA is often noted to have difﬁculty clearing saliva. Episodes of coughing, choking and even

transient cyanosis may be observed shortly after birth. These signs are frequently overlooked and attempts to feed the infant result in immediate respiratory distress. The diagnosis is readily conﬁrmed by the failure of passage of a ﬁrm nasogastric tube. A characteristic resistance is felt at the blind ending upper esophageal pouch, and the tube cannot be introduced into the stomach. A plain X-ray, which should include the chest and abdomen, demonstrates the nasogastric tube coiled in the upper pouch. An associated TEF is conﬁrmed by the presence of gas-ﬁlled intestinal loops below the diaphragm (Fig. 34.2). In isolated or pure EA, a featureless gasless abdominal X-ray is observed (Fig. 34.3). The presence of a double bubble on the abdominal ﬁlm suggests associated duodenal atresia (Fig. 34.4). A careful search for associated abnormalities is mandatory, speciﬁcally checking for patency of the anus. The cardiovascular system should be examined to exclude a major congenital heart defect whose treatment may take priority over correction of the EA. Having established the diagnosis, i.v. ﬂuids are started, and a sump suction (Replogle) catheter introduced into the upper pouch to allow continuous aspiration of secretions. Alternatively, the upper pouch and oropharynx should be cleared of secretions by frequent intermittent suction. The infant is nursed in the supine or lateral position. Vitamin K should be administered intramuscularly after parental consent. Arrangements should be made for transfer of the infant to the nearest neonatal surgical unit. Surgery is ideally performed within the ﬁrst 24 hours in an otherwise healthy

Figure 34.2 Chest X-ray ﬁlm of a neonate with EA and TEF. Note the nasogastric tube coiled in the blind-ending upper esophagus. Air outlining intestinal loops below the diaphragm conﬁrms the existence of a distal TEF

Surgical treatment 341

Figure 34.3 Case of ‘pure’ EA. The nasogastric tube is lying coiled in the upper esophageal pouch. Absence of air-ﬁlled abdominal intestinal loops suggests that there is no distal esophageal ﬁstula

be repeated with gentle downward pressure on the Replogle tube. On rare occasions the current authors have observed that a ﬁne nasogastric tube may coil in an otherwise normal proximal esophagus, and the successful passage of the Replogle tube into the stomach prevents an unnecessary thoracotomy. More commonly, the diagnosis is conﬁrmed, but an estimation of the length of the upper pouch will give some idea as to the ease or difﬁculty of the primary anastomosis. An echocardiogram performed prior to surgery will alert the surgeon and anesthetist to an underlying cardiac defect that may adversely inﬂuence prognosis, and may inﬂuence the operative approach by identifying the side of the aortic arch. Blood should be taken for crossmatching, and a hematological and biochemical proﬁle preoperatively. Broad-spectrum antibiotics should be administered and i.v. ﬂuids continued. Other investigations including whole-spine X-rays, and both renal and cranial ultrasonography can be deferred until after surgery. Contrast studies of the upper pouch to identify the rare upper pouch ﬁstula have been superseded by preoperative bronchoscopy.

SURGICAL TREATMENT

Figure 34.4 EA and TEF with duodenal atresia. Nasogastric tube coiled in upper pouch. ‘Double-bubble’ appearance conﬁrms duodenal atresia

newborn, as pneumonitis is an ever-present risk due to aspiration of saliva and reﬂux of gastric acid through the lower pouch TEF. Following transfer to the neonatal surgical unit for deﬁnitive care, the infant should be carefully reexamined, and the radiology reviewed. The X-rays may

Most surgical units advocate preliminary rigid bronchoscopy after induction of general anesthesia. Depending on the infant’s size, a 2.5–3.5 Fr. neonatal bronchoscope (Storz) is used, as this permits the use of a suction catheter. Bronchoscopy allows conﬁrmation of the diagnosis and in most cases will demonstrate the ﬁstula just proximal to the carina. Occasionally the ﬁstula arises at the level of the carina, or from one of the main bronchi. A careful search should be made to exclude an associated upper pouch ﬁstula. The larynx should also be inspected to exclude a laryngotracheoesophageal cleft. Following bronchoscopy, an endotracheal tube is passed, taking care not to intubate the TEF. The infant is positioned for right thoracotomy in a lateral position, with the right arm raised across the head so that the scapula can be easily manipulated (Fig. 34.5). The surgeon may ﬁnd that the use of a headlamp and optical loupe magniﬁcation facilitate the operation. A curved skin crease incision is made 1 cm below the angle of the scapula, extending from the anterior axillary line to the lateral margin of the erector spini muscles. Bianchi has described a high axillary incision, which gives excellent cosmesis.52 The traditional Dennis Brown vertical incision is least acceptable from an esthetic point of view. The anterior ﬁbers of the latissimus dorsi are divided with electrocautery in the posterior aspect of the incision and the inferior digitations of the serratus anterior are separated from the ribs anteriorly. A retractor is used to lift the scapula off the chest wall, and the ribs are counted

342 Esophageal atresia and tracheo-esophageal ﬁstula

(a)

(b)

(c)

(d)

(e)

(f)

(g)

Figure 34.5 (a) The most frequent tracheo-esophageal anomaly. (b) Infant in lateral position prior to operation. Location of skin incision indicated. (c) Division of lateral thoracic and fourth space intercostal muscles. (d) Commencement of gentle stripping of parietal pleura from chest wall to develop extrapleural space. (e) Operative ﬁeld when pleura and lung have been retracted medially. The azygos vein is easily seen. The other structures, i.e. the blind proximal esophageal pouch and the ﬁstulous distal esophagus, with vagal ﬁbers lying on its surface, will require some dissection, and are not as easily seen as is depicted in the diagram. (f) The ﬁstula ligated and divided ﬂush with trachea (g) Lateral and posterior sutures and transanastomotic tube in place

downwards from the second interspace. The chest is opened through the fourth interspace, dividing the intercostal muscle ﬁbers using bipolar diathermy down to the level of the parietal pleura. The pleura is carefully separated from the ribs to commence an extra-pleural approach towards the ﬁstula. The dissection is usually started with moist pledgets and, having developed the plane, may be continued by inserting a moistened gauze swab into the extra-pleural space, sweeping the pleura away from the chest wall superiorly and inferiorly. Exposure is improved by introducing a Finochettio retractor for rib retraction. Great care is required with the dissection as it is particularly easy to create a pleural tear in the anterior aspect of the incision. If a signiﬁcant pleural tear occurs during the dissection, it is probably

wise to convert to a transpleural approach. The advantages of the extra-pleural over the transpleural approach, include the possibility of avoiding a chest drain, and in the event of an anastomotic leak, the potential containment of contamination within the extra-pleural space. The extra-pleural exposure is completed by retracting the posterior mediastinal pleura forwards with a maleable retractor until the azygos vein is visualized as it enters the superior vena cava in the depths of the wound. The azygos vein is mobilized and controlled with suture slings. The current authors advocate temporary occlusion of the vein before ligation, as venous return to the heart may rarely be critically dependent on the azygos system. Provided this maneuver does not affect cardiac output, the azygos vein is ligated and divided as

Long-gap EA with distal TEF 343

it enters the superior vena cava. Following division of the vein, the site of the ﬁstulous communication between the trachea and the distal esophagus is usually apparent. Having conﬁdently identiﬁed the distal esophagus, a vascular sling is carefully passed around it. Traction on the sling controls the ﬁstula and enables its junction with the trachea to be located precisely. Although it is possible to suture ligate the ﬁstula, it is preferable to divide the ﬁstula in stages and apply interrupted 5-0 or 6-0 prolene sutures to the tracheal component of the ﬁstula. The distal esophagus is secured with a stay suture of the same material. The integrity of the TEF repair is evaluated by instilling saline into the thoracic cavity and asking the anesthetist to exert positive airway pressure to ensure that no bubbles leak from the suture line. Occasionally, difﬁculty is encountered in identifying the distal esophagus, and it is quite possible to mobilize the descending aorta in the erroneous impression that this is the distal esophagus. The inexperienced operator may recognize the distal esophagus by following the vagus nerve as it courses distally, and by observing its rhythmic distension in time with ventilation. Attention is then focused on the upper pouch, which is easily identiﬁed by requesting the anesthetist to push ﬁrmly on the Replogle tube. The upper pouch is usually a thick-walled bulbous structure, with a base readily identiﬁed by this maneuver. The upper pouch may be secured using a transﬁxion suture driven through the Replogle tube, which is used for traction during the mobilization of the upper pouch (H. Lindahl, personal communication). Bipolar diathermy is ideal for this dissection, which should proceed to the thoracic inlet unless the gap is small. Mobilization is relatively easy except where the esophagus is closely applied to the trachea. Separation of this plane often requires sharp dissection, and should be performed with great care to avoid injury to the trachea. An upper pouch ﬁstula may be identiﬁed at this stage, and should be repaired using 5-0 or 6-0 interrupted prolene sutures. The esophageal defect is closed with 5-0 or 6-0 interrupted PDS sutures. Following full mobilization of the upper pouch it is usually possible to gauge whether a primary anastomosis is feasible. In most cases of EA with distal TEF, a primary anastomosis is possible, although occasionally considerable tension is required to complete the repair. The upper pouch is opened at its most distal extremity. The posterior wall of the anastomosis is commenced by placing two 5-0 or 6-0 PDS sutures through all layers of the lateral margins of the distal esophagus, taking great care to avoid handling and trauma with tissue forceps. Sutures are completed by including all layers of the corresponding aspect of the upper pouch, so that the knot comes to lie on the inside. Before tying these sutures, two further posterior wall sutures are inserted. All are individually tied drawing the esophageal ends together. Having completed the posterior wall of the anastomosis, a 6–8 Fr. nasogastric

tube is passed by the anesthetist via the nose to the suture line, where it is grasped by the surgeon and carefully introduced into the lower esophagus and stomach. The anterior layer of the anastomosis is completed by laying the knots on the outside. Occasionally, generous mobilization of the lower pouch is also required to enable an anastomosis to be performed without excessive tension. Even when the gap seems too large to permit a primary anastomosis, this can sometimes be achieved by using either a Livaditis myotomy of the upper pouch, or an upper pouch ﬂap as described by Gough. If the anastomosis is under tension, or has required one of these maneuvers, a chest drain is advisable. Under most circumstances where a satisfactory anastomosis has been completed without undue tension and where the extra-pleural plane has been maintained, the current authors, like others, consider a chest drain unnecessary.53 The ribs are loosely approximated using absorbable pericostal sutures, and an anatomical closure of all muscle layers is performed. The chest drain, if present, should be attached to under-water drainage, and the patient transferred to intensive care for postoperative monitoring and ventilatory support. Should additional surgical pathology be present, such as duodenal atresia or imperforate anus, these should be dealt with accordingly under the same anesthetic in the stable infant.

Long-gap EA with distal TEF Rarely the gap between the upper pouch and the distal esophagus is clearly too long to permit a primary anastomosis after division of the ﬁstula, and full mobilization of both the proximal and distal esophagus. Under such circumstances, it is probably wise to proceed to cervical esophagostomy and feeding gastrostomy, accepting the need for esophageal replacement surgery at a later date.

Right-sided aortic arch Opinion is divided amongst pediatric surgeons regarding the optimum surgical strategy when a right-sided aortic arch is encountered. The overall incidence of right-sided arch in association with EA is 1.8–2.5%.54,55 Preoperative echocardiography is at best 20% accurate in identifying this anomaly.55 If a right-sided arch is identiﬁed preoperatively, experience from specialist centers recommends left thoracotomy. More commonly the surgeon will encounter the anomaly unexpectedly during a standard right thoracotomy. The presence of a right-sided arch does not preclude a successful anastomosis in this situation, but the procedure is signiﬁcantly more challenging as is evidenced by the 42% leak rate

344 Esophageal atresia and tracheo-esophageal ﬁstula

seen at Great Ormond Street.55 A trial dissection, including repair of the ﬁstula, via right thoracotomy is appropriate, with completion of the esophageal anastomosis if this seems technically feasible. Where signiﬁcant difﬁculty is encountered with the dissection in preparation for the esophageal anastomosis, left thoracotomy is advisable following division of the ﬁstula through the right chest. The second thoracotomy may be performed immediately or delayed, depending on the stability of the infant, and the experience of the surgeon.

PREMATURE INFANT WITH RDS In premature babies with lung immaturity, emergency surgical intervention may become imperative if ventilation is compromised by the TEF, resulting in abdominal distension and diaphragmatic splinting. The surgical priority is urgent division of the ﬁstula via a transpleural approach. Should the infant’s condition stabilize sufﬁciently after closure of the ﬁstula, a primary repair of the esophagus is appropriate. Otherwise, a delayed repair is undertaken when the infant is stable. Sudden collapse due to gastric perforation is also a signiﬁcant risk in these neonates. In such situations, needle paracentesis prior to laparotomy and gastrostomy formation may be a life-saving measure.56

Postoperative care The infant should be nursed in intensive care following repair of EA and TEF. I.v. ﬂuids and broad-spectrum antibiotics are continued. Weaning from ventilation need not be unduly prolonged in the stable infant with a satisfactory anastomosis. Where the anastomosis is under considerable tension, elective paralysis and ventilation for a period of 3–5 days is widely practised.57 It must be conceded however, that there is no evidence to support the claim that this technique favorably inﬂuences anastomotic healing.58 There is experimental data indicating that the level of tension in the anastomosis correlates with the severity of GER.59 It is the current authors practice to commence all patients on H2-antagonists (e.g. ranitidine), as prophylaxis against anastomotic stricturing potentiated by GER. A contrast esophagogram is optional after 5–7 days to evaluate the anastomosis, although major anastomotic leaks are clinically evident before this time. Minor (radiological) leaks are often seen on the postoperative contrast study. These are of no clinical signiﬁcance and do not preclude the infant from being offered feeds.60 In most cases, transanastomotic tube feeding can be commenced after 48 hours, and slowly increased as tolerated by the infant. Although some authors recommend prophylactic esophageal dilatation at 3 weeks (Rintala, personal

communication), it is uncertain whether this reduces the rate of symptomatic anastomotic strictures.

SURGICAL MANAGEMENT OF ISOLATED (‘PURE’) ESOPHAGEAL ATRESIA The diagnosis of isolated EA is conﬁrmed by the inability to pass a nasogastric tube, and a featureless gasless abdomen on X-ray evaluation (Fig. 34.3). The absence of intestinal gas below the diaphragm however does not always completely exclude the presence of a distal ﬁstula, as a small proportion of children may have a ﬁbrotic connection between the lower pouch and the trachea, which does not permit the passage of air.61 Surgical management of these neonates is challenging and controversial. The majority of pediatric surgeons consider delayed primary anastomosis of the native esophagus, the optimum approach. This strategy demands meticulous nursing care, physiotherapy, and careful attention to nutrition by supervised gastrostomy feeding. A prolonged period of hospitalization is required to achieve this objective. Delayed primary esophageal anastomosis however, is associated with signiﬁcant morbidity, and further procedures to manage esophageal strictures and signiﬁcant GER are commonly required.62 The desire to preserve the infant’s esophagus must be counterbalanced by the humility of knowing when to accept defeat, and to abandon the esophagus in favor of a replacement procedure. The infant with isolated EA is initially managed by feeding gastrostomy and continuous suctioning of the upper pouch. At operation, bronchoscopy should be performed to exclude an associated upper pouch ﬁstula, and rarely an unsuspected atretic distal ﬁstula. Gastrostomy is performed either through a small midline incision, or an oblique left subcostal incision depending on the preference of the operator for later fundoplication. A Stamm gastrostomy is made using an 8–10 Fr. Malecot or Foley catheter. Caution should be taken when performing gastrostomy as the stomach is small and vulnerable to injury. Signiﬁcant morbidity has been reported with gastrostomy insertion in pure EA patients.63 After a period of approximately 3 weeks, the extent of the gap can be assessed by ﬂuoroscopy (Fig. 34.6). A radiopaque tube is pushed into the upper pouch and either contrast instilled via the gastrostomy, or a metal sound is introduced through the gastrostomy and directed via the esophageal hiatus into the distal esophageal stump. This procedure can be repeated at 2-weekly intervals, to assess whether the ends of the esophagus are sufﬁciently close to attempt delayed primary anastomosis.64 A distance of less than two vertebral bodies separating upper and lower pouches is ideal. In practice however, there is little to be gained by delaying restorative surgery beyond 12 weeks of age.

Surgical management of isolated (‘pure’) esophageal atresia 345

Figure 34.6 Gap assessment in a case of pure EA. The scale bar represents gap length (cm)

The operation of delayed primary anastomosis is essentially the same as has been described earlier for EA and TEF. It is to be expected that the anastomosis will be performed under considerable tension. The upper pouch should be fully mobilized to the thoracic inlet. The distal esophagus may be difﬁcult to visualize, and the surgeon should be prepared to pass sounds or an endoscope via the gastrostomy to aid identiﬁcation of the esophageal stump. The esophagus may be dissected to the diaphragmatic hiatus to reduce tension on the anastomosis.65 A Livaditis myotomy,14 or upper pouch ﬂap16,66 may be required to achieve an anastomosis. The current authors perform Livaditis myotomy over the inﬂated balloon of a Foley catheter, and either one or two myotomies can be created. Extra length can be obtained on the lower pouch if necessary by proceeding to laparotomy and performing either a Scharli lesser curve myotomy,67 or a Collis gastroplasty.68 If a primary anastomosis is still not possible using these techniques, the options are immediate esophageal replacement, or cervical esophagostomy and later substitution surgery. The delay in restoration of esophageal continuity has signiﬁcant drawbacks. Firstly, the ever-present risk of aspiration pneumonitis, and secondly, the inability to feed the infant via the normal oral route. Although the child’s nutritional needs are met by gastrostomy feeding, the inability to establish oral feeds may lead to long-term feeding and speech problems. Spitz recommends formally assessing the length of the gap when the gastrostomy is performed. A gap length > 6 vertebral bodies (6 cm), would prompt him to abandon the esophagus and perform a cervical esophagostomy.69 This approach of early cervical esophagostomy and delayed

esophageal replacement permits early sham feeding, which theoretically promotes neuronal maturation and development of the learning skills needed for feeding and later speech acquisition (Bianchi, personal communication). A number of other innovative approaches to the deﬁnitive operative treatment of long-gap EA have been described. True primary repair has been performed even with gap lengths exceeding 5 cm. The hypothesis tested by Foker was that a well-constructed esophageal anastomosis can withstand considerable tension.70 The value added technique for esophageal reconstruction (VATER) operation involves mobilizing the gastric fundus and performing a limited Thal fundoplication. At thoracotomy the proximal stomach is drawn into the chest and a primary esophageal anastomosis is performed.71 Staged neonatal colon esophagoplasty involves the isolation of a short length of transverse colon based on the ascending branch of the left colic vessels at the time of open gastrostomy. The conduit is positioned transhiatally in the posterior mediastinum to be retrieved at thoracotomy several days later, when continuity is restored.72 Several operations are available to restore gastrointestinal continuity in long-gap EA, where the infant’s own esophagus has been abandoned. Colonic or ileocolonic replacement was originally popularized by Waterston.13 The colonic conduit may be isoperistaltic (left colon based on the left colic vessels), or anteperistaltic (right colon based on the ileocolic vessels). The colon may be routed retrosternally, transmediastinally (via the hiatus), or through right or left chest cavities. Either pyloromyotomy or pyloroplasty is performed to promote gastric emptying. Cervical esophago-colonic anastomosis is prone to leakage. The colonic conduit tends to dilate, and kinking is common due to excessive tortuosity. Respiratory problems are seen due to recurrent aspiration. The stomach may be utilized to create a neoesophagus. A gastric tube esophagoplasty is fashioned from the greater curvature of the stomach, based on the left gastroepiploic (ante-peristaltic) or right gastroepiploic arcades (iso-peristaltic), and retrosternal, mediastinal, or thoracic routes may be used.73 The long suture line both of the tube and new greater curve are prone to bleeding and leaking. Reﬂux is a problem and may predispose to anastomotic narrowing. However, dilatation and kinking are not encountered; reﬂux may be controlled by performing a posterior partial wrap fundoplication.74 Gastric transposition has been advocated by Spitz and has the merit of simplicity. The vascular supply is based on the right gastric and right gastroepiploic vessels, which allows full mobilization of the greater and lesser curvatures. After pyloroplasty, the stomach is passed transmediastinally and the gastro-esophageal anastomosis is competed in the neck. Anastomotic leakage occurs in 12%, and strictures in a similar percentage of infants.75

346 Esophageal atresia and tracheo-esophageal ﬁstula

Jejunal interposition is less commonly employed. The vascular anatomy allows only for replacement of the lower esophagus in standard Roux-en-Y fashion. Isolated jejunal segments may be used to replace the esophagus using microvascular techniques, but this approach carries a high risk of graft necrosis.76

H-TYPE TEF H-type TEF is perhaps more accurately described as an N-type ﬁstula, as the ﬁstula runs obliquely from trachea to esophagus. This is a rare anomaly comprising approximately 4% of all EA and TEF variants. Infants with H-type TEF usually present within the ﬁrst month after birth, with a characteristic history of choking on feeds and cyanotic episodes. Marked abdominal distension mimicking intestinal obstruction is an occasional presenting feature. Older children may have frequent chest infections with recurrent right upper lobe pneumonia due to aspiration. The diagnosis may be established by a prone video esophagogram. In this study, contrast is injected through a nasogastric tube, which is slowly withdrawn from the esophagus. However, H-type ﬁstulas may be missed in approximately half of all contrast studies. Where suspicion remains, bronchoscopy should be performed. At bronchoscopy, a size 4 Fr. ureteric catheter is passed through the ﬁstula into the esophagus to facilitate identiﬁcation during subsequent neck dissection. A nasogastric tube is passed into the stomach, and broad-spectrum antibiotics commenced. A right transverse skin crease incision is marked a ﬁnger’s breadth above the clavicle, before positioning the neck in extension with a sandbag placed under the shoulders. The sternomastoid is retracted laterally and if necessary its sternal head divided. The carotid sheath is mobilized after division of the middle thyroid vein. The ipsilateral recurrent laryngeal nerve should be identiﬁed and carefully preserved. The esophagus is dissected and slung with vascular sloops both above and below the ﬁstula. Care should be taken with this maneuver, as the contralateral recurrent nerve is vulnerable to injury at this point. Traction on the esophagus enables the ﬁstula to be identiﬁed and secured with stay sutures. After withdrawing the ureteric catheter, the ﬁstula is divided and the tracheal component repaired with 5-0 or 6-0 interrupted prolene sutures. The esophagus is closed with 5-0 or 6-0 PDS sutures. Some authors recommend tissue interposition between esophageal and tracheal suture lines to prevent a recurrent ﬁstula. The infant should remain intubated and ventilated in the early postoperative period, as tracheal edema can result in progressive stridor. The vocal cords should be checked on extubation, given the signiﬁcant risk of

recurrent nerve palsy. Nasogastric tube feeding may commence after 48 hours and oral feeds may be slowly introduced thereafter. The Nd:YAG laser has also been successfully used to treat congenital H-type TEF. Repeated short duration pulses of laser light are used to coagulate the ﬁstula.77 Despite some success with this approach, the technique has not gained widespread acceptance, and open repair remains the gold standard. Complications following open surgery include recurrent laryngeal nerve palsy (both unilateral and bilateral), and rarely, recurrent ﬁstula.

COMPLICATIONS AND SPECIAL CONSIDERATIONS Anastomotic leak The incidence of anastomotic leak following repair of EA and TEF ranges from 11–21%.60,78 Major anastomotic disruption is uncommon and is usually manifested by early tension pneumothorax and gross salivary drainage from the chest drain. In these situations, it is rare for the anastomosis to be completely disrupted. Provided a transanastomotic tube is in place, it is usually possible to control the leak with an adequately sized chest drain. With good drainage, broad-spectrum antibiotics and total parenteral nutrition, the esophagus will usually heal, although a prolonged period of chest drainage may be necessary. Some surgeons have used hyoscine patches in an attempt to ‘dry up’ the salivary leak (Upadhyay, personal communication). Others advocate early reexploration (<48 hours), with direct repair of the esophagus if possible, and the establishment of satisfactory drainage.79 This early re-operative approach may prove hazardous and further compromise a tenuous anastomosis.26 Where conservative management of a major leak proves unsatisfactory due to uncontrolled sepsis, the establishment of a cervical esophagostomy and a feeding gastrostomy are essential. This usually commits the child to some form of delayed esophageal replacement after recovery. It has been suggested that a clinical anastomotic leak predisposes to the development of an esophageal stricture.80 While this association may seem logical, others have not been able to conﬁrm such a correlation.78

GER Signiﬁcant GER occurs in 40–50% of children following repair of EA and TEF. GER may cause failure to thrive, can predispose to recurrent aspiration episodes, and may lead to esophagitis and stricture formation. Management of symptomatic GER initially entails aggressive medical therapy. Postural therapy and close attention to feeding

Anastomotic stricture 347

regimes, with calorie supplementation of formula feeds, combined with the selective use of overnight continuous pump feeding by nasogastric tube and frequent small daytime bolus feeds may prove effective management strategies. Feed thickeners (e.g. Carobel), antacid preparations (e.g. Gaviscon), H2-antagonists (e.g. Ranitidine), proton pump inhibitors (e.g. Omeprazole), and pro-kinetic agents (e.g. Domperidone), may be used in various combinations if vomiting is signiﬁcant. However, should such measures fail to control GER, surgical treatment may be the only option. GER may contribute to recurrent aspiration episodes, with frequent symptoms of respiratory distress including tachypnea, apneic episodes, cyanosis, and X-ray evidence of patchy pneumonic changes. The differential diagnosis in this clinical setting also includes swallowing inco-ordination, and respiratory distress due to signiﬁcant tracheomalacia. It is not uncommon to see infants in whom all of these factors are operating to a variable degree. It is important not to overlook the possibility of a recurrent TEF as a cause of repeated episodes of respiratory distress, although the history of choking and cyanotic episodes during feeding is usually much more evident in infants with a recurrent ﬁstula. The selective use of esophageal pH monitoring, contrast meal, bronchoscopy, and assessment of swallowing by video ﬂuoroscopy, may assist in evaluating the contribution of GER and other pathologies to respiratory symptoms. Failure to control GER-related symptoms despite full medical therapy is an indication for fundoplication. Fundoplication rates following surgery for EA vary widely between centers (6–45%), reﬂecting the differing enthusiasm for anti-reﬂux operations in this clinical setting.81 There are several reasons for caution when considering fundoplication in EA patients. Dysphagia may be aggravated as a consequence of underlying esophageal dysmotility. Furthermore, fundoplication following EA has a higher failure rate (15–38%) than is generally seen in otherwise normal patients with isolated GER.81 Some authors recommend a partial wrap (Thal) fundoplication, because of the lower incidence of postoperative dysphagia.81 Despite these concerns, many pediatric surgeons prefer a short (1.5–2.0 cm) 360° ﬂoppy Nissen wrap for its proven effectiveness in reducing GER.82 The high failure rate of fundoplication and the signiﬁcant complications associated with surgical treatment of GER, demand vigilant follow-up in this group of patients.

rarely of a sufﬁcient degree to cause symptoms in the early postoperative period. Parents should be counselled to report symptoms of prolonged feeding, incomplete feeding or associated respiratory difﬁculty. Such symptoms prompt us to arrange a contrast study to assess the calibre of the esophageal anastomosis. Balloon dilatation is our preferred method of treating the symptomatic stricture. The radial dilating forces generated during balloon dilatation are considered to be less traumatic than the longitudinal shearing forces caused by conventional bougienage.83 Balloon dilatation is performed under ﬂuoroscopic control, by passing a guide wire through the stricture, over which a balloon dilator of appropriate size is introduced. Its position is conﬁrmed by partially ﬁlling the balloon with contrast medium, so that ‘waisting’ due to the stricture is centrally located (Fig. 34.7). The balloon is then maximally inﬂated using contrast medium to dilate the stricture. A contrast esophagogram is performed after removing the balloon to ensure there has been no perforation. Balloon dilatation may be performed under endoscopic or radiological control, and should be followed by maximal medical treatment of GER. If a stricture requires repeated dilatations, GER should be fully investigated by a combination of an upper GI contrast study, pH study and endoscopy. Recalcitrant strictures may require repeated dilatations, fundoplication, and rarely formal resection at thoracotomy.

Tracheomalacia Tracheomalacia, like GER, is present to a variable degree in all patients with EA. It is thought to be responsible for

Anastomotic stricture Reported deﬁnitions of esophageal stricture following repair of EA lack consistency. The incidence of symptomatic strictures requiring dilatation varies from 37–55%.60,80 Some degree of anastomotic narrowing is seen in all postoperative contrast studies, but this is

Figure 34.7 ‘Wasting’ due to anastomotic stricture at balloon dilatation

348 Esophageal atresia and tracheo-esophageal ﬁstula

the characteristic barking TEF cough. Infants with tracheomalacia demonstrate expiratory stridor, which may result in episodes of desaturation, apnea, cyanosis and bradycardia (often associated with feeding), and lifethreatening so-called ‘dying episodes’. Severe tracheomalacia may be evident in the early postoperative period, when it proves difﬁcult to wean the infant from the ventilator. Indications of the severity of tracheomalacia include ventilator dependency, respiratory distress characterized by stridor and chronic carbon dioxide retention, and dying episodes. Full investigation of GER is advisable alongside evaluation of tracheomalacia, as aspiration secondary to GER can mimic these symptoms. The extent of tracheomalacia is assessed by bronchoscopy under conditions of spontaneous respiration. The lumen of the trachea is signiﬁcantly compressed anteroposteriorly and assumes a scabbard-like appearance during expiration due to tracheal cartilage deﬁciency. A signiﬁcant contribution is often made by the upper esophagus, which may bulge posteriorly into the airway. Tracheobronchomalacia can extend beyond the carina into the main bronchi. As tracheomalacia can be self-limiting, surgical intervention is reserved for patients with life-threatening symptoms. Treatment options include continuous positive airway pressure (CPAP), aortopexy, tracheostomy, and, more recently, tracheal stenting. CPAP is a useful temporizing measure, but may be required for several weeks. Aortopexy is traditionally performed by anterior left thoracotomy through the third interspace. The left lobe of the thymus is excised to gain access to the root of the aorta taking care not to damage the phrenic nerve. Plegetted sutures incorporating reinforcing dacron squares are placed through the adventia of the aortic root and the ascending aorta. The sutures are passed through the periostium of the manubrium and tied, hitching the aorta forwards, thereby relieving pressure on the trachea. Although this operation cannot resolve distal tracheobronchomalacia, it often provides immediate dramatic symptomatic relief. Failure of aortopexy may be an indication for tracheostomy, although some authors advocate tracheal stenting in this situation.84

Recurrent TEF This complication is thought to occur in 5–15% of cases.85 A recurrent TEF may result from an anastomotic leak, but the possibility of a missed upper pouch ﬁstula should be considered. Symptoms include recurrent chest infections and choking attacks during feeding. A high index of suspicion is required if the diagnosis is not to be overlooked. The initial investigation is prone video esophagography. If this study fails to demonstrate a ﬁstula and the diagnosis remains strongly suspected,

combined esophagoscopy and bronchoscopy should be performed. Rigid bronchoscopy is performed initially, and the site of the original ﬁstula carefully examined. The ﬁstula is gently probed with a ureteric catheter and methylene blue is carefully instilled into the ﬁstula pit. Synchronous ﬂexible esophagoscopy is performed to see if the dye can be seen entering the esophagus. Should this fail to demonstrate the ﬁstula, an ‘air/water test’ is a useful supplementary investigation. The esophagus is ﬁlled with water and positive pressure ventilation applied to the bronchoscope. Occasionally, bubbles of air can be seen emanating from the ﬁstulous opening into the esophagus (Rintala, personal communication). Several strategies have been described to deal with the recurrent TEF. The traditional approach is formal repair via right thoracotomy. At bronchoscopy, an attempt should be made to pass a ﬁne ureteric catheter through the ﬁstula into the distal esophagus. If this maneuver fails, it is necessary to separate the esophagus and trachea over a considerable length to ensure that the ﬁstula has been identiﬁed. Having repaired the ﬁstula as described earlier (see H-type ﬁstula), tissue interposition between suture lines is advisable in an attempt to reduce the chances of further ﬁstula formation. A 10–22% risk of reﬁstulation has been reported.85 Therefore, other less invasive approaches have been employed to treat recurrent TEF including diathermy fulguration of the ﬁstula tract.86 This technique has been reﬁned using the Nd:YAG laser to obliterate the epithelial communication. Sclerosing agents, Histoacryl, and ﬁbrin glues have all been injected subepithelially to occlude the ﬁstula. A recent review of endoscopic treatment reported an overall closure rate of 55% with several treatments required to effect closure. The Oxford study concluded that formal surgical re-exploration remained the treatment of choice, except in high-risk patients.85

Quality of life and long-term outcome The improved survival of babies born with EA and TEF has prompted a more detailed analysis of morbidity, with emphasis on long-term outcome data. Several studies have examined respiratory function in EA children. Symptoms of asthma and bronchitis are frequent, especially in the young child, and may persist into adolescence.87 Almost half of all children require future hospitalization due to ongoing respiratory morbidity.88 In a large Melbourne series comprising 334 EA children, episodes of pneumonia were seen in 31% of children under the age of 5, compared with 5% of those over 15. The prevalence of annual attacks of bronchitis in these two age groups was 74% and 41%, respectively, with asthmatic symptoms reported in 40% of patients from each age range.88 Spirometry studies have demonstrated

References 349

both obstructive and restrictive abnormalities in over half the patients, and a similar proportion had a maximal working capacity below the normal range.89 Tracheo-bronchial inﬂammation and airway narrowing have been demonstrated by bronchoscopy in one-third of patients, with histological evidence of inﬂammation in a further third.90 It is plausible that abnormalities of bronchial anatomy, which are common in EA and TEF, may contribute to respiratory morbidity. Regular clinical assessment by a respiratory physician, with chest physiotherapy and aggressive antibiotic treatment for infective exacerbations is recommended. The contribution of aspiration episodes, whether due to esophageal dysmotility or GER, to respiratory symptoms, should be actively investigated. Recognition of the long-term respiratory morbidity associated with EA patients, has prompted the establishment of a specialist TEF clinic at Alder Hey Children’s Hospital, which is staffed by surgeons, respiratory physicians, physiotherapists and dieticians. This multidisciplinary approach ensures that attention is focused on all aspects of the child’s ongoing welfare. Esophageal dysmotility is a signiﬁcant factor in longterm morbidity. It is clearly implicated in many cases of absolute dysphagia due to bolus impaction, when endoscopy reveals no signiﬁcant anastomotic narrowing. Less severe symptoms of dysphagia have been reported in 20% of adolescents91 and in 48% of adults87 in long-term follow-up studies. Esophageal manometry and ﬂuoroscopy studies will demonstrate dysmotility in virtually all patients.89 The dysmotility associated with EA may reﬂect intrinsic innervation abnormalities of the esophagus.92 This may further contribute to respiratory morbidity through repeated ‘silent’ aspiration episodes. GER may persist into adult life. Reported incidence of symptoms of heartburn and acid brash ranges from 18%90 to 50%89 in some long-term follow-up studies. Clinical symptoms may underestimate the true incidence of GER as demonstrated by esophageal pH monitoring. An 8% incidence of Barrett’s esophagus has been reported,93 but the risk of esophageal adenocarcinoma is uncertain. Endoscopic surveillance has also revealed a twofold increase in the incidence of Helicobacter pylori infection,90 which may also have signiﬁcant implications in adult life. It has been proposed that medical treatment for GER in all EA infants might reduce the incidence of long-term respiratory complications.88,90 However, caution should be exercised when considering anti-reﬂux surgery, as esophageal dysmotility may be exacerbated by surgery, which in turn might aggravate respiratory symptoms. Various quality of life measures have been applied to young adults treated for EA and TEF. Using a global quality of life measure, the Spitzer Index, and a gastrointestinal quality of life index, adults who underwent primary anastomosis as newborns were shown to enjoy an unimpaired quality of life. Quality of life measures

were more favorable in those patients who had a primary anastomosis, compared to those who required colonic interposition.87 Standardized psycho-social assessment scores have demonstrated more learning, emotional, and behavioral problems in EA adults than in the general population. Cognitive performance was signiﬁcantly impaired in a high-risk group characterized by associated major congenital abnormalities or the requirement for prolonged ventilation in the neonatal period.94 A parental support group based in the UK (the TOFS society) provides useful information for families, opportunities for them to share problems and experiences, and raises valuable funds for research.95

REFERENCES 1. Myers NA. The history of oesophageal atresia and tracheo-oesophageal ﬁstula: 1670–1984. In: Rickham PP, editor. Progress in Pediatric Surgery. 20th edn. Heidelberg: Springer-Verlag, 1986:106–57. 2. Waterston DJ, Carter RE, Aberdeen E. Oesophageal atresia: tracheo-oesophageal ﬁstula. Lancet 1962; 1:819–22. 3. Durston W. A narrative of a monstrous birth in Plymouth October 22, 1670, together with the anatomical observations taken thereupon by William Durston, Doctor of Physick, and communication to Dr Tim Clerk. Philosophical Transactions of the Royal Society V: 1670:2096. 4. Gibson T. The Anatomy of Human Bodies Epitomised. 5th edn. London: Awnsham and Churchill, 1697. 5. Lamb DS. A fatal case of congenital tracheo-esophageal ﬁstula. Philad Med Times 1873; 3:705. 6. Hoffman W. Atresia oesophagi congenita et communicatio inter oesophagum et tracheum. Inaugural dissertation. Greifswald: Julius Abel, 1899. 7. Richter HM. Congenital atresia of the esophagus. An operation designed for its cure, with a report of two cases operated upon by the author. Surg Gynec Obstet 1913; 17:397–402. 8. Lanman TH. Congenital atresia of the oesophagus. A study of 32 cases. Arch Surg 1940; 41:1060–83. 9. Imperatori CJ. Congenital tracheoesophageal ﬁstula without atresia of the esophagus – report of a case with plastic closure and cure. Arch Otorhinolaryngol 1939; 30:352–9. 10. Ladd WE. The surgical treatment of esophageal atresia and tracheo-esophageal ﬁstulas. N Engl J Med 1944; 230:625–37. 11. Leven NL. Congenital atresia of the esophagus with tracheoesophageal ﬁstula, report of successful extrapleural ligation of ﬁstulous communication and cervical esophagostomy. J Thorac Surg 1941; 10:648–57. 12. Haight C, Towsley HA. Congenital atresia of the esophagus with tracheo-esophageal ﬁstula: extrapleural ligation of ﬁstula and end to end anastomosis of esophageal segments. Surg Gynec Obstet 1943; 76:672–88.

350 Esophageal atresia and tracheo-esophageal ﬁstula 13. Waterston D. Colonic replacement of the esophagus. Surg Clin North Am 1964; 44:1441–7. 14. Livaditis A. End-to-end anastomosis in esophageal atresia. A clinical and experimental study. Scand J Thorac Cardiovasc Surg 1969; 2 (Suppl 2):7. 15. Cohen DH, Middleton AW, Fletcher J. Gastric tube esophagoplasty. J Pediatr Surg 1974; 9:451–60. 16. Gough MH. Esophageal atresia – use of an anterior ﬂap in the difﬁcult anastomosis. J Pediatr Surg 1980; 15:310–11. 17. Spitz L. Gastric transposition via the mediastinal route for infants with long-gap esophageal atresia. J Pediatr Surg 1984; 19:149–54. 18. Spitz L, Kiely EM, Morecroft JA, Drake DP. Oesophageal atresia: at risk groups for the 1990’s. J Pediatr Surg 1994; 29:723–5. 19. Vogt EC. Congenital esophageal atresia. Am J Roent 1929; 22:463–5. 20. Gross RE. Atresia of the oesophagus. In: Gross RE, editor. Surgery of Infancy and Childhood. 1st edn. Philadelphia: W.B. Saunders, 1953. 21. Kluth D. Atlas of esophageal atresia. J Pediatr Surg 1976; 11:901–19. 22. Teich S, Barton DP, Ginn-Pease ME, King DR. Prognostic classiﬁcation for esophageal atresia and tracheoesophageal ﬁstula: Waterston versus Montreal. J Pediatr Surg 1997; 32:1075–80. 23. Yagyu M, Gitter H, Richter B, Booss D. Esophageal atresia in Bremen, Germany – evaluation of preoperative risk classiﬁcation in esophageal atresia. J Pediatr Surg 2000; 35:584–7. 24. Choudhury SR, Ashcraft KW, Sharp RJ et al. Survival of patients with esophageal atresia: inﬂuence of birth weight, cardiac anomaly, and late respiratory complications. J Pediatr Surg 1999; 34:70–4. 25. Brown AK, Tam PKH. Measurement of gap length in esophageal atresia: a simple predictor of outcome. J Am Coll Surg 1996; 182:41–5. 26. Cudmore RE. Oesophageal atresia and tracheooesophageal ﬁstula. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990:231–58. 27. Kyyronen P, Hemminki K. Gastro-intestinal atresia in Finland in 1970–79, indicating time-place clustering. J Epidemiol Community Health 1988; 42:257–65. 28. Myers NA. Oesophageal atresia: epitome of modern surgery. Ann R Col Surg Engl 1974; 54:227–87. 29. Haight C. Some observations on esophageal atresias and tracheoesophageal ﬁstulas of congenital origin. J Thorac Surg 1957; 34:141–72. 30. Harris J, Kallen B, Robert E. Descriptive epidemiology of alimentary tract atresia. Teratology 1995; 52:15–29. 31. Harmon CM, Coran AG. Congenital anomalies of the esophagus. In: O’Neill JA Jr et al. editors. Pediatric Surgery. 5th edn. St Louis: Mosby, 1998:941–67. 32. Pletcher BA, Friedes JS, Breg WR, Touloukian RJ. Familial occurrence of esophageal atresia with and without tracheoesophageal ﬁstula: report of two unusual kindreds. Am J Med Genet 1991; 39:380–4.

33. Merei J, Kotsios C, Hutson JM, Hasthorpe S. Histopathologic study of esophageal atresia and tracheoesophageal ﬁstula in an animal model. J Pediatr Surg 1997; 32:12–14. 34. Thompson DJ, Molello JA, Strebing RJ et al. Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 1978; 17:151–8. 35. Motoyama J, Lui J, Mo R et al. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 1998; 20:54–7. 36. Kim PCW, Mo R, Hui C. Murine models of VACTERL syndrome: role of sonic hedgehog signaling pathway. J Pediatr Surg 2001; 36:381–4. 37. Xia H, Otten C, Migliazza L et al. Tracheobronchial malformations in experimental oesophageal atresia. J Pediatr Surg 1999; 34:536–9. 38. Kulkarni B, Rao RJ, Oak S, Upadhyay MA. 13 pairs of ribs – a predictor of long gap atresia in tracheoesophageal ﬁstula. J Pediatr Surg 1997; 32:1453–4. 39. Litingtung Y, Lei L, Westphal H, Chiang C. Sonic hedgehog is essential to foregut development. Nat Genet 1998; 20:58–61. 40. Canty TG Jr, Boyle EM Jr, Linden B et al. Aortic arch anomalies associated with long gap esophageal atresia and tracheoesophageal ﬁstula. J Pediatr Surg 1997; 32:1587–91. 41. Driver CP, Shankar KR, Jones MO et al. Phenotypic presentation and outcome of oesophageal atresia in the era of the Spitz classiﬁcation. J Pediatr Surg 2001; 36:1419–21. 42. Quan L, Smith DW. The Vater association. Birth Def 1972; 8:75–8. 43. Nora AH, Nora JJ. A syndrome of multiple congenital anomalies associated with teratogenic exposure: the VACTERL syndrome. Arch Environ Health 1975; 30:17–21. 44. Lillquist K, Warburg M, Andersen SR. Colobomata of the iris, ciliary body and choroid in an infant with oesophagotracheal ﬁstula and congenital heart defects. An unknown malformation complex. Acta Paediat Scand 1980; 69:427–30. 45. Kutiyanawala M, Wyse RKH, Brereton RJ et al. CHARGE and esophageal atresia. J Pediatr Surg 1992; 27:558–60. 46. Chittmittrapap S, Spitz L, Kiely EM, Brereton RJ. Oesophageal atresia and associated anomalies. Arch Dis Child 1989; 64:364–8. 47. Spitz L, Hitchcock RJ. Oesophageal atresia and tracheooesophageal ﬁstula. In: Freeman NV, editor. Surgery of the Newborn. 1st edn. New York: Churchill Livingstone, 1994:353–73. 48. Usui N, Kamata S, Ishikawa S et al. Anomalies of the tracheobronchial tree in patients with esophageal atresia. J Pediatr Surg 1996; 31:258–62. 49. Farrant P. The antenatal diagnosis of oesophageal atresia by ultrasound. Br J Radiol 1980; 53:1202–3. 50. Sparey C, Jawaheer G, Barrett AM, Robson SC. Esophageal atresia in the Northern Region Congenital Anomaly Survey, 1985–1997: prenatal diagnosis and outcome. Am J Obstet Gynecol 2000; 182:427–31.

References 351 51. Stringer MD, McKenna KM, Goldstein RB et al. Prenatal diagnosis of esophageal atresia. J Pediatr Surg 1995; 30:1258–63. 52. Bianchi A, Sowande O, Alizai NK, Rampersad B. Aesthetics and lateral thoracotomy in the neonate. J Pediatr Surg 1998; 33:1798–1800. 53. Kay S, Shaw K. Revisiting the role of routine retropleural drainage after repair of esophageal atresia with distal tracheoesophageal ﬁstula. J Pediatr Surg 1999; 34:1082–5. 54. Bowkett B, Beasley SW, Myers NA. The frequency, signiﬁcance, and management of a right aortic arch in association with esophageal atresia. Pediatr Surg Int 1999; 15:28–31. 55. Babu R, Pierro A, Spitz L et al. The management of oesophageal atresia in neonates with right-sided aortic arch. J Pediatr Surg 2000; 35:56–8. 56. Maoate K, Myers NA, Beasley SW. Gastric perforation in infants with oesophageal atresia and distal tracheooesophageal ﬁstula. Pediatr Surg Int 1999; 15:24–7. 57. Mackinlay GA, Burtles R. Oesophageal atresia: paralysis and ventilation in management of the wide gap. Pediatr Surg Int 1987; 2:10–12. 58. Beasley SW. Does postoperative ventilation have an effect on the integrity of the anastomosis in repaired oesophageal atresia? J Paediatr Child Health 1999; 35:120–2. 59. Guo W, Fonkalsrud EW, Swaniker F, Kodner A. Relationship of esophageal anastomotic tension to the development of gastroesophageal reﬂux. J Pediatr Surg 1997; 32:1337–40. 60. Nambirajan L, Rintala RJ, Losty PD et al. The value of early postoperative oesophagography following repair of oesophageal atresia. Pediatr Surg Int 1998; 13:76–8. 61. Davison P, Poenaru D, Kamal I. Esophageal atresia: Primary repair of a long gap variant involving distal pouch mobilization. J Pediatr Surg 1999; 34:1881–3. 62. Lindahl H, Rintala R. Long-term complications of isolated esophageal atresia treated with esophageal anastomosis. J Pediatr Surg 1995; 30:1222–3. 63. Kimble RM, Harding JE, Kolbe A. The vulnerable stomach in babies born with pure oesophageal atresia. Pediatr Surg Int 1999; 15:467–9. 64. Rossi C, Domini M, Aquino A et al. A simple and safe method to visualize the inferior pouch in esophageal atresia without ﬁstula. Pediatr Surg Int 1998; 13:535–6. 65. Lessin MS, Wesselhoeft CW, Luks FI, DeLuca FG. Primary repair of long-gap esophageal atresia by mobilization of the distal esophagus. Eur J Pediatr Surg 1999; 9:369–72. 66. Davenport M, Bianchi A. Early experience with oesophageal ﬂap oesophagoplasty for repair of oesophageal atresia. Pediatr Surg Int 1990; 5:332–5. 67. Scharli AF. Esophageal reconstruction in very long atresias by elongation of the lesser curvature. Pediatr Surg Int 1992; 7:101–5. 68. Evans M. Application of Collis gastroplasty to the management of esophageal atresia. J Pediatr Surg 1995; 30:1232–5.

69. Spitz L, Ruangtrakool R. Esophageal substitution. Semin Pediatr Surg 1998; 7:130–3. 70. Foker JE, Linden BC, Boyle EM Jr, Marquardt C. Development of a true primary repair for the full spectrum of esophageal atresia. Ann Surg 1997; 226:533–43. 71. Varjavandi V, Shi E. Early primary repair of long gap esophageal atresia: the VATER operation. J Pediatr Surg 2000; 35:1830–2. 72. Lipshutz GS, Albanese CT, Jennings RW et al. A strategy for primary reconstruction of long gap esophageal atresia using neonatal colon esophagoplasty: a case report. J Pediatr Surg 1999; 34:75–8. 73. Anderson KD, Randolph JG. The gastric tube for esophageal replacement in infants and children. J Thorac Cardiovasc Surg 1973; 66:333–42. 74. Ashcraft KW. The esophagus. In: Ashcraft KW, Holder TM, editors. Pediatric Surgery. 3rd edn. Philadelphia: W.B. Saunders, 1993:325–47. 75. Spitz L. Esophageal atresia: past, present, and future. J Pediatr Surg 1996; 31:19–25. 76. Ring WS, Varco RL, L’Heureux PR, Foker JE. Esophageal replacement with jejunum in children: an 18 to 33 year follow-up. J Thoracic Cardiovasc Surg 1982; 83:918–27. 77. Schmittenbecher PP, Mantel K, Hofmann U, Berlein HP. Treatment of congenital tracheoesophageal ﬁstula by endoscopic laser coagulation: preliminary report of three cases. J Pediatr Surg 1992; 27:26–8. 78. Auldist AW, Beasley SW. Esophageal complications. In: Beasley et al. editors. Oesophageal Atresia. 1st edn. London: Chapman & Hall, 1991:305–22. 79. Chavin K, Field G, Chandler J et al. Save the child’s esophagus: management of major disruption after repair of esophageal atresia. J Pediatr Surg 1996; 31:48–52. 80. Chittmittrapap S, Spitz L, Kiely EM et al. Anastomotic stricture following repair of esophageal atresia. J Pediatr Surg 1990; 25:508–11. 81. Snyder CL, Ramachandran V, Kennedy AP et al. Efﬁcacy of partial wrap fundoplication for gastroesophageal refux after repair of esophageal atresia. J Pediatr Surg 1997; 32:1089–92. 82. Bergmeijer JHLJ, Tibboel D, Hazebroek FWJ. Nissen fundoplication in the management of gastroesophageal reﬂux after repair of esophageal atresia. J Pediatr Surg 2000; 35:573–6. 83. Sandgren K, Malmfors G. Balloon dilatation of oesophageal strictures in children. Eur J Pediatr Surg 1998; 8:9–11. 84. Filler RM, Forte V, Fraga JC, Matute J. The use of expandable metallic airway stents for tracheobronchial obstruction in children. J Pediatr Surg 1995; 30:1050–6. 85. Willetts IE, Dudley NE, Tam PKH. Endoscopic treatment of recurrent tracheo-oesophageal ﬁstulae: long-term results. Pediatr Surg Int 1998; 13:256–8. 86. Rangecroft L, Bush GH, Irving IM. Endoscopic diathermy of recurrent tracheo-esophageal ﬁstula. J Pediatr Surg 1984; 19:41–3.

352 Esophageal atresia and tracheo-esophageal ﬁstula 87. Ure BM, Slaney E, Eypasch EP et al. Quality of life more than 20 years after repair of esophageal atresia. J Pediatr Surg 1998; 33:511–15. 88. Chetcuti P, Phelan PD. Respiratory morbidity after repair of oesophageal atresia and tracheo-oesophageal ﬁstula. Arch Dis Child 1993; 68:167–70. 89. Montgomery M, Frenckner B, Freyschuss U, Mortensson W. Esophageal atresia: long-term-follow-up of respiratory function, maximal working capacity, and esophageal function. Pediatr Surg Int 1995; 10:519–52. 90. Somppi E, Tammela O, Ruuska T et al. Outcome of patients operated on for oesophageal atresia: 30 years experience. J Pediatr Surg 1998; 33:1341–6. 91. Romeo C, Bonanno N, Baldari S et al. Gastric motility disorders in patients operated on for esophageal atresia

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and tracheoesophageal ﬁstula: long-term evaluation. J Pediatr Surg 2000; 35:740–4. Nakazato Y, Landing BH, Wells TR. Abnormal Auerbach plexus in the esophagus and stomach of patients with esophageal atresia and tracheo-esophageal ﬁstula. J Pediatr Surg 1986; 11:831–7. Lindahl H, Rintala R, Sariola H. Chronic esophagitis and gastric metaplasia are frequent late complications of esophageal atresia. J Pediatr Surg 1993; 28:1178–80. Bouman NH, Koot HM, Hazebroek FWJ. Long-term physical, psychological, and social functioning of children with esophageal atresia. J Pediatr Surg 1999; 34:399–404. Martin V. The TOF Child. 1st edn. TOFS, Nottingham, Blueprint Group (UK) Limited.

35 Congenital esophageal stenosis SHINTARO AMAE, MASAKI NIO, YUTAKA HAYASHI, AND RYOJI OHI

INTRODUCTION The difﬁculties in obtaining the differential diagnosis of congenital esophageal stenosis (CES) from achalasia and secondary esophageal stenosis, especially stricture due to reﬂux esophagitis,1 has resulted in various clinical problems in its treatment. CES is deﬁned as an intrinsic stenosis of the esophagus caused by the congenital malformation of the esophageal wall architecture. This malformation may result from: • Tracheobronchial remnants in the esophageal wall2–16 • Fibromuscular thickening of the esophageal wall1,11,17–21 • Membranous mucosal diaphragm or web.8, 11, 22–30 Achalasia, inﬂammatory esophagitis, and stenosis caused by tumor or extrinsic compression of the esophagus should be excluded from this category. The localization of the stenosis varies with the type of pathology. Stenosis due to tracheobronchial remnants is the most common type of pathological anomaly, and is localized to the distal esophagus,12 whereas ﬁbromuscular thickening is generally found in the middle or lower portions of the esophagus.11,21 Membranous webs are normally observed in the upper or middle levels of the esophagus.11,26–30 In general, the stenotic area in cases with tracheobronchial remnants is usually identiﬁed, and that of ﬁbromuscular stenosis varies from one to several centimeters in length with circular thickening of the esophageal wall. In almost all cases of membranous web, a single web is found in children,26,28,30 however plural webs, termed multiple trachea-like rings, are observed in young adults.31–33

PATHOLOGICAL FEATURES In the stenotic segment caused by tracheobronchial remnants, mature or immature cartilage, the seromucous tracheobronchial glands and ciliated epithelium are generally found microscopically. Tracheobronchial

remnants are believed to be the result of failure in the normal separation of the embryonic respiratory tract from the foregut. In ﬁbromuscular cases, circumferential proliferation of smooth muscle ﬁbers with moderate ﬁbrosis was revealed.11,21,34 Singaram et al. reported a signiﬁcant reduction of myenteric nitrinergic neurons and ﬁbers in the muscle layer of two young adults diagnosed with CES.35 Lack of submucosa27 and loose, vascular connective tissue and diffuse lymphocytes26 were observed microscopically in specimens of membranous web.

CLINICAL FEATURES Congenital esophageal stenosis is a rare condition and is found in 1 in 25 000–50 000 live births.1,11 Although the reason is unknown, the incidence of CES is higher in Japan.8,36 There is no sex predisposition. The incidence of other anomalies in association with CES has been reported to be 17–33%.11,36 For instance, the association of CES with congenital esophageal atresia,9–11,18,19,24,37–39 cardiac anomalies,11,24 intestinal atresia,11,23 anorectal malformation,10,36 chromosomal anomalies,7,11,21,23 etc. has been reported in the literature. Surgeons should keep in mind the association of congenital esophageal atresia with distal CES due to tracheobronchial remnants. Symptoms of CES include: vomiting or regurgitation, dysphagia, recurrent respiratory tract infections and growth retardation. The onset of regurgitation coincides characteristically with the introduction of semi-solid and solid foods around the age of 6 months in patients with tracheobronchial remnants.34 However, the development of symptoms rarely occurs in the newborn.25 In some patients, a foreign body in the esophagus may be the ﬁrst symptom noted.1

DIAGNOSIS Patients who develop the symptoms described earlier should undergo a barium swallow. Esophagograms show

354 Congenital esophageal stenosis

a tapered or abrupt narrowing of the esophagus in association with various degrees of dilatation of the suprastenotic portion of the esophagus (Fig. 35.1). Most of the stenosis due to tracheobronchial remnants is observed as demonstrated by an abrupt narrowing on the esophagogram, while ﬁbromuscular stenosis usually shows a tapered narrowing. Following surgery for the treatment of esophageal atresia, an esophagogram should be evaluated with great care without failing to ﬁnd a narrowing at the mid-distal esophagus. Newman et al. carried out a retrospective review of 225 records and radiographs, and reported that 8% of tracheo-esophageal ﬁstula (TEF) cases were associated with CES.40 Esophagoscopy, manometric study and pH monitoring are helpful tools for the differential diagnosis of CES from achalasia and secondary esophageal stricture due to gastro-esophageal reﬂux. Esophageal endoscopy can directly evaluate not only the stenotic area (Fig. 35.2) and the site of the gastro-esophageal junction but also the

presence of esophagitis. The mucosa distal to the stenosis is normal in CES. In cases of CES, preoperative esophageal manometry demonstrates the normal pattern of lower esophageal sphincter and a small high-pressure zone in the resting pressure proﬁle (Fig. 35.3), which corresponds to the stenotic area of the esophagus (this small high-pressure zone disappears after corrective surgery). Moreover, an esophageal motility study reveals aperistalsis corresponding to the stenosis. pH monitoring reveals that signiﬁcant positive reﬂux is not a feature in patients with CES in contrast to that seen in patients with gastro-esophageal reﬂux.

Figure 35.3 Preoperative (a) and postoperative (b) resting pressure proﬁle of the gastro-esophageal junction and the esophagus in a case of CES with tracheobronchial remnants. A small high-pressure zone in the lower esophagus is noted and this disappeared after the corrective operation (a)

(b)

Figure 35.1 Abrupt (a) and tapered (b) narrowing on esophagograms

Figure 35.2 Endoscopic view of the stenotic portion of the esophagus

TREATMENT The principles in the treatment of CES patients are the relief of the symptoms caused by the esophageal stenosis and the maintenance of the anti-reﬂux mechanism of the gastro-esophageal junction. This condition can be treated conservatively or by surgical intervention. Bougienage, as a conservative treatment, is the ﬁrst choice of treatment for CES patients. Bougienage should be tried not only for patients with tapered narrowing but also in patients with abrupt narrowing, when the catheter can be passed safely through the stenotic area. Previously, we have attempted retrograde bougienage through a gastrostomy using Tucker’s bougie. We now use the low-compliance (Rigiﬂex) balloon catheter. The effect of balloon dilatation or bougienage varies with the type of pathology. Recent cases with membranous web of the esophagus and some cases of ﬁbromuscular stenosis can be treated successfully by suitable dilatation or bougienage.11,26,28,29 Surgical resection of the stenosis is necessary for tracheobronchial remnants6,8,10–16,36,39 and several cases with ﬁbromuscular thickening.21,34 As a rule, when patients fail to respond to repeated (4–6 times)

Operative procedure 355

attempts of bougienage, surgical intervention should be considered. Complications of treatment, as reported in the literature, are iatrogenic esophageal perforation by bougienage,10,41 anastomotic stenosis and leakage. In particular, iatrogenic esophageal perforation often requires an emergency operation.

PREOPERATIVE PREPARATION Those patients who are undernourished should have their nutritional status corrected prior to surgery. Such patients may require total parenteral nutrition and/or enteral nutrition via a nasogastric tube or gastrostomy. Prior to the surgical procedure, it is essential that the surgeon know the exact site and extent of the stenosis, and the distance from the gastro-esophageal junction. When the stenosis is situated in the distal portion of the esophagus, the current authors always perform cineradiography and another special ﬂuorographic procedure. In this procedure, ﬁrst, a balloon catheter is inserted through the esophagus across the stenosis, and then barium is orally administered. Immediately following this, the balloon is inﬂated and pulled up. Adequate traction should position the balloon just below the stenosis and give a clear image of the stenotic area (Fig. 35.4).

abdominal esophagus, the abdominal approach may be utilized. In the thoracic approach, right thoracotomy is employed for a stenosis in the middle portion of the esophagus, and left thoracotomy for a stenosis of the lower part of the esophagus. After exposing the esophagus, the current authors insert a balloon catheter beyond the stenotic segment from the mouth. The balloon catheter is inﬂated and pulled up to conﬁrm the distal margin of the stenosis. Following resection of the distal end of the stenosis, a sterile balloon catheter is passed through the stenotic area from the oral stump of the esophagus. The upper margin of the stenosis is decided by pulling down the catheter (Fig. 35.5). Complete removal of the stenotic area should be performed. Anastomosis should be made without tension. The use of single- or double-layer interrupted sutures using absorbable material is justiﬁed. The surgeons should, of course, pay attention to the preservation of the phrenic and vagal nerves during surgery. The possibility of simple excision of cartilaginous remnants and subsequent repair of the esophageal wall is limited.5,11 Therefore, segmental resection with end-toend anastomosis of the esophagus should be a standard procedure for patients with a stenosis in the mid or lower

L

OPERATIVE PROCEDURE D

Most cases of CES can be operated upon via the thoracic approach. However, when the stenosis is localized in the

(a)

Esophagus

L

Stenosis

D

Stomach

(b)

Figure 35.4 A special ﬂuorographic examination for the evaluation of the exact site and extension of the stenosis. Stenosis is located between the dilated pouch of the esophagus and the balloon

Figure 35.5 An intraoperative procedure by the use of a Foley catheter to determine the distal (a) and proximal (b) sites of stenosis (arrow), Resection line (solid line), Diaphragm (D), Lung (L)

356 Congenital esophageal stenosis

esophagus which is not close to the gastro-esophageal junction. However, to prevent postoperative reﬂux, an anti-reﬂux procedure, for example a Nissen’s fundoplication (Fig. 35.6), may be necessary, in addition to segmental resection, when the stenosis is situated close to the gastro-esophageal junction. If the vagal nerve is severed by accident, a pyloroplasty should be performed. Patients with extensive ﬁbromuscular stenosis necessitating resection of the esophagus of more than 3 cm may require esophageal replacement with a colon, jejunum or gastric tube. Complications, such as an iatrogenic esophageal perforation following bougienage10,41 and a leakage after segmental resection and reconstruction of the esophagus,11 have been reported. Perforations and major leakages require surgical drainage, but minor leakages can be treated successfully by maintaining the patient on total parenteral nutrition. When gastro-esophageal reﬂux develops following simple resection and anastomosis, the anti-reﬂux procedure should be carried out.

Tacking of the esophagus to the hiatus Transection and end-to-end anastomosis

Nissen's fundoplication

Figure 35.6 Transection of the distal esophagus with end-toend anastomosis combined with an anti-reﬂux procedure (Nissen’s fundoplication)

REFERENCES 1. Bluestone CD, Kerry R, Sieber WK. Congenital esophageal stenosis. Laryngoscope 1969; 79:1095–1103. 2. Frey EK, Duschl L. Der Kardiospasmus. Erge Chirurg Orthopaed 1936; 29:637–716. 3. Bergmann M, Charnas RM. Tracheobronchial rests in the esophagus. J Thorac Surg 1958; 35:97–104. 4. Kumar R. A case of congenital oesophageal stricture due to a cartilaginous ring. Br J Surg 1962; 69:533–4. 5. Pauline E, Roselli A, Aprigliano F. Congenital esophageal stricture due to tracheobronchial remnants. Surgery 1963; 53:547–50.

6. Ishida M, Tsuchida Y, Saito S et al. Congenital esophageal stenosis due to tracheobronchial remnants. J Pediatr Surg 1969; 4:339–45. 7. Rose JS, Kassner EG, Jurgens KH et al. Congenital esophageal strictures due to cartilaginous rings. Br J Radiol 1975; 48:16–18. 8. Ohkawa H, Takahashi H, Hoshino Y et al. Lower esophageal stenosis in association with tracheobronchial remnants. J Pediatr Surg 1975; 10:453–7. 9. Ibrahim NBN, Sandry RJ. Congenital esophageal stenosis caused by tracheobronchial structures in the esophageal wall. Thorax 1981; 36:465–8. 10. Deiraniya AK. Congenital oesophageal stenosis due to tracheobronchial remnants. Thorax 1974; 29:720–5. 11. Fekete CN, Backer AD, Jacob SL. Congenital esophageal stenosis. A review of 20 cases. Pediatr Surg Int 1987; 2:86–92. 12. Sneed WF, LaGarde MS, Kogutt MS et al. Esophageal stenosis due to cartilagious tracheobronchial remnants. J Pediatr Surg 1979; 14:786–8. 13. Spitz L. Congenital esophageal stenosis distal to associated esophageal atresia. J Pediatr Surg 1973; 8:973–4. 14. Briceno LI, Grases PJ, Gallego S. Tracheobronchial and pancreatic remnants causing esophageal stenosis. J Pediatr Surg 1981; 16:731–2. 15. Tubino P, Marouelli LF, Alves E et al. Choristoma: esophageal stenosis, due to tracheobronchial remnants. Z Kinderchir 1982; 35:14–17. 16. Shoshany G, Bar-Maor JA. Congenital stenosis of the esophagus due to tracheobronchial remnants: A missed diagnosis. J Pediatr Gastroenterol Nutr 1986; 5:977–9. 17. Bonilla KB, Bower WF. Congenital esophageal stenosis; pathologic studies following resection. Am J Surg 1959; 97:772–6. 18. Mahour GH, Jounston PW, Gwinn JL et al. Congenital esophageal stenosis distal to esophageal atresia. Surgery 1971; 69:936–9. 19. Tuqan NA. Annular stricture of the esophagus distal to congenital tracheoesophageal ﬁstula. Surgery 1962; 52:394–5. 20. Vidne B, Levy MJ. Use of pericardium for esophagoplasty in congenital stenosis. Surgery 1970; 68:389–92. 21. Todani T, Watanabe Y, Mizuguchi T. Congenital oesophageal stenosis due to ﬁbromuscular thicking. Z Kinderchir 1984; 39:11–14. 22. Beatty CC. Congenital stenosis of the oesophagus. Br J Child Dis 1928; 25:237–70. 23. Huchzermeyer H, Burdeiski M, Hruby M. Endoscopic therapy of a congenital oesophageal stricture. Endoscopy 1979; 11:259–62. 24. Overton RC, Creech O. Unusual esophageal atresia with distant membranous obstruction of the esophagus. J Thorac Surg 1953; 35:674–7. 25. Schwaetz SI. Congenital membranous obstruction of esophagus. Arch Surg 1962; 85:480–2. 26. Grabowski ST, Andrews DA. Upper esophageal stenosis: two case reports. J Pediatr Surg 1996; 31:1438–9.

References 357 27. Takayanagi K, Ii K, Komi N. Congenital esophageal stenosis with lack of the submucosa. J Pediatr Surg 1975; 10:425–6. 28. Sarihan H, Abes M. Congenital esophageal stenosis. J Cardiovasc Surg 1997; 38:421–3. 29. Komuro H, Makino S, Tsuchiya I et al. Cervical esophageal web in a 13-year-old with growth failure. Pediatr International 1999; 41:568–70. 30. Roy GT, Cohen RC, Willeams SJ. Endoscopic laser division of an esophageal web in a child. J Pediatr Surg 1996; 31:439–40. 31. Younes Z, Johnson DA. Congenital esophageal stenosis: Clinical and endoscopic features in adults. Dig Dis 1999; 17:172–7. 32. Katzka DA, Levine MS, Ginsberg GG et al. Congenital esophageal stenosis in adults. AJG 2000; 95:32–6. 33. Pokieser P, Schima W, Schober E et al. Congenital esophageal stenosis in a 21-year-old man: clinical and radiographic ﬁndings. AJR 1998; 170:147–8. 34. Murphy SG, Yazbeck S, Russo P. Isolated congenital esophageal stenosis. J Pediatr Surg 1995; 30:1238–41.

35. Singaram C, Sweet MA, Gaumnitz EA. Peptidergic and nitrinergic denervation in congenital esophageal stenosis. Gastroenterology 1995; 109:275–81. 36. Nishina T, Tsuchida Y, Saito S. Congenital esophageal stenosis due to tracheobronchial remnants and its associated anomalies. J Pediatr Surg 1981; 16:190–3. 37. Sheridan J, Hyde I. Oesophageal stenosis distal to oesophageal atresia. Clin Radiol 1990; 42:274–6. 38. Yeung CK, Spitz L, Brereton RJ et al. Congenital esophageal stenosis due to tracheobronchial remnants: a rare but important association with esophageal atresia. J Pediatr Surg 1992; 27:852–5. 39. Neilson IR, Croitoru DP, Guttman FK et al. Distal congenital esophageal stenosis associated with esophageal atresia. J Pediatr Surg 1991; 26:478–81. 40. Newman B, Bender TM. Esophageal atresia/tracheoesophageal ﬁstula and associated congenital esophageal stenosis. Pediatr Radiol 1997; 27:530–4. 41. Morger R, Muller M, Sennhauser F et al. Congenital esophagostenosis. Eur J Pediatr Surg 1991; 1:142–4.

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36 Esophageal duplication cysts LEELA KAPILA AND HOWARD W. HOLLIDAY

Esophageal duplication cysts are intrathoracic foregut anomalies which may be classiﬁed into two types – intramural and neurenteric. The former is an intrinsic abnormality of the esophagus, whereas the latter is a separate structure closely adherent to the esophagus, lying in the posterior mediastinum and embryologically distinct.

ANATOMY Intramural cysts share a common wall with the esophagus, but communicate with the lumen in less than 10% of cases. The cysts are usually spherical, but can be tubular and vary in size from a few centimeters in diameter to complete ﬁlling of the hemithorax. Embryologically, esophageal epithelial cells proliferate in the sixth week of gestation, forming a solid core which vacuolates by the tenth week to give a lumen.1 Failure of a vacuole to the incorporated into the lumen leaves a rest of cells in the wall of the esophagus, so producing a cyst. Rarely, more than one intramural cyst may form at different levels in the esophagus.2 The cyst wall contains two layers of muscle and is lined by squamous, gastric or ciliated columnar epithelium. The presence of ciliated mucosa does not infer a bronchogenic cyst, which contains cartilage also. Neurenteric or posterior mediastinal cysts are fused with the esophagus but are not incorporated in the wall (Fig. 36.1). Embryologically, in the third week of gestation the notochord separates from the entoderm. Failure of complete separation or adhesion between ectoderm and entoderm produces a traction diverticulum of entoderm, so forming a cyst which is closely related at one point to the vertebrae and at another to the esophagus. This cyst may be associated with incomplete vertebral fusion and may have attachment to the dura or spinal cord. It never communicates with the lumen or the esophagus. Most neurenteric cysts are intrathoracic, but the length of the duplication depends on the eventual destiny of the entoderm: a cyst associated with

Figure 36.1 Mediastinal cross-section showing a neurenteric duplication cyst, closely related to the esophagus and extending through a biﬁd vertebral body, with attachment to the dura

entoderm of the upper gastrointestinal tract will extend below the diaphragm, via the paravertebral fossa, and may even open into duodenum or jejunum.

INCIDENCE Post-mortem studies give an estimated incidence for esophageal duplication cysts of 1 in 8200.3 Ten to ﬁfteen per cent of all alimentary duplications are of the esophagus and 70% of esophageal duplications present in childhood, with a male preponderance of 2 to 1.4,5 The

360 Esophageal duplication cysts

majority (60%) are of the upper esophagus and the remainder are divided equally between the mid and lower esophagus. Approximately 3% of mediastinal masses in infants are due to esophageal duplication cysts.6 It is unlikely that the pediatric surgeon in routine practice will see more than two or three cases in his working lifetime.7

PRESENTATION Esophageal duplication cysts cause symptoms by virtue of their site or because of their secretory linings and present in three situations – incidental, pressure and hemorrhage.

ASSOCIATED ABNORMALITIES The association of thoracic duplication and vertebral anomalies, ranging from spina biﬁda to vertebral fusion defects, has been well documented. In up to 80% of neurenteric cysts, there are vertebral abnormalities. The presenting symptoms in these children can be neurological. The cyst may communicate with the dura and rarely with the alimentary tract below the diaphragm. In a few cases, separate intra-abdominal duplications also had separate intestinal duplications.10 Esophageal duplication has also been reported in association with esophageal atresia.11

CLINICAL COURSE AND DIAGNOSIS

Incidental Older children in particular may have asymptomatic cysts and the lesion only comes to light on a routine chest X-ray. These cysts are usually in the mid or lower esophagus and tend to follow a benign course. They may present eventually in adult life where malignant change has been recorded.

Pressure All cysts are lined by secretory epithelium and have the potential for expansion and therefore compression. Compression by the duplication causes either respiratory or gastrointestinal symptoms. Respiratory symptoms are more common and the diagnosis should always be considered in a neonate with respiratory distress. The neonate may present with stridor, apneic episodes, dyspnea or cyanosis. These symptoms can vary with the position of the child and are due to a cyst of the upper esophagus compressing the trachea or bronchus. Gastrointestinal symptoms are less common and include a variety of complaints, including dysphagia, epigastric pain, retrosternal pain, vomiting and hematemesis. These symptoms are typical of cysts of the mid and lower esophagus, but more commonly present in older children.8

Hemorrhage Hemorrhage depends on communication of the cyst with the esophageal lumen and is therefore more likely with intramural cysts. However, both types of cyst may contain ectopic gastric mucosa9 (up to 50%) and can ulcerate to cause hemoptysis and hematemesis by direct perforation. The exact origin of this bleeding can be difﬁcult to determine in neonates. Overall, hemorrhage is an infrequent presentation, although major hemorrhage may occur and death has been recorded in this situation.

The neonate with respiratory distress due to an esophageal cyst may have one or more of the above features at presentation and demonstrate signs such as nasal ﬂaring, intercostal recession, tachypnea and cyanosis with reduced or absent breath sounds on auscultation. Signs may be limited to the upper thorax but can apply to the whole hemithorax. Differential diagnosis at this stage includes congenital lobar emphysema. Intermittent stridor may later be associated with dysphagia as compression progresses, suggesting an alimentary tract problem. For either respiratory or alimentary symptoms, a plain chest X-ray, posteroanterior and lateral, usually demonstrates the mass and draws attention to other anomalies, e.g. vertebral (Fig. 36.2a,b). For symptoms related to the esophagus, a barium swallow is useful and will help to determine the length of involved esophagus (Fig. 36.3). In patients with a vertebral anomaly, myelography is worth while, even in the absence of neurologic symptoms (Fig. 36.4). Ultrasound is a simple, non-invasive test that will determine whether a mass seen on plain X-ray is solid or cystic, but more information can be gained from computed tomography (CT) scanning. CT has the advantage over conventional diagnostic procedures because it demonstrates the cystic nature of the mass and its relationship to adjacent structures. It permits simultaneous imaging and evaluation of the spine, pulmonary parenchyma, airway and adjacent structures. CT can be combined with myelography for those lesions with suspected communication to the vertebral column. More recently, nuclear magnetic resonance imaging has been used to achieve similar data while having the advantage of being totally non-invasive.12 The differential diagnosis of esophageal cysts includes neuroblastoma, neuroﬁbroma, ganglioneuroma, schwannoma, lymphoma, ﬁbroma, hemangioma and bronchogenic cysts. Once diagnosed, an esophageal duplication cyst should be excised, even if asymptomatic, because of its potential for compression, bleeding, perforation or infection.

Preoperative management 361

(a) Figure 36.3 Barium swallow, showing marked anterior deviation of the esophagus throughout a considerable length by an extrinsic giant esophageal cyst

(b) Figure 36.2 (a,b) Chest X-ray, posteroanterior and lateral, showing a large esophageal duplication cyst with vertebral anomalies

PREOPERATIVE MANAGEMENT In infants presenting with hemorrhage or severe respiratory distress, emergency surgery may be necessary, otherwise surgery should be arranged as soon as the

Figure 36.4 Myelogram, showing cervical spine anomalies with intraspinal extension of a neurenteric cyst

neonate has been fully resuscitated. A full blood count and electrolytes and urea are measured and blood crossmatched. If the neonate has hemorrhaged, a preoperative transfusion may be necessary, and in neonates with respiratory distress blood gases will determine whether ventilatory support is required prior to surgery. In such a patient, both venous and arterial lines are inserted. No further preparation is required for intramural cysts, but where there is suspicion of a neurenteric cyst, then a two-stage procedure should be planned:

362 Esophageal duplication cysts

● if respiratory distress is the presenting complaint, then thoracic surgery is performed ﬁrst ● if the patient has neurologic symptoms, then spinal surgery is performed ﬁrst.

OPERATION All general measures for neonatal cases are observed. A nasogastric tube is inserted. The child is placed in the right or left lateral thoracotomy position with the ipsilateral arm raised over the head, palm upwards. Duplications in the upper third of the esophagus are best approached from the right side, but lower lesions may be approached through the left chest. Most surgeons use an intercostal incision placed over the level of the cyst. The author prefers the vertical Denis Browne incision (Fig. 36.5) in the mid-axillary line; subcutaneous fat and fascia are divided in the same direction using blended diathermy. Care is taken to avoid the long thoracic nerve, which can be recognized by the accompanying vein, and serratus anterior is divided anterior to this nerve. The scapula is then freed and lifted upwards and posteriorly. Depending on the site of the lesion, the chest is entered through a suitable rib space between the fourth and seventh ribs. In neonates, adequate exposure is usually possible without rib resection. The ribs are held apart with a Denis Browne ring retractor which will also hold the scapula away from the wound. The anesthetist temporarily suspends respiration as the intercostal muscles are divided with diathermy and then the pleura is opened. The lung is retracted medially and the duplication cyst is easily visualized. On the right side, the azygous vein may be ligated and divided to give better access. If the cyst is extra-esophageal, then the entire cyst with all its layers is excised by ligating and dividing the blood supply as each vessel is encountered. For a large cyst occupying the whole hemithorax, it may be necessary to puncture and deﬂate the cyst to make access to these vessels easier and safer. Care must be taken posteriorly where there may be an intraspinal connection and, when

Figure 36.5 Patient in position for right thoracotomy as seen from above, with incision in mid-axillary line

encountered, this is ligated as close as possible to the vertebrae, leaving the ﬁnal excision to the spinal operator. At no point in the dissection is it necessary to enter the esophageal wall. For an intramural cyst it is safer to excise only the mucosal lining of the cyst and leave the muscle layers to cover any defect in the esophageal wall. The cyst wall is incised longitudinally in the line of the esophagus (Fig. 36.6) and the muscle layers gently separated from the cyst lining (Fig. 36.7a). Small moist swabs on an artery forcep are used to free the cyst lining (Fig. 36.7b) and bleeding is best controlled with bipolar diathermy. Any breach of the true esophageal mucosa which occurs during this dissection must be repaired. The success of the procedure depends on the careful removal of all the cyst lining (Fig. 36.7c). The muscle of the cyst wall is then trimmed to the appropriate size of the normal esophagus and is repaired with a continuous absorbable suture (Fig. 36.8). This step may not be absolutely necessary and some surgeons leave the muscle layer open with no apparent sequelae.2 The anesthetist reinﬂates the lung and the chest wall is repaired in layers with a chest drain to an underwater seal. Postoperatively the patient should be extubated as soon as condition allows; infants with respiratory distress will require ventilation until their blood gases are satisfactory. Initially the child is nursed with the operating side lowermost, and in the upright position as soon as possible thereafter. Lung expansion is checked by postoperative chest X-ray on the patient’s return to the ward and the chest drain may be removed the next day if there is little or no drainage. Provided that the esophageal mucosa was not breached the nasogastric tube is also removed and oral ﬂuids commenced. The child may progress rapidly to oral feeding and full recovery may be expected within the week.

Figure 36.6 Diagrammatic appearance of a typical intramural cyst of the esophagus, with a longitudinal incision extending over its length

References 363

Figure 36.8 Esophageal wall reconstituted using a continuous absorbable suture

THORACOSCOPIC TREATMENT OF ESOPHAGEAL CYSTS Recently the development of thoracoscopic surgery has made this approach feasible in the treatment of esophageal cysts in children.13,14 Thoracoscopy would seem to have several potential advantages over open techniques in terms of the attendant postoperative pain and pulmonary complications. Compressive cysts with lung compression and mediastinal shift still remain a contraindication for this type of surgery.

REFERENCES

Figure 36.7 (a–c) The muscle wall is held open with stay sutures and the cyst lining is gently separated from the normal esophageal tissue with a moist swab, leaving the esophageal mucosa intact (see text for details)

1. Scherer LR, Grosfeld JL. Congenital oesophageal stenosis, oesophageal duplication, neurenteric cyst and oesophageal diverticulum. In: Holder TD, Ashcraft KW, editors. Paediatric Oesophageal Surgery. New York: Grune and Stratton, 1986: 53–71. 2. Robinson RL, Pavlina PM, Scherer LR et al. Multiple oesophageal duplication cysts. J Thorac Cardiovasc Surg 1987; 94:144–53. 3. Arbona JL, Figueroa Fazi JG, Mayoral J. Congenital oesophageal cysts: case report and review of literature. Am J Gastroenterol 1984; 97:177–82. 4. Whitaker JA, Deffenbaugh LD, Cooke AR. Oesophageal duplication cyst. Am J Gastroenterol 1980; 73:320–2. 5. Bower RJ, Kieswebber WB. Mediastinal masses in infants and children. Arch Surg 1977; 112:1003–9. 6. Pokorny WJ, Sherman JO. Mediastinal masses in infants and children. J Thorac Cardiovasc Surg 1974; 68:869–75. 7. Mekki M, Belghith M, Krichene M et al. Esophageal duplication in children. Report of 7 cases. Arch Pediatr 2001; 8:55–61.

364 Esophageal duplication cysts 8. Sab JA, Ala-Kulija KV. Congenital oesophageal cysts in adults. Ann Thorac Surg 1987; 44:135–8. 9. Ferguson CC, Young LN, Sutherland JR et al. Intrathoracic gastrogenic cyst – pre-operative diagnosis by technetium pertechnetate scan. J Pediatr Surg 1973; 8:827–8. 10. Holcomb GW, Gheissari A, O’Neill J. Surgical management of alimentary tract duplication. Ann Surg 1989; 209:167–74. 11. Helund GL, Bisset GS. Esophageal duplication cyst and aberrant right subclavian artery mimicking a

symptomatic vascular ring. Pediatr Radiol 1989; 19:543–4. 12. Fabris S, Cavazzana A, Gamba P. Vater syndrome and esophageal foregut duplication. A new association. Pediatr Surg Int 1995; 10:252–4. 13. Michel JL, Revillon Y, Montupet P et al. Thoracoscopic treatment of mediastinal cysts in children. J Pediatr Surg 1998; 33:1745–8. 14. Urschel JD, Horan TA. Mediastinoscopic treatment of mediastinal cysts. Ann Thorac Surg 1994; 58:1698–1700.

37 Esophageal perforation in the newborn HIRIKATI S NAGARAJ

INTRODUCTION Accidental perforation of the esophagus and the hypopharynx occurs rarely in newborn infants despite numerous instrumentation, including intubation of the esophagus, pharynx and airway. Iatrogenic perforation of the esophagus in neonates was ﬁrst reported in the literature in 1969 by Eklof and colleagues.1 In the past decade, perforation of the esophagus in premature infants has been increasingly recognized and reported. Spontaneous perforation of the esophagus in neonates (neonatal Boerhaave’s syndrome) is extremely rare, and Fryfogle reported the ﬁrst successful repair.2 Esophageal perforation may be fatal without early diagnosis, and delayed treatment causes an increase in morbidity and mortality.3,4

CLASSIFICATION AND ETIOLOGY Esophageal perforation in newborns can be classiﬁed as iatrogenic or non-iatrogenic. Non-iatrogenic perforations are extremely rare, and are usually seen in full-term infants when they do occur. The most common site of perforation is the lower end of the esophagus. Etiological hypotheses for spontaneous perforation vary and include increased abdominal pressure at delivery, perinatal hypoxemia, peptic esophagitis and gastro-esophageal reﬂux.5–8 Iatrogenic perforation of the esophagus is more commonly seen in premature, small for gestational age (SGA) infants9 and usually occurs in the cervical esophagus. Pharyngeal suctioning with a stiff catheter, endotracheal intubation, traumatic laryngoscopy and digital manipulation of the infant’s head during breech delivery have all been described as etiological factors.10 Esophageal dilatation, intraoperative technical error and postoperative anastomotic leak are potential iatrogenic surgical causes.11,12 During instrumentation, when the neck is hyperextended, traumatic perforation of the proximal

esophagus may occur at the level of the cricopharyngeus muscle, where the posterior esophageal wall is compressed by the body of the sixth or seventh cervical vertebra. Submucosal injury by a laryngoscope blade or endotracheal tube may be the initial injury to the hypopharynx, resulting in cricopharyngeal spasm.13 Endotracheal intubation, particularly in small premature infants, may further compromise the esophageal introitus. Oropharyngeal suctioning or insertion of the nasogastric tube can extend the submucous injury into a full-thickness perforation. Perforation of the middle esophagus is usually associated with dilatation of a stricture or a postoperative anastomotic leak after an esophageal atresia repair.14,15 An improperly placed postoperative chest tube may inadvertently penetrate a fresh esophageal anastomosis or an upper pouch myotomy site.16 Direct pressure necrosis of a normal esophagus in a premature infant has been associated with esophageal perforation.17 Perforation of the distal esophagus may be associated with dilatation of a stricture secondary to esophagitis, technical error during anti-reﬂux procedure or a misplaced gastrostomy Foley balloon.18

CLINICAL MANIFESTATIONS The newborn with an iatrogenic cervical esophageal perforation demonstrates excessive salivation and mucous secretion due to difﬁculty swallowing; the examiner will ﬁnd it difﬁcult to pass a nasogastric tube and respiratory distress may be apparent. An abnormal position of the nasogastric tube by X-ray of the chest may be the ﬁrst indication of esophageal perforation.9 In premature infants, blood-tinged oral secretions after tracheal intubation warrant frequent and careful X-ray examinations of the chest. The proper diagnosis often will be missed in the absence of such an examination. The symptoms of perforation may not be recognized until the child develops esophageal obstruction, which may be mistaken for esophageal atresia.12,19

366 Esophageal perforation in the newborn

Esophageal perforation can be differentiated from esophageal atresia if there is a history of repeated attempts at intubation, vigorous suctioning, absence of polyhydramnios in the perinatal history, and the position and course of the nasogastric tube. Some perforations of the esophagus into the pleural cavity may create acute respiratory distress secondary to right pneumothorax or hydrothorax. Thoracocentesis or placement of a tube thoracostomy may yield serosanguineous, bloody ﬂuid, or contents of the previous feeding. Anteroposterior and lateral X-rays of the chest and neck should be obtained and studied in all suspected cases of perforation. An unusual course of the nasogastric tube (63% will be in the pleural cavity, pericardial cavity (Fig. 37.1) or right side of the mediastinum or retroperitoneum) may be the ﬁrst indication of this diagnosis. More subtle changes such as widening of the mediastinum and blurring of the mediastinal margin may indicate a mediastinitis secondary to a perforation, but they sometimes are not as evident. These latter clues should prompt careful esophagography. Mollit et al.20 described three types of injuries that are seen in premature infants: (1) a pharyngeal diverticulum created in a local cervical leak; (2) mucosal perforation extending posterior and parallel to the esophagus, and (3) free intrapleural perforation where there is obvious leakage of air and esophageal contents into the pleural cavity. If the sudden onset of respiratory distress leads to a chest X-ray that shows the presence of a nasogastric tube in the pleural cavity, the diagnosis of perforation of the

Figure 37.1 Chest X-ray shows displacement of the nasogastric tube to the pericardial sac

esophagus can be conﬁrmed (Fig. 37.2). In this situation, precise localization of the site of perforation by esophagography may not be necessary unless the patient’s clinical condition deteriorates after removal of the nasogastric tube and treatment of pneumothorax by tube thoracostomy drainage. If the symptoms suggest esophageal obstruction, esophagography should be performed by injecting a small quantity of diatrizoate meglumine (Hypaque), diatrizoate sodium (Renograﬁn) or metrizamide, but Gastrograﬁn and barium should be avoided.21 Cricopharyngeal spasm may be so severe in cases of pharyngo-esophageal perforation that no contrast will enter the native esophagus. In this case, several clues should be looked for to differentiate submucous perforation, pseudodiverticular formation and congenital esophageal atresia. The following three features have been suggested:17 • The distance between the tracheal and opaciﬁed tract of a perforation is greater than that of the pouch in a congenital esophageal atresia, which is usually closely associated with the trachea • The opaciﬁed tract in perforation is elongated and more irregular than in esophageal atresia, and • The trachea is slightly compressed on the lateral X-ray ﬁlm by the upper pouch in esophageal atresia, but this is not so in esophageal perforation. Esophagoscopy is usually not indicated in the diagnosis of esophageal perforation and may, in fact, enlarge the perforation. Neonatal spontaneous perforation of the esophagus usually presents with respiratory distress that may be immediate or delayed for several hours after perforation. There is a greater predilection to right-sided pneumothorax in neonatal Boerhaave’s syndrome13 instead of the left pneumothorax found in adults. This may be explained by the close adherence of the aorta to the left side of the esophagus in a small infant, providing additional support to the left side. If the perforation

Figure 37.2 Anteroposterior view demonstrates coiled nasogastric tube in the right pleural cavity and chest tube placed for tension pneumothorax

Management 367

remains undiagnosed, respiratory distress will worsen with subsequent feedings. Esophagography must be promptly performed in all suspected free perforations to evaluate the extent of damage and to localize it.

MANAGEMENT The management of esophageal perforation in newborns has undergone signiﬁcant change in recent years.22 Esophageal perforation can be a rapidly fatal condition that requires immediate recognition and aggressive management for a successful outcome. The concept of treatment of esophageal perforation must be individualized according to the site, size, systemic response of the neonate, and interval between injury and initiation of treatment. Small submucosal perforations of the hypopharynx and the esophagus, limited to the mediastinum with no systemic symptoms, can be managed by nonoperative methods (Figs 37.3a,b). Actual localization of

(a)

the perforation is not essential in these infants. If the nasogastric tube is noted in the mediastinum or pericardial cavity, the tube can be withdrawn and a new tube can be placed by an experienced radiologist under ﬂuoroscopic control. A broad-spectrum antibiotic must be given for 7–14 days. I.v. ﬂuids and hyperalimentation should be started, since oral feedings must be withheld. Esophagography should be performed 7–10 days after the injury. If the perforation is completely healed, oral feeding may be started, but if the perforation has not healed, conservative treatment for another week will usually allow complete healing. Routine surgical intervention does not appear to improve the rate of survival in these critically ill newborns. Tube thoracostomy must be placed where the chest X-ray indicated pneumomediastinum, pneumothorax or hydrothorax. If purulent drainage or esophageal material continues to drain into the chest tube, further closed chest tube drainage may be pursued (Fig. 37.4). All newborn infants with esophageal perforation must be carefully monitored during treatment, including white blood cell counts, blood gases, platelet counts and chest X-rays. If there is clinical deterioration or respiratory compromise, and closed chest tube drainage does not handle the leak, direct repair of the perforation is indicated. In cases where direct repair of the lesion is not technically feasible because of scarring, inﬂammation and friability of the tissue, cervical esophagostomy, and ligation of the perforated area with concomitant gastrostomy, is indicated. All efforts should be made to avoid future esophageal replacement. Long, linear perforations to the lower end of the esophagus require an immediate thoracotomy, débridement of necrotic edges and primary repair with a ﬂap of normal pleura to cover the defect. A concomitant gastrostomy will minimize the risk of gastric reﬂux postoperatively. If there is a delay of more than 24 hours in the diagnosis of a spontaneous perforation, primary repair cannot be accomplished. After adequate débridement,

(b) Figure 37.3 (a) Anteroposterior view shows the nasogastric tube in the mediastinum. Note the absence of pneumothorax. (b) The presence of the long sinus tract parallel to the esophagus without free spillage of contrast media indicates submucosal perforation

Figure 37.4 Free spillage of contrast material into right pleural cavity indicates a free perforation in this infant. Clinical deterioration warranted direct repair

368 Esophageal perforation in the newborn

the treatment should be local esophagectomy with closure of proximal and distal esophagus, proximal cervical esophagostomy, and a gastrostomy. Critically ill newborns should be treated by chest tube drainage, cervical oesophagostomy (with or without ligation of the cardio-esophageal junction) and gastrostomy.23 Broad-spectrum antibiotic therapy, i.v. ﬂuids and hyperalimentation should be continued until clinical signs of sepsis improve. Gastrostomy feedings may be attempted after 48 hours. Where there is extensive debridement or esophageal substitution is indicated after an interval of at least 6 months and resolution of the mediastinal inﬂammatory reaction.

CONCLUSION Iatrogenic perforation of the esophagus is more common than reported in the literature and may be fatal without early diagnosis. The incidence of recognized pharyngeal or esophageal perforation, however, is low considering the large number of suctions and intubations performed in intensive care units.20 Gentle laryngoscopy, proper visualization of the vocal cords during intubation, careful avoidance of protruding stylets, careful suctioning of the pharynx and avoidance of forceful placement of nasogastric tubes are essential factors in the prevention of this injury. It is generally accepted that most iatrogenic perforations of the esophagus occurring in newborns are cervical and made when inexperienced people try to intubate the trachea. With early diagnosis, most of these perforations can be managed non-operatively with successful outcomes.24 However, small infants should be monitored closely. If they appear to be ill, appropriate operative intervention may be required. Early recognition of an esophageal perforation gives many more treatment options which may include non-operative therapy, drainage, or primary repair. Delayed diagnosis may result in the loss of the esophagus necessitating esophageal replacement. The mortality rate in children with esophageal perforation (4%) is signiﬁcantly less than that for adults (25–50%).25 Surgical consultation is warranted in all esophageal perforations for selective management.

REFERENCES 1. Eklof O, Lohr G, Okmian L. Submucosal perforation of the esophagus in the neonate. Acta Radiol 1969; 8:1987. 2. Fryfogle JD. Discussion of the paper by Anderson RL. Rupture of the esophagus. J Thorac Cardiovasc Surg 1952; 24:369–88. 3. Michael L, Grillo HC, Malt RA. Operative and nonoperative management of esophageal perforations. Ann Surg 1981; 194:57. 4. Van der Zee DC, Slooff MJH, Kingma LM. Management of

5. 6.

7.

8. 9.

10. 11. 12. 13.

14. 15. 16.

17.

18. 19.

20.

21.

22.

23.

24.

25.

esophageal perforations: a tailored approach. Neth J Surg 1966; 38:31. Aaronson IA, Cywess S, Louw JH. Spontaneous esophageal rupture in the newborn. J Pediatr Surg 1975; 10:459. Johnson JF, Wright DR. Chest tube perforation of esophagus following repair of esophageal atresia. J Pediatr Surg 1990; 25:1227. Cairns PA, McClure BG, Halliday HL et al. Unusual site for oesophageal perforation in an extremely low birth weight infant. Eur J Pediatr 1999; 158:152–3. Kenigsberg K, Levenbrown J. Esophageal perforation secondary to gastrostomy. J Pediatr Surg 1986; 21:946. Ducharme JC, Bertrano R, Debie J. Perforation of the pharynx in the newborn: a condition mimicking esophageal atresia. Med Assoc J 1971; 104:785. Astley R, Roberts KD. Intubation perforation of the esophagus in the newborn baby. Br J Radiol 1970; 43:219. Lee SB, Kuhn JP. Esophageal perforation in the neonate. Am J Dis Child 1976; 130:325. Wychulis AR, Fontana RS, Payne WS. Instrumental perforation of the esophagus. Chest 1969; 55:184. Girdany BR, Sieber W, Osman MZ. Pseudodiverticulum of the pharynx in the newborn infants. N Engl J Med 1969; 280:237. Sloan EI, Haight C. Congenital atresia of the esophagus in brothers. J Thorac Surg 1956; 32:200. Eraklis AJ, Gross RE. Esophageal atresia, management following an anastomotic leak. Surgery 1966; 60:919. Johnson JF, Wright DR. Chest tube perforation of esophagus following repair of esophageal atresia. J Pediatr Surg 1990; 25:1227. Cairns PA, McClure BG, Halliday HL et al. Unusual site for oesophageal perforation in an extremely low birth weight infant. Eur J Pediatr 1999; 158:152–3. Kenigsberg K, Levenbrown J. Esophageal perforation secondary to gastrostomy. J Pediatr Surg 1986; 21:946. Ducharme JC, Bertrano R, Debie J. Perforation of the pharynx in the newborn: a condition mimicking esophageal atresia. Med Assoc J 1971; 104:785. Mollit DC, Schullinger JW, Santulli T. Selective management of iatrogenic esophageal perforation in the newborn. J Pediatr Surg 1981; 16:989. Blair GK, Filler RM, Theodorescu D. Neonatal pharyngoesophageal perforation mimicking esophageal atresia: clues to diagnosis. J Pediatr Surg 1987; 22:770. Johnson DE, Foker J, Munson DP et al. Management of esophageal and pharyngeal perforation in the newborn. Pediatrics 1982; 70:592–9. Urschel HC Jr, Razzuk MA, Wood RE et al. Improved management of esophageal perforations: exclusion and diversion of continuity. Ann Surg 1974; 179:587. Krasna IH, Rosenﬁeld D, Benjamin BG et al. Esophageal perforation in the neonate: an emergency problem in the newborn nursery. J Pediatr Surg 1987; 227:784. Engum SA, Grosfeld JL, West KW et al. Improved survival of children with esophageal perforation. Arch Surg 1996; 131:604–11.

38 Gastro-esophageal reﬂux VICTOR E. BOSTON

INTRODUCTION Gastro-esophageal reﬂux (GER) is recognized to occur in the majority, if not all neonates. In most of these children, GER will disappear spontaneously and will cause no signiﬁcant clinical problems. A minority however, will run a less benign course and will develop serious pathological complications of their reﬂux, which will require treatment.1–3 Diagnostically, there are difﬁculties in identifying those children who are most at risk.2–5 On the one hand, this is often caused by a lack of speciﬁcity and sensitivity of the tests which are employed; on the other, it may be difﬁcult to be sure that GER is the cause of the clinical complex from which the child is suffering. Treatment may therefore be inappropriate either because pathological reﬂux has been missed or because the child’s problems are unrelated to GER.

FACTORS WHICH INFLUENCE OCCURRENCE OF GER In the past, the gastro-esophageal junction (GEJ) was simply regarded as a valve. However, it is now realized that a complex dynamic relationship exists between several factors acting at the GEJ to prevent or permit GER. In this respect, the pinchcock action of the diaphragm at the hiatus, the cardio-esophageal angle and local thickening of the esophageal mucosa at the GEJ, probably play a minor role. These have not to date been objectively assessed and will not be discussed further. Generally speaking, the risk of reﬂux is inﬂuenced by factors which control the pressure gradient which exists between the lumen of the stomach and the intrathoracic esophagus. A relative increase in intragastric pressure and/or a decrease in the lumenal pressure of the intrathoracic esophagus, will increase this gradient, while a segment of intra-abdominal esophagus if present will reduce it (vide infra). The single most important

factor in preventing reﬂux however, is the physiological lower esophageal sphincter (LES).

Lower esophageal sphincter A high-pressure zone can be identiﬁed at the lower end of the esophagus whether or not the GEJ is above or below the diaphragm. Therefore, while an anatomical sphincter does not exist, there does appear to be tonic contraction of the circular esophageal muscle which behaves like a sphincter and which can be identiﬁed manometrically.6–9 Basal tone is known to vary with post-conceptual age,10 being lower in premature infants than in those at full term or in older children.9 This may be a reﬂection of the bulk of the smooth muscle at the LES, which is known to vary with age.11 These observations may help to explain the frequency of GER in neonates, particularly in those who are premature.9,12–16 In addition, the LES is under the control of the endocrine, paracrine and neurocrine systems. Basal tone is constantly being modulated by humoral factors released from the endocrine and paracrine systems. Gastrin for example, will induce a prolonged increase in LES activity.4,5 On the other hand, ﬁne adjustments appear to be superimposed upon this background activity and are controlled by locally and centrally mediated neural reﬂex arcs through the enteric nervous or neurocrine system. Swallowing is one of the most common of these reﬂexes, with relaxation of the LES following a distally propagated stripping wave of contraction in the esophagus.4 Transient GER is usually observed to coincide with this event. Less frequently, spontaneous relaxation of the LES (SRLES) is observed, which is not preceded by deglutition.4,8,17 This is also associated with GER. Of the two types of relaxation of the LES, this is probably the most important, because it is often associated with a more protracted and pathological form of reﬂux.4 In many situations the cause of SRLES is not apparent. However, it has been noted in patients who have proven esophagitis7,18,19 and experimentally when

370 Gastro-esophageal reﬂux

acid is instilled into the lower esophagus.5 Thus, the GER which causes esophagitis tends to be self-perpetuating.5,7 Knowledge of these control mechanisms will facilitate pharmacological manipulation of the LES and gastric emptying. It is in this important area that most progress is likely to be made in the control of GER (vide infra).

Intra-abdominal esophagus In normal circumstances the GEJ lies below the diaphragm. This anatomical relationship is thought to be maintained by the attachment of the phreno-esophageal ligament from the lower end of the esophagus to the diaphragm at the hiatus.20 The lumen of this segment of the esophagus is thus exposed to the same variations in intra-abdominal pressure as the stomach and hence the gradient between the latter and the former is minimized.2,6,20 This effectively reduces the risk of GER. On the other hand, if the intra-abdominal esophagus is short or if the GEJ lies above the diaphragm, exposing the lower esophagus to the relatively negative mean intrathoracic pressure, the gradient between the stomach and the esophagus is signiﬁcantly increased and GER is more likely to occur.21 Hiatus hernia1,4 and conditions where shortening of the esophagus is present such as tracheoesophageal ﬁstula and esophageal atresia following repair,22,23 are more likely to be associated with GER than if the GEJ were situated below the diaphragm. The length of the intra-abdominal esophagus is related to post-conceptual age, being shorter in preterm than full-term infants.11 Some years will be necessary for this to increase beyond a few millimeters. In addition, the GEJ is mobile relative to the hiatus and as a consequence, the effective length of the intra-abdominal esophagus will be reduced to a greater extent in small preterm infants than older children. The risk of developing signiﬁcant GER in small babies, will therefore be greater than in more mature neonates.

EFFECT OF INCREASED PRESSURE GRADIENT ACROSS THE GEJ It is well documented that even in the presence of otherwise normal anatomy and tone in the LES at the GEJ, GER can still occur.6 These circumstances are often associated with increased gradients across the GEJ. This can result from either excessive negative pressure being generated above the diaphragm in the lumen of the esophagus, or by an increase over and above normal in intragastric pressure. Respiratory efforts associated with idiopathic respiratory distress syndrome (IRDS) or bronchopulmonary dysplasia (BPD), will cause excessive negative intrathoracic pressure during the respiratory cycle.13,15,24, 25

Conversely, such problems as primary gastric dysmotility,4,6,26–28 hypertrophic pyloric stenosis29 or intestinal malrotation30 can raise intragastric pressure. These conditions are recognized to be associated with an increased risk of GER. In addition, food intolerences such as cows milk protein allergy or certain medications can cause a secondary generalized intestinal dysfunction which can delay gastric emptying and predispose to GER.31,32

COMPLICATIONS OF NEONATAL GER The types of pathological problem caused by GER in neonates are similar to those which occur in older children. However, their relative frequency is different. Aspiration of gastric contents into the tracheo-bronchial tree is more common than failure to thrive (FTT) due to protein–calorie deﬁciency or reﬂux esophagitis.33

Aspiration into tracheo-bronchial tree ASPIRATION PNEUMONITIS Generally, a large volume of aspirate ﬂooding the lungs will be more serious than minor contamination of the larynx. The extent to which this occurs will depend ﬁrstly upon the volume which is reﬂuxing from the stomach into the pharynx,12,15,34,35 and secondly, upon the ability of the child to clear the pharynx and upper esophagus of this reﬂuxed material.36 In the ﬁrst instance, aspiration leads to atelectasis and this is rapidly followed by bacterial colonization and pneumonitis. The gag reﬂex and coordination of swallowing are recognized to be poorly developed in small preterm infants.36–38 In addition, these babies may at the same time have IRDS. If this problem is superimposed upon aspiration pneumonitis, then there will be a signiﬁcant increase in morbidity.

APNEIC ATTACKS These have been demonstrated to occur in babies who have had simultaneous polygraphic monitoring of vital functions and esophageal pH. Most often, episodes of GER appear to coincide with apnea associated with an obstructed airway and this is usually followed by hypoxemia and bradycardia.6,34,39,40 It is thought that aspiration of gastric contents into the lungs has caused reﬂex laryngo-bronchospasm. However, less frequently, apnea has also been shown to occur even in the absence of aspiration,39,41,42 either on the basis of reﬂex inhibition of respiration caused by exposure of the esophagus to low pH or abnormal function of the respiratory center. In preterm infants in particular, apneic attacks may not be related to clinically recognized reﬂux episodes.41–43

Diagnosis of neonatal GER 371

STRIDOR Occasionally laryngo-bronchospasm secondary to reﬂux, may present with stridor instead of apneic attacks.44-48 This must be distinguished from tracheomalacia, which can cause the same symptom.49 In tracheo-esophageal ﬁstula and esophageal atresia for example, there is frequently associated tracheomalacia and GER. The relative contribution of both of these as the cause of stridor, must be assessed, in order to plan rational therapy for the child.

SUDDEN INFANT DEATH SYNDROME There is no doubt that GER can sometimes be shown to be associated with near-death episodes of apnea, cyanosis and bradycardia.50–53 There is some evidence that treating GER in known risk groups will reduce the incidence of sudden infant death syndrome (SIDS).54 On the other hand, there is no direct evidence that children who have died from SIDS, have died from aspiration of gastric contents.55 While the etiology of SIDS remains speculative, it is possible that GER may be a cause in at least some cases. As a consequence, surgical treatment is justiﬁable in those cases where aspiration associated with GER has already been documented.25,56

BRONCHO-PULMONARY DYSPLASIA Some studies report a high incidence of reﬂux-related respiratory symptoms in premature infants and in infants with broncho-pulmonary dysplasia (BPD).15,25 Chronic aspiration pneumonitis will lead to progressive scarring of the lungs.15,57 However, the clinical and radiographic picture in these children may be indistinguishable from pulmonary disease often encountered in the same preterm infant population, who because of IRDS, require chronic ventilatory support. GER may be identiﬁable in these cases but may not necessarily account for the lung disease.12 Treatment of GER will be necessary when either there is positive proof that the respiratory disease is caused by GER, e.g. when lipidladen alveolar macrophages are identiﬁed in tracheal lavage ﬂuid,25 or where there is a reasonable suspicion that GER is the cause of the problem. Otherwise these babies will often fall into a cycle of events which are selfperpetuating. Pulmonary disease will predispose to GER13,15 and this will cause further lung disease,12,58 which will lead to GER and so on.

Failure to thrive (FTT) The association between FTT and GER is well recognized.1,2,5,33,55,59 It occurs when the volume of retained feed after vomiting is insufﬁcient for the baby to grow normally. This of course assumes that the volume and the type of feed given to the baby is satisfactory and that the child is otherwise well. Not infrequently, because of

the complexity of the clinical problems in the preterm neonate, there is difﬁculty in deciding whether GER is the sole cause of the FTT.60,61

Reﬂux esophagitis In most cases, it is well documented that this complication is associated with prolonged periods of low pH in the esophagus.2,4 It is not the number of reﬂux episodes which appear to be important, but the duration for which the pH is low. During esophageal pH monitoring, if the pH is < 4 for more than 5% of the study period, the risk of esophagitis being present is recognized to be high. This level of pH leads to activation of the gastric protease pepsin, which will have reﬂuxed with the acid, into the esophagus. Thus, autodigestion of the esophageal squamous epithelium may occur.4,6 Excessive exposure of the esophagus to activated pepsin can result from either increased acid and pepsin production, or, poor clearance of the reﬂuxate. On the one hand, delayed gastric emptying, as in hypertrophic pyloric stenosis,32 will cause an increase in serum Gastrin, which will lead to increased gastric acid and pepsin production. This condition is often associated with esophagitis.62 On the other hand, esophageal dysmotility 4,19,38,60,63,64 will delay the return of reﬂuxed material to the stomach. It is worth noting that, poorly coordinated esophageal motility is common in preterm infants 36,37 compared to other children and thus esophagitis might be expected to be relatively common in this group of patients who also have GER. Once established, esophagitis will tend to be selfperpetuating because it causes further disruption of coordinated esophageal motility as well as increasing the frequency of episodes of SRLES.19 Stricture formation rarely occurs in neonates following inadequately treated esophagitis. However, this complication can occur in babies treated for esophageal atresia, where esophagitis can cause narrowing at the site of the anastamosis.65

DIAGNOSIS OF NEONATAL GER Clinical signs and symptoms Signiﬁcant non-bile stained vomiting, particularly when it occurs after feeding and dating from birth, is suggestive of, but not speciﬁc for GER.1 As a consequence, it is important to distinguish vomiting due to GER from other causes, for example, hypertrophic pyloric stenosis, urinary tract infection, meningitis or raised intracranial pressure.66 It is unusual not to ﬁnd a history of vomiting.2 Hematemesis when it occurs, is relatively sensitive and speciﬁc for GER associated with esophagitis. However, not all neonates with esophagitis will have hematemesis

372 Gastro-esophageal reﬂux

and some will have a rather nonspeciﬁc history of ‘bringing up mouthfuls’ or ‘poor feeding’, a symptom analagous to dysphagia in older children.33 Cyanotic attacks or apnea whether or not accompanied by vomiting, may point to GER as the cause, but without simultaneous polygraphic recording of vital functions and esophageal pH, these events cannot be related to it with certainty.16,50,51,67,68 Recurrent pneumonitis69,70 and stridor48,50 present similar difﬁculties with diagnosis in as much that even with documented evidence of aspiration using radiographic or radioisotopic techniques, it is often difﬁcult to be certain that GER with aspiration is the sole cause of the problem.5,71 While most complications will be associated with a history which points to GER as the cause, rarely this is not so and delays in diagnosis and appropriate treatment will be inevitable.

INVESTIGATIONS The majority of neonates have GER and this is usually symptomatic. Most will resolve spontaneously without complication. Therefore, during the neonatal period, it is only necessary to investigate those children who have potentially serious or life-threatening complications of the condition. No single test will diagnose GER and its complications, and it is important to employ as many investigations as are available in order to reduce the risk of errors (vide infra).

Figure 38.1 Marked esophageal reﬂux in a 3-week-old infant

RADIOGRAPHY Contrast studies are important in determining the presence of structural abnormalities such as a hiatus hernia, gastric outlet obstruction or malrotation29 as well as identifying GER (Figs 38.1 & 38.2). Real-time observation of coordination of swallowing and gastric emptying will give an indication of esophageal and gastric dysmotility, although radioscintigraphy72 or electrical impedance studies73,74 may be the better methods for detecting these important problems. Aspiration into the lungs can sometimes be identiﬁed but radioscintigraphy is more sensitive in this respect.5,71 However, signiﬁcant GER may be missed, or conversely, it may be induced during the examination by excessive use of abdominal pressure, when in physiological circumstances, it is absent.5,71 Esophagitis is usually not detected,5 because secondary stenosis rarely occurs in neonates except when associated with an anastomotic stricture following repair of tracheoesophageal ﬁstula and esophageal atresia.65 Radiographic screening of the upper GI tract is highly subjective and requires an experienced operator to obtain satisfactory results.5 While the speciﬁcity and sensitivity for GER of a contrast study is not as good as with other investigations, it is still an important part of the work up of any patient suspected of having this condition or its complications.5

Figure 38.2 Coarse gastric mucosal folds extending across the diaphragm in continuity, giving characteristic appearance of hiatus hernia

ENDOSCOPY Modern ﬂexible ﬁberoptic endoscopes make it possible to safely examine all but the smallest of neonates. Esophagitis can be directly observed although a minority will appear normal when a biopsy shows signs of inﬂam-

Management of neonatal GER 373

mation35,75 Biopsy is therefore indicated in all cases. Some limited information can usually be obtained about the LES: it’s tone and position, and whether a hiatus hernia is present. This is the only reliable method of detecting esophagitis.

ESOPHAGEAL PH MONITORING Miniaturization of pH electrodes has permitted prolonged esophageal pH monitoring in even the smallest baby.76 Computerized data collection and analysis is now commonplace and this has aided prolonged study periods, which were not previously possible.77 Extensive investigation of affected and otherwise normal infants has facilitated normal and abnormal ranges for esophageal pH to be generated.78 The parameters measured include the number of reﬂux episodes of a speciﬁc pH or less, their duration and the total time for which this occurred as a percentage of the study period.77 The latter appears to be the most important of these as this not only reﬂects the frequency of reﬂux but also the esophageal clearance of reﬂuxed acid. Results however will be dependent upon gastric contents. If a child has had a recent milk feed then gastric acid will be buffered. The pH will by necessity be higher than if the child had been fed on fruit juice. This problem can to some extent be overcome using electrical impedence measurement in the lumin of the esophagus, which is a new and experimental measure of GER and is independent of pH.73 In addition, it should also be recognized that different types of feed will have an effect on gastric emptying and this will indirectly affect the predisposition to GER.79 In the past it has been assumed that pH monitoring has been reproducible and reliable.77,78,80 However, signiﬁcant day-to-day variation can occur between tests.81 This does not invalidate pH monitoring but suggests that results should be interpreted with caution and if necessary the investigation should be repeated. There appears to be considerable variation in the frequency of reﬂux episodes while the baby is awake as compared to when sleeping. Reﬂux episodes are unusual when the child is asleep and this type of GER is usually pathologically associated with recurrent pneumonia, stridor, sleep apnea, acute life-threatening events and possibly SIDS.54,57,67,68,81,82 For this reason it is important that the study period extends over at least 16 hours. In general, GER is likely to be pathological when the esophageal pH is < 4 for more than 5% of the study period (bearing in mind minor age-related differences).78 While this investigation will not be diagnostic of the complications of GER, it does offer a simple objective test which can be used to monitor the effectiveness of anti-reﬂux therapy in preventing or controlling GER within acceptable limits. This is now usually regarded as the ‘gold standard’ in the diagnosis of reﬂux.77

Other investigations MANOMETRY Using either perfusion catheters or strain gauges passed into the esophagus, it is possible to measure intraluminal pressure. This technique has been used to measure the basal tone7,8 and pressure changes in the LES7 and it’s position relative to the diaphragm.9 The pressure gradient between the stomach and the esophagus can also be easily determined.9 By employing simultaneous recording of pressure at several points, it is possible to plot the progression of a wave of contraction down the esophagus and the response of the LES to it.4 Esophageal dysmotility,36 reduced basal tone in the LES and SRLES8 are now recognized to be important in GER4,8 and the type of treatment employed. Some of this information can be obtained in part from other sources but not with the same accuracy.

RADIOSCINTIGRAPHY Gastro-esophageal scintiscanning using Technetium (100 mTc) sulphur colloid has been shown to be at least as sensitive or better than radiography or pH monitoring in detecting GER providing this is continued for several hours.66,75–77,83 It has the added advantage of facilitating the quantiﬁcation of esophageal and gastric emptying2,66,72 while employing different types of test feed mixed with the isotope.76 Gastric electrical impedence studies provide similar advantages in measuring gastric emptying but without the radiation risk.74 Pulmonary aspiration can be directly observed when this may be missed using other techniques.2,66 The main disadvantages for most units are ﬁrstly, that the availability of scintillation scan time is often limited and secondly, that immobilization of the child is necessary for prolonged periods to yield meaningful results. If radioscintigraphy is not available, aspiration can be implied by detection either of lipid-laden macrophages in tracheal lavage25,56 or impairment of respiratory epithelial ciliary activity.84

MANAGEMENT OF NEONATAL GER GER has a tendency to undergo spontaneous improvement and resolution with increasing age.1,3 This has in the past encouraged clinicians to treat these children conservatively, in anticipation of a cure without recourse to surgery. At the same time, this approach may place these babies at unnecessary risk. Fortunately, it is now possible to predict the outcome of GER with greater certainty, so that the patient can be targeted more precisely for the most appropriate therapy. In general, where GER is not life threatening, conservative management with posturing, thickening of

374 Gastro-esophageal reﬂux

feeds and antacids or acid suppression, should be considered ﬁrst.1,3 This may be supplemented with one of the prokinetic agents designed to improve esophageal and gastric emptying. Of course if GER is secondary to a structural problem such as hypertrophic pyloric stenosis or malrotation, then this should receive speciﬁc attention. Reﬂux associated with a hiatus hernia is less likely to resolve spontaneously than if the GEJ is normal. However, a signiﬁcant proportion of these children will get better without surgery and conservative management is initially justiﬁable in most cases.1 The only accepted indication for immediate surgical intervention in the neonatal period, is where there is a history of aspiration associated with GER, causing either apneic attacks, stridor or recurrent pneumonitis, and where there is clearly an ongoing risk of SIDS.43,48,51,54,57,85,86 Uncontrolled esophagitis or FTT will be an indication for surgery in slightly older infants and most in the ﬁrst instance can safely be treated conservatively.

Conservative management POSTURAL THERAPY This form of treatment originated from the observation that children often resolved their tendency to vomit when they achieved the upright walking position. It was assumed that gravitational forces were assisting in keeping gastric contents in the stomach. This argument was taken further and it was recommended that infants suffering from signiﬁcant GER should be treated in the supine position at 60° horizontally, both by day and night. It was claimed that the patients’ symptoms were subjectively improved, that there was possibly an improvement in the radiographic demonstration of a hiatus hernia (or partial thoracic stomach) and that this form of posturing shortened the natural history of resolution in the majority of cases.1 More recent pH studies appear to demonstrate that the supine position, even with the head elevated, may not as previously thought, result in a reduction in low pH GER. The prone position with the head up seems to be more efﬁcient in controling reﬂux and is probably preferred.87–89 On the other hand, the risk of SIDS is recognized to be increased when the baby is nursed in the prone position91,92 and in any case, in practice, the beneﬁts from appropriate posturing may not be worth the effort.92 To be of value this form of treatment, if employed, must clearly be used both by day and night in those patients who are considered to be at risk from ‘pathological’ GER and who at the same time have no risk factors for SIDS.42–57,82,85,86,90,91 This should be continued until low pH GER can no longer be demonstrated or until approximately 1 year of age, when posturing should only be necessary at night, if at all. Beyond this age, this form of therapy appears to be of little clinical value.1

DIET Children with GER often improve spontaneously at the time of weaning when the consistency of their feed is increased by the introduction of solids. It is also observed that children who vomit will be improved if the volume at each feed is reduced (implying more frequent feeding).1 Thickening agents have been extensively employed, carob seed vegetable preparations of low caloriﬁc value (such as Nestergel or Carobel),1,6 being preferred over cereals,55 which contribute signiﬁcantly to the calorie intake in the diet. While thickening the feed appears to have a beneﬁcial clinical effect,1,6 objective scientiﬁc evidence does not support this form of therapy being applied blindly in every case of GER.93–95 While gastric emptying can be inﬂuenced by different feeds,79 manipulation of the diet to enhance this to reduce the risk of GER has not generally been clinically effective. The exception is where there is a true cow’s milk protein allergy which affects gastrointestinal motility and thus predisposes to GER.30,96 These babies are often dramatically improved when placed on formula feeds which do not contain cow’s milk and the possibility of this diagnosis as the cause of GER should always be borne in mind.

ANTACIDS These agents theoretically neutralize the acid gastric contents. It is known that elevation of gastric pH results in a decrease in peptic activity and an increase in LES tone.97 This should reduce the tendency to reﬂux and the severity of it’s complications. However, objective evidence of the effect of antacids compared to placebo in children with GER has not to date been presented. Where data is available comparing different antacids,98 there appears to be no advantage in using the mixture of magnesium trisilicate, aluminium hydroxide and alginic acid (Gaviscon). The high sodium content of Gaviscon means that there are probably few indications for it’s use in neonates.99 If a reduction in the amount of acid reﬂux is the therapeutic aim, then a more effective group of drugs will be those which suppress gastric acid production.

Agents which suppress gastric acid production Histamine, acting through cell surface H2 receptors, stimulates a proton pump in gastric parietal cells, which is responsible for HCL production in the stomach. Acid secretion can be signiﬁcantly reduced either by inhibiting the proton pump or blockade of the H2 receptors using speciﬁc antagonists. This will result in an improvement in clinical status in most cases. As with antacids, this improvement may not only be related to a reduction in the amount of acid in the esophagus, but also to the degree of GER.97

Management of neonatal GER 375

H2 receptor antagonists Cimetidine, the ﬁrst of this group to be employed therapeutically, is effective in most cases although there are reported cases where an adequate dosage has failed to control acid GER.5,100 Ranitidine, a more effective alternative with fewer side effects, is now usually employed as the ﬁrst choice H2 receptor antagonist.101

PROTON PUMP INHIBITORS Omeprazol was the ﬁrst of this group of drugs. It is generally more effective than the H2 receptor anatagonists. It is not licenced for children but can be given on a named-patient basis and can be administered either intravenously or enterally. Long-term usage of both groups of drugs should only be undertaken with caution in view of the nitroso compound production in the stomach and the possible long-term risk of malignancy.

NEUROCRINE AGONISTS AND ANTAGONISTS While detailed knowledge of the neurocrine system is at present incomplete, understanding of some of the more basic mechanisms has resulted in the development of powerful therapeutic tools to counter such abnormalities as esophageal and gastric dyskinesia and poor LES tone. To date most of these pharmacologic agents at our disposal are too nonspeciﬁc in their action and side effects are therefore common. The future may provide a drug designed to counter a speciﬁc abnormality with fewer unwanted actions. Bethanechol This is a choline ester with a selective action on muscarinic receptors. Double blind cross-over trials appear to have demonstrated a beneﬁcial effect in GER by increasing LES tone and increasing esophageal and gastric emptying.102 However these actions do not appear to be superior to simple antacids and the frequency of side effects preclude its widespread use.103 Metoclopramide This benzamide has a dual action being both a dopamine antagonist and a cholinergic agonist. It is very effective in increasing gastric transit and LES tone14,104,105 and has been shown to signiﬁcantly reduce GER.105,106 Unfortunately, the dopaminergic blockade is not speciﬁc to the GIT and unpleasant extrapyramidal side effects occur relatively frequently.105 In addition, a number of patients will develop methemoglobinemia.107 These side effects have generally restricted its use to older patients. Domperidone This imidazole is predominantly a dopamine-receptor blocker. Compared to metoclopramide, it crosses the blood–brain barrier poorly thus CNS side effects are signiﬁcantly reduced and therapeutic efﬁcacy has been

signiﬁcantly improved. Side effects are generally mild and infrequent.108 However, in very small babies, where the blood–brain barrier may not be completely developed, some extrapyramidal signs may be occasionally encountered.109 Cisapride This substituted benzamide was developed in an effort to avoid some of the nonspeciﬁc effects of the above agents. It’s action is through the release of acetylcholine in the enteric plexus and because of this there appear to be few side effects. Compared to other drugs it has a greatly improved effect upon gastrointestinal transit and because of this action it has been called a prokinetic agent. LES tone and gastric emptying are increased and GER is signiﬁcantly reduced.110–113 However, it is now recognized to be the cause of cardiac arrhythmias in some children who will develop abnormalities of the Q-T interval.114,115 It is advisable therefore to perform a preliminary ECG before commencing this drug and to monitor the child’s ECG while therapy continues. Erythromycin This antibiotic has been shown to have prokinetic properties when given in a sub-antibiotic dose.116,117 This is particulary useful as an alternative to Cisapride in small preterm infants who are at risk of GER. However, not all children will beneﬁt from its use and some may develop hypertrophic pyloric stenosis (HPS) while under treatment.118 This can cause signiﬁcant problems with diagnosis and treatment if it is assumed that the child’s continued vomiting is caused by GER and not HPS.

Operation Anti-reﬂux surgery is not commonly performed in the neonate.1,6 As indicated earlier, aspiration associated with GER is perhaps the only indication for intervention in this age group. The principles of any anti-reﬂux procedure are to ﬁrstly control GER and secondly to avoid as many of the unpleasant complications of surgery as possible. Increasingly, these operations are being performed laparoscopically. However there have been no randomized trials in children to suggest that this approach produces a better long-term result or has any other major beneﬁt. Regardless of the method, most of the operations which are employed use the fundus of the stomach, which is wrapped around the lower esophagus after this has been mobilized from the hiatus.6,83–88 This wrap around or fundoplication, acts as a plug, preventing the abdominal esophagus so created, from escaping back into the chest. This mechanism will only continue to work if the hiatus is relatively small and thus some form of plication of the diaphragmatic opening is usually necessary as well.6,119–122 Fundoplication may also act to prevent GER, by creating a ﬂutter valve at the

376 Gastro-esophageal reﬂux

GEJ, by creating an acute angle between the esophagus and the cardia of the stomach.6 This additional mechanism in preventing GER, may not be active in operations where an incomplete wrap around has been performed. Recurrent GER following fundoplication will occur in less than 10% of cases.6,123–125 As a general statement this happens when the GEJ has moved from its immediate postoperative situation below the diaphragm to a position within the chest. This has been recognized for many years both in adults and in children. Consequently there has been a tendency to perform a type of procedure which will tend to work even though the GEJ has been displaced into the chest. The Nissen operation which employs a 360° wrap around behaves in this way.22,120 However, these children tend to be unable to ‘bring up wind’ and unpleasant, painful abdominal distension can often be a problem.22,126 Others have argued that wrap arounds of <360° are just as satisfactory and avoid the other problems associated with the Nissen operation.3,6,127 These children appear postoperatively to be able to ‘bring up wind’ and to vomit if they wish, and GER is adequately controlled. However, this may recur if the GEJ rises into the chest. ‘Gas bloat syndrome’ is probably a signiﬁcant complication of all procedures, although possibly more frequently associated with the Nissen operation.22,126 It was at one time thought to be related entirely to the competence of the new GEJ and the inability of the individual to eructate.22,128 However, intestinal dysmotility causing delay in gastric emptying129,130 is now thought to contribute to this unpleasant complication which might be helped by one of the prokinetic agents described earlier. Pyloroplasty has in the past been employed as an alternative, however, ‘dumping’ may follow such a procedure and there is little evidence to suggest that it improves gastric emptying.25,129 Adhesive obstruction occurs in up to 10% of cases and is an important source of morbitity.123,131 This does not appear to be inﬂuenced by the type of operation employed. Unfortunately, no controlled data exists comparing one type of operation to another in terms of long-term success in controling GER and the incidence of postoperative complications. It would appear that 85% or more of children will have long-term control of GER following fundoplication and less than 10% will have signiﬁcant postoperative complications of their surgery.6,88,123–131

SUMMARY GER is a common disorder in the neonatal period affecting the GEJ. Multiple inter-related factors will inﬂuence the occurrence of GER but the most important of these are the LES and the intra-abdominal esophagus.

In most units, diagnosis will depend on an adequate history, radiographic and endoscopic assessment of the esophagus and stomach and prolonged esophageal pH studies. Radioscintigraphy, esophageal manometry and other investigations, such as measurement of electrical impedance, are unavailable in most units, however the data obtainable from these should in future, make them an important part of the general work up of all patients. GER usually runs a benign course and is more common in premature infants than in those born at term or in older children. As a consequence, most children can be managed conservatively using posturing in the headup position and thickening of feeds, which are given more frequently and in smaller volume. Some in addition will require the use of either antacids or drugs which suppress gastric acid production or one of the prokinetic agents to improve LES tone or gastric emptying. Aspiration of gastric contents into the tracheobronchial tree, associated with GER and the complications which this causes, is the main indication for operation. The best procedure has yet to be determined, but most surgeons favor a type of operation which will allow the patient to ‘bring up wind’ or vomit and this implies a fundoplication with an incomplete type of wrap around.

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124. Turnage RH, Oldham KT, Coran AG et al. Late results of fundoplication for gastroesophageal reﬂux in infants and children. Surgery 1989; 105:457–64. 125. Caniano DA, Ginn-Pease ME, King DR et al. The failed antireﬂux procedure: Analysis of risk factors and morbidity. J Pediatr Surg 1990; 25:1022–6. 126. Shirazi SS, Schulze K, Soper RT. Long-term follow-up for treatment of complicated chronic reﬂux esophagitis. Arch Surg 1987; 122:548–52. 127. Scarli AF. To Nissen or not to Nissen. Prog Pediatr Surg 1985; 18:96–100. 128. Leape LL, Ramenofsky ML. Surgical treatment of gastroesophageal reﬂux in children. Am J Dis Child 1980; 134:935–8. 129. Mulvihill SJ, Fonkalsrud EW. Pyloroplasty in infancy and childhood. J Pediatr Surg 1983; 18:930–6. 130. Papaila JG, Wilmot D, Grosfeld JL, Rescorla FJ, West KW, Vane DW. Increased incidence of delayed gastric emptying in children with gastroesophageal reﬂux. A prospective evaluation. Arch Surg 1989; 124(8):933–6. 131. Wilkins BM, Spitz L. Adhesion obstruction following Nissen fundoplication in children. Br J Surg 1987; 74:777–9.

5 Gastrointestinal

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39 Pyloric atresia and prepyloric antral diaphragm VINCENZO JASONNI

INTRODUCTION Gastric outlet obstruction in the newborn may be due to pyloric atresia, antral web or hypertrophic pyloric stenosis. The most common cause of gastric outlet obstruction is hypertrophic pyloric stenosis.

PYLORIC ATRESIA Pyloric atresia is a rare congenital malformation representing less than 1% of all atresias and diaphragms of the gastrointestinal tract.1–3 About 30% of these patients have associated abnormalities, of which epidermolysis bullosa is the most common.1,4,5 Familial occurrence of pyloric atresia has been reported.5,6 Puri et al. have encountered pyloric atresia in three consecutive siblings in a family.7 Bar-Maor et al. and El Shaﬁe et al. concluded that there is strong evidence to support a genetic determination in an autosomal recessive mode.8,9 Junctional epidermolysis bullosa associated with pyloric atresia (EB-PA; (congenital disorders and malformations) OMIN ≠ 226730) is a rare autosomal recessive inherited disease in which mucocutaneous fragility is associated with this type of gastrointestinal atresia.10 This association is usually fatal during the ﬁrst few weeks or months of life, even following surgical correction of intestinal obstruction. Recently, mutations in the genes encoding the subunit polypeptides alpha 6 beta 4 of integrin (ITGA6 and ITGB4) have been identiﬁed in several patients with peidermolysis bullosa and pyloric atresia.10–12 Prenatal diagnosis of pyloric atresia can be suspected when polyhydramnios is present (this occurs in about half of the cases) associated with dilated stomach. Prenatal diagnosis of pyloric atresia and epidermolysis bullosa was performed in pregnancies at risk for recurrence of this severe syndrome. However, some sonographic signs suggest the possibility of signiﬁcant cutaneous desquamation and blister formation in a fetus, especially when there is positive amniotic acetylcholinesterase coupled with elevated alphafetoprotein.13

The sex distribution is equal and there are a high proportion of infants with low birth weight.14, 15

Clinical presentation and diagnosis The newborn with complete pyloric obstruction presents shortly after birth with persistent non-bilious vomiting and often with epigastric distension.16 Respiratory problems are common, and dyspnea, tachypnea, cyanosis and excessive salivation may be mistaken for esophageal atresia.17 Very rarely, congenital gastric outlet obstruction is associated with esophageal atresia.18 Late diagnosis of pyloric atresia can cause rupture of stomach, although this complication has been reported as early as 12 hours postdelivery.19 A plain X-ray of the abdomen will usually conﬁrm the clinical diagnosis. The typical X-ray (Fig. 39.1) will show gas in the dilated stomach and no gas beyond the pylorus. Contrast study, although unnecessary, can conﬁrm complete obstruction at the pyloric region. The radiological diagnosis is based on the identiﬁcation of three radiological signs: the single gas bubble sign, the absence of beak sign (typical of hypertrophic pyloric stenosis), and the presence of the pyloric dimple sign on a contrast study.20 The single gas bubble sign is not speciﬁc for the diagnosis of pyloric atresia, but is an indicator of a gastric outlet obstruction. The ultrasonographic examination is helpful in the diagnosis of pyloric atresia.20 It demonstrated the absence of the normal echo pattern of the pyloric muscle and the pyloric canal; this is speciﬁc for the diagnosis of this entity. Table 39.1 represents the clinical features of pyloric atresia with their incidence.2,3

Pathological anatomy and operative surgery There are three main different types of pyloric obstruction: (1) membranous pyloric obstruction – type A; (2) longitudinal segmental atresia – type B; and (3) pyloric aplasia – type C (Fig. 39.2). In Table 39.2, the incidence of the different types of pyloric obstruction is shown.2,3

384 Pyloric atresia and prepyloric antral diaphragm

Type A

Type B

Type C

Figure 39.2 Anatomical varieties of congenital pyloric obstruction: type A – membranous pyloric obstruction; type B – longitudinal segmental atresia; type C – pyloric aplasia

Figure 39.1 Abdominal X-ray showing absence of air beyond the stomach

the membrane and pyloroplasty according to HeinekeMikulicz or Finney.1–4 Recently, transgastric excision of the pyloric membrane without pyloroplasty has been reported.21 With longitudinal segmental atresia, the operative method depends on the length of the atresia. When the atresia is short, a Finney pyloroplasty can be carried out, but for longer atresia and aplasia, the surgical procedure of choice is an excision and end-to-end gastroduodenostomy.4 Gastrojejunostomy is not recommended, due to the high mortality rate4 and because of the risk of marginal ulcer and blind loop syndrome.

Table 39.1 Clinical features of pyloric atresia (n = 140 patients) Symptoms and signs

Occurence (%)

Bile-free vomiting Single stomach bubble (one bubble) on X-ray Passage of meconium Distended epigastrium Polyhydramnios Birth weight <2500 g Prematurity Jaundice Peristaltic movements in the epigastrium Hemorrhagic vomiting

100 98 69 68 63 53 45 21 18 12

Preoperative preparation Generally newborns are admitted within the ﬁrst 2 days of life and generally in good physical condition, except those cases of pyloric atresia associated with epidermolysis bullosa. Preoperative preparation should consist of relief gastric distension by nasogastric tube, supplemented by lavage with warm normal saline if there is much thick mucus or if feeding has been attempted. An i.v. infusion should be started and correction of dehydration electrolyte imbalance and metabolic alkalosis is required in most cases.

Data from Muller et al.2 and Lorenzet and Morger3

Table 39.2 Incidence of the different pyloric atresia types (n=140) Type of atresia

n

%

Membranous (type A) Atresia (type B) Aplasia (type C) No details

77 cases 46 cases 12 cases 5 cases

57 34 9 3.5

Data from Muller et al.2 and Lorenzet and Morger3

Corresponding to the classiﬁcation of pyloric obstruction, different operative procedures are used. In the literature, the best results from operative treatment of membranous obstruction were obtained by excision of

OPERATIVE TECHNIQUE Incision A transverse abdominal incision is made 2 cm above the umbilicus, starting 2 cm to the left of the midline and running laterally in a skin crease for about 5 cm (Fig. 39.3a). The abdominal cavity is opened in the line of the incision. Careful exploration and search of other intestinal atresias are performed at this site.9 Identiﬁcation of pathology After the operation, it may be difﬁcult to diagnose the pathology and gastrotomy is often helpful in this regard.16 Another way to ﬁnd the exact location of the web and prevent the gastrotomy can be achieved by advancing a ﬁrm 14 Fr. gauge nasogastric catheter by the anesthesiologist, to the region of the obstruction.22

Pyloric atresia 385

(a)

(b)

(c)

(d)

Figure 39.3 Operative technique of pyloroplasty. (a) skin incision. (b) pyloric longitudinal incision. (c) incision of the membrane and suture. (d) longitudinal incision closed transversely

Pyloroplasty This procedure is for membranous pyloric obstruction (type A) and short atresia (type B).4,7,8 After identiﬁcation of the pylorus, a longitudinal incision is made with cutting diathermy or scissors, starting on the gastric side of the pylorus to the duodenum (Fig. 39.3b). A blunt dissecting forceps, which is inserted into the lumen, is useful at this stage. Care must be taken that no inadvertent damage is done to the posterior wall of the stomach or duodenum. The total length of the incision should be 1.5–2 cm, extending approximately 1 cm on the gastric side and 1.5–1 cm on the duodenal side of the pylorus; it should be midway between the greater and lesser curvatures of the stomach and superior and inferior borders of the duodenum. The greater length on the gastric side is to allow for greater thickness of the gastric wall in making the alignment for closure of the pyloroplasty incision in the transverse direction. The membrane is excised circumferentially and the mucosa approximately with 5-0 Vicryl sutures (Fig. 39.3c). The interior of the duodenum is inspected and a catheter is inserted down the duodenum to ensure that there is no distal atresia. The longitudinal incision is then closed transversely in two layers after meticulous hemostasis (Fig. 39.3d). The

inner layer is done by the Connell suture technique with Vicryl 4-0 sutures. The outer layer is divided by Lambert sutures. Closure of abdomen Gastrostomy is generally not necessary. The abdomen is closed in two layers and the nasogastric tube is left in the stomach for decompression.

Postoperative outcome Early diagnosis and surgical intervention with current neonatal supportive care have improved the survival of pure pyloric atresia. Mortality has been associated with delayed diagnosis8,9 and is mainly due to the associated malformation. The overall mortality rate is about 45% and the majority of these fatal cases are those with epidermolysis bullosa and other multiple intestinal atresias.23 Prenatal diagnosis of epidermolysis bullosa lethalis can be made by fetoscopic skin biopsy, and the parent should undergo genetic counselling due to the familial occurrence and suspicion of transmission by the autosomal recessive mode. Rosenbloom and Ranter suggested the nonoperative management of pyloric atresia, unless the skin disease is responsive to treatment.24 However, Hayashi et al. have recently reported long-term survival in four out

386 Pyloric atresia and prepyloric antral diaphragm

of ﬁve patients with pyloric atresia and epidermolysis bullosa.6

Prepyloric antral diaphragm Prepyloric antral diaphragm is a rare anomaly involving a submucosal web of gastric tissue covered by gastric mucosa and found in the distal gastric antrum. A total of about 150 cases have been reported, divided between the pediatric and adult age ranges.25 Reports have suggested both acquired and congenital forms, citing epidemiological and histological evidence.26 There are three groups of patients: a neonatal group with complete or partial obstruction, a group presenting later in childhood, and a group not diagnosed until later in life.27 Signiﬁcant associated abnormalities are noted in about 30% of children with antral web, including mainly the gastrointestinal tract and cardiovascular system.26

Clinical presentation and diagnosis In the neonatal group, vomiting, often projectile, is the predominant presenting symptom. The vomiting is usually non-bilious. Other symptoms include apnea, cyanosis and no weight gain.26 The older children complained of abdominal pain, vomiting, fullness after eating and eructation. In the elderly group, the clinical history consists of episodic cramping, epigastric pain or fullness following meals and intermittent vomiting. There is one report describing a case in the eighth decade of life.28 The diagnosis of antral web with a central aperture is made radiologically following a barium meal in 90% of cases.26 The typical appearance of a web in an infant is a thin, membranous septum, projecting into the antral lumen, perpendicular to its longitudinal axis 1–2 cm proximal to the pylorus (Fig. 39.4a). Gastroscopy has recently been noted to be of use in conﬁrming clinical and radiological evidence of the web in older infants and in children.29 Features of the web include: • A small ﬁxed central aperture surrounded by gastric mucosa that is smooth and devoid of folds • No change in the opening size of the web with peristalsis, and • That the gastric wall proximal and distal to the web is seen to contract normally.30

TREATMENT The treatment of partially obstructing antral web consists of surgical excision of the web, combined with pyloroplasty if the web is very close to the pylorus (described previously under ‘Pyloric atresia’). Furthermore, at operation, it is important in these cases to pass a Foley catheter from the stomach as far as possible

(a)

(b)

Figure 39.4 (a) Prepyloric antral web. (b) Windsock antral membrane protruding into the duodenum

distally, and then to inﬂate the balloon and to withdraw the catheter.22 Windsock pyloric and antral membranes protruding into the duodenum have been reported (Fig. 39.4b), and would be missed at laparotomy by simple inspection of the gastric lumen.31 Other methods are reported, most notably a recent report of successful endoscopic transection using a standard papillotome32 and forceful dilatation of antral membrane without pyloroplasty.33 Medical treatment consisting of thickened feed and antispasmodics has been reported to be successful in infants with vomiting and a radiographically demonstrable antral web but without pronounced obstruction.34 While this concept of conservative management is supported by some surgeons, the majority of the literature preferred the surgical correction of this entity, which will reduce and prevent the morbidity and unnecessary psychiatric counselling in this group of babies and children.4,25

REFERENCES 1. Dessanti A, Iannuccelli M, Dore A et al. Pyloric atresia: an attempt at anatomic pyloric sphincter reconstruction. J Pediatr Surg 2000; 35:1372–4. 2. Muller M, Morger R, Engert J. Pyloric atresia: report of four cases and review of the literature. Pediatr Surg Int 1990; 5:276–9. 3. Lorenzet CA, Morger R. Beirgrag zur kongenitalen, Pylorus Atresie. Innauguraldisseration, Universitat Zurich, 1987. 4. Hall WH, Read RC. Gastric acid secretory differences in patients with Heineke–Mikulicz and Finney pyloroplasties. Am J Dig Dis 1975; 20:947–50. 5. Kadowaki J, Takeuchi S, Nakahira M et al. Congenital pyloric atresia: a report of three cases. Am K Gastroenterol 1981; 76:449–52. 6. Hayashi AH, Galliana CA, Gillis DA. Congenital pyloric atresia and junctional epidermolysis bullosa: a report of long-term survival and a review of the literature. J Pediatr Surg 1991; 26:1341–5.

References 387 7. Puri P, Guiney EJ, Carroll R. Multiple gastro-intestinal atresias in three consecutive siblings: observations on pathogenesis. J Pediatr Surg 1985; 20:22–4. 8. Bar-Maor JA, Nissan S, Nevo S. Pyloric atresia. J Pediatr Surg 1972; 20:22–4. 9. El Shaﬁe M, Stidham GL, Klippel CH et al. Pyloric atresia and epidermoylsis bullosa letalis: a lethal combination in two premature newborn siblings. J Pediatr Surg 1979; 14:446–9. 10. Mellerio JE, Pulkkimen L, McMillan JR et al. Pyloric atresia – junctional epidermolysis bullosa syndrome: mutations in the integrin bega4 gene (ITGB4) in two unrelated patients with mild diseases. Br J Dermatol 1998; 139:862–71. 11. Dellambra E, Prislei S, Salvati AL et al. Gene correction of integrin beta 4- dependent pyloric atresia epidermolysis bullosa keratinocytes establishes a role for beta 4 tyrosines 1422 and 1440 in hemidesmosome assembly. JK Biol Chem 2001; 44:41336–42. 12. Nakana A, Pulkkinen L, Murrell D et al. Epidermoylsis bullosas with congenital pyloric atresoa: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res 2001; 49:618–26. 13. Lapinard C, Descampo P, Menegurri G et al. Prenatal diagnosis of pyloric atresia – junctional epidermolysis bullosa syndrome in a fetus not known to be at risk. Prenat Diagn 2000; 20:60–75. 14. Kume K, Ikeda K, Hayashida Y et al. Congenital pyloric atresia: a report of three cases and review of literature. Jpn J Pediatr Surg 1980; 16:259–68. 15. Lloyd JR, Clatworthy HW. Hydramnios as an aid for the early diagnosis of congenital obstruction of the alimentary tract: a study of the maternal and fetal factors. Pediatrics 1958; 21:903–9. 16. Ducharme JC, Benoussan AL. Pyloric atresia. J Pediatr Surg 1975; 10:149–50. 17. Campbell JE. Other conditions of the stomach. In: Welch KJ, Randolp JG, Ravitch MM et al. editors. Pediatric Surgery. 4th edn. Chicago: Year Book, 1986:821–2. 18. Friedman AP, Velcek FT, Ergin MA et al. Oesophageal atresia with pyloric atresia. Br J Radiol 1980; 53:1009–11.

19. Burnett HA, Halpert B. Perforation of the stomach of a newborn infant with pyloric atresia. Arch Pathol 1947; 44:318–20. 20. Grunebaum M, Kornreich L, Ziv N et al. The imaging diagnosis of pyloric atresia. Z Kinderchir 1985; 40:308–11. 21. Narasimhan KL, Road KLN, Mitra SK. Membranous pyloric atresia – local excision by a new technique. Pediatr Surg Int 1991; 6:159–60. 22. Raffensperger JG. Pyloric and duodenal obstruction. In: Swenson’s Pediatric Surgery. 5th edn. Norwalk, CT: Appleton & Lange 1990: 509–16. 23. Chittmittrapap S. Pyloric atresia associated with ileal and rectal atresia. Pediatr Surg Int 1988; 3:426–30. 24. Rosenbloom MS, Ranter M. Congenital pyloric atresia and epidermolysis bullosa letalis in premature siblings. J Pediatr Surg 1987; 22:374–6. 25. Blazek FD, Boeckman CR. Prepyloric antral diaphragm: delays in treatment. J Pediatr Surg 1987; 22:948–9. 26. Bell MJ, Gternberg JL, Keating JP et al. Prepyloric gastric antral web: a puzzling epidemic. J Pediatr Surg 1978; 13:307–13. 27. Patnaik DN, Sun S, Groff DB. Newborn gastric outlet obstruction caused by an antral web. J Med Soc N Jers 1976; 73:736–7. 28. Rona A, Sylvestre J. Prepyloric mucosal diaphragm. J Can Assoc Radiol 1975; 26:291–4. 29. Schwatx SE, Rowden DR, Dudgeon DL. Antral mucosal diaphragm. Gastrointest Endosc 1977; 24:33–4. 30. Banks PA, Waye JD. The gastroscopic appearance of the antral web. Gastrointest Endosc 1969; 15:228–9. 31. Haller JA Jr, Cahill JL. Combined congenital gastric and durodenal obstruction: pitfalls in diagnosis and treatment. Surgery 1968; 63:503–6. 32. Berr F, Rienmueller R, Sauerbruch T. Successful endoscopic transection of a partially obstructing antral diaphragm. Gastroenterology 1985; 89:1147–51. 33. Lugo-Vincent HL. Congenital antral membrane: prenatal diagnosis and treatment. J Pediatr Surg 1994; 29:1589–90. 34. Tunell WP, Smith EI. Antral web in infancy. J Pediatr Surg 1980; 15:152–5.

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40 Hypertrophic pyloric stenosis PREM PURI AND GANAPATHY LAKSHMANADASS

INTRODUCTION

GENETICS

Hypertrophic pyloric stenosis (HPS) is the most common condition requiring surgery in the ﬁrst few months of life. It is characterized by hypertrophy of the circular muscle of the pylorus, causing pyloric channel narrowing and elongation. The incidence of pyloric stenosis varies widely with geographic location, season and ethnic origin.1 The incidence has been reported to be approximately three per 1000 live births.2 There is some evidence that in recent years the incidence of pyloric stenosis has increased signiﬁcantly in some parts of the UK.3–5 Boys are affected four times more often than girls.6 A recent study reported a dramatic rise in incidence among male infants but not for females, so that rates for the two sexes were 6.2 and 0.9 per 1000 infants per year.7

As infantile hypertrophic pyloric stenosis (IHPS) tends to run in families, genetic factors have been implicated in its etiology. IHPS is relatively rare in babies of African, Indian, and Chinese extraction.10,11 Boys are affected four times more often than girls,9 and IHPS has been reported in multiple siblings and multiple births.12–14 Siblings of patients with IHPS are 15 times more likely to suffer the condition than children who have no family history of IHPS.15 In a follow-up study extending over 45 years, Carter and Evans found that 5–20% of the sons and 2.5–7% of the daughters of affected patients developed IHPS.16 Sons and daughters of affected female patients had 3–4 times the incidence of IHPS than sons and daughters of affected male patients.15

ABNORMALITIES OF HORMONAL CONTROL ETIOLOGY Although earlier diagnosis, advances in ﬂuid and electrolyte therapy, and pediatric anesthesia have reduced the mortality to practically zero, the exact etiology of pyloric stenosis is unknown.8 This condition is usually classiﬁed as a congenital disorder. It is almost unknown in stillbirths, associated anomalies are very uncommon and the patient usually presents with vomiting after the second week of life. For these reasons it has been suggested that it may be an acquired condition. Recently, Rollins et al. measured pyloric muscle dimensions on ultrasonography in 1400 consecutive newborn infants.9 Nine of these infants subsequently developed pyloric stenosis and were operated upon. Their pyloric muscle measurements at birth were all within the normal range. This study clearly showed that congenital performed muscular hypertrophy is not present in babies who later develop pyloric stenosis.

The human pylorus is characterized by a zone of elevated pressure that relaxes with antral peristalsis, contracts in response to intraduodenal stimulation, and prevents the retrograde movement of duodenal contents into the stomach.17 The hormonal control of the pyloric sphincter function by mediators such as gastrin, cholecystokinin, and secretin, has been reported to be the same as in other gastrointestinal (GI) sphincters.4 Since Dodge successfully induced pyloric stenosis by prolonged perinatal maternal stimulation with pentagastrin in approximately one-half of a litter,18 together with the ﬁnding of elevated serum gastrin levels in infants with IHPS,19 much attention has been paid to the role of gastrin in the pathogenesis of IHPS. It has been suggested that repeated hyperacid stimulation of the duodenum induced by gastrin evokes repeated pyloric sphincter contractions with work hypertrophy of the pylorus.20 However, Janik et al. failed to induce pyloric stenosis in other species by prenatal administration of pentagastrin.21 Some investigators found signiﬁcantly

390 Hypertrophic pyloric stenosis

high plasma gastrin levels in affected infants compared to healthy controls,19,22 whereas others failed to conﬁrm this ﬁnding.23,24 Since raised serum gastrin levels return to normal following pyloromyotomy, it is believed that they are secondary to antral stasis.24

ABNORMALITIES OF PYLORIC INNERVATION A variety of morphological and molecular studies have suggested that the enteric nervous system plays an important role in normal GI smooth-muscle development. It has been reported that the reciprocal interactions between the developing enteric nervous system and GI smooth muscle play a signiﬁcant role in the normal differentiation, maturation, and function of both of these tissue types.25–27 The innervation of the musculature regulating motility is particularly dense at the level of the smooth-muscle sphincters of the GI tract.28 Relaxation of the sphincter is accomplished by activation of inhibitory motor neurons.29 As a defect in pyloric relaxation has been thought to be responsible for the gastric-outlet obstruction and the development of pyloric muscle hypertrophy, many investigators have sought evidence for a neural abnormality in specimens of IHPS that may explain the failure of pyloric muscle relaxation.8 Earlier studies concentrated on abnormalities in the myenteric plexus,30–37 and more recent studies have focused on the neurotransmitter status in both the myenteric plexus and pyloric muscle layers.37–49

Ganglion cells Many investigators have reported conﬂicting morphologic ﬁndings as regards ganglion cells in the myenteric plexus in IHPS. A number of early authors found decreased numbers of ganglion cells, which were attributed either to degenerative changes related to vagal overstimulation 30–32 or to immaturity.33,34 On the other hand, Rintoul and Kirkman suggested that Dogiel type I ganglion cells (primarily motor) were selectively absent in IHPS.35 Belding and Kernohan30 and Spitz and Kaufmann36 found that the majority of myenteric ganglion cells in the hypertrophic pylorus showed degenerative changes. However, Tam, using immunohistochemical stains for neuronspeciﬁc enolase, stated that neurons were neither immature nor severely degenerated.37 In a recent study using electron microscopy, Langer et al. demonstrated that there were fewer nerve cell bodies in the myenteric plexus in IHPS and the total number of ganglia was lower than that in control samples.50

Peptidergic innervation It has been demonstrated that the relaxation mechanism of pyloric smooth muscle appears to be dependent on

non-adrenergic, non-cholinergic (NANC) inhibitory innervation, which is mediated by some neuropeptides. With the advent of immunohistochemical techniques speciﬁc for GI peptides, a number of investigators have examined the peptidergic nerves in the myenteric plexus and smooth-muscle layer in IHPS.37–41 These studies suggested a reduction of immunoreactivity in peptidergic nerve ﬁbers containing enkephalin, neuropeptide Y, substance P, vasoactive intestinal polypeptide (VIP), and gastrin-releasing peptide supplying the circular muscle.37–41 No such reduction was observed in the nerves or cell bodies within the myenteric plexus. Among these neuropeptides, of particular importance is the absence of the inhibitory peptides (VIP and neuropeptide Y) in the intramuscular nerves. These observations are highly suggestive of a mechanism involving failure of pyloric relaxation owing to depletion of inhibitory peptides, resulting in pyloric smooth-muscle hypertrophy and gastric-outlet obstruction in IHPS.

Nitrergic innervation Nitric oxide (NO) has been recognized as a potent mediator of NANC inhibitory nerves, which regulate smooth-muscle relaxation in the mammalian digestive tract.51 Vanderwinden et al.42 and Kobayashi et al.43 have reported that enzyme NADPH diaphorase, which is identical to NO synthase (NOS), is absent or markedly reduced in hypertrophic pyloric muscle while it is preserved in the myenteric plexus in IHPS. Furthermore, a NOS gene-deleted knockout mouse model is described in which the only abnormality is gastric-outlet obstruction due to pyloric hypertrophy.52 Recently, Kusafuka and Puri, using RT-PCR technique, demonstrated low levels of nNOS mRNA in pyloric muscle of IHPS patients compared to normal controls.44 Since a low level of nNOS mRNA may lead to impaired local production of NO, it is suggested that the excessively contracted hypertrophied circular muscle in IHPS is a result of reduced expression of the nNOS gene at the mRNA level.44

Synapse formation Synapses provide the ﬁnal neuronal control of the GI tract by regulating neurotransmission at the neuromuscular terminals. Recent studies have demonstrated reduction of synaptic vesicles and presynaptic terminals in hypertrophied pyloric muscle layers.47,48 Furthermore, a study from the current authors’ laboratory reported markedly reduced neural-cell adhesion molecule (NCAM) expression on nerve ﬁbers within circular and longitudinal muscles in patients with IHPS compared with normal pylorus.43 NCAM plays an important role in the formation of initial contacts between nerve and muscle cells and affects tissue formation during embryo-

Abnormalities of extracellular matrix proteins 391

genesis.53,54 These reports suggest that there is impairment of neurotransmission between nerves and muscle in IHPS.

Nerve-supporting cells The nerve-supporting cells (NSCs) permit cell bodies and processes of neurons to be ordered and maintained in a proper spatial arrangement, and are essential in the maintenance of basic physiological functions of neurons.55 The NSCs of the intrinsic enteric nervous system are often referred to as enteric glia.8 Enteric glia have been reported to express various markers for both astrocytes and Schwann cells, such as: (1) glial ﬁbrillary acidic protein (GFAP), a speciﬁc marker for astrocytes within the central nervous system; (2) S-100, a marker for astrocytes and Schwann cells; and (3) D7, a marker for Schwann cells. A recent study from the current authors’ laboratory demonstrated that in IHPS cases S-100, D7 and GFAP-immunoreactive ﬁbers were either absent or markedly reduced within the hypertrophied circular and longitudinal muscles.49 There is evidence to suggest that NSCs also act as neurotrophic factors.56,57 The limited availability of neurotrophic factors is thought to control the extent of neuronal survival, and thus (indirectly), the density of innervation. Conversely, the presence of nerve ﬁbers is essential for the existence of NSCs; supporting cells degenerate after proximal transection of the nerve ﬁber. The absence or marked reduction of NSC in IHPS corresponds to the absence or reduction of peptidergic, nitrergic, cholinergic, and adrenergic nerve ﬁbers, and is additional evidence that a defect of intramuscular innervation exists in IHPS.

Neurotrophins Neurotrophins are a family of related, target-derived neuronal growth factors that support neuronal growth, survival and differentiation. It is well established that peripheral sensory and postganglionic sympathetic neurons are under the control of neurotrophins for development and maintenance. A recent study showed reduced levels of nerve growth factor (NGF), neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) in pyloric muscle in IHPS compared with normal controls.58 NT-3 immunoreactivity normally is localized to ganglion cells, enteric glia, and connective tissue rich in extracellular matrix, which forms the framework in which NT-3 accumulates. BDNF and NGF normally are localized to ganglion cells and adjacent glia. In IHPS a selective reduction in intramuscular nervesupporting cells (enteric glia) has been reported.49 It is tempting to speculate that the reduction of mature glia in IHPS may partly be responsible for the diminished production of NT-3, BDNF, and NGF. Recently, the current authors have analyzed the expression of glial-

derived neurotrophic factor (GDNF), which is expressed normally by mature enteric glial cells, and found that in IHPS there is a lack of GDNF-positive nerve ﬁbers.59 In contrast to neurotrophins, however, GDNF is produced very early in gut mesenchyme, and in IHPS the pyloric muscle retains the capacity to produce GDNF perhaps compensating for the lack of mature enteric glia. It also is possible that the reported abnormalities of extracellular matrix proteins8 in IHPS could alter neuronal maturation by providing an insufﬁcient latticework for neurotrophins to attach.

ABNORMALITIES OF THE INTESTINAL PACEMAKER SYSTEM (INTERSTITIAL CELLS OF CAJAL) Interstitial cells of Cajal (ICC) are small fusiform or stellate cells with prominent nuclei and varicose processes that form networks in the GI tissues. Morphologic studies have suggested three major functions of ICC: (1) they are pacemaker cells in GI smooth muscle; (2) they facilitate active propagation of electrical events; and (3) they mediate neurotransmission.60,61 A number of investigators have reported a lack of ICC in hypertrophic pyloric muscle from patients with IHPS using C-KIT antibody and electron microscopy.62,63 The lack of ICC in IHPS suggests the disruption of their network and the interruption of the generation of slow waves may contribute to the motility disturbances of the pyloric sphincter.63

ABNORMALITIES OF EXTRACELLULAR MATRIX PROTEINS Previous studies have reported an increase in connective tissue in IHPS, particularly in the septa that run between the circular muscle bundles.30,32 Recent studies have demonstrated that ECM proteins, particularly collagen, are important microenvironmental factors of the neuronal processing pathway in the early embryonal stage and an important matrix for cell adhesion and movement.8 Cass and Zhang reported an increase in extracellular matrix (ECM) proteins such as chondroitin sulfate, ﬁbronectin, and laminin in specimens of pyloric muscle in IHPS.64 Another study reported abnormal amounts of elastin ﬁbers and elastin in the pyloric muscle in IHPS.65 Using M-57 antibody, which can distinguish newly synthesized type I procollagen from fully processed mature collagen, a recent study from the current author’s laboratory demonstrated that type I procollagen was markedly increased in not only the connective tissue septa between circular muscle bundles, but also among the circular muscle ﬁbers in patients with IHPS, suggesting that the hypertrophied circular muscle in IHPS is

392 Hypertrophic pyloric stenosis

actively synthesizing collagen.65,66 These studies suggested that increased ECM proteins may be responsible for the characteristic ‘ﬁrm’ nature of the pyloric tumor.

ABNORMALITIES OF SMOOTH-MUSCLE CELLS The ongoing contractile tone in the smooth-muscle sphincters is generated by myogenic mechanisms. This implies that the contractile state is an intrinsic property of the muscle and independent of the nervous system. On the other hand, transient relaxation of the sphincter to permit the forward passage of material is accomplished by activation of inhibitory motor neurons.29 Dieler et al. examined 37 pyloric specimens from IHPS patients with electron microscopy, comparing the severity and frequency of degenerative changes in the myenteric plexus and smooth-muscle cells (SMCs), and reported primarily myogenic-type abnormality in some and predominently neurogenic-type abnormality in others.67 In the predominantly myogenic type, they observed degenerative or regressive changes of SMCs in hypertrophied pyloric muscle such as swelling and necrosis, various nuclear abnormalities, glycogen accumulation, increased amounts of connective tissue between SMCs, and in particular, alterations of the endoplasmic reticulum (ER) and the presence of numerous dense granules within the cytoplasm. Langer et al.50 found SMCs in IHPS to be morphologically normal, containing contractile ﬁlaments, intermediate ﬁlaments, dense bodies, and caveolae. They found, however, that SMCs in IHPS were frequently in a proliferative phase, with large amounts of dilated rought ER with a lower proportion of contractile ﬁlaments, and very few gap junctions exhibited between SMCs compared with control specimens. In contrast, they demonstrated signiﬁcant ultrastructural abnormalities of the inhibitory enteric nervous system in IHPS. We performed quantitative evaluation of proliferative activity in pyloric muscle in IHPS and showed that proliferative activity is markedly increased in SMCs in IHPS.68

ABNORMALITIES OF GROWTH FACTORS Although the mechanisms responsible for smooth-muscle hypertrophy are unknown, with progress in molecular biology, there is increasing evidence to suggest that the growth of SMCs is regulated by several growth factors.69–71 IGF-I and PDGF-BB are potent SMC mitogens in vitro and act synergistically to stimulate SMC proliferation. IGF-I mediates the growth-promoting effects of PDGF in mesenchymal cells.72 IGF-I and PDGF have been shown to be produced by SMCs, and their effects are mediated via their receptors.73,74 Transforming growth factor alpha

(TGF-α) is a growth regulatory peptide found in a wide range of embryonic and adult tissues. It has been recognized that TGF-α has a growth-promoting effect on vascular and visceral SMCs.75 EGF is best known as a potent growth stimulator. It appears to play a critical role early in growth of cultured smooth muscle, in which its production is highest and its growth-promoting effects are greatest.75 The studies from our laboratory have reported increased expression of IGF-I, PDGF-BB, TGF and EGF, in hypertrophic pyloric muscle in IHPS,76–79 suggesting that the increased local synthesis of peptide growth factors in SMCs may play a critical role in the development of pyloric muscle hypertrophy in IHPS.

CLINICAL FEATURES The usual onset of symptoms occurs between 3 and 6 weeks of age. It may present earlier and has been rarely reported in premature infants.80 Presentation of HPS in infants older than 12 weeks of age is considered rare and reports in the literature are few and far between.81,82 The current authors reviewed 1481 consecutive cases of pyloric stenosis treated at three children’s hospitals in Dublin between 1969 and 1990. A total of 53 (3.6%) patients presented with pyloric stenosis between 12 and 30 weeks of age. Vomiting is the most common presenting symptom. Initially there is only regurgitation of feeds, but soon it is characteristically projectile and free of bile. In 17–18% of cases the vomitus may contain fresh or altered blood, usually attributed to irritative gastritis or esophagitis.83 Spitz and Batcup examined endoscopically 13 infants presenting with hematemesis and found evidence of esophagitis in all cases.84 Owing to inadequate ﬂuid and calorie intake, dehydration and weight loss soon become apparent. In patients who present late, there is disappearance of subcutaneous fat and wrinkled skin. Stools become infrequent, dry, ﬁrm and scanty. Jaundice occurs in about 2% of cases and has been shown to be related to decrease in glucoronyl transferase, which occurs as a consequence of starvation.85 Associated anomalies are found in 6–20% of patients.6,12 These include: esophageal atresia, malrotation of bowel, Hirschsprung’s disease, anorectal anomalies, cleft lip and palate, and urological anomalies.

DIAGNOSIS It should be possible to diagnose HPS on clinical features alone in 80–90% of infants.86–88 The important diagnostic features of pyloric stenosis are visible gastric peristalsis and a palpable pyloric tumor. Physical examination of the infant is best carried out during a test feed which

Management 393

relaxes the abdominal wall and makes the detection of pyloric tumor easier. The abdomen is completely exposed and observation made for gastric peristalsis, which is often visible in this condition as a bulge appearing in the left upper quadrant and moving slowly to the right across the epigastrium. On palpation of the abdomen, an olive-shaped pyloric tumor is palpable in most cases just above the umbilicus at the lateral border of the rectus muscle below the liver edge. In general, the diagnosis of pyloric stenosis can be made with conﬁdence on the basis of the history and clinical examination alone. When the clinical ﬁndings are equivocal, the diagnosis can be conﬁrmed by sonography or barium meal. In 1977, Teele and Smith reported on the sonographic diagnosis of HPS.89 The diagnosis relies on the measurement of the pyloric diameter, pyloric length and muscle thickness. Of the three parameters, muscular wall thickness is considered to be the most precise on sonography. Blumhagen and Coombs were the ﬁrst to point out that pyloric muscle thickness of the hypoechoic ring is the most important sonographic parameter in the diagnosis of pyloric stenosis (Fig. 40.1).90 They considered a thickness of 4 mm or more to be pathological. Other investigators believe that muscle thickness of 5 mm or more is most reliable for the diagnosis of pyloric stenosis.91 Falsepositive results are rare, but false-negative rates range from 0–19% and largely depend upon the skill of the ultrasonographer.6,91 Barium meal usually conﬁrms the diagnosis in patients in whom the pyloric tumor cannot be palpated. A barium study may also detect gastro-esophageal reﬂux or intestinal malrotation. Before barium study, the stomach should be emptied with a nasogastric tube and 30–60 ml of barium is instilled under ﬂuoroscopic control. The characteristic radiological feature of pyloric stenosis is a narrowed elongated pyloric canal giving a ‘string’ or ‘double track’ sign caused by compressed invaginated folds of mucosa in the pyloric canal (Fig. 40.2).

Figure 40.1 Longitudinal real-time sonogram section reveals hypoechoic ring with echogenic center typical of pyloric tumor

Figure 40.2 Pyloric stenosis. Severe narrowing of pyloric region giving the ‘string sign’ in this 3-week-old infant who presented with projectile vomiting

MANAGEMENT Preoperative management Persistent vomiting in these patients results in chloride depletion and metabolic alkalosis. Estimation of serum electrolyte level, urea, hematocrit and blood gases should be done to determine the state of dehydration and acid–base abnormalities. A nasogastric tube is passed to keep the stomach empty. Saline irrigation through the nasogastric tube may help in removing mucus and milk curd. Nowadays, many babies with pyloric stenosis do not show any clinical evidence of dehydration on admission and their serum electrolyte levels are usually normal. They are given their maintenance requirements of ﬂuid as half-straight saline, and are operated on as soon as feasible. If the infant is mildly dehydrated and has hypochloremic alkalosis, maintenance ﬂuids can be given as 0.45% saline with 5% dextrose containing 10 mmol of potassium chloride per 500 ml, together with adequate volumes of isotonic saline to correct for continuing nasogastric losses. If the infant is more severely dehydrated (>5%), sodium and chloride ions must be replaced with isotonic saline to enable the kidney to excrete bicarbonate, thereby correcting the acid–base status.6,92 The operation for pyloric stenosis is not an emergency and should never be undertaken until serum electrolyte levels have returned to normal.

394 Hypertrophic pyloric stenosis

Operation The Ramstedt’s pyloromyotomy is the universally accepted operation for pyloric stenosis.

INCISION A 3 cm transverse right upper quadrant incision provides excellent exposure and direct access to the pylorus with minimal retraction (Fig. 40.3). Another incision which is commonly used is an umbilical fold incision.93–96

PROCEDURE The transverse incision lateral to the rectus muscle is cut through all layers of muscle and peritoneum. The pyloric tumor is delivered by gentle traction on the stomach (Fig. 40.4). The surgeon applies an index ﬁnger to the duodenal end of the pylorus and stabilizes the pyloric tumor. An incision is then made over the anterosuperior

part of the pylorus, beginning at the clearly demarcated pyloroduodenal junction about 2 mm proximal to the pyloric vein and extending onto the gastric antrum, where muscle is thin (Fig. 40.5). The pyloric muscle is then widely split down to the mucosa using mosquito forceps (Fig. 40.6). Some surgeons prefer a Denis Browne pyloric spreader. When the pyloric muscle has been adequately split, the mucosa can be seen to be bulging (Fig. 40.7). The pylorus is dropped back into the abdomen. The peritoneum is closed with 4-0 polyglactin (Vicryl) and muscles approximated using 3-0 polyglactin (Vicryl). 5-0 Vicryl is used for subcuticular stitches. The supraumbilical skin fold incision for pyloromyotomy has been used by several surgeons.93–96 Although this incision does not offer any advantage as regards postoperative feeding tolerance or duration of hospital stay, it certainly gives a superior cosmetic result. The problem with the supraumbilical incision is that it does not always

Pyloric vein

Figure 40.3 Skin incision for pyloromyotomy Figure 40.5 Incision through the serosa of the pyloric tumor

Mucosa

Figure 40.4 Delivery of pyloric tumor

Figure 40.6 Splitting of pyloric muscle

References 395

was begun in the immediate postoperative period or 2–6 hours postoperatively decreased the length of hospitalization and hospital costs without adverse effects.103

COMPLICATIONS

Figure 40.7 Bulging mucosa seen after complete splitting of pyloric muscle

allow easy access to the hypertrophic pyloric muscle. Delivery of a large pyloric tumor can be fairly difﬁcult and time consuming and may damage the serosa of the stomach or duodenum by tearing. Extending the muscle sheath incision vertically has been described to resolve this problem.95

LAPAROSCOPIC PYLOROMYOTOMY Recently, extramucosal pyloromyotomy has been performed successfully by laparoscopy in infants with HPS.97–99 There are no signiﬁcant advantages as regards overall operating time, postoperative feeding tolerance and duration of hospital stay. The main advantage of laparoscopic pyloromyotomy is the superior cosmetic result. However this must be balanced against the ﬁnancial implications of offering a laparoscopic pyloromyotomy.

Postoperative care Maintenance i.v. ﬂuids are continued postoperatively until the infant is feeding satisfactorily. The timing of reintroduction of feeds continues to be controversial.100–103 Several studies have investigated postoperative feeding regimens for IHPS patients with respect to time of reintroduction of feeding and speed of advancement in an attempt to discover the safest and most cost-effective method. Some surgeons recommend starting oral feeds 4–6 hours after operation and gradually increasing the volume and concentration so as to resume normal feeds by the third or fourth day. Others have shown that postoperative vomiting is reduced if feeds are not started until 24 hours postoperatively. The vomiting following pyloromyotomy is usually self-limiting and independent of the timetable or composition of the postoperative dietary regimen.102 A recent study showed that a postoperative standardized feeding regimen for patients with IHPS where feeding

Duodenal perforation is usually the result of excessive separation of ﬁbers at the distal end of the pylorus. It is not serious provided that it is recognized and closed with one or two sutures. A patch of omentum should be brought up and tied over the wound. Other complications included hemorrhage, wound infection and wound dehiscence. With improvements in techniques, the incidence of complications after pyloromytomy is very low.

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65. Oue T, Puri P. Abnormalities of elastin and elastic ﬁbers in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1999; 15:540–2. 66. Miyazaki E, Yamatakia T, Ohshiro K et al. Active collagen synthesis in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1998; 13:237–9. 67. Dieler R, Schroder JM, Skopnik H, Steinau G. Infantile hypertrophic pyloric stenosis: myopathic type. Acta Neuropathol 1990; 80:295–306. 68. Oue T, Puri P. Smooth muscle cell hypertrophy versus hyperplasia in infantile hypertrophic pyloric stenosis. Pediatr Res 1999; 45:853–7. 69. Chen Y, Bornfeldt KE, Arner A, Jennische E, Malmqvist U, Uvelius B, Arnqvist HJ. Increase in insulin-like growth factor-I on hypertrophying smooth muscle. Am J Physiol 1994; 266:E224–9. 70. Yamamoto M, Yamamoto K. Growth regulation in primary culture of rabbit arterial smooth muscle cells by plateletderived growth factor, insulin-like growth factor-I and epidermal growth factor. Exp Cell Res 1994; 212:62–8. 71. Pfeifer TL, Chegini N. Immunohistochemical localization of insulin-like growth factor (IGF-I), IGF-I receptor, and IGF binding proteins in the cardiovascular system. Cardiovasc Res 1994; 30:281–9. 72. Clemmones DR, Van Wyk JJ. Evidence for a functional role of endogenously produced somatomedin like peptides in the regulation of DNA synthesis in cultured human ﬁbroblast and porcine smooth muscle cells. J Clin Invest 1985; 75:1914–18. 73. Libby P, Waener SJC, Salmone RN, Brinyi LK. Production of platelet derived growth factor-like mitogen by smooth muscle cells from atheroma. N Engl J Med 1988; 318:1493–6. 74. Ultlrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, LeBon T, Kathuria S, Chen F. Insulin like growth factor I receptor primary structural determinants that deﬁne functional speciﬁcity. EMBO J 1986; 5:2503–12. 75. Kuemmerle JF. Autocrine regulation of growth in cultured human intestinal muscle by growth factors. Gastroenterology 1997; 113:817–24. 76. Ohshiro K, Puri P. Increased insulin-like growth factor-I and platelet-derived growth factor system in pyloric muscle in infantile hypertrophic pyloric stenosis. J Pediatr Surg 1998; 33:378–81. 77. Ohshiro K, Puri P. Increased insulin-like growth factor-I mRNA expression in pyloric muscle in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1998; 13:253–5. 78. Shima H, Puri P. Increased expression of transforming growth factor-α in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1999; 15:198–200. 79. Shima H, Ohshiro K, Puri P. Increased local synthesis of epidermal growth factors in infantile hypertrophic pyloric stenosis. Pediatr Res 2000; 47:201–7. 80. Tack ED, Perlman JM, Bower RJ et al. Pyloric stenosis in the sick premature infant. Clinical and radiological ﬁndings. Am J Dis Childh 1988; 142:68–70.

398 Hypertrophic pyloric stenosis 81. Evans AL. Hypertrophic pyloric stenosis presenting in childhood. Postgrad Med J 1987; 63:919. 82. Konvolinka CW, Wermutr CR. Hypertrophic pyloric stenosis in older infants. Am J Dis Child 1971; 122:76–9. 83. Cook RCM. Hypertrophic pyloric stenosis. In: Lister J, Irving IM, editors. Neonatal Surgery. London: Butterworths, 406–20. 84. Spitz L, Batcup G. Haematemesis in infantile hypertrophic pyloric stenosis: the source of bleeding. Br J Surg 1979; 66:827–8. 85. Wooley MM, Felsher BF, Asch J. Jaundice hypertrophic pyloric stenosis and hepatic glucuronyl transferase. J Pediatr Surg 1974; 9:359–63. 86. Zeidan B, Wyatt J, MacKensie A et al. Recent results of treatment of infantile hypertrophic pyloric stenosis. Arch Dis Childh 1988; 63:1060–4. 87. Scharli A, Sieber WK, Kiesewetter WB. Hypertrophic pyloric stenosis at the Children’s Hospital of Pittsburgh from 1912 to 1967. J Pediatr Surg 1969; 4:108–14. 88. Forman HP, Leonidas JC, Kronfeld GD. A rational approach to the diagnosis of hypertrophic pyloric stenosis; do the results match the claims? J Pediatr Surg 1990; 25:262–6. 89. Teele RL, Smith EH. Ultrasound in the diagnosis of iopathic hypertrophic pyloric stenosis. N Engl J Med 1977; 296:1149–50. 90. Blumhagen JD, Coombs JB. Ultrasound in the diagnosis of hypertrophic pyloric stenosis. J Clin Ultrasound 1981; 9:289–92. 91. Gribner R, Pistor G, Abou-Touk B et al. Signiﬁcance of ultrasound for the diagnosis of hypertrophic pykloric stenosis. Pediatr Surg Int 1986; 1:130–4. 92. Spicer RD. Infantile hypertrophic pyloric stenosis: a review. Br J Surg 1982; 69:128–35.

93. Tan KC, Bianchi A. Circumbilical incision for pyloromyotomy. Br J Surg 1986; 73:399. 94. Fitzgerald PG, Lau GY, Langer JC et al. Umbilical fold incision for pyloromyotomy. J Pediatr Surg 1990; 25:1117–18. 95. De Caluwe D, Reding R, de Ville de Goyet J, Otte JB. Intraadominal pyloromyotomy through the umbilical route: a technical improvement. J Pediatr Surg 1998; 33:1806–7. 96. Shankar KR, Losty PD, Jones MO, Turnock RR, Lamont GL, Lloyd DA. Umbilical pyloromyotomy – an alternative to laparoscopy? Eur J Pediatr Surg 2001; 11:8–11. 97. Bufo AJ, Merry C, Shah R, Cyr N, Schropp KP, Lobe TE. Laparoscopic pyloromyotomy: a safer technique. Pediatr Surg Int 1998; 13:240–2. 98. Downey EC Jr. Children’s Surgical Associates, Orange, CA 92668, USA. Semin Pediatr Surg 1998; 7:220–4. 99. Fujimoto T, Lane GJ, Segawa O, Esaki S, Miyano T. Laparoscopic extramucosal pyloromyotomy versus open pyloromyotomy for infantile hypertrophic pyloric stenosis: which is better? J Pediatr Surg 1999; 34:370–2. 100. Leahy A, Fitzgerald FJ. The inﬂuence of delayed feeding on post-operative vomiting in hypertrophic pyloric stenosis. Br J Surg 1982; 69:658–9. 101. Foster ME, Lewis WG. Early postoperative feeding – a continued controversy in pyloric stenosis. J Roy Soc Med 1989; 82:532–3. 102. Wheeler RA, Najamaldin AS, Stoodley N et al. Feeding regimens after pyloromyotomy. Br J Surg 1990; 77:1018–19. 103. Leinward MJ, Shaul DB, Anderson KD. A standardized feeding regimen for hypertrophic pyloric stenosis decreases length of hospitalization and hospital costs. J Pediatr Surg 2000; 35:1063–5.

41 Gastric volvulus MARK D. STRINGER

INTRODUCTION Gastric volvulus is a rare, potentially life-threatening condition ﬁrst described by Berti in 1866.1 A review of the world literature in 1980 identiﬁed only 51 cases in children under 12 years of age.2 Of these, 26 (52%) were infants and half of these were younger than 1 month of age. In recent series, neonates have accounted for an even greater proportion of cases.3,4 In older children, gastric volvulus may be associated with neurodevelopmental handicap but in neonates there is a strong link with diaphragmatic defects. In the last 2 decades, numerous descriptions of acute and chronic gastric volvulus in children have been published, bringing the total number of reported cases to more than 100.3–8

DEFINITION Gastric volvulus may be deﬁned as an abnormal rotation of one part of the stomach around another;9 the degree of twist varies from 180o to 360o and is associated with closed loop obstruction and the risk of strangulation. Lesser degrees of gastric torsion are probably common, frequently asymptomatic, and are not diagnostic of volvulus. Such cases may be associated with transient vomiting in infants but spontaneous resolution is the rule.7,10 Gastric volvulus may be either organoaxial, occurring around an axis joining the esophageal hiatus and the pyloroduodenal junction, or mesenteroaxial, around an axis joining the midpoint of the greater and lesser curves of the stomach (Fig. 41.1). Both types of volvulus occur with similar frequency.4 A mixed picture occurs if the stomach rotates around both axes simultaneously. The usual direction of rotation is anterior, i.e. in organoaxial volvulus the greater curve moves upwards and forwards above the lesser curve, causing the posterior gastric wall to face anteriorly. The gastroesophageal junction and the pylorus may both become obstructed. In anterior mesenteroaxial rotation, the

Axes of rotation in gastric volvulus

Organoaxial volvulus (anterior)

Mesenteroaxial volvulus (anterior)

Figure 41.1 Diagrammatic representation of the main types of gastric volvulus

antrum comes to lie anterosuperior to the fundus and obstruction is usually in the antropyloric region. Acute, complete volvulus is most often seen in infancy in contrast to chronic and partial varieties, which more often occur in older children and adults. More complex patterns of gastric volvulus have been described in neonates and infants with abnormal gastric bands or adhesions (see later), and in older children after gastrostomy11 or Nissen fundoplication.12–14

CLINICAL CASES The following three cases illustrate different aspects of the presentation and management of gastric volvulus in infancy.

400 Gastric volvulus

Case 1

Case 2

A full-term male infant presented soon after birth with cyanotic attacks during feeding. A tracheo-esophageal ﬁstula was initially suspected, but a plain chest radiograph (Fig. 41.2a) showed a gastric shadow lying in front of the heart and a barium swallow (Fig. 41.2b) demonstrated an organoaxial gastric volvulus within the chest. Via a left thoracotomy, the stomach was derotated and reduced into the abdomen with repair of the esophageal hiatus. A gastropexy was not performed and subsequent progress was uneventful.

A full-term male infant presented at 4 days of age with intermittent vomiting. This was initially attributed to a urinary infection, but the vomiting continued and a barium meal showed that there was delayed passage of contrast into the stomach from the esophagus. When the barium was injected via a nasogastric tube, the stomach was seen to lie horizontally and to empty very slowly. At laparotomy, the pylorus was hypertrophied and the stomach was distended. The gastrocolic omentum was deﬁcient along most of the greater curve, allowing free organoaxial rotation of the stomach. A pyloromyotomy and anterior gastropexy were performed, after which the child became symptom-free.

Case 3 A female infant presented at the age of 2 months with a history of loud borborygmi, inability to bring up wind after feeding, and occasional vomiting. On examination, bowel sounds were heard in the chest. Barium meal showed an organoaxially rotated intrathoracic stomach. Via an abdominal approach, a large paraesophageal hernia was reduced, followed by a crural repair and Nissen fundoplication. The child remained asymptomatic 4 years later.

(a)

PATHOGENESIS The stomach is relatively ﬁxed at the esophageal hiatus and at the pyloroduodenal junction and is also stabilized by four ‘ligamentous’ attachments – the gastrohepatic, gastrosplenic, gastrocolic and gastrophrenic ligaments (Fig. 41.3). Despite these attachments, considerable changes in shape and position of the normal stomach are possible. This is highlighted by the gastric rotation that can sometimes be observed during air insufﬂation of the stomach at the time of laparoscopically assisted percuta-

(b) Figure 41.2 (a) Plain chest radiograph showing an air-ﬁlled viscus in the chest (case 1). (b) Barium study showing the stomach lying above the diaphragm with the greater curve uppermost (case 1)

Figure 41.3 Diagrammatic view of the stabilizing gastric ligaments

Clinical features 401

neous endoscopic gastrostomy insertion.15 Absence or attenuation of the normal anatomical anchors results in abnormal gastric mobility, which may be encouraged still further by a coexistent diaphragmatic defect. Most cases of gastric volvulus in the newborn are secondary to diaphragmatic defects with or without deﬁcient ligamentous attachments.2,16–22 The contribution of the gastrocolic and gastrosplenic ligaments to ﬁxation of the stomach is demonstrated by the observation in the cadaver that their division allows 180o rotation of the normal stomach.2,5,23 Eventration or herniation of the diaphragm is present in about two-thirds of all children presenting with gastric volvulus. However, this proportion is as high as 80% in some series of infants.2,17 Diaphragmatic hernias are typically paraesophageal or posterolateral defects but gastric volvulus within a Morgagni hernia is also possible.24 The presumed mechanism of gastric volvulus in this situation is upward displacement of the transverse colon, which pulls up the greater curve of the stomach into the expanded left upper quadrant. Acute gastric volvulus may therefore present as an early complication of diaphragmatic defects. Gastric distension may encourage the development of gastric volvulus.23 Infantile hypertrophic pyloric stenosis may rarely be a predisposing factor, as in the second case described earlier. One similar case has been reported but that infant also had a diaphragmatic defect.25 Air swallowing can also cause gastric distension, and intermittent gastric volvulus has been reported in an aerophagic neurologically handicapped infant.21 Other rare causes of gastric volvulus in the neonate and infant include: abnormal bands or adhesions producing an axis of rotation for the stomach;6,17,21,26 rectal atresia with consequent overdistension of the transverse colon;27 congenital absence or resection of the left lobe of the liver which may promote abnormal gastric mobility;28 and congenital deﬁciency of the gastrocolic omentum.5,29 The asplenic syndrome (asplenia, congenital heart disease, with or without intestinal malrotation and deﬁciency of the gastric ligaments) is increasingly recognized as a predisposing condition.30 Nakada et al. reported gastric volvulus as a complication in three of 25 patients with asplenia, the youngest of whom was 1 month of age.31 Anchoring gastric ligaments were deﬁcient in all cases. Because of the potentially fatal outcome of acute gastric volvulus in this situation, Okoye et al. have recommended prophylactic gastropexy.32 Defective ﬁxation and ligamentous laxity also account for the association between gastric volvulus and a wandering spleen.33,34 Intestinal malrotation is associated with gastric volvulus, even in the absence of asplenia.6,21,26,31,35 Gastric volvulus in children may rarely arise as a postoperative complication. It has been described after Nissen fundoplication, presumably because the stomach has been extensively mobilized by division of gastrosplenic and gastrocolic attachments.12–14,36 There is one recorded case of gastric volvulus developing after repair

of a diaphragmatic hernia17 and another as an iatrogenic complication of gastric transposition in infancy.37

CLINICAL FEATURES The clinical features depend on the degree of rotation and obstruction. In adults, the triad of Borchardt is diagnostic of acute volvulus: (1) unproductive retching; (2) acute localized epigastric distension; and (3) inability to pass a nasogastric tube.38 These features are difﬁcult to assess in the infant and may be absent. Persistent regurgitation and vomiting (sometimes unproductive) are common, although non-speciﬁc, presenting symptoms in the newborn. The vomitus may or may not contain bile, depending on the degree of pyloric obstruction. Hematemesis and anemia are well described and occasionally the vomiting is described as projectile. Failure to thrive and chest infections are sometimes evident.35 Upper abdominal pain and distension may be noted in older infants and children. However, abdominal signs may be minimal if the stomach is intrathoracic, when respiratory distress and tachypnea are the dominant features.2,18,20,39,40 Failure to pass a nasogastric tube may have several causes in the newborn and the successful passage of a tube does not exclude the diagnosis.14,17 In neonates, confusion with esophageal atresia is possible but arrest of the nasogastric tube in the distal esophagus and radiographic abnormalities on routine ﬁlms should raise suspicion and prompt investigation by contrast studies.41 In older children, presenting symptoms may be intermittent, chronic and also non-speciﬁc.14 Plain abdominal and chest radiographs are essential. A distended stomach in an abnormal position should suggest the possibility of gastric volvulus. In mesenteroaxial volvulus, the stomach is spherical on the plain ﬁlm taken with the patient in the supine position, and two ﬂuid levels are often visible on the erect ﬁlm – one in the fundus (the lower) and the other in the antrum (upper) (Fig. 41.4a). Contrast studies clarify the anatomy (Fig. 41.4b) and the site(s) of obstruction, which is usually at the pylorus, giving a so-called ‘beak’ deformity.18 Organoaxial volvulus is more difﬁcult to diagnose on plain ﬁlms (especially if there is no associated diaphragmatic defect) and may indeed be missed during a barium study.21 The distended stomach lies rather horizontally on the plain ﬁlm, with a single ﬂuid level. On contrast examination, the esophagogastric junction is lower than normal, the greater and lesser curves are inverted, and the antrum and duodenum are distorted (Fig. 41.5). Obstruction may be present at both the gastro-esophageal junction and the pylorus. In the presence of a diaphragmatic defect, such as a paraesophageal hernia, the antrum may herniate into the retrocardiac position, producing a ﬂuid level in the chest above the gastric fundus, and thus organoaxial volvulus can also rarely give rise to two ﬂuid levels.42

402 Gastric volvulus

(a)

Figure 41.5 Oblique view of barium meal demonstrating an organoaxial gastric volvulus in a neonate who presented with intermittent vomiting (case 2)

TREATMENT Acute gastric volvulus requires appropriate resuscitation and urgent surgery if ischemic necrosis and gastric perforation are to be avoided. If possible, the stomach should be decompressed preoperatively by nasogastric suction but vigorous attempts to pass a tube must be avoided because of a risk of gastric perforation.17 An abdominal approach is recommended, even when the stomach lies in the chest, since this allows identiﬁcation of any associated gastrointestinal anomalies and accurate diaphragmatic repair if required, and because the esophagus is normal in length. The volvulus should be reduced. Occasionally, preliminary needle aspiration of the stomach may be warranted before manipulating a tensely dilated stomach.43 Any associated diaphragmatic defect should be repaired and the stomach ﬁxed to the anterior abdominal wall (Box 41.1). Box 41.1 Surgical options for gastric volvulus in the neonate/infant (b) Figure 41.4 (a) Plain abdominal radiograph showing a distended stomach but only a single ﬂuid level in this neonate with mesenteroaxial gastric volvulus. (b) Barium study conﬁrming mesenteroaxial gastric volvulus

Repair of diaphragmatic defect, division of congenital bands, etc. and anterior gastrostomy Crural repair (if necessary) and anterior gastropexy Crural repair and fundoplication for cases with severe gastro-esophageal reﬂux

References 403

Gastrostomy alone may be used for gastric ﬁxation in neonates, since it provides adequate ﬁxation, postoperative decompression and a route for postoperative feeding. A Stamm gastrostomy using a 10 or 12 Fr. gauge Malecot catheter secured by a double pursestring suture of 4-0 Vicryl or Polydioxanone is appropriate (Fig. 41.6a). In infants with no predisposing diaphragmatic defect, an anterior gastropexy should be added (Fig. 41.6b). This involves suturing the greater curve of the stomach to the parietal peritoneum of the anterior abdominal wall and the undersurface of the diaphragm by a series of 4-0 nonabsorbable sutures. There are three recorded cases of recurrence following this approach44,45 but the initial gastric ﬁxation in these cases was inadequate. Fundoplication may be necessary if there is evidence of gross gastro-esophageal reﬂux but several authors have achieved good results in such cases with a crural repair alone and a more conservative approach is warranted provided the tendency to volvulus is prevented.35,36 Diaphragmatic crural repair must be performed meticulously – there is often a common hiatus for the esophagus and aorta in these patients.36 There is no justiﬁcation for gastrectomy, gastroenterostomy or the colonic displacement operation described by Tanner9 in

(a)

(b)

Figure 41.6 Operative techniques in neonatal gastric volvulus. (a) Anterior Stamm gastrostomy using a Malecot catheter. (b) Anterior gastropexy

this age group. Adults with gastric volvulus have also fared well with relatively simple surgery.46 In older children with isolated gastric volvulus preliminary nasogastric decompression followed by a laparoscopic anterior gastropexy is an option.29 In gastric volvulus due to a wandering spleen, splenopexy alone may be sufﬁcient.47 The mortality from gastric volvulus is difﬁcult to assess and available ﬁgures are subject to publication bias. Deaths have been reported due to missed or delayed diagnosis, with subsequent gastric necrosis and perforation, or inadequate gastric ﬁxation.4,8,17,19,21,22 Most recent series have reported uncomplicated early outcomes after surgery. One long-term follow-up study of nine infants demonstrated no recurrences or late complications.4

REFERENCES 1. Berti A. Singalore attortigliamento dell’esofago col duodeno sequito da rapida morte. Gazz Med Ital Prov Veneti 1866; 9:139. 2. Idowu J, Aitken DR, Georgeson KE. Gastric volvulus in the newborn. Arch Surg 1980; 115:1046–9. 3. Chatterjee H, Jagdish S, Rao KS, Srivastava KK. Volvulus of stomach in childhood. Ind J Gastroenterol 1993; 12:102–4. 4. McIntyre RC, Bensard DD, Karrer FM, Hall RJ, Lilly JR. The pediatric diaphragm in acute gastric volvulus. J Am Coll Surg 1994; 178:234–8. 5. Camerton AEP, Howard ER. Gastric volvulus in childhood. J Pediatr Surg 1987; 22:944–7. 6. Youssef SA, Di Lorenzo M, Yazbeck S et al. Volvulus gastrique chez l’enfant. Chir Pediatr 1987; 28:39–42. 7. Honna T, Kamii Y, Tsuchida Y. Idiopathic gastric volvulus in infancy and childhood. J Pediatr Surg 1990; 25:707–10. 8. Miller DL, Pasquale MD, Seneca RP, Hodin E. Gastric volvulus in the pediatric population. Arch Surg 1991; 126:1146–9. 9. Tanner NC. Chronic and recurrent volvulus of the stomach. Am J Surg 1968; 115:505–15. 10. Eek S, Hagelsteen H. Torsion of the stomach as a cause of vomiting in infancy. Lancet 1958; i:26–8. 11. Alawadhi A, Chou S, Soucy P. Gastric volvulus: a late complication of gastrostomy. Can J Surg 1991; 34:485–6. 12. Fung KP, Rubin S, Scott RB. Gastric volvulus complicating Nissen fundoplication. J Pediatr Surg 1990; 25:1242–3. 13. Trinh TD, Benson JE. Fluoroscopic diagnosis of complications after Nissen fundoplication in children. AJR 1997; 169:1023–8. 14. Cameron BH, Vajarvandi V, Blair GK et al. The intermittent and variable features of gastric volvulus in childhood. Pediatr Surg Int 1995; 10:26–9. 15. Croaker GD, Najmaldin AS. Laparoscopically assisted percutaneous endoscopic gastrostomy. Pediatr Surg Int 1997; 12:130–1.

404 Gastric volvulus 16. McDevitt JB. Intrathoracic volvulus of the stomach in a newborn infant. Ir J Med Sci 1970; 3:131–2. 17. Cole BC, Dickinson SJ. Acute volvulus of the stomach in infants and children. Surgery 1971; 70:707–17. 18. Campbell JB. Neonatal gastric volvulus. Am J Roentgenol 1979; 132:723–5. 19. Talukdar BC. Gastric volvulus with perforation of stomach in congenital diaphragmatic hernia in an infant. J Indian Med Assoc 1979; 73:219–21. 20. Starshak RJ, Sty JR. Diaphragmatic defects with gastric volvulus in the neonate. Wisc Med J 1983; 82:28–31. 21. Ziprkowski MN, Teele RL. Gastric volvulus in childhood. Am J Roentgenol 1989; 132:921–5. 22. El-Gohary MA, Etiaby A. Gastric volvulus in infants and children. Pediatr Surg Int 1994; 9:486–8. 23. Dalgaard JR. Volvulus of the stomach. Acta Chir Scand 1952; 103:131–53. 24. Estevao-Costa J, Soares-Oliveira M, Correia-Pinto J et al. Acute gastric volvulus secondary to a Morgagni hernia. Pediatr Surg Int 2000; 16:107–8. 25. Moreno Torres E. Estenosis per hipertroﬁa de piloro con volvulo gastrico. Bol Soc Valenciana Paediatr 1968; 10:231–2. 26. Iko BO. Volvulus of the stomach: an African series and a review. J Natl Med Assoc 1987; 79:171–6. 27. Mizrahi S, Vinograd I, Schiller M. Neonatal gastric volvulus secondary to rectal atresia. Clin Pediatr 1988; 27:302–4. 28. Chuang JH, Hsieh CS, Hueng SC, Wan Y-L. Gastric volvulus complicating left hepatic lobectomy. Pediatr Surg Int 1993; 8:255–6. 29. Odaka A, Shimomura K, Fujioka M et al. Laparoscopic gastropexy for acute gastric volvulus: a case report. J Pediatr Surg 1999; 34:477–8. 30. Aoyama K, Teteishi K. Gastric volvulus in three children with asplenic syndrome. J Pediatr Surg 1986; 21:307–10. 31. Nakada K, Kawaguchi F, Wakisaka M et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 1997; 32:91–4. 32. Okoye BO, Bailey DMC, Cusick EL, Spicer RD. Prophylactic gastropexy in the asplenia syndrome. Pediatr Surg Int 1997; 12:28–9.

33. Garcia JA, Garcia-Fernandez M, Romance A, Sanchez JC. Wandering spleen and gastric volvulus. Pediatr Radiol 1994; 24:535–6. 34. Spector JM, Chappell J. Gastric volvulus associated with wandering spleen in a child. J Pediatr Surg 2000; 35:641–2. 35. Samuel M, Burge DM, Grifﬁths DM. Gastric volvulus and associated gastro-oesophageal reﬂux. Arch Dis Child 1995; 73:462–4. 36. Stiefel D, Willi UV, Sacher P, Schwobel MG, Stauffer UG. Pitfalls in therapy of upside-down stomach. Eur J Pediatr Surg 2000; 10:162–6. 37. Chan KL, Saing H. Iatrogenic gastric volvulus during transposition for esophageal atresia: diagnosis and treatment. J Pediatr Surg 1996; 31:229–32. 38. Borchardt M. Zur Pathologie und Therapie des Magen volvulus. Arch Klin Chir 1904; 74:243–60. 39. Beckmann KR, Nozicka CA. Congenital diaphragmatic hernia with gastric volvulus presenting as an acute tension gastrothorax. Am J Emerg Med 1999; 17:35–7. 40. Mutabagani KH, Teich S, Long FR. Primary intrathoracic gastric volvulus in a newborn. J Pediatr Surg 1999; 34:1869–71. 41. Yadav K, Myers NA. Paraesophageal hernia in the neonatal period – another differential diagnosis of oesophageal atresia. Pediatr Surg Int 1997; 12:420–1. 42. Scott RL, Felker R, Winer-Muram H et al. The differential retrocardiac air-ﬂuid level: a sign of intrathoracic gastric volvulus. J Can Assoc Radiol 1986; 37:119–21. 43. Asch MJ, Sherman NJ. Gastric volvulus in children: report of two cases. J Pediatr Surg 1977; 12:1059–62. 44. Stephenson RH, Hopkins WA. Volvulus of the stomach complicating eventration of the diaphragm. Am J Gastroenterol 1964; 41:225–7. 45. Colijn AW, Kneepkens CM, van Amerongen AT, Ekkelkamp S. Gastric volvulus after anterior gastropexy. J Pediatr Gastroenterol Nutr 1993; 17:105–7. 46. Wastell C, Ellis H. Volvulus of the stomach. A review with a report of 8 cases. Br J Surg 1971; 58:557–62. 47. Zivkovic SM. Sutureless ‘button and hole’ splenopexy. Pediatr Surg Int 1998; 13:220–2.

42 Gastric perforation ROBERT K. MINKES

BACKGROUND Gastric perforation in the neonatal period is a rare event, however it continues to be associated with signiﬁcant morbidity and mortality. Spontaneous neonatal gastric perforation is estimated to occur in 1 in 2900 live births1 and accounts for approximately 10–15% of all gastrointestinal perforations in neonates and children (Table 42.1). Gastrointestinal perforations occur more frequently in males, however there appears to be no sex predilection for those occurring in the stomach.2–4 The terminology used to describe neonatal gastric perforation has been inconsistent and its etiology a subject of ongoing debate. Spontaneous gastric perforations refer to those with no identiﬁable underlying cause and account for the majority of gastric perforations in most reported series.1, 3, 5–10 Many pediatric surgeons now believe that a contributing cause can be found in most instances and an underlying etiology should be sought in any neonate with a gastric perforation.11 Siebold, in 1826 provided the ﬁrst description of a gastrointestinal perforation with no demonstrable cause, the so-named spontaneous perforation.12 In 1929, Stern et al.13 reported one of the ﬁrst attempts at surgical repair. Agerty et al. reported the ﬁrst successful repair of a neonatal intestinal (ileum) perforation in 194314 and Leger, in 1950, described the ﬁrst successful repair of a neonatal gastric perforation.15 Survival following a gastric perforation in the 1950s was uncommon. While the overall mortality rate has steadily improved it remains signiﬁcant and ranges from 25% to over 50% in most recent

series.1,2,4,11,16,17 The survival rate in premature neonates remains poor despite advances in intensive care, ventilator management, and operative and anesthetic techniques.

ETIOLOGY Gastric perforation in neonates can be broadly categorized as spontaneous (idiopathic), ischemic, or traumatic, however in many instances the etiology is multifactorial. Box 42.1 lists several causes and associations with gastric perforation in the neonate. Spontaneous gastric perforations occur most commonly on the greater curvature and have no identiﬁable cause.1 Spontaneous perforation occurs in full-term, premature, or small for gestational age neonates. Some infants appear to have been healthy and medically stable prior to the development of the perforation, whereas others have underlying medical conditions. Spontaneous perforation may result from unrecognized overdistention or ischemic insult. Ischemic perforations occur in the setting of physiologic stress such as prematurity, asphyxia, sepsis, and necrotizing enterocolitis. These perforations are associated with ulceration and have surrounding necrosis and ischemic tissue. Traumatic perforation results from pneumatic distention during mask ventilation, positive-pressure ventilation, or iatrogenic injury during gastric intubation. Several speciﬁc underlying causes of neonatal gastric perforation have been reported including intestinal atresias, perinatal stress, trauma, and exposure to cortico-

Table 42.1 Incidence of gastrointestinal perforation Author

Year

Total

Grosfeld et al.17 Tan et al.8 Bell4 Borzitta and Groff39 St-Vil et al.40

1996 1989 1985 1988 1992

179 56 60 29 81

16 9 5 2 10 6 5 1 7 stomach–duodenum

405

43 (10%)

Total

Stomach

Duodenum

18 (5%)

Small bowel

Colon/rectum

Non-designated

105 26 30 12 38

37 23 10 11 32

12 4 (multiple) 6 (multiple) 4

211 (52%)

113 (28%)

(5%)

406 Gastric perforation Box 42.1 Causes and associations of neonatal gastric perforation Idiopathic Perinatal stress • Hypoxia • Asphyxia Prematurity3, 8 Anatomic defect • Distal obstruction – Pyloric atresia41 – Duodenal atresia3 – Midgut volvulus25 • Tracheo-esophageal ﬁstula20, 42-45 • Congenital deﬁciency of gastric muscle Iatrogenic • Nasogastric tube22 • Aggressive bag ventilation with or without tracheoesophageal ﬁstula19, 20 • Cardiopulmonary resuscitation30, 46 • Positive pressure ventilation • Inadvertent perforation during surgery (ventriculoperitoneal shunt)27, 47 • Vaginal delivery18 Medication • Indomethacin29, 48 • Corticosteroids28

steroids and nonsteroidal anti-inﬂammatory agents (Box 42.1). A variety of theories on the etiology of spontaneous perforations have been suggested but no single theory is universally accepted. The theories include congenital absence of gastric muscle,5,6 forces exerted during vaginal delivery,18 and pneumatic distention.19, 20 Studies in dogs and human neonatal cadavers suggest that rupture is caused by overdistention and is in keeping with the law of Laplace.7 With gastric distention the greatest wall tension is exerted on the fundus, the site of most spontaneous perforations. Gastric distention can also produce ischemic changes, a ﬁnding present in 41% of cases in one series.2 A recent theory suggests that idiopathic gastric perforations result from a deﬁciency of C-KIT+, a receptor tyrosine kinase crucial for normal development of mast cells.21 Mice lacking C-KIT+ mast cells develop spontaneous gastric ulceration or perforation. In addition, postmortem examination of neonates who died of spontaneous gastric perforation revealed a lower number of gastric C-KIT+ mast cells when compared with those who died from gastric perforation with an identiﬁable underlying causes such as intestinal atresia. The number of CKIT+ mast cells in neonates with idiopathic perforation was also lower than those found in control neonates who died of other causes with no gastric perforation.21

CLINICAL PRESENTATION The clinical presentation of gastric perforation is variable. The majority of cases present within the ﬁrst 5

days of life.4,8,22 The neonates are often premature or have a history of asphyxia or hypoxia.2,3,8,16 Neonates may present with feeding intolerance and emesis that may contain blood. Typically, the neonates develop an abrupt onset of rapidly progressive abdominal distention. These infants develop respiratory distress, hemodynamic instability and signs of shock such as hypothermia, cyanosis, poor peripheral perfusion, and low urine output. The abdomen rapidly becomes tense and tender with signs of peritoneal irritation. Subcutaneous emphysema may develop in the abdominal wall and several authors have reported pneumoscrotum as a presenting feature.23,24 Infants with posterior perforations into the lesser sac may present with a more insidious course, making the diagnosis difﬁcult. Infants with perforation secondary to an underlying process often have evidence of the predisposing condition such as ﬁndings of tracheo-esophageal ﬁstula, duodenal atresia, malrotation, or diaphragmatic hernia.3,20,25,26 In some instances, a secondary cause is found at the time of operation. In cases of iatrogenic perforation a history of traumatic nasogastric intubation, prior surgery, corticosteroid or nonsteroidal administration, and aggressive ventilation or cardiopulmonary resuscitation may be obtained.22,27–30

DIAGNOSIS The diagnosis of gastric perforation is made from the clinical history, physical examination, and radiographic studies. In infants with massive pneumoperitoneum, a plain abdominal radiograph will demonstrate air under the diaphragm that extends laterally, trapping the abdominal viscera medially and producing a saddlebag appearance.31 The stomach is not visualized by plain radiograph in 90% of cases.32 Other plain radiograph ﬁndings include subcutaneous emphysema, pneumoscrotum, ascites, or a nasogastric tube outside the conﬁnes of the stomach. Pneumatosis intestinalis and portal venous air are signs of necrotizing enterocolitis, which may coexist with gastric perforation. Calciﬁcation and dilated loops of bowel are common ﬁndings of more distal perforation and a gasless abdomen is seen in cases of neonatal volvulus. A deﬁnitive diagnosis may not be made prior to laparotomy. A water-soluble contrast study will reveal extravasation from the stomach into the peritoneal cavity (Fig. 42.1). In premature infants with known lung disease pneumoperitoneum can result from air tracking from the mediastinum. A chest ﬁlm demonstrating pneumomediastinum, an air–ﬂuid level in the stomach, a negative peritoneal aspirate, and an intraperitoneal drain that bubbles with the ventilator cycle can help to exclude an intra-abdominal process.

Surgical technique 407

abdominal air. Infants who develop respiratory distress require intubation and increased ventilator support is needed as the abdomen becomes more distended. Appropriate laboratory investigations include blood cultures, white blood cell count, hemoglobin, hematocrit, platelet count, electrolyte proﬁle, and blood gas analysis. Broad-spectrum antibiotics should be initiated. Fluid boluses and blood transfusions are given to achieve hemodynamic stability and adequate urine output. A nasogastric tube should be carefully passed and placed on low intermittent suction. Once free intra-abdominal air is identiﬁed, the patient is stabilized and a laparotomy should be performed. Aspiration of the peritoneum with an i.v. cannula when an overly distended abdomen is impeding ventilation can be a life-saving measure.2

SURGICAL TECHNIQUE

Figure 42.1 Diagnosis. Contrast study demonstrating gastric perforation. Abdominal distention, pneumoperitoneum, and contrast extravasation into the peritoneal cavity are seen. There is no evidence of lung disease and no ﬁndings suggestive of enterocolitis

DIFFERENTIAL DIAGNOSIS

An upper abdominal transverse skin incision (Fig. 42.2) is made and dissection carried through the rectus muscle until the peritoneum is entered. The umbilical vein is divided. Peritoneal ﬂuid and debris are evacuated and the wound opened sufﬁciently for adequate exposure. The site of perforation is usually not known and the abdomen should be thoroughly explored. When a perforation of the stomach is not found, careful exploration of the gastro-esophageal junction, duodenum, small bowel and colon should be performed. The lesser sac should be opened in all cases and the posterior wall of the stomach inspected. The most common site of a spontaneous perforation is near the greater curvature, often found high on the stomach. The perforation is usually linear, ranging from 0.5–8 cm in length and may extend around the greater curvature to the posterior wall of the stomach.22,33–36 Great

The differential diagnosis is broad and includes conditions that cause sudden deterioration in the newborn and conditions that produce vomiting and abdominal distention. Conditions causing cardiovascular collapse include sepsis, pneumothorax, cardiac dysfunction, intraventricular hemorrhage, electrolyte abnormalities, hypoglycemia, necrotizing enterocolitis, perforated viscus and malrotation with midgut volvulus. Conditions associated with vomiting and abdominal distention include Hirschsprung’s disease, intestinal atresia, meconium ileus, meconium plug syndrome, imperforate anus, perforated viscus, necrotizing enterocolitis and midgut volvulus.

PREOPERATIVE CARE Infants with gastric perforation develop septic parameters and need to be resuscitated accordingly. Neonates may become unstable prior to the development of free intra-

Figure 42.2 Incision. Upper abdominal transverse skin incision. The incision can be enlarged to gain access to the entire abdomen

408 Gastric perforation

care should be taken to ensure that the entire perforation is exposed. The devitalized edges of the perforation are debrided back to bleeding tissue (Fig. 42.3). The defect is closed in one or two layers and may be reinforced with an omental patch (Fig. 42.4). A variety of techniques have been used to deal with more extensive perforations or necrosis that requires subtotal or total gastrectomy. The treatment of choice for a subtotal gastrectomy is reconstruction with an esophagogastric anastomosis37. Several techniques for reconstruction after total gastrectomy have been reported including transverse colon interposition, Roux-en-Y esophago-jejunal anastomosis and Hunt– Lawrence pouch reconstruction.22,36,38 Reconstruction following total gastrectomy in an unstable neonate can be delayed and performed in stages. In the initial surgery the esophagus is closed and a feeding tube placed through the

distal gastric remnant. The esophagus is decompressed through a nasoesophageal tube and the child supported on parenteral nutrition until feedings can be initiated through the feeding tube. The ﬁnal stage of the reconstruction is performed several weeks later, when the clinical condition and nutritional status have improved.36 Following repair of the perforation the abdomen is lavaged with warm saline. Some surgeons advocate lavage with antibiotic solution. Peritoneal drainage is not needed for most primary repairs. The fascia is closed with absorbable sutures and a subcuticular stitch is used on the skin. Postoperatively, the child is maintained on broad-spectrum antibiotics, H2 antagonists, and total parenteral nutrition. The stomach should be decompressed and feedings held until a contrast study conﬁrms the integrity of the stomach. If the child is stable the study may be performed 1 week after surgery.

REFERENCES

Figure 42.3 Exposure and resection. The entire perforation is exposed. A variable area of the stomach is found to be devitalized or necrotic. The edges of the perforation are resected back to bleeding viable tissue. On rare occasions, extensive resection, subtotal, or total gastrectomy are required

Figure 42.4 Closure. The free edges of healthy tissue are closed in one (depicted) or two layers. An omental patch may be used. Careful inspection of the posterior wall of the stomach and the entire small and large bowel should be performed to exclude additional areas of necrosis

1. Rosser S B, Clark CH, Elechi EN. Spontaneous neonatal gastric perforation. J Pediatr Surg 1982; 17:390. 2. Touloukian RJ. Gastric ischemia: the primary factor in neonatal perforation. Clin Pediatr 1973; 12:219. 3. Holgersen LO. The etiology of spontaneous gastric perforation of the newborn: a reevaluation. J Pediatr Surg 1981; 16:608. 4. Bell MJ. Perforation of the gastrointestinal tract and peritonitis in the neonate. Surg Gynecol Obstet 1985; 160:20. 5. Herbut P. Congenital defect in the musculature of the stomach with rupture in a newborn infant. Arch Pathol 1943; 36:191. 6. Braunstein H. Congenital defect of the gastric musculature with spontaneous perforation. J Pediatr 1954; 44, 55. 7. Shaw A, Blanc A, Santulli TV et al. Spontaneous rupture of the stomach in the newborn: A clinical and experimental study. Surgery 1965; 58:561. 8. Tan CE, Kiely EM, Agrawal M et al. Neonatal gastrointestinal perforation. J Pediatr Surg 1989; 24:888. 9. Young AE, Sury MR. Spontaneous neonatal gastric perforation. Paediatr Anaesth 1996; 6:143. 10. Chung MT, Kuo CY, Wang JW et al. Gastric perforation in the neonate: clinical analysis of 12 cases. Acta Paediatr Sin 1994; 35:565. 11. Leone RJ, Krasna IH. Spontaneous neonatal gastric perforation: Is it really spontaneous. J Pediatr Surg 2000; 35:1066. 12. Siebold AE. Brand in der kleinen kurvatier des magens eines atrophischen kindes. J Geburtsch Frauenzimmer Kinderk 1826; 5:3. 13. Stern MA, Perkins EL, Nessa NJ. Perforated gastric ulcer in a 2-day-old infant. Lancet 1929; 49:492.

References 409 14. Agerty HA, Ziserman AJ, Schollenberger CL. A case of perforation of the ileum in a newborn infant with operation and recovery. J Pediatr 1943; 22:223. 15. Leger JL, Ricard PM, Leonard C et al. Ulcere gastrique perfore chez un nouves-ne avec servie. Union Med Can 1950; 79:1277. 16. Zamir O, Hadary A, Goldberg M et al. Spontaneous perforation of the stomach in the neonate. Z Kinderchir 1987; 42:43. 17. Grosfeld JL, Molinari F, Chaet M et al. Gastrointestinal perforation and peritonitis in infants and children: experience with 179 cases over ten years. Surgery 1996; 120:650. 18. Silbergleit A, Berkas EM. Neonatal gastric rupture. J Minn Med 1966; 49:65. 19. Waltsad PM, Conklin WS. Rupture of the normal stomach after oxygen administration. N Engl J Med 1961; 264:1201. 20. Othersen HH, Gregorie HB. Pneumatic rupture of the stomach in an infant with esophageal atresia and tracheoesophageal ﬁstula. Surgery 1963; 53:362. 21. Yamataka A, Yamataka T, Kobayashi H et al. Lack of C-KIT+ mast cells and the development of idiopathic gastric perforation in neonates. J Pediatr Surg 1999; 34:34. 22. Graivier L, Rundell K, McWilliams N et al. Neonatal gastric perforation and necrosis: ninety-ﬁve percent gastrectomy and colonic interposition, with survival. Ann Surg 1973; 177:428. 23. Garcia C, Markowitz RI. Pneumoperitoneum and pneumoscrotum caused by gastric perforation. Am J Perinatol 1987; 4:75. 24. Aslan Y, Sarihan H, Dinc H et al. Gastric perforation presenting as bilateral scrotal pneumatoceles. Turkish J Pediatr 1999; 41:267. 25. Miller FA. Neonatal gastrointestinal tract perforation. Lancet 1957; 77:439. 26. Katz SM, Holgersen LO, Bishop HC. Eventration of the diaphragm with gastric perforation. J Pediatr Surg 1974; 9:411. 27. Christoph CL, Poole CA, Kochan PS. Operative gastric perforation: a rare complication of ventriculoperitoneal shunt. Pediatr Radiol 1995; 25:S173. 28. O’Neil EA, Chwals WJ, O’Shea MD et al. Dexamethasone treatment during ventilator dependency: possible life threatening gastrointestinal complications. Arch Dis Child 1992; 67:10. 29. Gray PH, Pemberton PJ. Gastric perforation associated with indomethacin therapy in a pre-term infant. Aust Paediatr J 1980; 16:65. 30. Custer JR, Polley TZ Jr, Moler F. Gastric perforation following cardiopulmonary resuscitation in a child:

31.

32. 33. 34. 35.

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38. 39. 40.

41.

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43.

44.

45.

46.

47.

48.

report of a case and review of the literature. Pediatr Emerg Care 1987; 3:24. Houck WS Jr, Grifﬁn JAD. Spontaneous linear tears of the stomach in the newborn infant. Ann Surg 1981; 193:763. Pochaczevsky R, Bryk D. New roentgenographic signs of neonatal gastric perforation. Radiology 1972; 102:145. Gathwala G, Rattan KN, Abrol P et al. Spontaneous gastric perforation in a neonate. Indian Pediatr 1994; 31:1013. Sharma A, Rattan KN, Nanda S et al. Spontaneous gastric perforation in neonates. Indian J Pediatr 1993; 60:822. Shashikumar VL, Bassuk A, Pilling GI et al. Spontaneous gastric rupture in the newborn: a clinical review of nineteen cases. Ann Surg 1975; 182:22. Durham MM, Ricketts RR. Neonatal gastric perforation and necrosis with Hunt-Lawrence pouch reconstruction. J Pediatr Surg 1999; 34:649. Bilik R, Freud N, Sheinfeld T et al. Subtotal gastrectomy in infancy for perforating necrotizing gastritis. J Pediatr Surg 1990; 25:1244. Quak SH, Joseph VT, Wong HB. Neonatal total gastrectomy. Clin Pediatr (Phila) 1984; 23:507. Borzotta AP, Groff DB. Gastrointestinal perforation in infants. Am J Surg 1988; 155:447. St-Vil D, LeBouthillier G, Luks FI et al. Neonatal gastrointestinal perforations. J Pediatr Surg 1992; 27:1340. Burnett HA, Halpert B. Perforation of stomach of newborn infant with pyloric atresia. Arch Pathol 1947; 44:318. Reyes HM, Meller JL, Loeff D. Management of esophageal atresia and tracheoesophageal ﬁstula. Clin Perinatol 1989; 16:79. Bloom BT, Delmore P, Park YI et al. Respiratory distress syndrome and tracheoesophageal ﬁstula: management with high-frequency ventilation. Crit Care Med 1990; 18:447. Holcomb GWD. Survival after gastrointestinal perforation from esophageal atresia and tracheoesophageal ﬁstula. J Pediatr Surg 1993; 28:1532. Maoate K, Myers NA, Beasley SW. Gastric perforation in infants with oesophageal atresia and distal tracheooesophageal ﬁstula. Pediatr Surg Int 1999; 15:24. Bush CM, Jones JS, Cohle SD et al. Pediatric injuries from cardiopulmonary resuscitation. Ann Emerg Med 1996; 28:40. Alonso-Vanegas M, Alvarez JL, Delgado L et al. Gastric perforation due to ventriculo-peritoneal shunt. Pediatr Neurosurg 1994; 21:192. Rajadurai VS, Yu VY. Intravenous indomethacin therapy in preterm neonates with patent ductus arteriosus. J Paediatr Child Health 1991; 27:370.

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43 Gastrostomy MICHAEL W. L. GAUDERER

INTRODUCTION Gastrostomy, one of the oldest abdominal operations in continuous use,1 has played an important role in the management of various surgical conditions of the neonate.1–6 The procedure was frequently employed for feeding as well as decompression. Additionally, a combination of gastric drainage with post-pyloric feeding via a jejunal tube was most helpful in the pre-parenteral nutrition era. In the past 3 decades, however, improvement in surgical techniques and postoperative care has led to a more selective use of gastrostomies in patients with major congenital anomalies of the gastrointestinal tract and abdominal wall. On the other hand, there has been an increased utilization of gastrostomies in infants and children without surgical pathology. In most of these, the indication is an inability to swallow, usually secondary to central nervous system impairment. Ironically, often these are patients who have survived because of aggressive neonatal resuscitation and technological advances.

Figure 43.1 A 3-month-old child whose urinary tract obstruction, secondary to posterior urethral valves, was diagnosed in utero. A shunt was placed antenatally, but did not adequately decompress the urinary tract. End-stage renal failure required the placement of a peritoneal dialysis catheter on the third day of life. Because long-term administration of supplemental feedings, special diets and medications was anticipated, a Stamm gastrostomy was added at the same intervention. The initially placed long 16 Fr. catheter was converted to a skin-level device using the externally placed, changeable port-valve30 7 days after the procedure, without changing the original tube

INDICATIONS In infants, the three main indications are long-term feeding,1–9 decompression,1–3,5–8,10 or a combination of both modalities.1–3,5–7,11 Additional indications include gastric access for esophageal bougienage,1,12 and administration of medications1,8,9 (Fig. 43.1).

naso-oto-pharyngeal infections and gastro-esophageal reﬂux tend to increase. Gastrostomies should be considered when direct gastric access for feeding or the administration of medication is expected to last more than several months.

Nasogastric feeding tube vs gastrostomy Because the newer 5F and 8F infant feeding tubes are highly biocompatible and remain smooth and soft for prolonged periods of time, they are usually welltolerated, even by the smallest premature infants. In general, feeding tubes should be preferred if the expected length of enteral access is up to 1–2 months. Beyond this arbitrary time frame, complications such as

Nasogastric decompressing tube vs gastrostomy With careful attention to appropriate intragastric position and regular ﬂushing, naso- or orogastric tubes generally decompress more effectively than do gastrostomy tubes. The newer 8 or 10F tubes are well tolerated for up to several weeks. The author’s preference when performing

412 Gastrostomy

gastric decompression lasting from 3–4 weeks in newborns is a 15–20-inch- (38–51 cm)-long, 8F single-lumen tube with 4–6 side holes close to the catheter tip. It should be remembered that most commercially available 8F tubes are designed for feeding and have only two holes. Additional holes of appropriate size must therefore be added. These 8F tubes should be attached directly or via a short connecting tube to a spill-resistant open container and irrigated regularly. No suction should be applied to single lumen tubes. Double-lumen catheters, such as the 10F Replogle tube, designed for the aspiration of saliva in patients with esophageal atresia, tend to be much stiffer and are therefore more likely to cause problems.

GASTROSTOMY IN SELECT NEONATAL SURGICAL PATHOLOGY Esophageal abnormalities Once considered essential in the management of patients with esophageal atresia, gastrostomies are no longer employed routinely. The analysis of large series demonstrates that esophago-esophagostomy without the use of a gastrostomy is safe12–13 and may in fact be beneﬁcial by decreasing the incidence of gastro-esophageal reﬂux.14 A gastrostomy is indicated in esophageal atresia without ﬁstula, when a difﬁcult repair or a stormy course is anticipated, in staging procedures, and when the child has associated anomalies that may interfere with feeding. The stoma, employed for the decompression or feeding, can also be used to provide access for the management of anastomotic complications such as leakage or strictures.15

Duodenal obstruction Congenital duodenal obstruction is usually associated with proximal duodenal dilatation and atony as well as gastric dilatation. Prolonged gastric decompression may therefore be required after bowel continuity is reestablished. Total parenteral nutrition and nasogastric decompression are generally effective in postoperative management. On the other hand, a valuable alternative in this setting is the placement of a ﬁne silicone rubber catheter alongside the gastrostomy catheter, across the anastomosis and into the proximal jejunum1,11 (Fig. 43.2). Although these tubes are at times difﬁcult to place and maintain, this simple and time-honored technique can decrease or eliminate the need for parenteral nutrition.

Major abdominal wall defects Prolonged ileus typically follows the repair of gastroschisis. It may also occur after correction of other major

Figure 43.2 Combination gastric decompression and intrajejunal feeding, demonstrated diagrammatically in a newborn with repaired duodenal atresia

wall defects. Although decompressive gastrostomies are not routinely employed, they can be particularly helpful among patients with gastroschisis and associated atresia and those requiring long-term continuous feeding.

Short-gut syndrome Infants who have lost over 50% of their small bowel have profound alteration of gastrointestinal physiology. Initial gastric hypersecretion may require prolonged drainage. As the remaining intestine undergoes adaptive changes, continuous enteral feedings become necessary. As this latter process can be fairly lengthy, direct gastric access via gastrostomy is desirable.

Other surgical pathology In any neonatal or infant condition in which a prolonged ileus or partial luminal occlusion (e.g. recurrent adhesive bowel obstruction, complicated meconium ileus, small bowel Hirschsprung’s disease) is anticipated or in whom a complex feeding regimen is likely (e.g. those with intestinal lymphangiectasia), a gastrostomy can facilitate management.

‘Non-surgical’ pathology The number of pediatric patients with an inability to swallow referred to the surgeon for the placement of a gastrostomy continues to increase.1,8,9,16 The main indications in infants are an inability to swallow secondary to central nervous system lesions as well as other abnormalities of deglutition, feeding supplementation, and

Stamm gastrostomy 413

chronic malabsorption syndromes. Because the neurologically impaired children frequently have foregut dysmotility and gastro-esophageal reﬂux in addition to swallowing difﬁculties, anti-reﬂux procedures are often added to gastrostomies. The question of whether to use gastrostomy only or gastrostomy plus an anti-reﬂux procedure continues to be a subject of considerable debate.16

ADVANTAGES AND DISADVANTAGES OF GASTROSTOMIES Direct access to the stomach provides the surgeon with valuable perioperative access for drainage of air or ﬂuids, a reliable long-term source for intermittent or continuous administration of nutrients, or a combination of both. As stated, nasogastric tubes tend to drain better than gastrostomies in the immediate postoperative period. However, a gastrostomy can eliminate the need for long-term naso- or orogastric intubation and the complications associated with placement and maintenance of these tubes. Gastrostomies interfere less with oral feedings than do nasogastric tubes, although the newer, smaller catheters are better tolerated. Gastrostomies are preferred over jejunostomies because the latter are less physiological and more prone to mechanical complications.1 The disadvantages of gastrostomies in the neonatal period include the need for an operative intervention with or without celiotomy; the fact that the procedure is not always simple, particularly if the child has associated anomalies; and the fact that gastrostomy placement may interfere with gastric emptying and increase the incidence of gastro-esophageal reﬂux.1,14 It has also been recognized that both nasogastric tubes and gastrostomies may promote gastric colonization with bacteria.17 Gastrostomies, as well as any other enteral tubes placed in infants, are associated with a long list of potential early and late complications.1–9

wall ﬂap, the best known methods are Depage, BeckJianu, Hirsch and Janeway.1,19 3 Percutaneous techniques i.e. without celiotomy, in which the introduced catheter holds the gastric and abdominal walls in apposition.1,18–20 The addition of laparoscopy, which can be employed with each one of these methods, has further expanded the choices of gastric access techniques available to surgeons managing infants. The Stamm technique, illustrated here, is the most widely applied gastrostomy with celiotomy in the neonatal period, either as a single intervention or when employed in conjunction with another intra-abdominal procedure (Fig. 43.1). It can be used in children of any size and even on the smallest stomach (e.g. in patients with esophageal atresia without ﬁstula). It can be performed under local anesthesia, although general anesthesia is generally preferred because abdominal wall relaxation is required. The procedure is usually short. After the tract is well healed, it allows for the passage of dilators. The construction of a gastric wall tube can be difﬁcult in very young children. The technique is more time consuming, is not suited for the passage of dilators, is more prone to leak and interferes with reoperations on the stomach, because part of the gastric wall has been used. Percutaneous endoscopic gastrostomy (PEG) was initially developed for high-risk pediatric patients to allow precise tube placement with endoscopic assistance, without celiotomy. The diagrams represented here follow the initial description of the procedure.20 This procedure has been used in neonates weighing as little as 2.5 kg, usually for long-term enteral feeding.8 Although there is no need for abdominal wall relaxation, general endotracheal anesthesia is employed in this age group to protect the airway during endoscopy. The procedure time is very short and there is no postoperative ileus, no potential for bleeding or wound disruption and no interference with subsequent interventions on the stomach. The likelihood of an infection is very small and similar to that of the Stamm procedure. PEG is generally not suited for the passage of dilators.

TECHNIQUE STAMM GASTROSTOMY The three basic methods of constructing a gastrostomy are the following: 1 Formation of a serosa-lined channel from the anterior gastric wall around a catheter. This catheter is placed in the stomach and exits parallel to the serosa as in the Witzel technique, or vertically as in the Stamm or Kader methods.1,18,19 2 Formation of a tube from a full-thickness gastric wall ﬂap, leading to the skin surface. A catheter is then introduced intermittently for feeding. Depending upon the conﬁguration of the gastric

The child is placed on the table with a small roll behind the back. When possible, a nasogastric tube is inserted for decompression and to help identify the stomach, if necessary. A small transverse incision is made over the left upper rectus abdominis muscle (Fig. 43.3). This incision should be neither too high, because it would bring the catheter too close to the costal margin, nor too low, avoiding the colon and the small bowel. A short vertical incision is a commonly used alternative. However, this approach is less desirable because the linea

414 Gastrostomy

close to the greater curvature, to avoid the so-called gastric pacemaker and to minimize the potential for gastrocolic ﬁstula.1 A child with an esophageal abnormality may eventually need the greater curvature for construction of a gastric tube, and thus this must be avoided. The anterior gastric wall is lifted with two guy sutures (4-0 silk) at the site of the stoma, ensuring that the posterior wall is not included (Figs 43.4–7). One or two concentric pursestring sutures (4-0 synthetic, absorbable material) are placed (Figs 43.4–6). The gastrotomy, at the center of the inner pursestring, is made sharply through the serosa and muscular wall of the stomach (Fig. 43.6). Hemostasis is obtained with ﬁne hemostats and ligatures or precise electrosurgical coagulation of vessels. Caution should be exercised when using the cautery that the Figure 43.3 Gastrostomy incision and catheter exit site. An alternative is a short vertical midline incision as seen in Figure 43.1

alba is the thinnest area of the abdominal wall. Bleeders are simply clamped. Fascial layers are incised transversely and the rectus muscle retracted or transected. When identiﬁcation of the stomach is not immediate, downward traction of the ﬂimsy greater omentum readily allows visualization of the transverse colon and stomach. The site of gastrotomy placement on the anterior gastric wall is critical in infants. A position midway between the pylorus and esophagus is chosen (Fig. 43.4). The site should be neither too high, because this would interfere with a fundoplication should one be needed in the future, nor too low, because stomas at the level of the antrum are prone to leakage and pyloric obstruction by the catheter. The surgeon must not place the catheter too

Figure 43.4 Gastrotomy site on the anterior gastric wall. The traction guy sutures and the ﬁrst pursestring suture are depicted

Figure 43.5 An optional second pursestring suture has been placed. In small children this is not necessary. The lower guy suture pulls the stomach caudally, enhancing the exposure and allowing better gastric access

Figure 43.6 The gastrotomy. The guy sutures elevate the anterior gastric wall

Stamm gastrostomy 415

Figure 43.7 Introduction of a de Pezzer catheter using a simple stylet

anterior gastric wall must be lifted to avoid injury to the posterior wall. The gastrotomy is completed by opening the mucosa. A small hemostat is introduced to conﬁrm access into the gastric lumen. We prefer a mushroom-type catheter (de Pezzer), sizes 12–14 Fr. gauge, for neonates. The mushroom head of the catheter is stretched with a short stylet to allow atraumatic introduction into the stomach (Fig. 43.7). The pursestring(s) are tied sequentially to invert the seromuscular gastric wall around the tube (Fig. 43.8). Other suitable catheters are the Malecot or the ‘T tube’, but both have the disadvantage of becoming more

Figure 43.8 The pursestring sutures are tied. The continuous monoﬁlament suture, used to anchor the stomach to the anterior abdominal wall, has been partially placed. The catheter is brought out through the counter-incision

easily dislodged. However, a short ‘T tube’ is useful if the stomach is very small. It is also our preferred tube for infant jejunostomies. We avoid the Foley or balloon-type catheters because the main lumen is proportionately smaller and the balloon occupies more intragastric space. Balloon-type catheters, which may rupture, also have a greater propensity for distal migration into the small bowel. Skin-level devices (buttons or balloon type) may be inserted during the operation, instead of the traditional long tubes.19 The exit site for the catheter should be through the mid-portion of the rectus muscle, about 1 cm above or below the celiotomy incision (Figs 43.3 & 43.8–10). Although some surgeons bring the catheter out by way of the primary abdominal incision, wound complications that may occur in this setting tend to be more complex.1 Once the exit site is chosen, the anterior gastric wall is secured to the posterior aspect of the anterior abdominal wall with four equidistant sutures or, as illustrated, with a continuous suture of doubleended 4-0 synthetic monoﬁlament thread21 (Figs 43.8 & 43.9). This suture may be used as a substitute for the second pursestring suture, particularly in smaller infants. The catheter position is tested by injecting and aspirating saline. Gentle traction on the catheter assures that its intragastric position is maintained. The posterior rectus sheath is closed with a running suture of 4-0 absorbable, synthetic material. The anterior rectus sheath is approximated with interrupted sutures of the same material. The subcutaneous layer is closed with a couple of 5-0 or 6-0 synthetic, absorbable sutures. The skin can be approximated with either interrupted or continuous 5-0 or 6-0 subcuticular sutures of the same material. Adhesive strips cover the incision (Fig. 43.10). The catheter is ﬁrmly secured with two sutures of 3-0 or 4-0 synthetic monoﬁlament thread. These sutures are removed after 1 week and a small cross-bar is placed loosely to prevent distal catheter migration. Alternatively, the catheter may be converted to a skin-level device by using the external port-valve system (Fig. 43.1). Occlusive dressings are not used after the ﬁrst couple of postoperative days.

Figure 43.9 The continuous monoﬁlament suture placement is completed and the suture is tied

416 Gastrostomy

Figure 43.10 Completed procedure. The subcuticular closure, adhesive strips and secured gastrostomy catheter are depicted. The immobilizing sutures are removed after several days and a small cross-bar is placed to prevent distal catheter migration. The long tube can be converted to a skin-level device any time after the operation using an external port-valve.30 Another alternative is the placement of a ‘button’ or balloon-type skinlevel device, instead of a long tube, at the initial procedure19

Figure 43.11 Percutaneous endoscopic gastrostomy. The endoscope insufﬂates the stomach with air, approximating it to the anterior abdominal wall and displacing the colon caudally. The cannula is inserted through abdominal and gastric walls under direct vision by the endoscopist. The inset shows the gastrostomy site

Percutaneous endoscopic gastrostomy The PEG technique, as initially described,20,22 is applicable to neonates and small infants.8,9 The procedure must, however, be done with great precision and endoscopic skill. PEG incorporates four basic elements: 1 Gastroscopic insufﬂation brings the stomach into apposition to the anterior abdominal wall (Fig. 43.11). 2 With the stomach apposed to the abdominal wall, a tapered cannula is introduced percutaneously into the gastric lumen under direct endoscopic guidance (Fig. 43.11). 3 This cannula serves as access to introduce a suture, which is then withdrawn out of the patient’s mouth with the gastroscope (Fig. 43.12). A loop or tract is thus established. 4 A PEG catheter with a tapered end is attached to the oral end of the suture and pulled in a retrograde fashion until it assumes its ﬁnal position, keeping the stomach ﬁrmly apposed to the abdominal wall (Fig. 43.13). Although there are multiple variations of the original PEG technique1,18,23 and a variety of catheters, one must be cautious, because most of these are not suitable for use in infants. We employ a 16 Fr. gauge (or smaller) commercially available silicone rubber pediatric PEG catheter.8,22 Larger or stiffer catheters can easily tear the infant’s esophagus.

Figure 43.12 Inset: A guide wire is introduced through the cannula and grasped by the endoscopist’s snare. The guide wire is then pulled in a retrograde fashion, exiting through the mouth

Figure 43.13 The PEG catheter is attached to the oral portion of the string and pulled in a retrograde fashion through the child’s esophagus and stomach and across gastric and abdominal walls. The inset shows the position of the catheter at completion of the procedure

Complications of gastrostomies 417

A single dose of an i.v. broad-spectrum antibiotic is administered at the outset. The child remains in the supine position throughout the procedure. The abdomen is cleansed and sterilely draped. Gastroscopy is performed with the smallest pediatric gastroscope available. The scope is inserted and advanced slowly into the stomach, at which point the light is seen through the left upper quadrant abdominal wall. With the gastroscope in place, insufﬂation distends the stomach, apposes it against the anterior abdominal wall, and displaces the colon downward (Fig. 43.11). When the room lights are dimmed, the gastric contour is clearly visible, particularly in small children. The preferred gastrostomy site is over the mid-portion of the left rectus muscle, as depicted in the inset of Figure 43.11. Digital pressure is exerted at this site, and this is seen by the endoscopist as a ‘polypoid lesion’ or ‘mound’ on the anterior gastric wall. (Gastric transillumination and endoscopically visualized digital indentation of the stomach are the most important factors in safe PEG placement.) The endoscopist then places an endoscopic polypectomy snare around this invagination of the anterior gastric wall. Digital pressure is released and a 0.5–1 cm skin incision made. A hemostat with slightly opened prongs is placed in the incision, recreating and maintaining the intragastric ‘mound’. Through this incision and through the prongs of the hemostat, a 16gauge, smoothly tapered, i.v. cannula and needle are thrust through abdominal and gastric walls under endoscopic visualization. This should be performed quickly to avoid displacing the stomach from the abdominal wall. The snare, if properly positioned initially, will be around the advancing cannula. If not, it can be maneuvered to encircle the cannula. A long, monoﬁlament synthetic suture or a plastic-covered steel guide wire is then advanced through the cannula and grasped by the snare (Fig. 43.12, inset). If there is difﬁculty with the snare, biopsy forceps may be used. As the gastroscope and snare are withdrawn, the suture is brought out of the patient’s mouth (Fig. 43.12). The previously selected PEG catheter is then connected to the suture outside the patient’s mouth and both suture and catheter are coated with a water-soluble lubricant. Traction on the abdominal portion of the suture or guide wire pulls the catheter in a retrograde fashion, through the mouth, esophagus, and stomach, and across the abdominal wall (Fig. 43.13). The gastroscope is reintroduced to verify the catheter position under direct vision. While re-endoscopy might theoretically be unnecessary, we believe it adds safety to the procedure. Traction on the catheter is continued until the inner catheter retainer or ‘dome’ loosely touches the gastric mucosa. Markings on the commercially available catheters, or markings added to tubes without marks, are helpful in indicating the ﬁnal position of the tube. The external cross-bar is then placed (Fig. 43.13). Although we no longer routinely employ immobilizing sutures,

these may add safety in the overactive child. Excessive pressure by the external cross-bar on the abdominal wall will produce pressure necrosis and eventual catheter extrusion, and should be avoided. The tapered catheter end is cut off and a connector attached. Tape is used for temporary catheter immobilization. Although the tube can be used immediately, we have arbitrarily placed it to gravity drainage for the ﬁrst 24 hours and instituted tube feedings the day after the procedure. The catheter may be converted to a skin-level device by using the external port valve at any time (Fig. 43.1). To replace the PEG catheter with a ‘button’ or balloon-type skin level device, we ﬁnd it is prudent to wait until ﬁrm adhesions between the stomach and abdominal wall are established. This may take 2–3 months or longer.

Laparoscopically aided gastrostomies The Stamm procedure can be modiﬁed for laparoscopic tube placement; however, the small abdominal cavity and the usually air-ﬁlled bowel loops of neonates may limit the applicability of this approach. Nevertheless, gastrostomies can be performed in infants, either as a sole procedure or as an addition to the other intracavitary procedures such as a fundoplication.24 The Janeway-type gastrostomy has also been constructed laparoscopically. However, at this time, the staples are far too big for neonatal use. A distinct advantage of laparoscopy is that it can be effectively combined with percutaneous techniques in children with abnormal upper abdominal anatomy to enhance safety.

COMPLICATIONS OF GASTROSTOMIES Although frequently considered a ‘simple’ procedure and often delegated to a junior member of the surgical team, a gastrostomy has a considerable potential for early and late morbidity, particularly among neonates.

Complications related to operative technique SEPARATION OF STOMACH FROM ABDOMINAL WALL This serious mishap most commonly occurs after early gastrostomy tube reinsertion, before a ﬁrm adhesion between gastric and abdominal walls has occurred. During the attempt to replace a dislodged catheter, the stomach is pushed away from the abdominal wall; that displacement leads to a partial or complete separation of the stoma. If recognition of the problem is delayed, severe peritonitis and death may result.1,3,5,6 To avoid this and other mechanical problems, the stomach must be ﬁrmly anchored to the anterior abdominal wall and the catheter

418 Gastrostomy

well secured to the skin, particularly with the open, Stamm-type techniques. In the event of early removal or dislodgment of the tube, the tract can be gently probed and a thin Foley catheter inserted. This must be followed by injection of a radio-opaque contrast material under ﬂuoroscopy to assure an intragastric position of the tube and absence of intraperitoneal leakage. If there is any question about the position of the catheter, prompt exploration is necessary. Although there are no sutures in the PEG technique, spontaneous gastric separation is rare. In the author’s experience, it has occurred in only one of more than 700 pediatric patients who underwent a PEG procedure. This occurred in an infant with severe cyanotic congenital heart disease.

WOUND SEPARATION, DEHISCENCE AND VENTRAL HERNIA These complications are usually the result of technical problems and carry high morbidity and mortality rates.1,3,5,6 Leakage from an enlarged incision can be life threatening.3 Such mishaps can be minimized by the use of appropriate, small incisions and by bringing the tube out through a counter-incision. These complications will not occur after a PEG procedure because there is no celiotomy.

HEMORRHAGE Major bleeding is described in pediatric series4,6 and usually is related to inadequate hemostasis at the time of catheter insertion. Gentle traction on the catheter usually controls the bleeding, but reoperation may become necessary. Hemorrhage has not been reported after PEG placement in children.

INFECTION This complication can occur with any type of gastrostomy.1,3–5 Although usually limited to the skin and subcutaneous tissue, it can lead to full-thickness abdominal wall loss. Infection can also follow PEG placement 8 but is usually avoidable through the use of prophylactic antibiotic administration and a skin incision only slightly larger than the diameter of the tube.

stomach, particularly in patients with intra-abdominal adhesions in whom mobility of intestinal loops is limited.

GASTRO-COLIC FISTULA This complication can occur with any gastrostomy but is more likely with percutaneous techniques. Six gastro-colic ﬁstulas were encountered in the current author’s series of more than 700 pediatric PEG placements. Of these, two were in children under the age of 1 year. Although in retrospect at least four of the six were preventable by closely following the PEG guidelines, injury to the colon is a possible hazard that must be kept in mind when one performs this type of procedure. The importance of gastric insufﬂation with downward colonic displacement, transillumination and digital pressure on the anterior abdominal wall cannot be overemphasized. On the other hand, overinﬂation must be avoided because air-ﬁlled small bowel will displace the colon cranially and move it between the stomach and the abdominal wall.

OTHER PROBLEMS Problems related to improper catheter placement were discussed in the section on technique. A variety of additional complications related to the operation include1 prolonged ileus, gastric atony, failure of the gastrostomy to decompress or permit feedings, gastric torsion around the catheter, adhesive bowel obstruction, complete prolapse of the stomach through the gastrostomy, pulled-out sutures with gastric perforation etc. We have observed a couple of instances in which the PEG catheter has traversed the edge of the liver. However, no adverse effects were observed. If the PEG technique is employed in small children, care must be taken to shorten the inner cross-bar in such a manner that possible damage to the esophagus is avoided. Pneumoperitoneum after PEG placement is not infrequent, but fortunately it is without side effects.9,22

Complications related to care of stoma SKIN IRRITATION AND MONILIASIS

The posterior gastric wall can be damaged or perforated not only during the initial procedure, but also later during catheter change.1 To avoid this mishap, the author currently uses guy sutures that help separate the gastric walls. Once the tube is introduced, air or saline should be injected to test the tube’s position and function.

Next to granulation tissue, these are the most frequent problems encountered. Usually related to leakage, and compounded by occlusive dressings, irritation is best prevented by avoiding any occlusive devices, including nipples, tape or gauze pads.1 The site should be kept open and dry at all times. Ointments and other solutions, except for the treatment of moniliasis, should be avoided. The catheters are kept long, as opposed to being shortened, as with a skin-level device. Catheters, if kept long, can be immobilized with a small external cross-bar.

INJURY TO OTHER ORGANS

TUBE PLUGGING

During open procedures, damage to the liver and spleen can occur through the improper use of retractors or other instruments. The distended colon may be mistaken for the

Catheters must be ﬂushed with water after each feeding. Balloon-type catheters, with a proportionately smaller lumen, are more prone to blockage.

INJURY TO THE POSTERIOR WALL OF STOMACH

Complications of gastrostomies 419

ADMINISTRATION OF IMPROPER FEEDINGS

INTERNAL MIGRATION

Careful and slow administration of the appropriate nutrient prevents metabolic abnormalities as well as diarrhea and excessive reﬂux.

Migration of a long catheter producing high intestinal obstruction is a well-known problem.1,3,5 It can occur with any gastric tube but is particularly common with balloon-type catheters.

DELAY IN THE REINTRODUCTION OF A DISLODGED CATHETER Accidental dislodgment of long gastrostomy catheters is fairly common. The catheter must be replaced before the tract closes, which can be in a few hours unless it is well matured and epithelium lined.

TRAUMA DURING REINSERTION OF CATHETER Improper catheter reintroduction can lead to damage to the pancreas, liver or spleen, particularly if long stylets or other traumatic instruments are used to elongate a mushroom-type tip. Small children are more prone to this complication, given the short distance of these organs from the abdominal wall. Gentle insertion using the device depicted in Figure 43.7 and aiming toward the gastric cardia or fundus is the method least likely to produce injury.

Complications related to catheters GRANULATION TISSUE This is by far the most frequent problem associated with gastrostomies. Usually, granulation tissue formation is mild, and a few applications of silver nitrate are curative. If this condition is neglected, however, granulation tissue will predispose to leakage, bleeding and chronic discharge. With excessive growth, excision and cauterization become necessary. Granulation tissue formation will cease once epithelialization of the tract has occurred. We have found that a cream combining an antifungal and a steroid preparation helps to minimize the formation of granulation tissue.

LEAKAGE Severe continuous leakage is uncommon in properly constructed gastrostomies.1,3 However, severe widening of the stoma can lead to skin excoriation, dislodgment of the tube, metabolic imbalance, and even death.1,3 The main cause of leakage in most children is enlargement of the stoma by the pivoting motion of the gastrostomy tube, often too large or too stiff. 1 Catheters brought through the incision or the thinner midline are more prone to this problem. Management of leakage begins with control of granulation tissue and placement of a smaller, softer catheter to avoid pivoting motion. A variety of other methods have been tried with varying degrees of success.1 In extreme cases, reoperation or stoma relocation25 becomes necessary.

EXTERNAL MIGRATION Over-zealous approximation of external immobilizing devices, such as the bumper, can lead to embedding of the inner cross-bar of a PEG catheter, mushroom tip or balloon in the gastric and abdominal wall.1 The usual presentations are malfunction with limited ﬂow, leakage, lack of to-and-fro motion of the catheter, or the formation of an abscess. The catheter should be removed and replaced. This problem can be avoided by giving the catheter enough ‘play’, i.e. a little to-and-fro motion.

PERFORATION OF ESOPHAGUS AND SMALL BOWEL The balloon of a Foley-type catheter can be accidentally inﬂated in the esophagus26 or small bowel,27 leading to wall disruption.

PERSISTENT GASTROCUTANEOUS FISTULA In the longstanding gastrostomy, an epithelium-lined channel will form. Although most stomas close spontaneously after a few days, excision of the tract with simple closure is indicated if drainage persists after several weeks.1

PREVENTION A long list of additional tube-related complications is recorded.1,3–9 Most of the common gastrostomy carerelated problems can be prevented or corrected with the use of skin-level devices or ‘buttons’.28 In addition to the original gastrostomy button, balloon-type skin-level devices are employed for long-term care. The main disadvantage of these two designs is that the long, original catheter must be removed in order for the skin-level device to be inserted. This conversion is associated with pain and the possibility of separating the stomach from the abdominal wall. One way to circumvent this problem is to insert a skin-level device at the time of the original open or laparoscopic Stamm-type procedure.19 An additional method is to employ a catheter–button combination using the PEG technique.29 A simpler approach is the conversion of the originally inserted long tube to a skin-level device by using an externally placed port valve.30 This system has proved very versatile because, among other advantages, the external valve can be changed when it fails, without removing the originally placed catheter (Fig. 43.1).

420 Gastrostomy

Figure 43.14 Completed percutaneous endoscopic gastrostomy and tracheostomy in a 4-month-old child, weighing 3.5 kg, with poor swallowing and severe bronchopulmonary dysplasia. The child was born prematurely at 29 weeks’ gestation and was hospitalized following an eventful neonatal course. Sutures are not used after the PEG and the catheter is connected to a small clear plastic trap. After 24 hours, the external cross-bar is checked and loosened, if necessary, to accommodate for wound edema. Feedings are then started. The catheter can be converted to a skin-level device at any time using the externally placed port valve.30 Notice the tracheal traction sutures used as safety measures with the child’s tracheostomy and the scar of a previously repaired inguinal hernia

Figure 43.15 Two former premature infants with complex neonatal courses. Both receive supplemental feedings and medication via the gastrostomy. The child on the left has a balloon-type skin level device and the one on the right has an original gastrostomy button

CONCLUSION Although gastrostomy is a basic and fairly simple procedure, the surgeon must carefully consider the advantages vs disadvantages when using it in conjunction with another major intervention in the

newborn. If the gastrostomy is used for long-term enteral feeding, careful consideration must be given not only to the often difﬁcult ethical problems encountered in some neonatal patients but also to the duration of these enteral feedings, potential complications and the problem of gastro-esophageal reﬂux. These children beneﬁt from a team approach, including the neonatologist, pediatric surgeon, pediatric gastroenterologist, primary nurse and nutritionist. It is also paramount that the parents or caregivers be an integral part of the decision-making process at the different stages of management. Long-term follow-up is essential and its importance cannot be over emphasized. Whether the gastrostomy is placed as an adjunct or for the prime purpose of feeding, every effort should be directed towards resuming oral feeding whenever possible.

REFERENCES 1. Gauderer MWL, Stellato TA. Gastrostomies: evolution, techniques, indications and complications. Curr Prob Surg 1986; 23:661–719. 2. Meeker IA, Snyder WH. Gastrostomy for the newborn surgical patient: a report of 140 cases. Arch Dis Childh 1962; 37:159–66. 3. Haws EB, Sieber WK, Kiesewetter WB. Complications of tube gastrostomy in infants and children: 15 year review of 240 cases. Ann Surg 1966; 164:284–90. 4. Vengusamy S, Pildes RS, Raffensperger JF et al. A controlled study of feeding gastrostomy in low birth weight infants. Pediatrics 1969; 43:815–20. 5. Campbell JR, Sasaki TM. Gastrostomy in infants and children: an analysis of complications and techniques. Ann Surg 1974; 40:505–8. 6. Meier H, Willital GH. Gastrostomy in the newborn – indication, technique, complications. Z Kinderchir 1981; 34:82–6. 7. Juskiewenski S, Vaysse P, Bacque P et al. Gastrostomies temporaires en chirurgie neo-natale. Ann Chir Inf 1975; 16:263–8. 8. Gauderer MWL. Percutaneous endoscopic gastrostomy: a 10 year experience with 220 children. J Pediatr Surg 1991; 26:288–94. 9. Wilson L, Oliva-Hemker M. Percutaneous endoscopic gastrostomy in small medically complex infants. Endoscopy 2001; 33:433–5. 10. Michaud J, Guimber D, Carpentier B et al. Gastrostomy as a decompression technique in children with chronic gastrointestinal obstruction. J Pediatr Gastroenterol Nutr 2001; 32:82–5. 11. Coln D, Cywes S. Simultaneous drainage gastrostomy and feeding jejunostomy in the newborn. Surg Gynecol Obstet 1977; 145:594–5. 12. Rehbein F. Oesophagusatresie. In Kinderchirurgische Operationen: Hippokrates. Verlag: Stuttgart, 1976:24–152.

References 421 13. Louhimo I, Lindahl M. Esophageal atresia: primary results of 500 consecutively treated patients. J Pediatr Surg 1983; 18:217–29. 14. Spitz L, Kiely E, Brereton RJ. Esophageal atresia: ﬁve year experience with 148 cases. J Pediatr Surg 1987; 22:103–8. 15. Gauderer MWL, Izant RJ Jr. Distally placed transanastomotic drainage tube in the management of the severely leaking esophageal anastomosis. J Pediatr Surg 1983; 18:829–32. 16. Gauderer MWL. Gatrostomy only or gastrostomy plus antireﬂux procedure? (Editorial) J Pediatr Gastroenterol Nutr 1988; 7:795–6. 17. Kraeft M, Roos R, Ring-Mrozik E. Gastrostomy and gastric colonization: impact on neonatal septicemia. Pediatr Surg Int 1986; 1:125–9. 18. Gauderer MWL. Gastrostomy techniques and devices. Surg Clin N Am 1992; 72:1285–98. 19. Gauderer MWL. Gastrostomy. In: Spitz L, Coran AG, editors. Pediatric Surgery. 5th edn. London: Chapman & Hall Medical, 1995:286–97. 20. Gauderer MWL, Ponsky JL, Izant RJ Jr. Gastrostomy without laparotomy: a percutaneous endoscopic technique. J Pediatr Surg 1980; 15:872–5. 21. Strodel WE, Lemmer JH, Knol JA et al. A modiﬁed suture technique for tube gastrostomy. Surg Gynecol Obstet 1984; 158:505–6. 22. Gauderer MWL, Stellato TA. Percutaneous endoscopic

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gastrostomy in children: the technique in detail. Pediatr Surg Int 1991; 6:82–7. Robertson FM, Crombleholme TM, Latchaw LA et al. Modiﬁcation of the ‘push’ technique for percutaneous endoscopic gastrostomy in infants and children. J Am Coll Surg 1996; 182:215–18. Thompson WR, Hicks BA, Guzzetta PC Jr. Laparoscopic Nissen fundoplication in the infant. J Laparoendosc Surg 1996; 6 (Suppl 1): 55–7. Gauderer MWL. A simple technique for correction of severe gastrostomy leakage. Surg Gynecol Obstet 1987; 165:170–2. Abrams LD, Kiely EM. Oesophageal rupture due to gastrostomy catheter. Z Kinderchir 1981; 33:274–5. Ballinger WF II, McLaughlin ED, Baranski EJ. Jejunal overlay closure of the duodenum in the newborn: lateral duodenal tear caused by gastrostomy tubes. Surgery 1966; 59:450–4. Gauderer MWL, Olsen MM, Stellato TA et al. Feeding gastrostomy button: experience and recommendations. J Pediatr Surg 1988; 23:24–8. Ferguson DR, Marig JM, Kozarek RA et al. Placement of a feeding button (‘One-Step Button’) as the initial procedure. Am J Gastroenterol 1993; 88:501–4. Gauderer MWL, Abrams RS, Hammond JH. Initial experience with the changeable skin-level port-valve: A new concept for long-term gastrointestinal access. J Pediatr Surg 1998; 33:73–5.

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44 Duodenal obstruction YECHIEL SWEED

INTRODUCTION Congenital duodenal obstruction may be due to intrinsic lesions, extrinsic lesions, or both. Intrinsic duodenal obstruction may be caused by duodenal atresia, stenosis, diaphragm, a perforated diaphragm or a ‘wind-sock’ web. The wind-sock web is a duodenal membrane which is ballooned distally as a result of peristalsis from above.1,2 Extrinsic duodenal obstruction may be caused by the annular pancreas, malrotation or preduodenal portal vein. Although the annular pancreas forms a constricting ring around the second part of the duodenum, it is not believed to be the cause of duodenal obstruction3–5 and there is usually an associated atresia or stenosis in patients with an annular pancreas.6,7

Atresias have traditionally been classiﬁed by the method described by Gray and Skandalakis,8 who identiﬁed three types of lesions. Type I defects, the most common, are represented by a mucosal web with a normal muscular wall, type II by a short ﬁbrous cord connecting the two atretic ends of the duodenum, and in type III by a complete separation of the atretic ends. The recently reported prevalence of type I is about 65% and of types II and III 18% each; duodenal stenosis is approximately half as prevalent as atresia.9 Figure 44.1 shows the various types of duodenal obstruction. The proximal and distal segments of the duodenum may end blindly and be separated by a gap (Fig. 44.1a), be in apposition (Fig. 44.1b), or be joined by a ﬁbrous cord (Fig. 44.1c). Other types include duodenal

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 44.1 Various types of duodenal obstruction. (a) Blind ends separated by a gap. (b) Two ends in apposition. (c) Ends joined by a ﬁbrous cord. (d) Duodenal stenosis. (e) Complete duodenal membrane. (f) Perforated diaphragm. (g) ‘Wind-sock’ web. (h) Annular pancreas

424 Duodenal obstruction

stenosis (Fig. 44.1d), complete diaphragm (Fig. 44.1e), a perforated diaphragm (Fig. 44.1f), a wind-sock web (Fig. 44.1g) and an annular pancreas (Fig. 44.1h). The incidence of intrinsic duodenal obstruction is reported to be 1 in 5000 to 10 000 births.10,11 In the large Californian population-based registry of 2.5 million infants, the risk of duodenal atresia was found to be 265 times higher in infants with Down syndrome compared to those without it, and the corresponding frequencies were 46 and 0.17 per 1000 births.12 Although duodenal obstruction is usually not regarded as a familial condition, there have been a few reports of familial cases,13–17 dizygotic twins18 and a very rare group of hereditary multiple intestinal atresias with fatal outcome.19 Duodenal atresia, web and stenosis usually occur in the second part of the duodenum, close to the area of the intense embryological activity involved in the development of the biliary and pancreatic structures. These anomalies are believed to result from a developmental error during early fetal life.20–22 It has been demonstrated that from the ﬁfth to the tenth week of gestation the duodenum is a solid cord, the lumen of which is formed by vacuoles which coalesce. Duodenal atresia results from failure of vacuolization and recanalization. Duodenal stenosis and web result from incomplete recanalization of the duodenum. An annular pancreas results when the anterior and posterior anlage of the pancreas become fused to form a ring of pancreatic tissue that surrounds the second part of the duodenum. The obstruction usually occurs at or below the ampulla of Vater. Pre-ampullary obstruction is much less common, occurring in about 20% of cases.13 Occasionally, there may be a biﬁd termination of the bile duct with one limb of the duct system opening into the duodenum above the atresia and one below.21–23

ASSOCIATED MALFORMATIONS There is a high incidence of associated anomalies in patients with intrinsic duodenal obstruction, especially Down syndrome, which occurs in about 30% of these patients.6,10,13,14,24,25 Table 44.1 presents the overall prevalence and distribution of associated anomalies of duodenal atresia. The associated anomalies in order of frequency are: Down syndrome, annular pancreas, congenital heart disease, malrotation, esophageal atresia, urinary tract malformation, anorectal anomalies and other bowel atresia. Vertebral anomalies were reported to range between 2%33 and 37%35 in these patients. Reports of duodenal atresia have shown a low incidence of musculoskeletal anomalies.25 Other rare anomalies include de Lange syndrome,33 chromosomal abnormalities,36–38 immunodeﬁciency,39 and tracheomalacia.25

Associated malformations are the most important of the three factors known to contribute to a high mortality rate in patients with duodenal atresia; the others are prematurity and low birth weight.31 This mortality rate is even higher in neonates born with three or more anomalies of the VACTERL association with an overall survival rate of 40–77%.40–42 Spitz and colleagues reported the combination of esophageal and duodenal atresia as particularly lethal, with mortality rates ranging from 67–94% in various series.43 Jackson et al. inferred that the majority of these deaths is caused by failure to recognize the second abnormality preoperatively.44 Recently, Dalla Vecchia et al, attributed all the operative mortality to the associated complex congenital heart anomalies.9

PRENATAL DIAGNOSIS Maternal polyhydramnios has been reported to be present in 17–75% of cases of duodenal atresia6,9,13,28,31,34,45 and is the commonest ultrasonographic ﬁnding in fetuses with intrinsic duodenal obstruction.10 Ultrasound is usually performed for suspected fetal or maternal abnormalities when polyhydramnios or a large-for-dates pregnancy is established. Although the majority of cases are diagnosed during the seventh and eighth months of gestation,31,46 sonographic detection of duodenal atresia was reported as early as 12 gestational weeks by Tsukerman et al.47 and 19 weeks by Romero.48 There has been an increase in prenatal ultrasonographic diagnoses of duodenal atresia during the last 2 decades, from 13%49 and 18%32 to the high rate of 57% for the period of 1991–1995.34 With improved ultrasonography, a larger proportion of infants may be diagnosed during the second trimester. Ultrasonographic diagnosis relies on the demonstration of the double bubble sign, which is due to the simultaneous distension of the stomach and the ﬁrst portion of the duodenum (Fig. 44.2). The combination of polyhydramnios and the sonographic appearance of the stomach and duodenum suggests that an imbalance between amniotic ﬂuid production and resorption is present. Often, other anomalies can also be diagnosed by ultrasound. Kawana et al.46and Pameijer et al.50 reported the ultrasonic prenatal diagnosis of a fetus with combined duodenal and esophageal atresias, associated with VACTERL anomalies. Rarely, a fetal annular pancreas can be also recognized.51 Hancock and Wiseman investigated the impact of antenatal diagnosis of congenital duodenal obstruction in a series of 34 infants, 15 of whom were diagnosed by antenatal ultrasound.31 They concluded that although surgery was performed sooner, the outcome of infants with duodenal obstruction was not changed by providing an antenatal diagnosis. However, the antenatal

Table 44.1 Incidence of associated congenital anomalies (%) Study

Year

No.

Fonkalsrud et al.13 Nixon & Tawes26 Reid27 Girvan & Stephens6 Wesley & Mahour28 Davey29 Danismend et al.30 Hancock & Wiseman31 Akhtar & Guiney 32 Bailey et al.33 Dalla Vecchia et al. 9 Murshed et al.34

1969 1971 1973 1974 1977 1980 1986 1989 1992 1993 1998 1999

503 62 164 158 72 68 98 34 49 138 138 275

Overall

1759

Down syndrome

Annular Congenital Malrotation pancreas heart disease

30 27 33 31.6 22 34 13 21 69 11 24 30

21 26 30 – – – – 15 37 8 33 –

17 23 22 21.5 11 28 12 24 41 4 38 37

19 24 25 13.3 18 13 – 29 18 – 28 17

28.2%

23.1%

22.6%

19.7%

Esophageal atresia/ tracheo-esophageal ﬁstula 7 13 10 12 7 4 19 12 – 2 6 9.5 8.5%

Genitourinary

Anorectal

6 – 11 11 3 3 9 12 4 – 14 –

3 3 7 7 3 3 6 6 1 4 5 4

– 2 – 1.9 7 – – 9 – 2 6.6 2.5

4.4%

3.5%

8.0%

Other bowel atresia

Other

None

Survival with surgery

6 26 – 17 6.9 – 2 41 8 19 17 7

52 31 21 – 54 – – 35 22 62 – –

68 57 49 67 74 67 74 94 94 93 86 –*

10.9%

45.3

71.4%

* Cannot be calculated because the periodic breakdown does not include number of patients. During the 45 years covered, survival has increased from 51% to 95%.

Prenatal diagnosis 425

426 Duodenal obstruction

Figure 44.2 Ultrasonographic scan at 35 weeks’ gestation demonstrating a double bubble sign in utero in a case of duodenal atresia. (Courtesy Dr M.El-Shaﬁe, Oh)

diagnosis of duodenal obstruction inﬂuenced parents positively in coping with the anomaly, because it allowed them time to prepare for the medical and surgical interventions required after the birth of their infant. The authors also cautioned that a normal ultrasound in the presence of polyhydramnios does not rule out the diagnosis of duodenal obstruction, and is an indication for repeat sonography. The rapid advancement in imaging technology, including magnetic resonance imaging (MRI), should allow for diagnosis during the ﬁrst and early second trimester, enabling abortion.47 Alternatively, early prenatal diagnosis of duodenal obstruction should lead to karyotype analysis for prenatal screening for trisomy 21 and other associated anomalies.48–50

The diagnosis of duodenal obstruction is conﬁrmed on X-ray examination. An abdominal radiograph will show a dilated stomach and duodenum, giving the characteristic appearance of a double bubble sign (the stomach and the proximal duodenum are air-ﬁlled) with no gas beyond the duodenum (Fig. 44.3). In partial duodenal obstruction, a plain ﬁlm of the abdomen will show a double bubble appearance but there is usually some air in the distal intestine (Fig. 44.4). Occasionally, in cases of duodenal atresia, air may be seen distal to the site of obstruction due to associated bile duct bifurcation.52 Radiographic ﬁndings in the annular pancreas are usually indistinguishable from duodenal atresia or stenosis. In a few cases of partial duodenal obstruction, plain ﬁlms may be normal. An upper gastrointestinal tract contrast radiography is indicated in these patients to establish the cause of incomplete duodenal obstruction. This may show a stenotic segment of duodenum with dilatation of the proximal segment, or a sharp termination of the dilated segment, indicating a perforated diaphragm (Fig. 44.5). Incomplete duodenal obstruction usually leads to delayed onset of symptoms, and the diagnosis of duodenal diaphragm with a central aperture is sometimes delayed for many months. Mikaelsson et al. reported recently on the late diagnosis and treatment of eight out of 16 patients with membranous duodenal stenosis. They were diagnosed and operated on at 1 month to 4 years of age.53 Occasionally a duodenal diaphragm may be stretched and ballooned distally,

CLINICAL PRESENTATION AND DIAGNOSIS About half of these patients are premature9,11,13 and are of low birth weight.6,13,31 Vomiting is the most common symptom and it is usually present on the ﬁrst day of life. Since 80% of the obstructions are located in the postampullary region of the duodenum, vomitus in the majority of cases is bile stained. In supra-ampullary atresia it is non-bilious. Orogastric aspiration also yields signiﬁcant volumes of bile-stained gastric ﬂuid. There is minimal or no abdominal distension because of the high level of obstruction. The infant may pass some meconium in the ﬁrst 24 hours of life and thereafter constipation may develop. Dehydration with weight loss and electrolyte imbalance soon follow if ﬂuid and electrolyte losses have not been adequately replaced. Incomplete duodenal obstruction usually leads to the delayed onset of symptoms.

Figure 44.3 Abdominal erect radiograph showing grossly distended stomach and duodenum with a double bubble sign with no air beyond the duodenum

Clinical presentation and diagnosis 427

Figure 44.4 Duodenal stenosis. Erect abdominal X-ray demonstrating a double bubble sign but with air beyond the duodenum

Figure 44.5 Contrast study showing marked distension of duodenum terminating abruptly with narrow caliber distally. A perforated diaphragm was found at operation

giving the ‘wind-sock’ appearance on a contrast study (Fig. 44.6). The most important differential diagnosis is duodenal obstruction caused by malrotation which results in extrinsic compression related to Ladd’s bands across the duodenum, or volvulus of the midgut loop, although this

Figure 44.6 ‘Wind-sock’ web. Dilated duodenum demonstrated with duodenal membrane ballooned distally, giving characteristic ‘wind-sock’ appearance. Reﬂux of contrast medium into pancreatic and common bile duct is seen

is rare. The latter can result in gangrene of the entire midgut within hours and so diagnostic investigation is urgently required, even though the symptoms may relent because the obstruction may be incomplete or intermittent in malrotation. Part of these extrinsic obstructions exhibit the double bubble sign with distal air on plain ﬁlm, while the majority can be identiﬁed from the coil spring appearance of a small bowel volvulus following barium injection.54 However Samuel et al. observed that in neonates with duodenal atresia and stenosis who had associated malrotation, volvulus neonatorum was not encountered. They suggested that duodenal obstruction could perhaps be a ﬂood-gate mechanism that prevents volvulus in these children.55 Preduodenal portal vein, a rare cause of duodenal obstruction, is often impossible to diagnose prior to surgery.56,57 The wide variety of the additional congenital anomalies, that often are severe, make the preoperative diagnoses imperative. Anterio-posterior and lateral chest and abdominal radiographs, ascertaining visualization of the entire spine, should be made. Soon after the X-ray, cardiac and renal ultrasound should be carried out routinely in all these babies. A micturating cystourethrogram should be performed in those babies with abnormal urogenital ultrasound or an associated anorectal anomaly. Rectal biopsy should be taken in babies with constipation and the combination of Down syndrome and duodenal atresia, to exclude Hirschsprung’s disease.25

428 Duodenal obstruction

PREOPERATIVE MANAGEMENT Once the diagnosis is established, the infant should be prepared for surgery. Little preoperative preparation is required if the diagnosis is made within the ﬁrst 36 hours. Preoperative preparation consists of nasogastric decompression and ﬂuid and electrolyte replacement. Care is taken to preserve body heat and avoid hypoglycemia, since most of these newborn patients are premature and small for dates. Very low birth weight infants or those with respiratory distress syndrome and associated severe anomalies, e.g. congenital heart disease, will need special preparation such as resuscitation and ventilation.

(a)

OPERATION In patients with duodenal atresia, stenosis and annular pancreas, the recommended and most commonly employed surgical procedure is duodenoduodenostomy.6,9–11,28,56–58 This technique is a physiological operative procedure with a low complication rate and high survival rate. In 1977, Kimura et al. described a technique of ‘diamond-shaped’ duodenoduodenostomy59 that seemed to allow earlier feeding, earlier discharge and good long-term results.58,60 Some authors advocated duodenojejunostomy because of ease of repair and minimal operative dissection.61,62

Incision A transverse supraumbilical abdominal incision is made 1–2 cm above the umbilicus starting 1 cm to the left of the midline and running laterally in a skin crease for about 6 cm (Fig. 44.7a). The abdominal muscles are divided transversely with cutting diathermy and the peritoneal cavity is opened in the line of incision.

Exploration and identiﬁcation of pathology Following the exploration for other sites of obstruction and other abdominal malformations, the hepatic ﬂexure of the colon is mobilized by reﬂecting it downwards to expose the dilated duodenum. The duodenum is then adequately mobilized by the Kocher maneuver and the level and nature of obstruction is assessed. The ligament of Treitz is divided in those cases in which there is a wide gap between the two segments. The mobilization and displacement of the distal duodenum is performed behind the superior mesenteric vessels, thus allowing a satisfactory anastomosis to be performed without any tension.57

(b)

(c)

Figure 44.7 Operative technique of duodenoduodenostomy (see text for details)

ANASTOMOSIS – SIDE-TO-SIDE DUODENODUODENOSTOMY This technique is the procedure of choice. The dilated proximal duodenum and the distal collapsed duodenum are approximated using two stay sutures and a few interrupted Lembert sutures (5-0 Vicryl or Dexon). Then parallel incisions are made in the proximal and distal duodenum (Fig. 44.7b). The posterior layer of anastomosis is completed using inverting mattress sutures of 5-0 Vicryl (Fig. 44.7c). Some surgeons prefer to use a continuous suture for the inner layer.60 At this stage, a transanastomotic 5 Fr. gauge silastic nasojejunal tube may be inserted for an early enteral feeding.32 Others, however, do not use the nasojejunal tube because it delays the commencement of oral feeding.9,63 In premature infants, some surgeons prefer to perform a gastrostomy and insert the transanastomotic tube via the gastrostomy. The tip of the tube should be well down in the jejunum so as to decrease the chance of it becoming displaced. A mixture of air and saline is injected into the distal bowel lumen to rule out downstream atresias. The distal duodenum and jejunum can be distended to a larger size during this maneuver by gently occluding the proximal jejunum with the surgeon’s ﬁnger or an intestinal clamp. The anastomosis is then completed using inverting mattress 5-0 Vicryl sutures for the anterior layer followed by a few Lembert

Operation 429

sutures (4-0 Vicryl or Dexon) in the outer layer. Although most surgeons use a two-layer anastomosis, some prefer a one-layer anastomosis.58 Then the right colon is returned to its former position so that the mesocolon covers the anastomosis. The Ladd procedure with ‘inversion appendectomy’64 is performed in patients with malrotation.49 In these patients the cecum should be placed in the left lower quadrant to reduce the risk of midgut volvulus. A nasogastric tube should be left for gastric decompression for several days, as required.

Closure of incisional wound

(a)

The wound is closed in layers: the peritoneum and posterior fascia, and the anterior fascia by two layers using continuous 4-0 Dexon or Vicryl sutures. The skin is closed with running intracuticular sutures using Dexon or Vicryl 5-0. If gastrostomy has been placed, the gastrostomy catheter is ﬁxed by 3-0 nylon sutures to the adjacent skin and by adhesive strapping.

‘DIAMOND-SHAPED’ DUODENODUODENOSTOMY59,60 After entering the abdomen, the duodenum is adequately mobilized by the Kocher maneuver. The ligament of Treitz is divided as needed. With two traction sutures, the redundant wall of the proximal duodenum is brought down to overlie the proximal portion of the distal duodenal segment (Fig. 44.8a): if this cannot be done easily, more mobilization of the megaduodenum is needed. The distal duodenum can be distended to a larger size during this maneuver by gently occluding the proximal jejunum either by the surgeon’s ﬁnger or an intestinal clamp. A transverse incision in the distal end of the proximal duodenum and a longitudinal incision of the same length in the distal duodenum are made (Fig. 44.8a). The papilla of Vater is located by observing bile ﬂow, following gentle compression of the gallbladder. Using 5-0 or 6-0 Vicryl continuous inner and 5-0 Vicryl interrupted outer layer sutures, a double layer anastomosis is completed (Fig. 44.8b,c). No gastrostomy or transanastomotic tube is used. The duodenoduodenostomy achieved by this technique takes the shape of a diamond.

OPERATIVE TECHNIQUE FOR DUODENAL WEB A longitudinal incision is performed above the ‘transitional zone’ between the wide and narrow segments of the duodenum (Fig. 44.9a) and the duodenum is opened. The membrane usually is localized in the second part and occasionally in the third portion of the duodenum. It can be complete or have a hole. Anatomically, the ampulla of Vater may open directly into the medial part of the membrane, or posteriorly close to it, thus the close relationship of the membrane to the papilla of Vater makes its identiﬁcation mandatory, before

(b)

(c)

Figure 44.8 Diamond-shaped anastomosis for duodenal atresia (Kimura) (see text for details)

excision of the web. A radial incision starting in the central ostium is performed and excision of the membrane from the duodenal wall takes place, leaving 3 mm of the medial portion of the web intact, with a circumferential rim of tissue of 1–2 mm (Fig. 44.9b). The resection line is then oversewn using continuous sutures of Dexon 5-0 and the duodenum is closed transversely in two layers using Dexon or Vicryl 4-0 (Fig. 44.9c). Because of the pitfalls in the cases of the lax membrane that may bulge downwards distally into the distended duodenum (the so-called ‘wind-sock’ phenomenon), and in order to avoid missing the anomaly, the distal patency of the distal duodenum must be veriﬁed by inserting a catheter through the duodenotomy. The experience with ﬁberoptic duodenoscopy indicates the usefulness of the technique for both the diagnosis and non-operative management of duodenal membrane.65–69 However, based on reports describing anomalous entry of the pancreaticobiliary channels,70 the delineation of the ducts at endoscopic retrograde cholangiopancreatography (ERCP) may be necessary prior to endoscopic intervention. Most surgeons believe that a duodenotomy is preferable to the potential risk of inadvertent pancreatic or bile duct injury.70

430 Duodenal obstruction

MANAGEMENT OF PERSISTENT MEGADUODENUM BY DUODENOPLASTY

(a)

(b)

(c)

Figure 44.9 Operative technique for duodenal web (see text for details)

POSTOPERATIVE CARE The baby is returned to an incubator (or radiant heat cot) at the thermoneutral temperature for its size and maturity. An i.v. infusion of dextrose/saline is continued in the postoperative period and further ﬂuid and electrolyte management depends on clinical progress, loss by gastro-duodenal aspiration and serum electrolyte levels. Postoperatively, patients have a prolonged period of bile-stained aspirate through the nasogastric tube, which is mainly due to the inability of the markedly dilated duodenum to produce effective peristalsis, and to a lesser extent, partial mechanical obstruction by the feeding tube. Enteral feeding through the transanastomotic jejunal tube is generally started within 24–48 hours postoperatively. The tip of the transanastomotic tube should be checked by X-ray prior to starting feeds. The commencement of oral feeding depends on the decrease of the gastric aspirate, and may be delayed for several days and occasionally for 2 weeks or longer. Once the volume of the gastric aspirate decreases, the nasojejunal tube is withdrawn and the infant can be started on oral feeding. Spigland and Yazbeck, in their follow-up of 33 neonates, found that bowel transit was established for an average of 13.1 days, 7.5 days after partial web excision (Heineke-Mickulicz duodenoplasty), 12.4 days following duodenoduodenostomy, and 15 days after duodenojejunostomy.71

The deformity and dysfunction of the ﬁrst part of the duodenum – the megaduodenum – are the causes of wellknown morbidity71,72 and occasionally these patients require duodenoplasty.73 The malfunction of the greatly dilated gut and the absence of effective peristalsis were demonstrated by Nixon in the small bowel,74 but the same phenomenon is thought to occur in the dilated duodenum proximal to the duodenal atresia. Several techniques of duodenoplasty have been described, and in all, it is of the utmost importance to visualize and identify the ampulla of Vater within the duodenal lumen prior to resection and tapering. Hutton and Thomas have reported success by extensive tapering duodenoplasty.75 Adzick et al.76 and Grosfeld and Rescorla49 emphasized the merit of tapering duodenoplasty at the primary operation of neonates with dilated duodenum, to improve the immediate postoperative gastrointestinal function and the prevention of further development of megaduodenum. Other techniques include resection and suturing,77 resection and stapling,76 elliptical seromuscular resection78 and imbrication.79 However, refashioning the anastomosis or bypass techniques usually fail.72,80,81 Recently a technique of subtotal duodenal resection with reconstruction of the duodenum by the proximal jejunum as an onlay patch, was demonstrated in two children. In this technique the diseased duodenal wall is completely removed, except for the area of the ampulla of Vater, and the duodenum is reconstructed by the jejunum.82

OUTCOME AND LONG-TERM RESULTS The outlook for neonates with congenital duodenal obstruction has improved in recent years.9,34 All agree that the three main factors contributing to the high mortality rate in this group of patients are: high incidence of associated anomalies, prematurity and low birth weight.9,13,26,30 The improvement in the survival of patients with duodenal atresia is shown from the recent studies cited in Table 44.1 and in other studies.49 In a recent review, covering 45 years (1951–1995) of management of duodenal obstruction, Murshed et al. found that in the ﬁrst 15 years, survival reached 51%, in the next 15 years it was 80%, and in the last 15 years 95%. During the latter period, mortality was almost entirely the consequence of associated anomalies.34 Irving reported a postoperative mortality rate of 29% in 159 patients over a period of 32 years;10 this rate decreased to only 18% in the last 10 years of the study. Dalla Vecchia et al. reported a relatively low rate of postoperative complications in a series of 138 infants.9 The early complication rate included anastomotic obstruction in 3%, congestive heart failure in 9%, prolonged adynamic

References 431

ileus in 4%, pneumonia in 5%, and wound infection in 3%. Late complications included adhesive bowel obstruction in 9%, megaduodenum and duodenal dysmotility that required tapering duodenoplasty in 4%, and gastro-esophageal reﬂux requiring surgery in 5%. Weber et al. reported the complication rate and morbidity of three methods of technical repair in a group of 41 newborns with duodenal atresia.58 The three techniques were: (1) side-to-side duodenoduodenostomy, (2) side-to-side duodenojejunostomy, and (3) diamond-shaped duodenoduodenostomy. There was a 100% survival rate. There was no difference in the complication rate, but the ‘diamond-shaped’ technique was found to be superior for repair, resulting in earlier feeding and discharge. Recently, Kimura et al. reported on their experience with 44 patients with the diamondshaped technique,60 without the use of gastrostomy or transanastomotic tube, and found a very low rate of complications and good long-term results. Long-term results of congenital duodenal obstruction were reported by Kokkonen et al., who studied 41 patients aged 15–35 years.83 They found that growth and development, including body weight, were satisfactory. Although the great majority was symptom-free, on barium meal examination all but two had abnormal ﬁndings, including megaduodenum in nine cases. They concluded that some gastrointestinal disturbances are common, even in asymptomatic patients, and careful follow-up is important. Salonen and Makinen reported previously on their experience in a small group of nine patients at age 3–21 years84 and found, in contrast, a normal barium meal in all groups except one. This result was similar to the documentation by Kimura et al. with the diamond shaped technique.60 Ein et al. encountered ﬁve patients with very late complications of duodenal atresia repair that appeared suddenly between the ages of 6 months to 24 years. The duodenal repair was functionally obstructed – caused by proximal, dilated, duodenal atony. Plication of the dilated atonic proximal duodenum was curative.72,81 It seems that the relatively high mortality rates encountered in the early reported series of patients were mainly related to the complications of associated anomalies and postoperative complications. Lately the results have markedly improved by better supportive management, especially respiratory and nutritional support of highrisk neonates in neonatal intensive care units.9,32,63

REFERENCES 1. Rowe MI, Buckner D, Clatworthy HW Jr. Wind sock web of the duodenum. Am J Surg 1968; 116:444–9. 2. Norton KI, Tenreiro R, Rabinowitz JG. Sonographic demonstration of annular pancreas and a distal duodenal diaphragm in a newborn. Pediatr Radiol 1992; 22:66–7.

3. Elliott GB, Kliman MR, Elliott KA. Pancreatic annulus: a sign or a cause of duodenal obstruction. Can J Surg 1968; 11:357–64. 4. Gourevitch A. Duodenal atresia in the newborn. Ann R Coll Surg Engl 1971; 48:141–58. 5. Verga G. Le pancreas annulaire est-il vraiment cause d’occlusion duodenale chez le noveau-ne. Ann Chir Infant 1972; 13:275–6. 6. Girvan DP, Stephens CA. Congenital intrinsic duodenal obstruction: a twenty-year review of its surgical management and consequences. J Pediatr Surg 1974; 9:833–9. 7. Grosfeld JL, Ballantine TV, Shoemaker R. Operative management of intestinal atresia and stenosis based on pathologic ﬁndings. J Pediatr Surg 1979; 14:368–75. 8. Gray SW, Skandalakis JE. Embryology for Surgeons. The embryological basis for the treatment of congenital defects. Philadelphia: Saunders, 1972:147–8. 9. Dalla Vecchia LK, Grosfeld JL, West KW et al. Intestinal atresia and stenosis: a 25-year experience with 277 cases. Arch Surg 1998; 133:490–6. 10. Irving IM. Duodenal atresia and stenosis: annular pancreas. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London :Butterworths, 1990:424–41. 11. Nixon HH. Duodenal atresia. Br J Hosp Med 1989; 41:134,138,140. 12. Torfs CP, Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 1998; 77:431–8. 13. Fonkalsrud EW, DeLorimier AA, Hays DM. Congenital atresia and stenosis of the duodenum. A review compiled from the members of the Surgical Section of the American Academy of Pediatrics. Pediatrics 1969; 43:79–83. 14. Young DG, Wilkinson AW. Abnormalities associated with neonatal duodenal obstruction. Surgery 1968; 63:832–6. 15. Best LG, Wiseman NE, Chudley AE. Familial duodenal atresia: a report of two families and review. Am J Med Genet 1989; 34:442–4. 16. Gahukamble DB, Khamage AS, Shaheen AQ. Duodenal atresia: its occurrence in siblings. J Pediatr Surg 1994; 29:1599–1600. 17. Gross E, Armon Y, Abu Dalu K et al. Familial combined duodenal and jejunal atresia. J Pediatr Surg 1996; 31:1573. 18. Yokoyama T, Ishizone S, Momose Y et al. Duodenal atresia in dizygotic twins. J Pediatr Surg 1997; 32:1806–8. 19. Lambrecht W, Kluth D. Hereditary multiple atresias of the gastrointestinal tract: report of a case and review of the literature. J Pediatr Surg 1998; 33:794–7. 20. Tandler J. Zur Entwicklungsgeschichte des menschlichen Duodenums in fruhen Embryonalstadium. Morphol Jahrb 1900; 29:187–216. 21. Boyden EA, Cope JG, Bill AH Jr. Anatomy and embryology of congenital intrinsic obstruction of the duodenum. Am J Surg 1967; 114:190–202.

432 Duodenal obstruction 22. Jona JZ, Belin RP. Duodenal anomalies and the ampulla of Vater. Surg Gynecol Obstet 1976; 143:565–9. 23. Reid IS. Biliary tract abnormalities associated with duodenal atresia. Arch Dis Child 1973; 48:952–7. 24. Puri P. Outlook after surgery for congenital intrinsic duodenal obstruction in Down syndrome. Lancet 1981; 2(8250):802. 25. Kimble RM, Harding J, Kolbe A. Additional congenital anomalies in babies with gut atresia or stenosis: when to investigate, and which investigation. Pediatr Surg Int 1997; 12:565–70. 26. Nixon HH, Tawes R. Etiology and treatment of small intestinal atresia: analysis of a series of 127 jejunoileal atresias and comparison with 62 duodenal atresias. Surgery 1971; 69:41–51. 27. Reid IS. The pattern of intrinsic duodenal obstructions. Aust NZ J Surg 1973; 42:349–52. 28. Wesley JR, Mahour GH. Congenital intrinsic duodenal obstruction: a twenty-ﬁve year review. Surgery 1977; 82:716–20. 29. Davey RB. Congenital intrinsic duodenal obstruction: a comparative review of associated anomalies. Aust Paediatr J 1980; 16:274–8. 30. Danismend EN, Brown S, Frank JD. Morbidity and mortality in duodenal atresia. Z Kinderchir 1986; 41:86–8. 31. Hancock BJ, Wiseman NE. Congenital duodenal obstruction: the impact of an antenatal diagnosis. J Pediatr Surg 1989; 24:1027–31. 32. Akhtar J, Guiney EJ. Congenital duodenal obstruction. Br J Surg 1992; 79:133–5. 33. Bailey PV, Tracy TF Jr, Connors RH et al. Congenital duodenal obstruction: a 32-year review. J Pediatr Surg 1993; 28:92–5. 34. Murshed R, Nicholls G, Spitz L. Intrinsic duodenal obstruction: trends in management and outcome over 45 years (1951–1995) with relevance to prenatal counselling. Br J Obstet Gynaecol 1999; 106:1197–9. 35. Atwell JD, Klidkjian AM. Vertebral anomalies and duodenal atresia. J Pediatr Surg 1982; 17:237–40. 36. Reyes HM, Meller JL, Loeff D. Neonatal intestinal obstruction. Clin Perinatol 1989; 16:85–96. 37. Waters BL, Allen EF, Gibson PC et al. Autopsy ﬁndings in a severely affected infant with a 2q terminal deletion. Am J Med Genet 1993; 47:1099–103. 38. Pulkkinen L, Kimonis VE, Xu Y et al. Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum Mol Genet 1997; 6:669–74. 39. Moore SW, de Jongh G, Bouic P et al. Immune deﬁciency in familial duodenal atresia. J Pediatr Surg 1996; 31:1733–5. 40. Muraji T, Mahour GH. Surgical problems in patients with VATER-associated anomalies. J Pediatr Surg 1984; 19:550–4. 41. Weber TR, Smith W, Grosfeld JL. Surgical experience in infants with the VATER association. J Pediatr Surg 1980; 15:849–54.

42. Iuchtman M, Brereton R, Spitz L et al. Morbidity and mortality in 46 patients with the VACTERL association. Isr J Med Sci 1992; 28:281–4. 43. Spitz L, Ali M, Brereton RJ. Combined esophageal and duodenal atresia: experience of 18 patients. J Pediatr Surg 1981; 16:4–7. 44. Jackson CH, Yiu-Chiu VS, Smith WL et al. Sonography of combined esophageal and duodenal atresia. J Ultrasound Med 1983; 2:473–4. 45. Longo MF, Lynn HB. Congenital duodenal obstruction: review of 29 cases encountered in a 30-year period. Mayo Clin Proc 1967; 42:423–30. 46. Kawana T, Ikeda K, Nakagawara A et al. A case of VACTEL syndrome with antenatally diagnosed duodenal atresia. J Pediatr Surg 1989; 24:1158–60. 47. Tsukerman GL, Krapiva GA, Kirillova IA. First-trimester diagnosis of duodenal stenosis associated with oesophageal atresia. Prenat Diagn 1993; 13:371–6. 48. Romero R. Duodenal atresia. In: Romero R, PiIu G, Jeanty P et al. editors. Prenatal Diagnosis of Congenital Anomalies. Norwalk, CT: Appleton and Lange, 1988:236–9. 49. Grosfeld JL, Rescorla FJ. Duodenal atresia and stenosis: reassessment of treatment and outcome based on antenatal diagnosis, pathologic variance, and long-term follow-up. World J Surg 1993; 17:301–9. 50. Pameijer CR, Hubbard AM, Coleman B et al. Combined pure esophageal atresia, duodenal atresia, biliary atresia, and pancreatic ductal atresia: prenatal diagnostic features and review of the literature. J Pediat Surg 2000; 35:745–7. 51. Weiss H, Sherer DM, Manning FA. Ultrasonography of fetal annular pancreas. Obstet Gynecol 1999; 94 (5 Pt 2):852. 52. Raine PA, Noblett HR. Duodenal atresia with biliary anomalies and unusual gas pattern. J Pediatr Surg 1977; 12:763–5. 53. Mikaelsson C, Arnbjornsson E, Kullendorff CM. Membranous duodenal stenosis. Acta Paediatr 1997; 86:953–5. 54. Eustace S, Connolly B, Blake N. Congenital duodenal obstruction: an approach to diagnosis. Eur J Pediatr Surg 1993; 3:267–70. 55. Samuel M, Wheeler RA, Mami AG. Does duodenal atresia and stenosis prevent midgut volvulus in malrotation. Eur J Pediatr Surg 1997; 7:11–12. 56. Raffensperger JG. Pyloric and duodenal obstruction. In: Swenson’s Pediatric Surgery. 5th edn. Norwalk, CT: Appleton and Lange, 1990:509–16. 57. Weitzman JJ, Brennan LP. An improved technique for the correction of congenital duodenal obstruction in the neonate. J Pediatr Surg 1974; 9:385–8. 58. Weber TR, Lewis JE, Mooney D et al. Duodenal atresia: a comparison of techniques of repair. J Pediatr Surg 1986; 21:1133–6. 59. Kimura K, Tsugawa C, Ogawa K et al. Diamond-shaped anastomosis for congenital duodenal obstruction. Arch Surg 1977; 112:1262–3.

References 433 60. Kimura K, Mukohara N, Nishijima E et al. Diamondshaped anastomosis for duodenal atresia: an experience with 44 patients over 15 years. J Pediatr Surg 1990; 25:977–9. 61. Kraeger RR, Gromoljez P, Lewis JE Jr. Congenital duodenal atresia. Am J Surg 1973; 126:762–4. 62. Harberg FJ, Pokorny WJ, Hahn H. Congenital duodenal obstruction. A review of 65 cases. Am J Surg 1979; 138:825–8. 63. Mooney D, Lewis JE, Connors RH et al. Newborn duodenal atresia: an improving outlook. Am J Surg 1987; 153:347–9. 64. Torres AM, Ziegler MM. Malrotation of the intestine. World J Surg 1993; 17:326–31. 65. Okamatsu T, Arai K, Yatsuzuka M et al. Endoscopic membranectomy for congenital duodenal stenosis in an infant. J Pediatr Surg 1989; 24:367–8. 66. Soreide JA, Seime S, Soreide O. Intraluminal duodenal diverticulum: case report and update of the literature 1975–1986. Am J Gastroenterol 1988; 83:988–91. 67. Abdel Haﬁz AA, Birkett DH, Ahmed MS. Congenital duodenal diverticula: a report of three cases and a review of the literature. Surgery 1988; 104:74–8. 68. Hajiro K., Yamamoto H, Matsui H et al. Endoscopic diagnosis and excision of intraluminal duodenal diverticulum. Gastrointest Endosc 1979; 25:151–4. 69. Pittschieler K, Gentili L. Endoscopic diagnosis of duodenal stenosis. J Pediatr Gastroenterol Nutr 1997; 24:359–60. 70. Adams DB. Management of the intraluminal duodenal diverticulum: endoscopy or duodenotomy. Am J Surg 1986; 151:524–6. 71. Spigland N, Yazbeck S. Complications associated with surgical treatment of congenital intrinsic duodenal obstruction. J Pediatr Surg 1990; 25:1127–30. 72. Ein SH, Shandling B. The late nonfunctioning duodenal atresia repair. J Pediatr Surg 1986; 21:798–801.

73. Dewan LA, Guiney EJ. Duodenoplasty in the management of duodenal atresia. Pediatr Surg Int 1990; 5:253–4. 74. Nixon HH. An experimental study of propulsion in isolate small intestine and applications to surgery in the newborn. Ann R Coll Surg Engl 1960; 27:105–24. 75. Hutton KA, Thomas DF. Tapering duodenoplasty. Pediatr Surg Int 1988; 3:132–4. 76. Adzick NS, Harrison MR, deLorimier AA. Tapering duodenoplasty for megaduodenum associated with duodenal atresia. J Pediatr Surg 1986; 21:311–12. 77. Weisgerber G, Boureau M. Immediate and secondary results of duodeno-duodenostomies with tapering in the treatment of total congenital duodenal obstructions in newborn infants. Chir Pediatr 1982; 23:369–72. 78. Kimura K, Perdzynski W, Soper RT. Elliptical seromuscular resection for tapering the proximal dilated bowel in duodenal or jejunal atresia. J Pediatr Surg 1996; 31:1405–6. 79. Sherman JO, Schulten M. Operative correction of duodenomegaly. J Pediatr Surg 1974; 9:461–4. 80. Young JS, Goco I, Pennell T. Duodenoplasty and reimplantation of the ampulla of Vater for megaduodenum. Am J Surg 1993; 59:685–8. 81. Ein SH, Kim PC, Miller HA. The late nonfunctioning duodenal atresia repair–a second look. J Pediatr Surg 2000; 35:690–1. 82. Endo M, Ukiyama E, Yokoyama J et al. Subtotal duodenectomy with jejunal patch for megaduodenum secondary to congenital duodenal malformation. J Pediatr Surg 1998; 33:1636–40. 83. Kokkonen ML, Kalima T, Jaaskelainen J et al. Duodenal atresia: late follow-up. J Pediatr Surg 1988; 23:216–20. 84. Salonen IS, Makinen E. Intestinal blind pouch- and blind loop-syndrome in children operated previously for congenital duodenal obstruction. Ann Chir Gynaecol 1976; 65:38–45.

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45 Malrotation LEWIS SPITZ

Malrotation is the term used to denote an interference with the normal process of orderly return of the fetal intestine from the physiological hernia to the abdominal cavity during which it undergoes systematic rotation and ﬁxation.1–11

throughout life. Malrotation may coexist in association with a number of other life-threatening congenital anomalies, e.g. exomphalos and diaphragmatic hernia.

CLINICAL PRESENTATION EMBRYOLOGY The intestine initially develops as a tube extending down the midline of the embryo. As the intestine lengthens it protrudes through the umbilical ring into the physiological umbilical hernia where it undergoes further lengthening before returning back into the abdominal cavity. Three stages of development of the midgut are recognized: Stage I Stage II

Stage III

4–10 weeks: midgut protrudes and develops in the physiological umbilical hernia. 10–12 weeks: midgut migrates back into the abdomen in an orderly manner, small bowel ﬁrst and cecocolic loop last. The cecum initially lies on the left but it rotates through 270° to attain its ﬁnal position in the right iliac fossa. Simultaneously, the duodenum undergoes a 270° anti-clockwise rotation. Final phase consisting of fusion of various parts of the mesentery with ﬁxation of cecum and ascending colon and the descending colon.

Neonatal period 1 Recurrent episodes of subacute obstruction with intermittent bilious vomiting. 2 Strangulating intestinal obstruction as a consequence of midgut volvulus. The infant presents with bile-stained vomiting which may contain altered blood, abdominal distension and tenderness, the passage of dark blood per rectum and shock. As the strangulation progresses to gangrene, perforation and peritonitis, edema and erythema of the anterior abdominal wall becomes evident.

Older infant and child 1 Intermittent or cyclical vomiting which often contains bile. 2 Failure to thrive. 3 Intermittent severe abdominal colic. 4 Anorexia as a result of pain associated with eating. 5 Malabsorption and/or diarrhea.

RADIOLOGICAL DIAGNOSIS INCIDENCE Although it is recognized that malrotation may exist undetected throughout life (0.2%), it is generally accepted that once the diagnosis has been established, surgical correction should be carried out to avoid the occurrence of a volvulus. Fifty-ﬁve per cent of malrotations present within the ﬁrst week of life and 80% in the ﬁrst month. Thereafter, sporadic cases occur

The plain abdominal X-ray in the infant with midgut volvulus typically shows a ‘gasless’ appearance with air in the stomach and duodenum and little or no gas in the rest of the intestines (Fig. 45.1). Contrast studies are diagnostic. The procedure of choice is the upper gastrointestinal contrast study which shows the abnormal conﬁguration of the duodenum, the duodenojejunal junction to the right of the midline and

436 Malrotation

Figure 45.3 Lateral view of an upper gastrointestinal contrast study showing a dilated proximal duodenum with a ‘twisted ribbon’ appearance of the upper small intestine indicating volvulus of the midgut Figure 45.1 Plain abdominal radiograph showing gas in the stomach and ﬁrst part of the duodenum with a paucity of gas in the rest of the intestinal tract

the small bowel located on the right side of the abdomen. Where volvulus has occurred, the duodenum and upper jejunum show a ‘twisted ribbon’ or ‘corkscrew’ appearance (Figs 45.2 and 45.3). The barium enema will show the cecum and appendix in an abnormal position, usually in the right hypochondrium or mid-abdomen.

Ultrasonography to determine the relationship between the superior mesenteric vein (SMV) and artery (SMA) has been advocated as a non-invasive method of diagnosing malrotation. Normally, the SMV lies to the right of the SMA whereas in malrotation the position is reversed with the SMV to the left of the SMA. Color Doppler ultrasound is particularly useful in this investigation.12

TREATMENT The operative correction of a malrotation should be regarded as a surgical emergency. Patients presenting with acute strangulating obstruction as a result of midgut volvulus require a brief period (not more than 2–3 h of intensive resuscitation in preparation for surgery. An intravenous infusion is set up and plasma (20 mg/kg) administered as rapidly as possible, repeated as required, followed by 0.18% saline in 5% dextrose at 10 ml/kg per hour until induction of anesthesia. A nasogastric tube of suitable size is passed and gastric content aspirated and a prophylactic dose of broad-spectrum antibiotics (penicillin, gentamicin and metronidazole) given parenterally. A specimen of blood is taken for crossmatch, hematology and serum electrolyte estimation. Blood for transfusion must be available at the commencement of the laparotomy.

THE OPERATION Figure 45.2 Upper gastrointestinal contrast study showing the duodenojejunal ﬂexure to the right of the vertebral column and small intestinal loops in the right upper quadrant of the abdomen

Incision A laparotomy is performed via a right upper abdominal transverse muscle-cutting incision extending across the

The operation 437

rectus abdominus muscle (Fig. 40.4). The obliterated umbilical vein in the free edge of the falciform ligament is ligated and divided. The bowel is delivered into the wound. A small volume of yellowish, free-peritoneal ﬂuid is present in any early intestinal obstruction, but blood-stained ﬂuid is indicative of intestinal necrosis.

MANAGEMENT OF A MIDGUT VOLVULUS The volvulus occurs around the base of the narrowed midgut mesentery (Fig. 45.5). The twist usually occurs in a clockwise direction and is untwisted by counterclockwise rotation of as many 180° rotations as required (Fig. 45.6). Moderately ischemic bowel, which appears congested or dusky, rapidly resumes a normal pinkish Figure 45.6 Untwisting of a midgut volvulus in a counterclockwise direction

Figure 45.4 Incision to right of midline in the upper abdomen but should be extended across to the left if additional exposure is required

Figure 45.5 Appearance of midgut volvulus which occurs in a clockwise direction

color on reduction of the volvulus. Frankly necrotic bowel may be extremely friable and may disintegrate on handling. Bowel of questionable viability should be covered, after untwisting, with warm moist swabs and left undisturbed for approximately 10 min before assessing the extent of ischemic damage. A Ladd’s procedure for the malrotation is carried out (see below). In patients with extensive intestinal gangrene, frankly necrotic bowel should be resected and the bowel ends either tied off or stomas fashioned with a view to a second-look laparotomy in 24–48 h when a clearer line of demarcation will have established. At this stage an end-to-end anastomosis may be feasible. In the intervening period the patient is electively ventilated and resuscitative measures continued.

MANAGEMENT OF THE UNCOMPLICATED MALROTATION (LADD’S PROCEDURE) Having untwisted a volvulus, attention is now directed at the narrow-based mesentery of the midgut and the orientation of the duodenum and colon. The peritoneal folds which extend from the cecum and ascending colon laterally across the second part of the duodenum and cranially towards the liver and gall bladder are carefully divided (Fig. 45.7). This procedure leaves the right colon freely mobile to allow its displacement to the left side of the peritoneal cavity. Attention is now directed to the duodenojejunal junction. The ligament of Treitz at the apex of the duodenojejunal ﬂexure is divided and the duodenal loop straightened by mobilizing the third and fourth parts of the duodenum from the head of the pancreas (Fig. 45.8). The superior mesenteric vessels coursing in the root of the mesentery between the duodenojejunal junction and the ascending colon are exposed by dividing the anterior layer of the mesentery (Fig. 45.9). The mesentery is often thickened and edematous and care should be taken to

438 Malrotation

Figure 45.7 Division of peritoneal folds extending from the cecum and ascending colon across the duodenum towards gall bladder and liver (Ladd’s bands)

Figure 45.9 Splaying of the root of the mesentery by dividing the anterior layer of mesentery and dividing ﬁbrous bands crossing over the superior mesenteric vessels

Figure 45.8 The duodenojejunal ﬂexure has been mobilized and the narrow-based mesentery is clearly obvious

avoid trauma to the main vessels. Numerous small lymphatic vessels require electrocoagulation or ligation before division to avoid a chylous leak. There is often quite dense ﬁbrous tissue in the root of the mesentery and this requires careful division in order to achieve adequate widening at the base of the mesentery. An appendicectomy is performed if the viability of the bowel permits, as the cecum will be placed in the left upper quadrant of the abdomen and appendicitis could pose considerable diagnostic difﬁculty in the future. The intestines are now replaced into the peritoneal cavity, commencing with the proximal jejunum which is placed on the right side and ending with the terminal ileum and cecum which are placed in the left upper quadrant (Fig. 45.10). No attempt is made to ﬁx the

Figure 45.10 Intestine has been replaced into the peritoneal cavity with the small bowel on the right side and the cecum and ascending colon in the left upper quadrant. An appendicectomy has been performed (an alternative is an inversion appendicectomy)

bowel in this position, although some authors advocate stabilization of the mesentery to prevent recurrent volvulus.

Closure The abdomen is closed with an interrupted en masse suture or in layers with a subcutaneous suture of the skin.

References 439

Laparoscopic correction of a malrotation with or without midgut volvulus but without intestinal necrosis has been reported.13–14

Postoperative management Return of bowel function may be delayed for prolonged periods during which parenteral nutrition may be required, but in general oral nutrition can be resumed in 5–7 days. Infants who have undergone massive small bowel resection will require parenteral nutrition for many months pending adaptation of the residual intestine. Recurrence of midgut volvulus is extremely rare but adhesion intestinal obstruction is not uncommon with a relative risk around 8–10%.

REFERENCES 1. Berardi RS. Anomalies of midgut rotation in the adult. Surg Gynecol Obstet 1980; 151:113. 2. Janik JS, Ein SH. Normal intestinal rotation with nonﬁxation: a cause of chronic abdominal pain. J Pediatr Surg 1979; 6:670. 3. Simpson AJ, Leonidas JC, Krasna IH, et al. Roentgen diagnosis of midgut malrotation: value of upper gastrointestinal radiographic study. J Pediatr Surg 1972; 7:243.

4. Tan WH. Incomplete rotation of the midgut in the newborn: a clinical and radiologic investigation of 54 patients. Med Radio Photogr 1981; 57:31. 5. Andrassy RJ, Mahour GH. Malrotation of the midgut in infants and children: a 25-year review. Arch Surg 1981; 116:158. 6. Filston HC, Kirk DR. Malrotation – the ubiquitous anomaly. J Pediatr Surg 1981; 16:614. 7. Stewart DR, Colodny AL, Daggett WC. Malrotation of the bowel in infants and children: a 15-year review. Surgery 1976; 79:716. 8. Yanez R, Spitz L. Intestinal malrotation presenting outside the neonatal period. Arch Dis Childh 1986; 61:682. 9. Bill AH, Grauman D. Rationale and technic for stabilization of the mesentery in cases of nonrotation of the midgut. J Pediatr Surg 1966; 1:127. 10. Powell DM, Otherson HB, Smith CD. Malrotation of the intestine in children. The effect of age on presentation and therapy. J Pediatr Surg 1989; 24:777–80. 11. Rescorla FJ, Shedd FJ, Crosfeld JL, et al. Anomalies of intestinal rotation in childhood. Analysis in 447 cases. Surgery 1990; 108:710–16. 12. Dufour-D, De Laet MH, Dassonville M, Cadranel S, Perlmutter M. Midgut malrotation, the reliability of sonographic diagnosis. Pediatr Radiol 1992; 22:21–3. 13. Gross E, Chen MK, Lobe TE. Laparoscopic revaluation and treatment of intestinal malrotation in infants. Surg Endosc 1996; 10:936–7. 14. Bax NM, Van der Zee. Laparoscopic treatment of intestinal malrotation in children. Surg Endosc 1988; 12:1314–16.

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46 Persistent hyperinsulinemic hypoglycemia of infancy LEWIS SPITZ

INTRODUCTION Hyperinsulinism is characterized by inappropriately high insulin levels for the concentration of blood glucose. Most infants with hyperinsulinism present within the ﬁrst few days after birth. The hyperinsulinism may be associated with a few well-deﬁned clinical conditions such as Beckwith–Wiedemann syndrome (exomphalos, macroglossia, gigantism = EMG), the infant of a diabetic mother or the ‘stressed neonate’ following birth asphyxia and Rh incompatibility. The hypoglycemia associated with these conditions is transient and will not be discussed further. It is also important to exclude leucin sensitivity and other endocrine disorders such as cortisol deﬁciency, or inborn errors of metabolism, e.g. glycogen storage disease.

CLINICAL PRESENTATION The clinical features of hypoglycemia may be nonspeciﬁc including ‘ﬂoppiness’, ‘jitteriness’, poor feeding and lethargy or the infant may present acutely with convulsions or coma. It is vitally important to measure blood glucose levels in an infant manifesting any of these symptoms.

DIAGNOSTIC CRITERIA Any infant with a blood glucose level persistently <2.6 mmol/L (40 mg%) should be investigated. The diagnostic criteria are as follows:1 • Glucose requirements >6.8 mg/kg/minute to maintain blood glucose level above 2.6–3 mmol/L • Laboratory blood glucose <2.6 mmol/L

• Detectable insulin at the point of hypoglycemia with raised C peptide • Inappropriately low blood free fatty acid and ketone body concentrations at the time of hypoglycemia • Glycemic response after administration of glucagon when hypoglycemic • Absence of ketonuria. Around 30–50% of infants with hyperinsulinism have demonstrable abnormalities in genes controlling intracellular metabolic pathways or membrane cation transport, i.e. sulphonyluria receptor (SUR 1) and Kir 6.2.2–4 Recently, ‘focal’ hyperplasia of the endocrine pancreas has been identiﬁed due to a somatic loss of the maternal allele on the short arm of chromosome 11 in a patient with SUR 1 mutation on the paternal allele.5,6 Hyperinsulinism has been reported in siblings. The possibility of familial hyperinsulinism should be considered (particularly in affected children of Jewish or Arabic ancestry) to ensure a prompt diagnosis as these infants are usually resistant to medical treatment and are likely to require surgery early to control the hypoglycemia.

IMAGING THE PANCREAS Special investigations including ultrasonography, computerized tomography, magnetic resonance imaging and selective angiography are of little value in infantile hyperinsulinism but may be helpful in localizing an adenoma in the older child. The technique of percutaneous transhepatic pancreatic venous sampling to distinguish focal from diffuse pancreatic disease has recently been shown to be highly selective.7,8 Multiple venous samples are taken from the splenic, superior mesenteric and portal veins as well as numerous small pancreatic veins in the head, body and tail of the pancreas. Concentration of insulin, glucose and

442 Persistent hyperinsulinemic hypoglycemia of infancy

C-peptide are measured and if a high concentration of insulin can be shown in one or two contiguous veins, the focal form of the disease can be suspected.

thorough search is made for sites of ectopic pancreatic tissue.

EXPOSURE

MANAGEMENT The main aim of management is to prevent hypoglycemic brain damage and to allow normal psychomotor development. In mild cases it may be possible to maintain acceptable levels of blood glucose by dietary measures alone. In the majority of cases i.v. administration of high concentrations of glucose are required to maintain blood glucose levels above 2.6 mmol/L. Glucose infusion rates in excess of 20 mg/kg/minute, i.e. 15–20% glucose, may be required. In these cases it is essential to insert a central venous catheter to provide a central route for administration of high concentrations of glucose and to allow frequent monitoring of blood glucose levels. Medical management1 comprises initially diazoxide (10–20 mg/kg/day in two to three divided doses) and chlorothiazide (7–10 mg/kg/day in two divided doses). The diazoxide opens KATP channels, increases adrenaline secretion and increases gluconeogenesis while chlorothiazide acts synergistically with diazoxide by activating non- KATP channels. Side effects of diazoxide include ﬂuid retention and potentially induction of cardiac failure and hypertrichosis. Other drugs which may be beneﬁcial included nifedipine (a calcium channel antagonist which inhibits insulin release), glucagons and octreotide.

SURGICAL MANAGEMENT

The anterior surface of the pancreas is exposed by entering the lesser peritoneal sac via the gastrocolic omentum, ligating and dividing vessels in the greater omentum along the greater curvature of the stomach (Fig. 46.2). The tail of the pancreas lies in the hilum of the spleen. The hepatic ﬂexure is reﬂected medially and the duodenum Kocherized to expose the head of the pancreas. The entire pancreas is carefully examined for the presence of an adenoma which appears as a reddish-

Figure 46.1 Transverse upper abdominal incision extending across both rectus abdominus muscles

Surgical treatment is indicated when the infant remains dependent on i.v. glucose administration despite maximum medical measures. Infants with diffuse disease will require a 95% or neartotal pancreatectomy to control the hyperinsulinism.9–14 In patients with suspected focal disease, it may be possible to distinguish between focal and diffuse form on frozen section histopathology of a pancreatic biopsy on the basis of nuclear size and nuclear crowding. The technique of 95% pancreatectomy will be described here.

THE OPERATION Incision A laparotomy is performed via a generous supraumbilical transverse muscle-cutting incision, extending through both rectus abdominus muscles (Fig. 46.1). A

Figure 46.2 Exposure of the head, body and tail of the pancreas by entering the lesser sac dividing the vessels in the greater omentum along the greater curvature of the stomach

The operation 443

brown nodule on the surface of the grayish pancreas. Such suspicious areas are excised and submitted to frozen section histologic examination. The coexistence of pancreatic adenoma and diffuse hyperinsulinism, particularly in early infancy, demands a generous biopsy of the tail of the pancreas before adenectomy alone is carried out.

95% PANCREATECTOMY In the diffuse form, the dissection of the pancreas proceeds medially from the tail towards the neck of the pancreas which lies just to the right of the superior mesenteric vessels. It is essential for future immunologic competence to preserve the spleen. This is accomplished by carefully exposing the short pancreatic vessels passing from the splenic vessels to the pancreas. These vessels, especially the veins, are extremely friable, but meticulous dissection will allow individual ligation, application of liga clips or bipolar electrocoagulation, and division of the vessels without traumatizing the main vessels (Fig. 46.3). Should hemorrhage occur from damage to the splenic vein, direct repair should be attempted. In the event of failure to achieve hemostasis, ligation of the splenic vein with preservation of the splenic function can be expected due to collateral supply from the short gastric vessels. When the dissection has progressed to the right of the superior mesenteric vessels, attention is directed to the head of the pancreas and in particular the uncinate process (Fig. 46.4).

EXCISION OF HEAD OF PANCREAS AND UNCINATE PROCESS The uncinate process is carefully dissected from behind the superior mesenteric vessels and, after positively deﬁning the course of the common bile duct, the head of the pancreas to the left of the common duct and in the concavity of the duodenal loop is excised, leaving a sliver of pancreatic tissue on the surface of the duodenum and

Figure 46.3 The short pancreatic vessels arising from the splenic vessels are divided and the body and tail of the pancreas are gradually dissected towards the head

Figure 46.4 The superior mesenteric vessels are displayed and retracted towards the left, exposing the uncinate process of the pancreas

on the left wall of the common duct. The pancreatic duct is identiﬁed and ligated with a non-absorbable ligature. Hemostasis is carefully and meticulously achieved. The remaining pancreatic tissue consists of that part of the gland between the duodenum and the common bile duct and the sliver of tissue on the medial wall of the second part of the duodenum (Fig. 46.5). This represents approximately 5% of the total volume of the pancreas. A suction drain via a separate stab incision is left in the pancreatic bed.

Closure The wound is closed in layers or with an en masse interrupted suture of 3-0 Dexon. The skin edges are approximated with a 5-0 Dexon subcuticular suture.

Figure 46.5 Final appearance following 95% pancreatectomy. The only remaining pancreatic tissue lies to the left of the common bile duct and a sliver in the C-curvature of the duodenum. Note splenic vessels and the complete excision of the uncinate process

444 Persistent hyperinsulinemic hypoglycemia of infancy

POSTOPERATIVE MANAGEMENT Nasogastric decompression and intravenous ﬂuids are continued during the period of postoperative ileus. Blood glucose levels are closely monitored postoperatively and soluble insulin administered as required. Rebound transient hyperglycemia is common in the early postoperative period. Occasionally, more prolonged use of small amounts of insulin is required, but adaptation usually occurs within 3–6 months.

COMPLICATIONS 1 Trauma to the common bile duct. The defect may be amenable to direct repair. If the duct has been transected, end-to-side anastomosis to the ﬁrst part of the duodenum should be performed. 2 Inadequate resection. This will become evident within 48–72 h of surgery and it is advisable to carry out a further resection at this early stage rather than later when ﬁbrosis can render the procedure extremely difﬁcult. 3 Wound sepsis. Note. Careful long-term follow-up is necessary to assess the adequacy of pancreatic exocrine function.

REFERENCES 1. Aynsley-Green A, Hussain K, Hall J, Saundubray JM, Nihoul-Fekete C, Lonlay-Debeney PD, Brunelle F, Otonkoski T, Thornton P, Lindley KJ. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82:F98–107. 2. Anguilar-Bryan L, Bryan J. The molecular biology of ATP sensitive K+ channels. Endocr Rev 1999; 20:101–35.

3. Thornton PS, Martha S, Smith S et al. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J Pediatr 1998; 132:9–14. 4. Glaser B, Thornton PS, Herold D, Stanley CA. Clinical and molecular heterogeneity of familial hyperinsulinism. J Pediatr 1998; 133:801. 5. Delonlay P, Fournet JC, Rashier J et al. Somatic deletion of the imprinted 11p15.1 region in sporadic persistent hyperinsulinaemic hypoglycaemia of infancy is speciﬁc of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997; 100:802–7. 6. Ryan F, Devaney D, Joyce C et al. Hyperinsulinism: the molecular aetiology of focal disease. Arch Dis Child 1998; 79:445–7. 7. Dubois J, Brunelle F, Touati G et al. Hyperinsulinism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases. Pediatr Radiol 1995; 25:512–16. 8. Delonlay-Debeney P, Poggi-Trovert F, Fournet JC et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340:1169–76. 9. Spitz L, Buick RG, Grant DB et al. Surgical treatment of nesidioblastosis. Pediatr Surg Int 1986; 1:26. 10. Carcassonne A, De La Rue A, Le Touneau JN. Surgical treatment of organic pancreatic hypoglycaemia in the pediatric age. J Pediatr Surg 1983; 8:75. 11. Gough MH. The surgical treatment of hyperinsulinism in infancy and childhood. Br J Surg 1984; 71:75. 12. Harken AH, Filler RM, AvRuskin TW et al. The role of total pancreatectomy in the treatment of unremitting hypoglycemia of infancy. J Pediatr Surg 1971; 6:284. 13. Warden MJ, German JC, Buckingham BA. The surgical management of hyperinsulinism in infancy due to nesidioblastosis. J Pediatr Surg 1988; 23:462. 14. Symm AY, Mulvihill SJ, Fonkalsrud EW. Surgical disorders of the pancreas in infancy and childhood. Am J Surg 1988; 156:201–5.

47 Jejuno-ileal atresia and stenosis HEINZ RODE AND A. J. W. MILLAR

INTRODUCTION

ETIOLOGY

Jejuno-ileal atresia, deﬁned as a congenital defect in continuity of the bowel, is a common cause of intestinal obstruction in the newborn, accounting for between 80% and 95% according to various reports.1–3 The incidence of jejuno-ileal atresia varies from 1 in 330 and 1 in 400 live births,4 to between 1 in 1500 and 1 in 3000 live births.5 Jejuno-ileal occlusions occur more frequently than duodenal or colonic ones do.1,6 With improved neonatal and perioperative care, safe anesthesia, reﬁned surgical techniques and management of short bowel syndrome, a survival rate of 90% can be expected. At the Red Cross War Memorial Children’s Hospital in Cape Town during the 41 years 1959–2000, 273 jejuno-ileal atresias, 194 (71%) jejunum and 79 (29%) ileum were seen (Table 47.1) compared to 189 duodenal and eight colonic atresias. Down syndrome is most uncommon in babies with jejuno-ileal atresia (only one baby in the Red Cross Hospital series) compared with duodenal atresias. The ﬁrst successful surgical repair of an intestinal atresia was in 1911.7 The mortality rate remained high over the next 4 decades and it was only in the mid 1950s that an improved understanding of the pathogenesis and pathology of the condition led to innovative surgical techniques which resulted in improved surgical outcome.5,6

In 1889, Bland Sutton postulated that atresia occurred at the site of ‘obliterative embryological events’ and he quoted atrophy of the vitelline duct.8 In 1900, Tandler9 supported by embryonal studies, suggested that intestinal atresia was related to a lack of recanalization of the solid stage of the intestine, while others have questioned these theories.10–12 In 1952, Louw published the results of an investigation of 79 patients treated at Great Ormond Street, London, and suggested that jejuno-ileal atresia was probably due to a vascular accident rather than the result of inadequate recanalization.5 At his instigation, Barnard perfected the experimental model in pregnant mongrel bitches. Mesenteric vascular insults, such as volvulus, intussusception and interference with the blood supply to a segment of bowel were created in the dog fetus.13 This not only conﬁrmed the hypothesis but led to a change in the surgical procedure for correcting atresias and stenosis of the jejunum and ileum with a marked improvement in outcome.14–16 Subsequently these experimental ﬁndings were conﬁrmed by others in several different animal models and in clinical practice.17–21 Evidence of bowel infarction was present in 42% of 449 cases of jejuno-ileal atresia in a collected series which further supported the vascular hypothesis.22 Furthermore the localized nature of the vascular accident occurring late in fetal life would explain the low incidence (less than 10%) of coexisting abnormalities of extra-abdominal organs. The anomaly is usually not genetically determined although affected monozygotic twins and siblings have been described. A genetic basis however has been established for type III b and IV multiple atresias.23–26

Table 47.1 Jejuno-ileal atresia and stenosis, 1959–2000 Type Stenosis Type I Type II Type IIIa Type IIIb Type IV Total

Jejunum

Ileum

No.

%

18 46 17 18 51 44

12 17 13 24 – 13

30 63 30 42 51 57

11 23 11 15 19 21

194

79

273

PATHOLOGY The classiﬁcation of jejuno-ileal atresia into three types by Bland Sutton in 1889 has stood the test of time, except for the subdivision of type III into two categories, (a and

446 Jejuno-ileal atresia and stenosis

b) and the addition of type IV.8,27,28 This subdivision has allowed a better long-term prognostication. In stenosis, the proximal dilated and narrower distal bowel are in continuity with an intact mesentery, but at the point of junction there is a short, narrow, somewhat rigid segment with a minute lumen. The small intestine is of normal length (Fig. 47.1a,b). In atresia type I (membrane or web) the dilated proximal and collapsed bowel are in continuity and the mesentery is intact. The intraluminal pressure in the proximal bowel produces bulging of the web into the distal intestine so that the transition from the distended to collapsed bowel is conical in appearance – the ‘windsock’ effect. The distal bowel is completely collapsed and the small intestine is of normal length (Fig. 47.2). In atresia type II (blind ends joined by a ﬁbrous band) the proximal bowel terminates in a bulbous blind end which is grossly distended and hypertrophied for several centimeters and is often aperistaltic. The bowel proximal to this is usually also considerably distended and hypertrophied for a further 5–10 cm. More proximally the distension is less marked and the bowel assumes a normal appearance. The distal collapsed bowel commences as a blind end which is sometimes bulbous due to remains of a fetal intussusception. The two blind ends are joined by a thin ﬁbrous band. The corresponding

intestinal mesentery is normal but may occasionally be deﬁcient, leaving a V-shaped gap. The small intestine is usually of normal length (Fig. 47.3a,b). In atresia type IIIa (disconnected blind ends) the appearance is similar to that in type II but the blind ends

Figure 47.2 Atresia type I. Obstruction caused by an intrinsic membrane. The proximal bowel is dilated and the distal collapsed, with intact mesentery

(a)

(a)

(b)

(b)

Figure 47.1 (a) Stenosis of the small bowel with proximal dilated and narrower distal bowel. The mesentery is intact. (b) The clinical appearance of stenosis

Figure 47.3 (a) Atresia type II. Blind ends joined by a band with an intact mesentery and normal length of bowel. (b) The clinical appearance of atresia type II

Pathology 447

are completely separate. There is always a V-shaped gap in the mesentery and the total bowel length is reduced (Fig. 47.4a,b). In atresia type IIIb (‘Apple peel,17 Christmas tree29 or ‘Maypole6 deformity), as in IIIa, the blind ends are disconnected and the mesenteric defect is substantial. This type is the consequence of an extensive infarction of the midgut secondary to a proximal superior mesenteric artery occlusion, producing a proximal jejunal atresia. The distal ileum remains viable, receiving its blood supply via a precarious collateral from the arterial supply to the right colon, around which the ileum is coiled. Occasionally additional type I or type II atresias are found along the distal blind end. There is always a signiﬁcant reduction in intestinal length (Fig. 47.5a,b). These babies are usually premature and of low birth weight. In addition, they may have associated anomalies

(a)

(a)

(b) (b) Figure 47.4 (a) Atresia type IIIa. Blind ends disconnected with a V-shaped defect in the mesentery. The bowel length is reduced. (b) The grossly dilated obstructed bowel tapers proximally into intestine of normal caliber. The distal collapsed bowel illustrates how difﬁcult it may be to assess the length of this segment

Figure 47.5 (a) Atresia type IIIb with a gross mesenteric defect and the coiled distal ileum with precarious collateral blood supply, producing the typical ‘apple-peel’ appearance. (b) The classical clinical appearance of the ‘apple-peel’ atresia. Note the precarious blood supply of the terminal portion of the distal bowel and the grossly dilated proximal jejunum. There is always signiﬁcant reduction in intestinal length

448 Jejuno-ileal atresia and stenosis

such as malrotation and may develop short bowel syndrome with increased morbidity and mortality.22 A familial incidence has been reported by Blyth and Dickson30 and Mishalany and Najjar.25 In atresia type IV, multiple atresias are present which could be a combination of types I–III and often has the appearance of a string of sausages. The bowel length is usually reduced (Fig. 47.6a,b). The most proximal atresia determines whether it is classiﬁed as jejunal or ileal. Pathologically the intestine proximal to the obstruction becomes enormously dilated and hypertrophied. This dilated bowel frequently has a cyanosed appearance and may have some necrotic areas either from sustained intraluminal pressure or secondary volvulus. Perforation may develop antenatally, leading to meconium peritonitis or as a postnatal event, especially if diagnosis is delayed. The peristaltic movements in this segment are subnormal and ineffective, and histologic and histochemical abnormalities can be observed up to 20 cm cephalad to the atretic segment31,32 (Fig. 47.4b). In contrast, the distal bowel is unused and worm-like, and potentially normal in length and function. Of the 273 patients in our series, there were 30 (11%) with stenosis, 64 (23%) with type I, 30 (11%) with type II, 42 (15%) with type IIIa, 51 (19%) with type IIIb and 56 (21%) with type IV atresias (Table 47.1).

(a)

(b) Figure 47.6 (a) Multiple atresias. (b) Typical ‘string of sausages’ seen clinically. The bowel length is usually reduced

CLINICAL FEATURES A prenatal history of polyhydramnios is helpful and many babies with intestinal atresia are diagnosed by ultrasonographic investigation of the fetus, showing dilated and obstructive fetal intestine.33 The family history may help to identify hereditary forms and conditions that may predispose to atresia, i.e. mucoviscidosis and anomalies of intestinal rotation. Postnatally atresia or severe stenosis of the small intestine present as neonatal intestinal obstruction with persistent bile-stained vomiting dated from the ﬁrst or second day of life. In general, the higher the obstruction the earlier and more forceful the vomiting, whereas in low intestinal obstruction the vomiting may be delayed. Abdominal distention is frequently present, more so with the lower intestinal atresias where the distension is generalized, whereas with the more proximal jejunal atresias it is conﬁned to the upper abdomen and is relieved by nasogastric tube aspiration. In delayed diagnosis or where perforation has occurred, the distension may be severe and associated with respiratory distress. There may also be some abnormality in evacuating meconium. Constipation is usually not absolute and the meconium passed varies from normal in color to the more common gray plugs of mucus. Occasionally if ischemic bowel is present, as in type IIIb atresia, blood may be passed rectally. Diseases that can mimic jejuno-ileal atresia include midgut volvulus, meconium ileus, duplication cysts, internal hernia, ileus due to sepsis, birth trauma, prematurity and transplacental crossing of maternal medication. The diagnosis of jejuno-ileal atresia is usually conﬁrmed on radiography. Erect and supine abdominal radiographs will reveal distended small bowel loops and air–ﬂuid levels (Fig. 47.7a). The lower the obstruction, the greater the distended loops of bowel and the more ﬂuid levels will be observed. A single large loop of bowel and air–ﬂuid level would indicate atresia rather than other causes of neonatal intestinal obstruction. A prone lateral view is useful to distinguish between low small bowel and colonic obstruction. In some instances the ﬁrst abdominal radiograph may reveal a completely opaque abdomen due to a ﬂuid-ﬁlled obstructed bowel. Emptying of the stomach by means of a nasogastric tube and injection of a bolus of air will demonstrate the level of the obstruction. With intestinal stenosis, an abnormal differentiation in caliber of the proximal obstructed intestine and the distal tract will be evident. However, due to its insidious nature the diagnosis is often delayed for months. When the radiograph suggests a complete obstruction, a contrast enema is performed to exclude colonic atresia, distinguish between small and large bowel distension, determine whether the colon has the typical microcolon appear-

Guidelines for management 449

ance, and locate the position of the cecum as an indication of malrotation. The classical appearance of the colon distal to jejunoileal atresia is an unused or microcolon (Fig. 47.7b). When an incomplete small bowel obstruction is diagnosed, an upper gastrointestinal contrast study is indicated to demonstrate the site and nature of the obstruction. Malrotation may also be observed in 10–30% of babies with jejuno-ileal atresia. Occasionally dystrophic intraperitoneal calciﬁcation of meconium peritonitis may be seen on plain radiograph, signifying intrauterine bowel perforation. If the atresia has formed late in intrauterine life, the bowel distal to the atresia may assume the caliber of a used colon.

GUIDELINES FOR MANAGEMENT

(a)

(b) Figure 47.7 (a) Erect abdominal radiograph of a newborn infant showing obstructed upper small bowel loops with ﬂuid levels. No air is visible in the distal bowel. (b) Contrast enema showing the unused or microcolon distal to a jejuno-ileal atresia. In addition, evidence of malrotation is present

The guidelines for management of jejuno-ileal atresia are as follows: 1 Prenatal • Polyhydramnios, affected family, ultrasonography 2 Preoperative preparation • Gastric decompression • Fluid management – Maintenance – Replacement of deﬁciency/ongoing losses • Plain abdominal radiograph (air contrast) • Barium enema • Correction of hematological and biochemical abnormalities • Prophylactic antibiotics 3 Operative • Identiﬁcation of pathological type and etiology • Establish patency of distal small bowel • Proximal resection of bulbous component, ischemic bowel • Derotation for high jejunal atresia • Limited distal bowel resection • Careful measurement of residual bowel length • End-to-back, single-layer anastomosis • Bowel length conservation method – tapering, plication 4 Postoperative • Gastrointestinal decompression • Antibiotics • Parenteral nutrition • Early and graduated enteral feeding with special or polymeric feeds • Surveillance for gastrointestinal dysfunction 5 Special problems • Anastomotic dysfunction • Short bowel syndrome • Associated congenital anomalies. Adapted from Haller et al. 198334

450 Jejuno-ileal atresia and stenosis

TREATMENT The newborn baby tolerates operative intervention all the better after a few hours of preoperative preparation, especially if the diagnosis has been delayed. In general, this preparation should pay particular attention to hypothermia, hypoxia, hypovolemia, hypoglycemia and hypo-prothrombinemia. The operation should not be delayed unduly as there is always a danger of further infarction of the bowel, ﬂuid and electrolyte disturbances, and increased risk of infection. In neglected cases with dehydration, more energetic therapy is required and when there has been perforation of the bowel with peritonitis and shock, colloid solutions – stabilized human serum and/or fresh blood 5–10 ml/kg should be added to the resuscitation formula.

Operation STERILIZATION OF SKIN AND DRAPING The umbilical cord is cleansed with 70% alcohol and is ligated and transected at the level of the abdominal wall. The operative ﬁeld is sterilized with prewarmed povodone–iodine 2% in 70% alcohol. Sterile warm Gamgee rolls are placed alongside the baby, who is then draped with towels, and a sterile transparent adhesive drape is applied over the operative ﬁeld to ensure that he/she remains dry during the operative procedure, thus preventing heat loss.

INCISION An adequate incision is required. Exposure is obtained through a supra-umbilical transverse incision transecting the recti muscles 2–3 cm above the umbilicus. The ligamentum teres is subsequently divided and ligated. Exploration If free gas escapes on opening the peritoneum, or if there is contamination of the peritoneal cavity, a pus swab is obtained for Gram stain and culture and the site of the perforation is sought and closed before further exploration is carried out. In the presence of peritoneal contamination, the cavity is irrigated with warm saline or antibiotic-containing ﬂuid – cefoxitin sodium 1 g/L. The entire bowel is exteriorized to determine the site and type of obstruction and to exclude other areas of atresia or stenosis and associated lesions such as incomplete intestinal rotation or meconium ileus. The appearance of the atretic segment depends upon the type of occlusion, but in all cases the maximal dilatation of the proximal bowel occurs at the point of obstruction; this segment is often aperistaltic and of questionable viability, while the bowel distal to the obstruction is collapsed, tiny and worm-like (Fig. 47.8).

Figure 47.8 The proximal atretic bowel is grossly dilated, aperistaltic and of questionable viability

After the location and type of lesion has been identiﬁed, the distal bowel is carefully examined to exclude other atretic segments, which are present in 10–20% of cases. Malrotation is corrected if present. Intraluminal membranes are best detected and localized by injecting half-normal saline into the lumen of the collapsed bowel and milking it down to the cecum. The total length of small bowel is measured as this has prognostic signiﬁcance and may determine the method of reconstruction. The normal length at full-term birth is approximately 250 cm. After complete patency of the distal small bowel and colon has been established, the next task is to splice the disproportionate proximal and distal blind ends. This is facilitated by applying an atraumatic bowel clamp about 6–8 cm from the distal blind end and distending the intervening segment by injection with half-normal saline, taking care not to split the serosa (Fig. 47.9a). Resection The atretic area and adjacent distended and collapsed bowel are isolated by walling off the rest of the abdominal cavity with moist packs. To ensure adequate postoperative function, the proximal distended and hypertrophied bowel must be liberally resected, even if it appears viable. If the bowel length is adequate (more than 75 cm plus ileocecal valve) the bulbous hypertrophied bowel proximal to the atresia is resected to approximately normal bowel diameter; usually a 10–15 cm section is removed. After milking the intestinal contents into the proximal bulbous end, an atraumatic bowel clamp is applied across the bowel a few centimeters proximal to the site selected for transection. The mesentery adjoining the portion to be resected is clamped, divided and ligated up to the proposed lines of section of proximal and distal bowel (Fig. 47.9b). A clamp is then applied to the proximal bowel, which is transected between this and the bowel clamp. The blood supply at this point should be excellent and therefore the bowel is divided at right angles, leaving an opening of about 1.5 cm in width. In addition, 4–5 cm of the distal

Treatment 451

bowel is removed. This bowel is transected slightly obliquely. The incision may be continued along the antimesenteric border to create a ‘ﬁsh-mouth’, which renders the opening about equal to that of the proximal bowel (Fig. 47.10).

(a)

Anastomosis An inverting mattress 5-0 or 6-0 polydioxanone sutures unites the mesenteric borders of the divided ends, and temporary stay sutures are inserted at the antimesenteric angles to facilitate accurate approximation. The ‘posterior’ edges of the bowel are united with interrupted through-and-through 5-0 or 6-0 polydioxanone sutures tied on the mucosal aspect (Fig. 47.11a). The ‘anterior’ edges are joined by similar through-and-through sutures tied on the serosal surface (Fig. 47.11b). Alternative suture techniques including extramucosal anastomosis and the use of 5-0 or 6-0 monoﬁlament absorbable sutures can be used. The completed anastomosis is not strictly end-to-end but a modiﬁcation of Denis Browne’s ‘end-to-back’ method. Where there is a discrepancy of less than 4:1 between the proximal and distal bowel lumens, an end-to-end extramucosal anastomosis may be fashioned. The suture line is tested for leakage and reinforcing sutures are inserted as required. The defect in the mesentery is repaired by approximating (and overlapping if necessary) the divided edges with interrupted

(b) Figure 47.9 (a) The distal bowel distended with saline proximal to the bowel clamp. The extent of the resection is indicated by the line. (b) The extent of resection in the clinical situation is depicted. Note that all grossly dilated bowel is resected

Figure 47.10 The proximal bowel has been transected at right angles and the distal obliquely with continuation of the incision along the antimesenteric border to create a ‘ﬁshmouth’

(a)

(b) Figure 47.11 (a) Anastomosis of the posterior wall with interrupted sutures. (b) The anterior anastomosis

452 Jejuno-ileal atresia and stenosis

5-0 or 6-0 polydioxanone or monoﬁlament sutures (Fig. 47.12a,b). The intestines, which are well moistened with warm saline, are returned to the peritoneal cavity. During this procedure, if the mesentery is kept in the conﬁguration of an open fan, kinking or volvulus of the bowel will be avoided. A similar technique is used for stenosis and intraluminal membranes. Procedures such as simple enteroplasties, excision of membranes and bypassing techniques are not recommended because they fail to remove the abnormal segment of bowel; side-to-side anastomosis is avoided due to the risk of creating blind loops. Gastrostomy/enteral decompression and early enteral feeding It was customary in babies with high jejunal atresias just beyond the duodenojejunal ﬂexure, to place a transanastomotic feeding tube for early enteral feeding when parenteral feeding techniques were less sophisticated.

The tube was passed into the small bowel distally to the anastomosis before completing the anterior layer of sutures and stabilized at the anastomotic site by a single tethering mucosal stitch, in order to prevent its retrograde displacement into the stomach. The transanastomotic tube was either passed via the nasogastric route or via a Stamm gastrostomy performed on the lesser curvature of the stomach. More recently, the value of such transanastomotic tubes has been questioned and the current authors have abandoned routine use of these for high jejunal and duodenal atresias.35 These babies regained full oral intake of feeds on average 10 days earlier without an anastomotic tube than with the tube in situ.

CLOSURE OF ABDOMINAL WOUND Where there has been soiling of the peritoneal cavity from a perforation, the abdominal cavity is again irrigated with copious amounts of saline or with an antibiotic solution (cefoxitin sodium 1 g/L) and all macroscopic debris removed. The abdominal wound is closed with a single continuous layer of polydioxanone 3-0 or 4-0 sutures to include all layers of the abdominal wall, excluding skin. In fat babies, the adipose layer is approximated with interrupted or continuous 4-0 sutures. The skin is approximated with a continuous subcuticular 5-0 monoﬁlament sutures.

OTHER SURGICAL MANEUVERS

(a)

(b) Figure 47.12 (a) Completed anastomosis and repair of mesenteric defect. (b) The clinical appearance of completed anastomosis

In babies in whom the initial insult has resulted in atresias with a markedly reduced length of small intestine or when large resections of multiple atretic segments are required, certain surgical maneuvers have been advocated in an attempt to preserve maximal intestinal length for survival and growth.36,37 In addition, disparity in anastamotic size is reduced and prograde duodenal function is facilitated. In high jejunal atresias, the duodenum is fully derotated and the proximal resection extended into the second part of the duodenum with antimesenteric tapering duodenoplasty or inversion plication of the proximal mega duodenum (Figs 47.13 & 47.14).38,39 The dilated bowel is trimmed to a lumen size of a 22 Fr. gauge catheter. An intestinal autostapling instrument may be used. Inversion plication without excision technique has the advantage of preserving valuable mucosa if the bowel length is short. Tapering may have an advantage over plication, as the latter has the tendency to unravel within a few months with subsequent duodenal dysfunction, especially if the mucosal strip technique has not been utilized. Following this tailoring, the anastomosis is performed as described earlier and the bowel is returned to the abdomen in the position of nonrotation. In type IIIb, any restricting bands along the free edge of the distal narrow mesentery are released to avoid kinking and interference with the blood supply. The mesentery from any

Postoperative care 453

Figure 47.13 The surgical procedure for high jejunal atresia includes: derotation of the bowel, back resection into the second part of the duodenum, tapering duodenoplasty or linear seromuscular stripping and inversion plication followed by bowel anastomosis

resected bowel is retained and may assist in closure of mesenteric defects. This technique is very helpful and prevents kinking or distortion of the anastomosis. Furthermore, the potential for kinking the single marginal artery and vein requires careful placement of the bowel into the peritoneal cavity at the completion of the anastomosis. Although isolated type I atresias are best dealt with by primary resection and anastomosis, multiple diaphragms have successfully been perforated and dilated with bougies passed along the length of the bowel. In multiple atresias, multiple resections and anastomosis may be advisable to save as much bowel length as possible. They are however often localized, requiring resection and a single anastomosis. A silastic tube passed through the lumen of the entire bowel facilitates these anastomotic procedures.40 The fashioning of stomas, e.g. Bishop–Koop,41 Santulli and Blanc17, Rehbein and Halsband42 or double barrel,43 as practised by some, is not routinely advocated unless there is gross intraperitoneal contamination, making a primary anastomosis unsafe. Jejuno-ileal atresia associated with a gastroschisis is treated by resection and primary anastomosis only if there is no evidence of edema and matting due to amniotic peritonitis.

Figure 47.14 The technique of seromuscular stripping and inversion plication. This technique preserves mucosal surface for absorption and prevents unravelling of the placation

Reduction of the eviscerated bowel with the atresia intact and primary closure of the abdominal wall defect, if possible, is preferred. After allowing for disappearance of the edema (10–14 days), a relaparotomy is performed with resection of the atretic segment and primary anastomosis. Stomas with subsequent wound infection are thus avoided. There is no place for any bowel lengthening procedures at the initial operation. It is advisable to delay such a procedure until the neonatal bowel length has grown to its maximum potential length and spontaneous bowel adaptation has occurred.

POSTOPERATIVE CARE Postoperative care is conducted according to current standards and guidelines. Nasogastric decompression is usually required for approximately 4 days postoperatively. High jejunal atresias may require a longer period of decompression. When the gastric aspirate is no longer bile stained, the abdomen is not distended, peristalsis is present, and the baby has passed meconium, graduated feeding is commenced. In babies with a transanastomotic tube, 1 ml isotonic solution 4 hourly is commenced 24 hours postoperatively and increased to

454 Jejuno-ileal atresia and stenosis

1 ml every hour to ensure patency of the tube. Graduated polymeric feeds are then commenced and increased as tolerated. Oral or gavage feeds are started with return of prograde proximal bowel function. If at any time there is a suspicion of a leak at the anastomosis as suggested by clinical deterioration, abdominal distension and vomiting, a plain erect radiograph of the abdomen should be taken. If this reveals free air in the abdomen when more than 24 hours have elapsed since surgery, immediate laparotomy should be performed. Other postoperative complications have been ischemia leading to frank necrosis or late onset stenosis, adhesive obstruction, and perforation of the bowel by the transanastomotic tube. Infants with human immunodeﬁciency virus (HIV) infection have poor healing with an increased incidence of anastomotic breakdown and wound sepsis with dehiscence. In babies in whom less than 75 cm of small bowel remains, especially if the ileocecal valve is absent, loose frequent stools and excessive water loss may become problematic. In these patients, and in every instance where normal enteral alimentation will not be established within 5 postoperative days, parenteral feeding is indicated. I.v. carbohydrate, amino acid and fatcontaining solutions are introduced in a graduated manner over a period of 3 days. Peripheral venous pushin lines are used for short-term total parenteral nutrition (TPN) but for long-term TPN (longer than 10 days), a central line is preferred. Once intestinal function has been re-established, the baby is gradually weaned from a parenteral to an enteral feeding program. Careful dietary tailoring is required, as each of the patients may have different tolerance thresholds. Predictions of the degree of intestinal dysfunction are based upon the known residual length of small intestine. The short bowel syndrome can be contemplated if more than 75% of the bowel length was lost or if the minimal bowel length left after surgery is less than 75 cm. These babies can be divided into four main functional groups: those with uncorrectable intestinal insufﬁciency, adequate bowel function for survival, adequate elementary function for growth and development, and normal elementary function with a degree of intestinal reserve. When gross intestinal insufﬁciency is expected, an isoosmolar elemental or semi-elemental diet is introduced in accurately titrated volumes. Regular monitoring for clinical signs and/or biochemical evidence of intestinal intolerance is required. Disaccharide and monosaccharide intolerance, an indication of gross brushborder malfunction of the intestine, should be detected before severe clinical signs become manifest, by regular biochemical assessment of stool ﬂuid samples. A falling pH and an associated increasing level of reducing substances denote unsatisfactory carbohydrate assimilation. The patient’s oral intake is gradually increased in volume and energy content, while the small intestine is allowed to adapt until maximum intake tolerance is reached,

which can take a few months.44 Pharmacological control of intestinal peristaltic activity has been achieved more effectively since the introduction of loperamide hydrochloride. Vitamin B12 and folic acid should be administered to patients without the terminal ileum to prevent megaloblastic anemia. The long-term outcome for most of the babies is optimistic although TPN-associated complications are frequent and sometimes fatal. In predicting the ultimate functional outcome, the following factors must be taken into consideration: the ileum adapts to a greater degree than the jejunum, the neonatal small intestine still has a period of maturation and growth ahead of it, and the actual residual small intestinal length is difﬁcult to determine accurately after birth. The proximal obstructed bowel segment is dilated and its functional potential may be overestimated, while that of the distal unused collapsed bowel may be underestimated. Of critical importance is an intact ileocecal valve, which allows for accelerated intestinal adaptation with shorter residual jejuno-ileal length. The absence of the ileocecal valve also leads to an increased transit-time, malabsorption, diarrhea and increased bacterial contamination of the small bowel.

RESULTS Before 1952 the mortality rate for congenital atresias of the small intestine in Cape Town was 90%. Between 1952 and 1955, 28% of the babies with this condition could be saved. At that stage most were treated by primary anastomosis without resection. With liberal resection of the blind ends and end-to-end anastomosis, the survival rate increased to 78% during 1955–58.45,46 During the 41-year period from 1959–2000, 273 patients with jejuno-ileal atresias and stenoses were admitted to the pediatric surgical service at the Red Cross War Memorial Children’s Hospital. There were 28 deaths, giving an overall survival rate of 89.8% (Table 47.2). Factors contributing to the mortality rate were: type of atresia (type III, 17%), proximal bowel infarction with peritonitis, anastomotic leaks, missed distal atresias, the short bowel syndrome, sepsis and more recently HIV infections. Table 47.2 Mortality related to type, 1959–2000 (n=273) Type

No.

Mortality

%

Stenosis Type I Type II Type IIIa Type IIIb Type IV

30 64 30 42 51 56

0 4 3 7 9 5

0.0 6.3 10.0 16.7 17.6 8.9

Overall mortality

.2%10.2%

References 455

REFERENCES 1. Grosfeld JL, Ballantine TVN, Shoemaker R. Operative management of intestinal stenosis based on pathological ﬁndings. J Pediatr Surg 1979; 14:31. 2. Cywes S, Davies MRO, Rode H. Congenital jejunoileal atresia and stenosis. S Afr Med J 1980; 57:630. 3. Evans CH. Atresias of the gastrointestinal tract. Int Abstr Surgery 1951; 92:1. 4. Hays DM. Intestinal atresia and stenosis. In: Ravitch M, editor. Current Problems in Surgery. Chicago: Year Book, 1969:3–48. 5. Louw JH. Congenital atresia and severe stenosis in the newborn. S Afr Clin Sci 1952; 3:109. 6. Nixon HH, Tawes R. Etiology and treatment of small intestinal atresia: analysis of a series of 127 jejunoileal atresias and comparison with 62 duodenal atresias. Surgery 1971; 69:41. 7. Fockens P. Operativ geheilter Fall von kongenitaler Dünndarmatresie. Zentralbl Chir 1911; 38:532. 8. Bland Sutton J. Imperforate ileum. Am J Med Sci 1889; 18:457. 9. Tandler J. Zur Entwicklungsgeschicte des menschlichen duodenum in fruhen Embryonalstadien. Morphol Jahrb 1900; 29:187. 10. Lynn HB, Espinas EE. Intestinal atresia; An attempt to relate location to embryologic processes. Arch Surg 1959; 79:13. 11. Moutsouris C. The ‘solid stage’ and congenital intestinal atresia. J Pediatr Surg 1966; 1:446. 12. Davis DL. Congenital occlusions of the intestine. SGO 1922; 34:35. 13. Louw JH, Barnard CN. Congenital intestinal atresia: observations on its origin. Lancet 1955; 2:I065. 14. Louw JH. Congenital atresia and stenosis of the small intestine. South African J Surg 1966; 4:57. 15. Louw JH, Cywes S, Davies MRQ et al. Congenital jejunoileal atresia: observations on its pathogenesis and treatment. Z Kinderchir 1980; 33:1. 16. Lloyd DA. From puppy dogs to molecules: small-bowel atresia and short-gut syndrome. S Afr J Surg 1999; 37:64. 17. Santulli TV, Blanc WA. Congenital atresia of the intestine: pathogenesis and treatment. Ann Surg 1961; 154:939. 18. Abrams JS. Experimental intestinal atresia. Surgery 1968; 64:185. 19. Kaga Y, Hayashida Y, Ikeda K et al. Intestinal atresia in fetal dogs produced by localized ligation of mesenteric vessels. J Pediatr Surg 1975; 10:949. 20. Tibboel D, Molenaar JC, van Nie CJ. New perspectives in fetal surgery: the chick embryo. 1. Pediatr Surg 1979; 14:438. 21. Nguyen DT, Lai E, Cunningham T, Moore TC. In utero intussusception producing ileal atresia and meconium peritonitis with and without free air. Pediatr Surg Int 1995; 10:406. 22. de Lorimier AA, Fonkalsrud EW, Hays DM. Congenital atresia and stenosis of the jejunum and ileum. Surgery 1969; 65:819.

23. Kimble RM, Harding JE, Kolbe A. Jejuno-ileal atresia, An inherited condition? Pediatr Surg Int 1995; 10:400. 24. Guttman EM, Braun I, Garance PH et al. Multiple atresia and a new syndrome of hereditary multiple atresia involving the gastrointestinal tract from stomach to rectum. J Pediatr Surg 1973; 8:66. 25. Mishalany HG, Najjar FB. Familial jejunal atresia: three cases in one family. J Pediatr 1968; 73:753. 26. Puri P, Fujimoto T. New observations on the pathogenesis of multiple intestinal atresias. J Pediatr Surg 1988; 23:221. 27. Martin LW, Zerella JT. Jejunoileal atresia: a proposed classiﬁcation. J Pediatr Surg 1976; 11:399. 28. Touloukian RJ. Intestinal atresia. Clin Perinatol 1978; 5:3. 29. Weitzmann JJ, Vanderhoof RS. Jejunal atresia with agenesis of the dorsal mesentery with ‘Christmas Tree’ deformity of the small intestine. Am J Surg 1966; 111:443. 30. Blyth H, Dickson JAS. ‘Apple-peel syndrome’. Med Genet 1969; 6:275. 31. Masumoto K, Suita S, Nada O, Taguchi T, Guo R. Abnormalities of enteric neurons, intesintal pacemaker cells, and smooth muscle in human intestinal atresia. J Pediatr Surg 1999; 34:1463. 32. Doolin EJ, Ormsbee HS, Hill JL. Motility abnormalities in intestinal atresia. J Pediatr Surg 1987; 22:320. 33. Tam PKH, Nicholls G. Implications of antenatal diagnosis of small-intestinal atresia in the 1990s. Pediatr Surg Int 1999; 15:486. 34. Haller JA, Tepas JJ, Pickard LR, Shermeta DW. Intestinal atresia. Current concepts of pathogenesis, pathophysiology and operative management. Am Surg 1983; 49:385. 35. Squire R, Kiely E. Postoperative feeding in neonatal duodenal obstruction. Abstract A9, British Association of Paediatric Surgeons 38th Annual International Congress, 24–26 July, Budapest, Hungary, 1991. 36. Millar AJW, Rode H, Cywes S. Intestinal atresia and stenosis. Chapter 30, pp 406–424, Pediatric Surgery, 3rd Edition. Ashcraft. WB Saunders, 2000. 37. Thomas CG Jr. Jejunoplasty for correction of jejunal atresia. Surg Gynecol Obstet 1969; 129:545. 38. Kling K, Applebaum H, Dunn J, Buchmiller T, Atkinson J. A novel technique for correction of atresia at the ligament of treitz. J Pediatr Surg 2000; 35:353. 39. Honzumi M, Okunda A, Suzuki H. Duodenal motility after tapering duodenoplasty for high jejunal and multiple intestinal atresia. J Pediatr 1993; 8:116. 40. Chaet MS, Warner BW, Sheldon Curtis A. Management of multiple jejunoileal atresias with an intraluminal silastic stent. J Pediatr Surg 1994; 29(12):1604. 41 Bishop HC, Koop CE. Management of meconium ileus. Ann Surg 1957; 145:410. 42. Rehbein F, Halsband H. The double tube technique for the treatment of meconium ileus and small bowel atresia. J Pediatr Surg 1968; 3:723. 43. Rosenmann JE, Kosloske AM. A reappraisal of the Mikulicz enterostomy in infants and children. Surgery 1982; 91:34.

456 Jejuno-ileal atresia and stenosis 44. Goulet OJ, Revillon Y, Jan D et al. Neonatal short bowel syndrome. J Pediatr 1991; 119:18. 45. Smith GHH, Glasson M. Intestinal atresia: factors affecting survival. Aust NZ J Surg 1989; 59:151.

46. Louw JH. Resection and end to end anastomosis in the management of atresia and stenosis of the small bowel. Surgery 1967; 62:940.

48 Colonic and rectal atresias TOMAS WESTER

COLONIC ATRESIA History According to Evans,1 Binninger for the ﬁrst time described colonic atresia in 1673. The ﬁrst survivor was reported in 1922 when Gaub2 opened a diverting colostomy in a child with an atresia of the sigmoid colon. Potts3 successfully performed a primary anastomosis in a neonate with an atresia of the transverse colon in 1947.

Incidence Atresia of the colon is a rare cause of low intestinal obstruction in the neonate. The incidence of colonic atresia related to live births has been difﬁcult to ascertain, but an incidence of approximately one in 20 000 live births has been considered to be realistic based on the experience in major pediatric surgical centers.4 In the north-west of England isolated colonic atresia has been reported to occur in one in 66 000 live births.5 Other investigators have reported that colonic atresias account for 1.8–10.5% of the total bowel atresias,6,7 the incidence of which has been estimated to be one in 1500 to one in 20 000 live births.1,8

Etiology Colonic atresia is probably the result of intrauterine vascular insufﬁciency. The ﬁnding of bile, squamous epithelium, and hair in the bowel distal to the atresia supports the hypothesis that the vascular accident occurs late in development.9 Several pathological conditions may result in compromised blood supply to the bowel, such as intussusception, volvulus, herniation, tight gastroschisis, and embolic or thrombotic events. It appears likely that focal resorption of the sterile gut occurs after ischemic necrosis. Animal experiments have been performed in which the blood supply was interrupted to different parts of the small intestine or colon,

thus inducing various types of atresias. These experiments conﬁrm the etiologic role of in utero vascular occlusion.9–11 Colonic atresia has been reported in monozygotic twins and genetic causes of colonic atresia have been discussed, although their role is not clear.12

Classiﬁcation Except for stenosis or incomplete occlusion of the colon, three different types of intrinsic occlusion have been distinguished: 1 Type I atresia or a membrane (Fig. 48.1a) 2 Type II atresia with blind ends of bowel joined together by a cord-like remnant of bowel, with or without a gap in the mesentery (Fig. 48.1b) 3 Type III atresia with separated blind ends of bowel and a gap in the mesentery (Fig. 48.1c).9,13 Furthermore, a hereditary form with multiple atresias of the gastrointestinal tract has been described, suggested to be of nonvascular origin.14,15 Type III atresia appears to be most common in atresias proximal to the splenic ﬂexure, whereas types I and II are more common in atresias distal to the splenic ﬂexure.16,17 Most series show an even distribution between atresias proximal and distal to the splenic ﬂexure.6,7,18,19

Associated anomalies Colonic atresia is associated with abdominal wall defects, such as omphalocele, gastroschisis and vesicointestinal ﬁssure, which complicates the management of the patient.4,17 Boles et al.17 found that four of their 11 patients had gastroschisis. In the series reported by Philippart,4 22 of 36 patients with colonic atresia had no associated anomalies, whereas six had vesicointestinal ﬁssures, and three had other abdominal wall defects. Five of the 36 patients in this series had jejunal atresia associated with the colonic atresia. Rarely, colonic atresia

458 Colonic and rectal atresias

anomalies, such as exophthalmos and optic nerve hypoplasia.16 In the series reported by Davenport et al.,5 one patient had trisomy 18 and esophageal atresia. The fact that chromosomal abnormalities do occur in patients with colonic atresia makes it reasonable to recommend chromosomal analysis, at least in those patients who have other associated anomalies.

Clinical presentation (a)

Neonates with colonic atresia present with symptoms of low intestinal obstruction. Abdominal distension is usually present at birth, but otherwise develops over the ﬁrst 24–48 hours of life. Vomiting of bile is very common, but this is not always an early symptom. Failure to pass meconium is the rule and neonates that do not pass meconium within the ﬁrst 24 hours of life should be viewed with suspicion. On examination the abdomen is distended and often slightly tender, sometimes with visible bowel loops. In those who have an abdominal wall defect, associated bowel atresias should always be suspected.

(b)

Diagnosis

(c) Figure 48.1 (a) Type 1: there is continuity of the outer layers of the bowel wall; the lumen is obstructed by a membrane covered with two layers of mucosa. (b) Type II: the bowel ends are connected by a ﬁbrous band and the mesentery is intact. (c) Type III: a defect in the mesentery is accompanied by a gap between the bowel ends

Prenatal diagnosis of colonic atresia has been reported. However, prenatally detected colonic dilatation may also be the result of Hirschsprung’s disease or anorectal malformations.22 Plain radiographs show a low bowel obstruction with multiple dilated loops with air-ﬂuid levels (Fig. 48.2a). A large right-sided loop, corresponding to the proximal dilated colon, has been considered characteristic in patients with colonic atresia.5 The level of obstruction is conﬁrmed by a contrast enema, which reveals the distal microcolon and incomplete colonic ﬁlling (Fig. 48.2b). Pneumoperitoneum, indicating colonic perforation, is not rare and has been reported in about 10% of the cases.4

Management has been reported to occur concomitantly with imperforate anus.7 Colonic atresia has also been reported in association with Hirschsprung’s disease in a few cases. Although the colonic atresia was diagnosed at birth in these patients, there was a considerable delay in diagnosing the associated aganglionosis. It is therefore recommended that the resected bowel is examined to rule out Hirschsprung’s disease, thus avoiding this diagnostic challenge.20 Rectal suction biopsies are suggested in patients that do not gain normal bowel function postoperatively.21 Isolated colonic atresia is also sometimes associated with skeletal anomalies such as syndactyly, polydactyly, absent radius, and clubfoot.4 Furthermore, colonic atresia has been reported in association with eye

Correction of ﬂuid and electrolyte abnormalities is started as soon as bowel obstruction is suspected. The gastrointestinal tract is decompressed with a nasogastric tube. Prophylactic antibiotics are administered. The neonate should be in a stable condition before the general anesthesia and operation are started. The two therapeutic options available are primary resection with anastomosis and primary colostomy with later anastomosis. Traditionally, many authors distinguished between the management of colonic atresias distal and proximal to the splenic ﬂexure. Atresias proximal to the splenic ﬂexure were treated with primary resection and anastomosis, whereas the distal atresias were treated with primary colostomy and delayed establishment of the gastrointestinal con-

Colonic atresia 459

(a)

tinuity.4,7,16,19,23 More recently, it has been suggested that staged repair should be undertaken in complex cases with, for instance, questionnable bowel viability, colonic perforation and peritonitis, and in patients with concomitant abdominal wall defects. On the other hand, in uncomplicated cases, resection and primary anastomosis is proposed to be the method of choice for atresias at all levels of the colon.24 There is no evidence that this later approach increases the mortality or complication rate.5 The abdomen is opened through a transverse incision one ﬁnger-breadth above the umbilicus and to the right. The incision may be extended as required. Cautery is used to divide the muscle layers of the abdominal wall and the umbilical vein is divided. The site and type of atresia is assessed. It is extremely important that additional atresias are excluded. The patency of the distal colon must always be tested by, for instance, injection of saline. In cases with colonic stenosis, a longitudinal incision, closed transversely is an alternative option for treatment. However, some authors have considered the experience with this approach to be limited and therefore recommended resection and primary anastomosis as a more reliable method.24 In those with type I atresias the bowel adjacent to the atresia is resected and a primary anastomosis is performed. In patients with types II and III atresias, with adequate bowel length, the excessively dilated proximal bowel should be resected (Fig. 48.3a). A few centimeters of the distal narrow bowel are also resected. The mesenteric vessels are divided close to the bowel wall to preserve the blood supply to the adjacent bowel. The distal bowel is incised along the antimesenteric border to achieve lumina of a similar size (Fig. 48.3b). A single-layer anastomosis is performed using interrupted 5-0 polydioxanone sutures (Fig. 48.4a–c). The wound is closed in layers with absorbable sutures, using subcuticular stitches for the skin. During the ﬁrst postoperative days parenteral nutrition is administered. Feeding can be started when the baby is well and the gastric aspirates have decreased.

Outcome

(b) Figure 48.2 (a) A plain abdominal radiograph often shows the hugely dilated bowel segment proximal to the atresia. (b) A contrast enema is diagnostic of a colonic atresia, as demonstrated in this infant with an isolated hepatic ﬂexure defect

Many factors have led to an improvement in the results of patients with colonic atresia, including early postnatal diagnosis, improved neonatal intensive care and anesthesia, and more efﬁcient transport facilities. Today, mortality related to the colonic atresia or its treatment is rare. In the series reported by Davenport et al.,5 no deaths occurred in the patients that underwent surgery, although one patient, who was never operated on, died of concomitant abnormalities. The mortality rate in earlier series varied from 9–33%, in many cases as a result of associated anomalies, but also attributable to late diagnosis, nutritional deﬁciencies, infectious complications, and technical errors.6,7,16,17,19 Powell et al.16 reported 15 postoperative complications in their 19

460 Colonic and rectal atresias

(a)

(a)

(b)

(c)

Figure 48.4 (a–c) The anastomosis is performed with a single layer of interrupted sutures

(b) Figure 48. 3 (a) The dilated proximal and the relatively ischemic portion of colon just distal to the atresia are resected. (b) The distal colon is incised along its antimesenteric border to match the luminal diameters of the two portions of bowel to be joined

patients. Problems related to the colostomy were encountered in three of 11 patients treated with colostomy and delayed anastomosis, whereas anastomotic strictures were seen in six of the 19 patients.16 Boles et al.17 reported signiﬁcant complications in four of 11 cases. The use of contemporary principles of neonatal surgery has, however, reduced the morbidity rate and Davenport et al.5 recently reported that their patients recovered without complications.

RECTAL ATRESIA Incidence Rectal atresia is a very rare lesion, which has been reported to account for 0.3–1.2% of all anorectal anomalies. 25–27 Interestingly, a much higher incidence of 14% has been reported from Tamilnadu in the southern part of India.28 The reason for this high incidence has been poorly understood. However, in recent years the incidence in Tamilnadu has been reduced and is now similar to that in other parts of the world. One possible reason for the reduction could be the national program

of care of pregnant mothers, in which they receive nutritional support consisting of folic acid and iron (Dorairajan, personal communication, 2000).

Etiology Magnus29 described the autopsy ﬁndings in a female neonate with multiple atresias of the small and large bowel, including a rectal atresia. It was found that there were intact remnants of the internal sphincter, that the epithelium of the anal canal was normally developed, and that the external sphincters were normal (Fig. 48.5). There was also a ﬁbromuscular band between the blind rectal pouch and the anal canal. Based on the ﬁndings in the autopsy specimen the author suggested that rectal atresia is the result of vascular insufﬁciency, rather than a developmental defect. It is speculated that this could be the result of an intrauterine infection. It was also estimated that the lesion occurred between the 65 mm and 112 mm stages of development. Dorairajan28 has suggested that the middle rectal artery is involved, rather than the superior rectal artery, which has been proposed by other investigators. The etiology of rectal atresia, involving vascular insufﬁciency, is thus identical to that proposed for small bowel and colonic atresias.

Classiﬁcation Although it has been proposed that rectal atresia should be classiﬁed as a colonic atresia,6 it is usually considered to be part of the spectrum of anorectal malformations.

Rectal atresia 461

lower bowel obstruction. The perineum and anal canal are normal and the diagnosis may therefore easily be delayed. The atresia is usually located 1–3 cm above the anal verge.

Diagnosis The condition is diagnosed when an attempt is made to pass a thermometer or a tube to decompress the colon. After a colostomy has been opened, a contrast study with simultaneous injection of contrast material through the colostomy into the rectal pouch and the anal canal clearly outlines the anatomy of the anomaly (Fig. 48.6). Figure 48.5 Diagrammatic representation of the anatomy in rectal atresia. Except for the high atresia, the anorectum is virtually normally developed

Rectal atresia was classiﬁed as a type IV anomaly in the Ladd and Gross classiﬁcation of anorectal anomalies.30 In the International classiﬁcation and the Wingspread classiﬁcation, it was classiﬁed as a separate type of high anomaly.31,32 In Peña’s classiﬁcation, rectal atresia is described as a separate entity.33,34 Five types of rectal atresia have been distinguished, namely: type 1 with a membrane and intact bowel wall; type 2 with blind ends separated by less than 2 cm, which is the most commonly encountered type; type 3 with a long distance between the blind ends; type 4, which is rectal stenosis; and type 5 with a urinary ﬁstula accompanying the rectal atresia.35

Management In the past, several different techniques, such as abdominoperineal, and sacroperineal pull-through procedures, referred to by Stephens and Smith37 and de Vries et al.38 were used to treat this condition. More recently, other methods have been described. Gauderer and Izant39 placed a string across the membrane using ﬂuoroscopy and progressively dilated the rectal canal in one patient. Zia-ul-Miraj Ahmad et al.40 used a Duhamel procedure in seven cases with rectal atresia or rectal

Associated anomalies The incidence of associated anomalies in patients with rectal atresia has been considered to be extremely low.36 In the series reported by Dorairajan,28 associated anomalies were found in 2% of the 147 cases. No signiﬁcant abnormalities were found in the urinary tract. Patients with rectal atresia usually have a normal perineum and a normal sacrum. However, associated malformations do occur and, for example, at the University Children’s Hospital, Sweden, the author and colleagues recently treated a boy with rectal atresia, who had a concomitant cardiac malformation and vertebral anomalies, similar to that usually seen in patients with Vertebral Anorectal Cardiac TracheoEsophageal Renal/Radial Limb (VACTERL) association. Rectal atresia also occurs in patients with multiple atresias of the bowel.29 Two of Dorairajan’s28 patients had ileal atresia and one had multiple small bowel atresias.

Clinical presentation Neonates with rectal atresia present with abdominal distension and failure to pass meconium, indicating a

Figure 48.6 Simultaneous injection of contrast material into the upper pouch (via the sigmoid colostomy) and the anorectum, clearly outlines the distance between the two pouches

462 Colonic and rectal atresias

stenosis. Dorairajan38 proposed a transverse colostomy in the newborn. At approximately 1 year of age the deﬁnitive procedure, a sacroperineal pull-through operation, was performed. If the blind rectal pouch ended above the pubococcygeal line, a sacroabdominoperineal or an abdominoperineal approach was preferred. The third stage comprised closure of the colostomy. In the ﬁrst edition of this textbook, Upadhyaya35 recommended his previously described approach, transanal end-to-end rectorectal anastomosis.41 One advantage of this technique is that luminal continuity is restored without injuring the functional anatomy of the region. A sigmoid colostomy is opened in the neonate. When the infant is approximately 3 months of age, the deﬁnitive procedure is performed. A Hegar dilator is advanced distally from the colostomy until it pushes the rectal pouch into the anal canal. The end of the anal canal is opened and the margins retracted with stay sutures. Then the rectal pouch is opened and the edges of the anal canal and the rectal pouch are approximated to form an end-to-end anastomosis. Peña et al.42 suggested that posterior sagittal anorectoplasty (PSARP) is a very successful method for the repair of rectal atresia and stenosis. It is recommended that a diverting colostomy be opened in the newborn with rectal atresia and the deﬁnitive procedure be performed at a later stage.33 A midline skin incision is performed and the levator muscle and muscle complex are separated exactly at the midline to expose the bowel. The blind end of the rectum is usually separated from the anal canal with a few millimeters of ﬁbrous tissue. The rectum has to be mobilized to allow an end-to-end anastomosis to be performed without tension. Then the wound is closed by reconstruction of the muscle structures. Postoperatively, daily dilatations are performed and the colostomy is closed approximately 3 months after the operation, provided the diameter is appropriate.42 Very few pediatric surgeons gain more than limited experience with the management of rectal atresia. However, in recent years many pediatric surgeons have become familiar with the posterior sagittal approach to treat other types of anorectal malformations. For this reason, an end-to-end anastomosis performed through the posterior sagittal approach seems to be a very attractive way to operate in the presence of rectal atresia. In utero repair of rectal atresia was recently reported in a fetus that also had a sacrococcygeal teratoma.43

Outcome In patients with rectal atresia, the anal canal, sacrum, and sphincteric mechanisms are virtually normal. Therefore, the prognosis with respect to functional outcome is favorable. Although the number of cases reported is very

limited, the outcome in patients with rectal atresia or stenosis treated through a posterior sagittal approach is excellent. Peña33 reported voluntary bowel movements with total continence and without soiling in all of his ﬁve cases. However, two of the ﬁve patients had constipation. Constipation has also been reported to occur frequently after other procedures used to treat rectal atresia or stenosis.40 Upadhyaya41 reported an uneventful recovery and normal continence in two patients treated with his method. Dorairajan28 was able to follow up 37 of 60 patients that were treated with sacroperineal pullthrough operations and who had their colostomy closed. The outcome was excellent in 20% of the patients, whereas 65% had occasional soiling at night and 15% had soiling also in daytime. The mortality rate in this series was 35%.

REFERENCES 1. Evans CW. Atresias of the gastrointestinal tract. International Abstracts of Surgery 1951; 92:1–8. 2. Gaub OC. Congenital stenosis and atresia of the intestinal tract above the rectum, with a report of an operated case of atresia of the sigmoid in an infant. Trans Am Surg Assoc 1922; 40:582–670. 3. Potts WJ. Congenital atresia of intestine and colon. Surg Gynecol Obstet 1947; 85:14–19. 4. Philippart AI. Atresia, stenosis, and other obstructions of the colon. In: Welch KJ, Randolph JG, Ravitch MM, O’Neill JA, Rowe MI, editors. Pediatric Surgery. 4th edn. Chicago,London, Boca Raton: Year Book Medical Publishers, 1986:984–8. 5. Davenport M, Bianchi A, Doig CM, Gough DCS. Colonic atresia: Current results of treatment. J R Coll Surg Edinb 1990; 35:25–8. 6. Freeman NV. Congenital atresia and stenosis of the colon. Br J Surg 1966; 53:595–9. 7. Benson CD, Lotﬁ MW, Brough AJ. Congenital atresia and stenosis of the colon. J Pediatr Surg 1968; 3:253–7. 8. Webb CH, Wangensteen OH. Congenital intestinal atresia. Am J Dis Child 1931; 41:262–84. 9. Louw JH. Investigations into the etiology of congenital atresia of the colon. Dis Colon Rectum 1964; 7:471–8. 10. Barnard CN, Louw JH. The genesis of intestinal atresia. Minn Med 1956; 39:745–748. 11. Louw JH, Barnard CN. Congenital intestinal atresia: observations in its origin. Lancet 1955; 2:1065–7. 12. Kim S, Yedlin S, Idowu O. Colonic atresia in monozygotic twins. Am J Med Genet 2000; 91:204–6. 13. Bland Sutton JD. Imperforate ileum. Am J Med Sci 1889; 98:457. 14. Guttman FM, Braun P, Garance PH. Multiple atresias and a new syndrome of hereditary multiple atresias involving the gastrointestinal tract from the stomach to rectum. J Pediatr Surg 1973; 8:633–634.

References 463 15. Puri P, Fujimoto T. New observations on the pathogenesis of multiple intestinal atresias. J Pediatr Surg 1988; 23:221–5. 16. Powell RW, Raffensperger JG. Congenital colonic atresia. J Pediatr Surg 1982; 17:166–70. 17. Boles ET, Vassy LE, Ralston M. Atresia of the colon. J Pediatr Surg 1976; 11:69–75. 18. Peck DA, Lynn HB, Harris LE. Congenital atresia and stenosis of the colon. Arch Surg 1963; 87:86–97. 19. Coran AG, Eraklis AJ. Atresia of the colon. Surgery 1969; 65:828–31. 20. Akgur FM, Olguner M, Hakguder G, Ozer E, Aktug T. Colonic atresia associated with Hirschsprung’s disease: it is not a diagnostic challenge. Eur J Pediatr Surg 1998; 8:378–379. 21. Kim PCW, Superina RA, Ein S. Colonic atresia combined with Hirschsprung’s disease: a diagnostic and therapeutic challenge. J Pediatr Surg 1995; 30:1216–17. 22. Anderson N, Malpas T, Robertson R. Prenatal diagnosis of colon atresia. Pediatr Radiol 1993; 23:63–4. 23. Defore WW, Garcia-Rinaldi R, Mattox KL, Harberg FJ. Surgical management of colon atresia. Surg Gynecol Obstet 1976; 143:767–9. 24. Oldham KT. Atresia, stenosis, and other obstructions of the colon. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, editors. Pediatric Surgery. St Louis: Mosby, 1998:1361–8. 25. Santulli TV, Schullinger JN, Kiesewetter WB, Bill AH. Imperforate anus: A survey from the members of the surgical section of the American Academy of Pediatrics. J Pediatr Surg 1971; 6:484–7. 26. Endo M, Hayashi A, Ishihara M et al. Analysis of 1992 patients with anorectal malformations over the past two decades in Japan. J Pediatr Surg 1999; 34:435–41. 27. Peña A. Posterior sagittal anorectoplasty: results in the management of 332 cases of anorectal malformations. Pediatr Surg Int 1988; 3:94–104. 28. Dorairajan T. Anorectal atresia. In: Stephens FD, Smith ED, Paul NW, editors. Anorectal malformations in children. New York: Liss, 1988:105–10. 29. Magnus RV. Rectal atresia as distinguished from rectal agenesis. J Pediatr Surg 1968; 3:593–8.

30. Gross RE. The surgery of infancy and childhood. Philadelphia & London: W B Saunders Company, 1953. 31. Stephens FD, Smith ED. Anorectal malformations in children. Chicago: Year Book Medical Publishers, 1971. 32. Stephens FD, Smith ED. Classiﬁcation, identiﬁcation, and assessment of surgical treatment of anorectal anomalies. Pediatr Surg Int 1986; 1:200–5. 33. Peña A. Anorectal malformations. Semin Pediatr Surg 1995; 4:35–47. 34. Kiely EM, Peña A. Anorectal malformations. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, editors. Pediatric Surgery. St Louis: Mosby, 1998:1425–48. 35. Upadhyaya P. Rectal atresia. In: Puri P, editor. Newborn surgery. Oxford: Butterworth-Heinemann, 1996: 395–8. 36. Peña A. Anorectal anomalies. In: Puri P, editor. Newborn Surgery. Oxford: Butterworth-Heinemann, 1996:379–94. 37. Stephens FD, Smith ED. Individual deformities in the male. In: Stephens FD, Smith ED, editors. Anorectal Malformations in Children. Chicago: Year Book Medical Publishers, 1971:33–80. 38. de Vries PA, Dorairajan T, Guttman FM et al. Operative management of high and intermediate anomalies in males. In: Stephens FD, Smith ED, Paul NW, editors. Anorectal Malformations in children: Update 1988. New York: Liss, 1988:317–401. 39. Gauderer MWL, Izant RJ. String placement and progressive dilatations in the management of high membranous rectal atresia. J Pediatr Surg 1984; 19:600–2. 40. Zia-ul-Miraj Ahmed M, Brereton RJ, Huskinsson L. Rectal atresia and stenosis. J Pediatr Surg 1995; 30:1546–50. 41. Upadhyaya P. Rectal atresia: transanal, end-to-end, rectorectal anastomosis: a simpliﬁed, rational approach to management. J Pediatr Surg 1990; 25:535–7. 42. Peña A, DeVries PA. Posterior sagittal anorectoplasty: important technical considerations and new applications. J Pediatr Surg 1982; 17:796–811. 43. Chiba T, Albanese CT, Jennings RW, Filly RA, Farrell JA, Harrison MR. In utero repair of rectal atresia after complete resection of a sacrococcygeal teratoma. Fetal Diagn Ther 2000; 15:187–90.

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49 Meconium ileus EDWARD KIELY

INTRODUCTION Neonatal small bowel obstruction by thick and tenacious meconium is known as meconium ileus (MI). A variable length of distal ileum is narrowed and ﬁlled with pellets of grey/green intestinal content of putty-like consistency. Proximal to this segment, the small bowel is dilated and ﬁlled with very adherent tenacious dark green meconium. The association of meconium ileus with pancreatic disease was ﬁrst recognized by Landsteiner.1 He described a newborn female who presented with intestinal obstruction. On the third day of life, a terminal ileostomy was fashioned in collapsed bowel ﬁlled with material likened to ‘glazier’s putty’. She did not survive and at the post-mortem, was diagnosed as having ﬁbrocystic disease of the pancreas. The majority – perhaps 80% – of infants with MI have cystic ﬁbrosis (CF).2,3 The remainder fall into two groups: full-term infants with non-CF MI and very low birth weight (VLBW) infants, often small for dates, who also have meconium obstruction. This latter group constitutes a small number of newborns presenting to surgeons with meconium obstruction. Of all infants born with CF, about 10–20% will present with MI.4,5

PATHOPHYSIOLOGY The abnormality in the meconium which results in MI is unclear. Earlier authors6 suggested that pancreatic insufﬁciency was the primary problem. Others have shown that the degree of pancreatic involvement is unrelated to the presence of MI;7 these authors have shown that abnormalities of the intestinal mucous glands were more prominent in infants with MI. It has also been shown that meconium from infants with MI contains 70% protein, mainly albumin, against 9% in normal controls.8 The albumin comes from swallowed amniotic ﬂuid.

Histologically the luminal content may be seen to extend into the mucosal glands over a wide area. The resulting adherence will impede the onward progress of meconium. At present however the mechanism underlying the development of the meconium found in the terminal ileum is not known. Neither is it clear why the obstruction should occur at this level in the intestine. On rare occasions signs of colonic obstruction predominate9 and are managed more easily. About half of patients with MI present with simple MI – luminal obstruction by meconium; the other half present with complicated MI – the underlying problem being complicated by volvulus, atresia, gangrene or perforation.10,11,12 The distended heavy loops of intestine appear to be prone to antenatal twisting and perhaps because of relative inﬂexibility are unable to untwist. On occasion the perforation gives rise to widespread peritonitis and on other occasions to a contained progressive cystic collection of ﬂuid.

GENETICS In Caucasian populations the incidence of CF is about one in 2000 live births.13 The disease is transmitted in autosomal recessive fashion and the gene is carried by about one in 20 of the population. The molecular basis of the genetic abnormality has yielded to an intense research effort. The defective gene has been localized to the long arm of chromosome 7.14–16 The gene encodes a membrane spanning protein – the CF transmembrane conductance regulator (CFTR).17–19 The CFTR protein is expressed in a wide variety of epithelial cells. It acts as a chloride channel and is activated by cyclic adenosine monophosphate (cAMP).20 More than 850 mutations of this CFTR gene have now been described. The commonest mutation is a three base pair deletion in the gene which results in loss of phenylalanine at codon 508 in the CFTR protein – the ΔF508 mutation.19

466 Meconium ileus

The reported frequency of the ΔF508 mutation across different CF populations is 68%.21 For the majority of affected individuals there is no correlation between genotype and phenotype in regard to severity of illness.22 However, the R117H genotype may be associated with a lesser incidence of MI.22 Recently a CF modiﬁer locus for MI has been found on chromosome 19.23 The manner in which the modiﬁer locus results in MI is unclear at present. It is apparent from studies on families that the recurrence rate for MI is higher than would be expected. In a study from Melbourne the recurrence risk for MI was 39% – twice the background rate of 18%.4 Finally it is unclear how the abnormal CFTR protein and the modiﬁer locus result in the clinical manifestations of CF and MI.

PRESENTATION Antenatal ultrasound scanning may detect abnormalities in the second and third trimesters. Distended loops of bowel with an echogenic bowel wall and echogenic meconium may be associated with MI.24–26 However, many such fetuses do not have CF and may need no postnatal treatment. Signs of meconium peritonitis, which include fetal ascites, calciﬁcation and bowel dilatation, may also be associated with MI but again many of these infants have a normal postnatal course.27,28The presence of a meconium cyst is associated with the likely need for postnatal treatment.28 At the time of delivery there may be a history of meconium-stained liquor. On occasion this represents bilious vomiting prior to delivery and this may delay recognition of the baby’s inability to pass meconium.29 Most infants are distended at birth. Vomiting commences later and the vomit is often green from the outset. Physical examination may reveal visible and palpable loops of distended intestine, which may indent on pressure. In the right lower quadrant, ﬁrm narrow loops of intestine are often palpable. Bowel sounds are usually present but infrequent. Rectal examination reveals a narrow rectum and there may be a little mucus on the ﬁnger when it is withdrawn. It is not usually possible to make a deﬁnitive diagnosis of MI on clinical grounds alone. A family history of CF will be important additional information and should always be sought under these circumstances. Differentiating between simple and complicated MI is frequently impossible on clinical grounds alone. On occasion a volvulus or perforation has occurred late in pregnancy and pronounced clinical signs are present. Pnemoperitoneum would be unusual but progressive abdominal wall erythema may be noted. This

latter sign is a result of bacteria reaching a section of gangrenous or perforated bowel. Giant cystic peritonitis occurs after an antenatal perforation which has been loculated. Subsequent ﬂuid accumulation may produce massive abdominal distension to the point where obstructed labor occurs. For the majority the signs are of a distal intestinal obstruction in an infant who is otherwise physiologically stable.

DIAGNOSIS Plain abdominal radiographs will reveal some distended air-ﬁlled loops of intestine (Fig. 49.1). When erect or decubitus ﬁlms are used, few air–ﬂuid levels are seen. In the right lower quadrant a soap bubble appearance may be noted – the result of air being mixed with meconium in the distal ileum (Fig. 49.1). This appearance is referred to as Neuhauser’s sign and is strongly suggestive of MI.30 If an abdominal ultrasound examination is performed, a distended, thick-walled intestine is noted, which is relatively inert and is ﬁlled with echogenic material. Intraperitoneal ﬂuid or an intraperitoneal cyst may be noted as well. About 13% of infants will show calciﬁcation on X-ray, the majority of which is intramural.31 A contrast enema will show a narrow, unused microcolon (Fig. 49.2). With persistence, contrast may enter

Figure 49.1 Plain X-ray showing distended loops of intestine and Neuhauser’s sign

Management 467

will produce a timely diagnosis when initial therapeutic measures are unsuccessful. Small bowel atresia is an operative diagnosis when non-operative measures have failed. A contrast enema will diagnose and treat the meconium plug and small left colon syndromes.35,36 Because of the known association of CF with meconium plug syndrome it would seem wise to positively exclude CF in babies who have this diagnosis.9

MANAGEMENT

Figure 49.2 Contrast enema showing micro colon and pellets in terminal ileum

the terminal ileum and outline collapsed bowel and intramural pellets of meconium. If there is further retrograde progression of contrast then dilated obstructed more proximal small bowel may be outlined. In countries where CF is common, routine screening of newborns is usual. This is done by measuring immunoreactive trypsin (IRT) in dried blood spots.32,33 Those with a positive result or those presenting with MI may progress to genetic analysis covering the more common mutations. Infants with MI usually present prior to the usual age of screening so do not beneﬁt from this measure. In addition these infants are too young to provide a sufﬁcient amount of sweat for a sweat test. Under these circumstances the quickest conﬁrmatory test for CF is usually genetic analysis.

DIFFERENTIAL DIAGNOSIS Initially all common causes of distal intestinal obstruction will be considered. These include Hirschsprung’s disease, small bowel atresia, meconium plug syndrome and small left colon syndrome. Hirschsprung’s disease extending into the ileum may produce a picture indistinguishable from CF-associated MI.34 A family history of Hirschsprung’s disease is more common with total colonic aganglionosis, but will not always be present. Only an awareness of the possibility

Initial management is as for any form of intestinal obstruction – nasogastric decompression, an i.v. infusion and consideration of broad-spectrum antibiotics. The likely diagnosis may have been entertained prior to a distal contrast study. Demonstration of a micro-colon raises the possibility of a therapeutic enema in addition. Various contrast solutions have been in use for years in an attempt to relieve the obstruction. In 1954 Olim and Ciuti described the successful use of a hydrogen peroxide enema in one patient.37 Donnison et al. reported 12 years later the use of pancreatin enemas for meconium ileus.10 Of 142 patients, 15 were successfully treated by this method. In 1969 Noblett described the successful use of Gastrograﬁn enemas for infants with meconium ileus.38 At that time, in addition to the X-ray contrast material, Gastrograﬁn contained Tween 80, a detergent. This is no longer present in the solution and it is not clear whether this makes the Gastrograﬁn less effective. The Gastrograﬁn is instilled by a catheter into the rectum under continuous X-ray screening. With patience and persistence, reﬂux through the ileocecal valve can frequently be obtained. The examination continues until the gas-ﬁlled distended bowel is reached. If this occurs then commonly the examination will be followed by the passage of large quantities of meconium over the next 6–8 hours. The manner by which Gastrograﬁn achieves its result is unclear. It is hyperosmolar and attracts a large quantity of ﬂuid into the intestine. This may serve to loosen the meconium from the bowel wall sufﬁciently enough to relieve the obstruction. Because of the potential for large ﬂuid shifts a reliable i.v. infusion should always be in place before undertaking the enema. On occasion, cardiovascular collapse is encountered but this is a relatively uncommon event and some other mechanism may be involved in infants who suffer this complication. Because of concern about the potential dangers of Gastrograﬁn, various other X-ray contrast materials have been used. A review of radiology departments in the USA and Canada suggested that the use of Gastrograﬁn was attended by the highest chance of success.39 Reported

468 Meconium ileus

success rates using Gastrograﬁn or other ﬂuids vary from 35–65%. In the institution of the author the success rate with this form of management in simple meconium ileus is 40%.2 The most feared complication of the enema technique is that of perforation. Perforations may occur either in the ileum or the colon and are usually recognized at the time. Late perforation can also occur.11,40 The reported perforation rate varies from 0–22% 41,42 with several reports being around the 10% level.43,44 Our own practice is to perform a single therapeutic enema using dilute Gastrograﬁn in cases with suspected simple MI. If dilated gas-ﬁlled bowel is reached the procedure is discontinued. If decompression does not occur we will consider a second enema. If the ﬁrst enema does not reach gas-ﬁlled loops then we would opt for immediate surgery. When simple MI is encountered at operation we would use enterotomy and irrigation. This procedure was ﬁrst popularized by Hiatt and Wilson in 1948;45 they treated eight infants in this manner of whom four survived to leave hospital. This method fell into disuse until it was repopularized in 1979 by Venugopal and Shandling.46 They reported on 12 infants treated by enterotomy and acetylcysteine irrigation, of which 11 survived. This favorable experience has been replicated by others,42 including ourselves.2 We now feel that this constitutes optimal management of infants with simple MI who come to surgery. We have used dilute Gastrograﬁn as the irrigation solution. The enterotomy is sited in dilated ileum several centimeters proximal to the obstructing pellets in the terminal ileum. Care is taken to shield the peritoneal cavity from the irrigation ﬂuid and bowel contents. The use of a catheter to perform the instillation is often described but frequently a syringe alone is sufﬁcient. Regardless of the method of instillation, patience and gentleness are necessary and the procedure may be prolonged. The enterotomy is closed with interrupted 7-0 extramucosal sutures. When dealing with complicated MI two scenarios may be encountered. The more common of these is an established perforation, cyst, volvulus or atresia; a less common situation is where the complication has occurred in the weeks preceding delivery. When performing deﬁnitive surgery for a complication of MI, a procedure involving resection and anastomosis is the most straightforward option. We have undertaken this in 17 patients with no anastomotic problems. We have used end-to-end anastomoses constructed with interrupted 6-0 or 7-0 sutures using an extramucosal technique.47 Others have reported similar success rates with resection and anastomosis.11,12,48,49 When the perforation of volvulus has occurred recently, the tissues in the abdomen may be extremely friable and hemorrhagic. Attempting a deﬁnitive procedure may produce severe and life-threatening

bleeding. Under these circumstances, the best option may be to make a stoma in the ﬁrst loop of gas containing bowel that is encountered. There seems little place for the chimney-type stomas which were previously widely used. The Bishop–Koop operation was ﬁrst described in 195750 and subsequently the Santulli stoma was described in 1961;51 these operations were devised when the operative mortality was in the region of 60% in the best centers.10 These methods were associated with an improved outcome at that time. Neonatal anesthesia, surgery and postoperative management have changed substantially and the early course of infants with CF has been transformed. Deﬁnitive procedures are usually possible at the present time and stomas are necessary only under exceptional circumstances. If a stoma is required then closure is usually possible after about 3 or 4 weeks, preceded by a distal contrast study. Intraperitoneal closure is the norm and other methods are outdated.

OUTCOME It is unusual for these babies to die at the present time. Because of the improved management of the common complications of CF, the survival of infants with MI differs little from that of other CF infants. Caniano and Beaver from Columbus OH, report a 100% survival rate in 42 neonates admitted between 1969 and 1984.11 We reported a 97% survival rate in 36 neonates admitted in the ten years to 1997.2 The impact of modern care is well shown by Mushtaq et al.,49 who reported a change in survival of 49% to 98% between the years 1953–70 and 1976–95. Postoperative complications are not uncommon. Del Pin et al.44 reported that 21 of 27 patients who had undergone a Bishop–Koop stoma closure required a further procedure. Those who had undergone resection and anastomosis required fewer subsequent procedures. We reported complications in ﬁve of 28 infants who had undergone laparotomy.2 Two infants who had undergone resection later developed adhesion obstruction. There were two infants who had stoma-related problems and ﬁnally, one patient who had undergone enterotomy and lavage had prolonged ileus. Fuchs and Langer reported long-term surgical complications in 20% of their surviving patients;52 these include adhesion obstruction in ﬁve patients. There were no late surgical problems in four patients who had undergone enterotomy and lavage. In addition there were no differences in overall status in these patients and a matched group of non-MI CF patients. In 1945 Swenson and Ladd reported that MI was uniformly fatal.53 At the end of the century virtually all infants with this condition now survive. In addition the

References 469

outlook for these infants does not seem different to nonaffected CF patients.

REFERENCES 1. Landsteiner K. Darmverschluss durch eingedicktes Meconium. Pankreatitis. Zentralb Allg Pathol 1905; 16:903–7. 2. Murshed R, Spitz L, Kiely E, Drake D. Meconium Ileus: A ten-year review of thirty six patients. Eur J Pediatr Surg 1997; 7:275–7. 3. Fakhoury K, Durie PR, Levison H, Canny GJ. Meconium ileus in the absence of cystic ﬁbrosis. Arch Dis Child 1992; 67:1204–6. 4. Allan JL, Robbie M, Phelan PD, Danks DM. Familial occurrence of meconium ileus. Eur J Pediatr 1981; 135:291–2. 5. Kerem E, Corey M, Kerem B et al. Clinical and genetic comparisons of patients with cystic ﬁbrosis, with or without meconium ileus. J Pediatr 1989; 114:767–73. 6. Farber S. The relation of pancreatic achylia to meconium ileus. J Pediatr 1944; 24:387–92. 7. Thomaidis TS, Arey JB. The intestinal lesions in cystic ﬁbrosis of the pancreas. J Pediatr 1963; 63:444–53. 8. Schutt WH, Isles TE. Protein in meconium from meconium ileus. Arch Dis Child 1968; 43:178–81. 9. Rosenstein BJ. Cystic ﬁbrosis presenting with the meconium plug syndrome. Am J Dis Child 1978; 132:167–9. 10. Donnison AB, Shwachman H, Gross RE. A review of 164 children with meconium ileus seen at the Children’s Hospital Medical Center, Boston. Pediatrics 1966; 37:833–50. 11. Caniano DA, Beaver BL. Meconium ileus: A ﬁfteen-year experience with forty-two neonates. Surgery 1987; 102:699–702. 12. Rescoria FJ, Grosfeld JL, West KJ, Vane DW. Changing patterns of treatment and survival in neonates with meconium ileus. Arch Surg 1989; 124:837–40. 13. Boat TF, Welsh MJ, Baudet AL. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989: 2649–80. 14. Knowlton RG, Cohen-Haguenauer O, Van Cong N et al. A polymorphic DNA marker linked to cystic ﬁbrosis is located on chromosome 7. Nature 1985; 318:380–2. 15. White R, Woodward S, Leppert M et al. A closely linked genetic marker for cystic ﬁbrosis. Nature 1985; 318:382–4. 16. Wainwright BJ, Scambler PJ, Schmidtke J et al. Localization of cystic ﬁbrosis locus to human chromosome 7cen-q22. Nature 1985; 318:384–5. 17. Rommens JM, Iannuzzi MC, Kerem B et al. Identiﬁcation of the cystic ﬁbrosis gene: Chromosome walking and jumping. Science 1989; 245:1059–65. 18. Riordan JR, Rommens JM, Kerem B et al. Identiﬁcation of the cystic ﬁbrosis gene: Cloning and characterization of complementary DNA. Science 1989; 245:1066–73.

19. Kerem B, Rommens JM, Buchanan JA et al. Identiﬁcation of the cystic ﬁbrosis gene: Genetic analysis. Science 1989; 245:1073–80. 20. Zielenski J. Genotype and phenotype in cystic ﬁbrosis. Respiration 2000; 67:117–33. 21. The Cystic Fibrosis Genetic Analysis Consortium. Worldwide survey of the DF508 mutation – report from the Cystic Fibrosis Genetic Analysis Consortium. AM J Hum Genet 1990; 47:354–9. 22. The Cystic Fibrosis Genotype – Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic ﬁbrosis. N Engl J Med 1993; 329:1308–13. 23. Zielenski J, Corey M, Rozmahel R et al. Detection of a cystic ﬁbrosis modiﬁer locus for meconium ileus on human chromosome 19q13. Nature Genet 1999; 22:128–9. 24. Shalev J, Navon R, Urbach D et al. Intestinal obstruction and cystic ﬁbrosis: antenatal ultrasound appearance. J Med Genet 1983; 20:229–30. 25. Caspi B, Elchalal U, Lancet M, Chemke J. Prenatal diagnosis of cystic ﬁbrosis: ultrasonographic appearance of meconium ileus in the fetus. Prenatal Diagnosis 1988; 8:379–82. 26. Sipes SL, Weiner CP, Wenstrom K et al. Fetal echogenic bowel on ultrasound: is there clinical signiﬁcance? Fetal Diagn Ther 1994; 9:38–43. 27. Foster MA, Nyberg DA, Mahony BS et al. Meconium peritonitis: Prenatal sonographic ﬁndings and their clinical signiﬁcance. Radiology 1987; 165:661–5. 28. Dirkes K, Crombleholme TM, Craigo SD et al. The natural history of meconium peritonitis diagnosed in utero. J Pediatr Surg 1995; 30:979–82. 29. Grifﬁths DM, Burge D. When is meconium stained liquor actually bile stained vomit? Arch Dis Child 1988; 63:201–2. 30. Neuhauser EBD. Roentgen changes associated with pancreatic insufﬁciency in early life. Radiology 1946; 46:319–28. 31. Lang I, Daneman A, Cutz E et al. Abdominal calciﬁcation in cystic ﬁbrosis with meconium ileus: radiologicpathologic correlation. Pediatr Radiol 1997; 27:523–7. 32. Crossley JR, Elliott RB, Smith PA. Dried – blood spot screening for cystic ﬁbrosis in the newborn. Lancet 1979; 1:472–4. 33. Wilcken B, Wiley V, Sherry G, Bayliss U. Neonatal screening for cystic ﬁbrosis: A comparison of two strategies for case detection in 1.2 million babies. J Pediatr 1995; 127:965–70. 34. Stringer MD, Brereton RJB, Drake DP et al. Meconium ileus due to extensive intestinal aganglionosis. J Pediatr Surg 1994; 29:501–3. 35. Clatworthy HW, Howard WHR, Lloyd JR. The meconium plug syndrome. Surgery 1956; 39:131–42. 36. Davis WS, Allen RP, Favara BE, Slovis TL. Neonatal small left colon syndrome. Am J Roentgenol Rad Ther Nuc Med 1974; 120:322–9.

470 Meconium ileus 37. Olim CB, Ciuti A. Meconium ileus: A new method of relieving obstruction. Ann Surg 1954; 140:736–40. 38. Noblett HR. Treatment of uncomplicated meconium ileus by Gastrograﬁn enema: A preliminary report. J Pediatr Surg 1969; 4:190–7. 39. Kao SC, Franken EA Jr. Nonoperative treatment of simple meconium ileus: a survey of the Society for Pediatric Radiology. Pediatr Radiology 1995; 25:97–100. 40. Ein SH, Shandling B, Reilly BJ, Stephens CA. Bowel perforation with nonoperative treatment of meconium ileus. J Pediatr Surg 1987; 22:146–7. 41. Docherty JG, Zaki A, Coutts JAP et al. Meconium ileus: a review 1972–1990. Br J Surg 1992; 79:571–3. 42. Waggett J, Bishop HC, Koop CE. Experience with Gastrograﬁn enema in the treatment of meconium ileus. J Pediatr Surg 1970; 5:649–54. 43. Nguyen LT, Youssef S, Guttman FM et al. Meconium ileus: Is a stoma necessary? J Pediatr Surg 1986; 21:766–8. 44. Del Pin CA, Czyrko C, Ziegler MM et al. Management and survival of meconium ileus. A 30-year review. Ann Surg 1992; 215:179–85. 45. Hiatt RB, Wilson PE. Celiac syndrome VII. Therapy of meconium ileus; report of eight cases with a review of the literature. Surg Gynecol Obstet 1948; 87:317–27.

46. Venugopal S, Shandling B. Meconium ileus: laparotomy without resection, anastomosis, or enterostomy. J Pediatr Surg 1979; 14:715–18. 47. Brain AJL, Kiely E. Use of a single layer extramucosal suture for intestinal anastomosis in children. Br J Surg 1985; 72:483–4. 48. Chappell JS. Management of meconium ileus by resection and end-to-end anastomosis. S Afr Med J 1977; 52:1093–4. 49. Mushtaq I, Wright VM, Drake DP et al. Meconium ileus secondary to cystic ﬁbrosis. The East London experience. Pediatr Surg Int 1998; 13:365–9. 50. Bishop HC, Koop CE. Management of meconium ileus: Resection, Roux-en-Y anastomosis and ileostomy irrigation with pancreatic enzymes. Ann Surg 1957; 145:410–14. 51. Santulli TV, Blanc WA. Congenital atresia of the intestine: pathogenesis and treatment. Ann Surg 1961; 154:939–48. 52. Fuchs JR, Langer JC. Long-term outcome after neonatal meconium obstruction. Pediatrics 1998; 101:e7. 53. Swenson O, Ladd WE. Surgical emergencies of the alimentary tract of the newborn. N Engl J Med 1945; 233:660–3.

50 Meconium peritonitis JOSE BOIX-OCHOA AND J. LLORET

INTRODUCTION Meconium peritonitis is an aseptic peritonitis caused by spill of meconium in the abdominal cavity through one or several intestinal perforations which have taken place during intrauterine life. Extravasation of sterile meconium into the fetal peritoneal cavity causes an intense chemical and foreign body reaction with characteristic calciﬁcation. Often, the perforation seals before the infant is born. Gastrointestinal perforations that occur following birth, even though the gut still contains meconium, constitute an entirely different group of clinical problems and should not be included in the syndrome of ‘meconium peritonitis’.1,2 Meconium peritonitis was ﬁrst reported by Morgagni in 1761 in ‘De Sedibus et Causis Morborum’. Simpson3 managed to ﬁnd 25 cases in 1838 and it was Agerty4 in 1943 who reported the ﬁrst successful operation. A review of the world literature up to 1995 revealed 1309 cases of meconium peritonitis with 603 survivors (Table 50.1). Previous collected series have made this task easier.5–11 The current authors’ experience is based on 53 cases of pure meconium peritonitis who underwent surgical treatment. All of these patients presented with the classical picture of meconium peritonitis at laparotomy and have histological evidence of: (1) meconium inclusions (Fig. 50.1) or reaction to foreign bodies, and (2) visible perforation or microscopic evidence of intestinal cicatrization. Table 50.1 Mortality rate in meconium peritonitis among 1309 cases reported in the world literature Years

Total

Survivors

Mortality (%)

Before 1952 1952–62 1963–68 1969–88 1989–95

100 102 145 752 210 1309

8 19 51 375 150 603

92.0 81.4 64.8 50.1 28.6 54.0

Figure 50.1 Granulomatous tissue with giant cells of foreign bodies related to meconial corpuscles

ETIOLOGY Intrauterine intestinal perforation may result from various causes. Patients with meconium peritonitis are divided into those with and without associated intestinal obstruction. In the case of meconium peritonitis without obstruction there is no clear-cut explanation for the perforation. Various hypotheses, such as segmental absence of the muscular coats,12 absence of the muscularis mucosa,13 vascular occlusion14 and general hypoxia of the fetus in the perinatal period15 have been put forward. None of these hypotheses has been substantiated. In the current authors’ research with rats, it has been clearly demonstrated that all these ﬁndings are a consequence of meconium peritonitis and not primary etiology.16 In the current authors’ experience, intestinal atresia, intestinal volvulus and meconium ileus constitute 94% of etiological factors (Table 50.2). Other causes include Hirschsprung’s disease, meconium plug syndrome, congenital bands, internal hernias, Meckel’s diverticulum and rectal perforation. However, in some cases it is impossible to ﬁnd its etiology, in spite of pathological changes. The tabulation of the medical and perinatal

472 Meconium peritonitis Table 50.2 Associated congenital malformations and operative ﬁndings Malformation Intestinal atresia Volvulus Meconium ileus Other

Total

Survivors

Mortality (%)

33 8 9 3

29 4 5 3

12.1 50.0 44.0 0.0

reports demonstrated that 80% of these patients had neonatal anoxia and respiratory distress. Labor research demonstrates the consequences of the hypoxia on the splanchnic area and blood distribution in the studied animals.17,18 If these ﬁndings are correlated with the current authors’ studies, it can be postulated that there is diminished blood ﬂow to the intestine of the hypoxic infant. The mucosa, which is very sensitive to ischemia, undergoes diminished mucin production and degenerative alterations. The proteolytic enzymes can now attack the bowel wall, which is normally protected by mucin. The consequence of this is a break in the mucosal integrity followed by perforation. Sometimes the ‘jamming’ of this reﬂex mechanism prevents the return to normality and can cause such severe ischemia that it leads directly to a covered perforation. The less vascularized zones, and therefore the more exposed to ischemia and perforation, are situated in the ileocecal region and splenic ﬂexure, where the current authors have found 60% of all idiopathic lesions.

PATHOLOGY In the current authors’ experimental work with rats, it has been shown that meconium gives rise to a peritoneal reaction with rapid ﬁbroblastic proliferation enveloping the lesion. Later, foreign body granulomas and calciﬁcations are seen. This reaction may be local or generalized, the parietal peritoneum having lost its sheen. The intestinal loops are intimately adherent structures with a ﬁbrous tissue which is difﬁcult to dissect, calciﬁcations or meconial inclusions are disseminated, and the perforation is hard to identify. When the intestinal perforation does not cicatrize and there is a ﬁbrinous reaction instead, the consequence is the formation of a cyst, the walls of which are formed of ﬁbrin, meconium and intestinal loops intimately united. Such a cyst may occupy two-thirds of the abdomen (Fig. 50.2). The possibility of meconium spreading out by a hemathologic or lymphatic route (via the brain or lungs) has been described.19 Lorimer and Ellis described three major types of meconium peritonitis: ﬁbro-adhesive, generalized and cystic.20 Two other types which have been described are

Figure 50.2 Typical roentgenogram of a giant meconium cyst. Prenatal ileal perforation was secondary to atresia of ileum

the healed form of meconium peritonitis and microscopic meconium peritonitis. The ﬁbro-adhesive type is the result of an intense ﬁbroblastic reaction in response to the severe chemical peritonitis caused by the digestive enzymes in the meconium. This type produces obstruction by adhesive bands and the site of perforation is usually sealed off. The cystic type occurs when the site of perforation is not effectively sealed and a thick-walled cyst is formed by the ﬁxed intestinal loops.21–24 This condition prevents communication of the perforation with the remainder of the viscera. Calcium deposits line the cyst wall. The generalized type usually occurs perinatally.25–31 Calciﬁed meconium is scattered throughout the peritoneal cavity and the bowel loops are adherent by thin ﬁbrinous adhesions. In the current authors’ experience, this is the most frequent type (74% of all cases). The healed form of meconium peritonitis, presenting as an inguinal or scrotal mass, is clinically and pathologically of special interest. These patients usually present with no relevant recent clinical history, although the majority show a unilateral hydrocele at birth. Radiological studies of the scrotum and abdomen are usually helpful in making the diagnosis by demonstrating scrotal as well as peritoneal calciﬁcations.32–41 This combination is pathognomonic of meconium peritonitis.33,40,41 In some cases the peritoneal calciﬁcations are the only symptomatology. In cases in which the diagnosis can be established clinically, no surgical intervention is necessary and, in the majority of these cases, the nodules regress spontaneously.42–45 Microscopic examination of the resected specimen shows a ﬁbrosis of the serous membrane, dissociation of the muscular layer, foci of calciﬁcation and granulomatous lesions with foreign body giant cells. There is another type of microscopic meconium peritonitis described by Molenaar,46 without clinical or therapeutic signiﬁcance. In the majority of cases it is a casual ﬁnding during laparotomy for other causes (Fig. 50.3). Many patients with this ‘microscopic’ type of

Symptomatology and diagnosis 473

Figure 50.3 Causal ﬁnding of calciﬁcations on an intestinal atresia without the clinical evidence and operative ﬁndings of meconium peritonitis. This case is not included in our material

meconium peritonitis present with atresia and the current authors feel that such an atresia should be regarded as scarring of the site of a perforation which must have occurred at a relatively early stage of fetal development. A careful microscopic examination of the visceral and parietal peritoneum will, however, reveal bile pigment and/or squamous cell remnants. The presence of these meconium components proves that a perforation must have occurred. The presence of collagen, calcium deposits and giant cells surrounding meconium particles indicates that the peritoneal cavity must have contained meconium for a considerable length of time. Its etiology should be examined for intestinal perforations at an early stage of development, resulting in intestinal atresia induced by a vascular lesion. At other times, the perforation can achieve complete recovery and not lead to any signiﬁcant tissue deterioration; the only remnant of this pathology is the microscopic meconium peritonitis as a casual ﬁnding and without clinical signiﬁcance.

prevented the physiological descent of the testicles. Pathognomonic of this is the appearance of a scrotal edema or hydrocele with retention of the testes and intrascrotal calciﬁcation.47 X-ray and ultrasound48 examination show the intestinal ileus, the ascites when it exists, the ground-glass appearance of the abdomen due to the meconium and rarely the presence of a pneumoperitoneum, since the quick formation of adhesions prevents the intestinal gas from escaping. Intra-abdominal calciﬁcations are characteristic49–51 and can easily be seen on plain abdominal ﬁlms (Fig. 50.4). It is the current authors’ belief that the origin of these calciﬁcations may be the catalytic effect of the fatty meconial compounds on the precipitation of calcium salts. Proof of this is that in their investigations in laboratory animals with low serum levels of calcium, it has not been possible to reproduce calciﬁcations. Faripor52 is of the opinion that the pathogenesis of calciﬁcations, after the analysis of seven cases with light microscopic observation, is undoubtedly in response to keratin debris. Keratin, however, cannot be the only source because of the presence of granulomas devoid of keratin. Due to the fact that some of these granulomas resemble gouty tophi, it may be as a result of inﬂammation caused by uric acid present in meconium. So early do the calciﬁcations appear, that the prenatal diagnosis of meconium peritonitis is easily made on sonographic examination.53–66 The diagnosis of associated pathology is of vital importance because of its repercussions in the immediate postoperative period.67,68 Finkel and Slovis indicate that the presence of intraperitoneal calciﬁcation does not exclude but favors a diagnosis of cystic ﬁbrosis,69 in spite of the fact that they are scarcer than in the other types of meconium peritonitis.

SYMPTOMATOLOGY AND DIAGNOSIS The diagnosis of meconium peritonitis in the postnatal period is based on clinical and radiological, and ultrasonographic ﬁndings of intestinal obstruction, and occasionally one or more of the following: calciﬁcation, pneumoperitoneum, cyst formation or ascites. The clinical symptomatology is that of any intestinal obstruction. A typical baby with meconium peritonitis is born with abdominal distension, or develops it soon after birth, and this is accompanied by bile-stained vomiting and failure to pass meconium. Occasionally, severe abdominal distension may result in dystocia or respiratory distress. Sometimes, cryptorchidism is the indication that the fetal abdominal pathology has

Figure 50.4 Pathognomonic abdominal calciﬁcation in a case of meconium peritonitis

474 Meconium peritonitis

Newborns presenting with scrotal swelling with or without discoloration resulting from calciﬁed meconium within the patent processus vaginalis have been described with increased frequency.36,41,42 Early diagnosis is a decisive factor for the prognosis of these newborns, because the commencement of bacterial colonization of the meconium starts after birth. In a study carried out by the current authors in 134 normal newborns, meconium cultures were positive in 24% at 12 hours of life and in 86% at 72 hours.16 On the other hand, the laboratory studies carried out by the current authors already demonstrated the existence of a ‘meconium spreading factor’ which accelerates and worsens the sepsis. Owing to this, it is not then surprising that early diagnosis is of paramount importance. In the current authors’ series of 53 cases, the patients that were operated on after 36 hours of life had a mortality rate three times higher than those that were operated on during the ﬁrst 24 hours of life (Table 50.3). Tibboel and Molenaar11 reported a 91% mortality rate for patients operated on after 48 hours of life. The natural history of meconium peritonitis diagnosed in utero is markedly different from that diagnosed in the newborn because some cases diagnosed prenatally normalize spontaneously during the gestational followup. The normal ultrasound features are polyhydramnios, fetal ascitis, intra-abdominal calciﬁcations and dilated intestinal loops.70 Dirkes71 reported that only 22% of fetuses with prenatal diagnosis of meconium peritonitis developed complications that required surgery, and the overall mortality rate in their series was 11%. Table 50.3 Time of operation related to prognosis Time < 24 hours postnatally 24–36 hours 36–48 hours > 48 hours

Total

Survivors

Mortality (%)

19 24 6 4 53

17 19 4 1 41

10.0 20.8 33.0 75.0 22.6

TREATMENT The indication for operation in newborns with meconium peritonitis is a clear sign of intestinal obstruction or perforation. The diagnosis of meconium peritonitis without intestinal obstruction or pneumoperitoneum does not constitute an indication for operation. Infants with neonatal meconium calciﬁcation, meconium ascites with hydrocele, or calciﬁed meconium found in the hernial sac do not require operation, but they have to be observed and feeding withheld for 48 hours. With an absence of clinical symptoms, enteral feeding can be started with caution, gradually progressing to formula. Antibiotic coverage is desirable.

Surgical treatment All the conditions for the preparation of the newborn for surgery, such as monitoring for vital signs, control of temperature and measures for impeding its loss and ambient temperature in the operating theater, should be adhered to. An i.v. cannula should be placed for i.v. ﬂuids. Blood should be cross-matched and prophylactic antibiotics started.

OPERATIVE TREATMENT Based on our experience of 53 cases and with a survival rate of 82% in the past 12 years, the current authors act according to the following protocol: 1 If the perforation is visible, do not try to suture it. Intestinal resection and end-to-end anastomosis is performed. 2 In cases of localized or generalized peritonitis, attempt the lysis of the adhesions only to discover the perforation or to relieve obvious obstructions. Only when necessary should an attempt be made to dissect the adhesions, since ﬁbro-adhesive peritonitis disappears after 8–14 days; this has been conﬁrmed in the current authors’ patients who had the twostage operation and investigation with laboratory animals. 3 Once the etiology has been determined (atresia, stenosis, or meconium ileus), an attempt must be made to perform an end-to-end anastomosis, according the Louw’s technique72 if the condition of the patient and the difference in the intestinal calibers allow it. The two-stage operation of Rehbein7 (exteriorization followed by laparotomy and anastomosis) is used only if the patient’s condition is very serious, or if the existing peritonitis can endanger the suture line, or when there are great differences in caliber of the two loops of bowel. The anastomosis is performed 2 weeks later, if the newborn’s general status allows the second stage of the operation. During the interval between the two operations, enteral and total parenteral nutrition are indispensable for maintaining the newborn in the best condition as well as the stimulation of the distal portion with the contents of the proximal end. The two-stage operation offers a series of advantages that should always be considered by the surgeon: • The rapid solution of the surgical problem • It allows the surgeon to deal with the peritonitis which would endanger the suture in a one-stage operation • It allows recovery of the general state of the patient with the increase of energy reserves by means of parenteral nutrition and antibiotic therapy • It gives time for the disappearance of bowel adhesions and the normalization in caliber and

References 475

absorptive function of the intestinal mucosa by means of the growth stimulation offered by perfusion of the enteral diet through a soft silicone feeding tube in the distal portion • It allows the maturation of the neuroendocrine system. The two-stage operation has been associated with a lower mortality rate in the current authors’ series when compared with the one-stage operation (17.9% vs 28%). 4 When faced with a meconial cyst, in view of the small number of successful cases published,20,73–75 the current authors always perform decortication with great care and a two-stage operation.76 Another option is cyst drainage by ultrasound-guided punction and later laparotomy.77 To summarize, the current authors are convinced that the low morbidity rate achieved by them is due to the planning of the operation in two stages, whenever faced with the slightest doubt as to the probable success of a primary anastomosis. With early diagnosis, the advances in surgical techniques and postoperative treatment, current survival of the patients with meconium peritonitis is near to 100%.78

COMPLICATIONS Among the postoperative complications, adhesion ileus is the most frequent. In the current authors’ series of 53 patients, six developed adhesion ileus, four had anastomotic leakage, two had necrosis of the ileostomy stump and one had an enterocutaneous ﬁstula. There were 12 deaths in the series, six directly attributable to lung complications in patients with cystic ﬁbrosis. The other six patients died of sepsis.

REFERENCES 1. Cerise EJ, Whitehead W. Meconium peritonitis. Am Surg 1969; 35:389. 2. Marchildon MB. Meconium peritonitis and spontaneous gastric perforations. Clin Perinatol 1978; 5:79. 3. Simpson JY. Peritonitis in the fetus in utero. Edinb Med Surg J 1838; 15:390. 4. Agerty HA. A case of perforation of the ileum in newborn infant with operation and recovery. J Pediatr 1943; 22:233. 5. Tow A, Hurwit ES, Wolff JA. Meconium peritonitis. Am J Dis Child 1945; 87:193. 6. White R. Meconium peritonitis. A surgical emergency. J Pediatr 1956; 48:793. 7. Rehbein F. Mekonium peritonitis. Chirurg 1959; 301:15–19.

8. Marion M et al. Les peritonites neonatales. Pediatrie 1962; XVII (3L):259. 9. Payne RM, Nielsen SM. Meconium peritonitis. Am Surg 1962; 28:224. 10. Boix-Ochoa J. Meconium peritonitis. J Pediatr Surg 1968; 3:715–22. 11. Tibboel D, Molenaar JC. Meconium peritonitis. A retrospective, pronostic analysis of 69 patients. Z Kinderchir 1984; 39:25–8. 12. Moretti J. Su di un caso di atresia congetia dell’ileo e peritonite cronica adesiva da meconio. Minerva Pediatr 1949; 1:239. 13. Rickham PP. Peritonitis of the neonatal period. Arch Dis Child 1955; 30:23. 14. Vilhena-Moraes R, Cappellano G, Mattosinho Franca LC et al. Peritonite meconial. Rev Paul Med 1964; 65:231. 15. Lloyd JR. The etiology of gastrointestinal perforations in the newborn. J Pediatr Surg 1969; 3:77. 16. Boix-Ochoa J. Patologia quirurgica del meconio. Med Esp 1982; 81:30–51. 17. Scholander PF. The master switch of Life. Sci Am 1963; 209:92–4. 18. Johanssen K. Regional distribution of circulating blood during submersion asphyxia in the duck. Acta Physiol Scand 1964; 62:1–3. 19. Patton WL, Lutz AM, Willmann JK et al. Systemic spread of meconium peritonitis. Pediatr Radiol 1998; 28:714–16. 20. Lorimer WS, Ellis DG. Meconium peritonitis. Surgery 1966; 60: 470–5. 21. Dickinson SJ, Moumgis B. Prenatal volvulus with pseudocyst perforating the perineum. J Pediatr Surg 1966; 1:288–91. 22. Kolawole TM, Bankole MA, Olurin EO et al. Meconium peritonitis presenting as giant cysts in neonates. Br J Radiol 1973; 46:964–7. 23. Tosovsky V, Kabelka M, Kolihova E. Encapsulated form of meconial peritonitis. Rozhl Chir 1975; 54:626–7. 24. Wedge JJ, Grosfeld JL, Smith JP. Abdominal masses in the newborn: 63 cases. J Urol 1971; 106:770–5. 25. Bednarz R, Konieczny J. Meconium peritonitis. PoI Przegl Chir 1978; 50:711–12. 26. Bhattacharyya R, Sadhu B. Meconium peritonitis with complication. Indian Pediatr 1969; 6:34–40. 27. Ceballos R, Hicks GM. Plastic peritonitis due to neonatal hydrometrocolpos: radiologic and pathologic observations. J Pediatr Surg 1970; 5:63–70. 28. Fonkalstrud EW, Ellis DG, Clatworthy HW Jr. Neonatal peritonitis. J Pediatr Surg 1966; 1:227–39. 29. Gugliantini P, Caione P, Rivosecchi M et al. Intestinal perforation in newborn following intrauterine meconium peritonitis. Pediatr Radiol 1979; 8:113–15. 30. Gupta S, Jayakrishnan VP, Bhama T et al. Meconium peritonitis. Indian J Pediatr 1967; 34:88–91. 31. Kiesewetter WB. Peritonitis in infancy and childhood. Am Fam Physician 1972; 5:105–12. 32. Berdon WE, Baker DH, Wigger HJ et al. Calciﬁed intraluminal meconium in newborn males with

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imperforate anus. Enterolithiasis in the newborn. Am J Roentgenol Radium Ther Nucl Med 1975; 125:449–55. Cook PL. Calciﬁed meconium in the newborn. Clin Radiol 1978; 29:541–6. Dodat H, Chappuis JP, Daudet M et al. Meconial peritonitis. Recordings about six observations. Diagnostic and prognostic value of calciﬁcations. Therapeutic given off (author’s transl). Chir Pediatr 1979; 20:21–6. Fletcher BD, Ullish BS. Intraluminal calciﬁcations in the small bowel of newborn infants with total colonic aganglionosis. Radiology 1978; 126:451–5. Gunn LC, Ghionzoli OG, Gardner HG. Healed meconium peritonitis presenting as a reducible scrotal mass. J Pediatr 1978; 92:847. Heydenrych JJ, Marcus PB. Meconium granulomas of the tunica vaginalis. J Urol 1976; 115:596–8. Katayama H, Inoue T, Tsunoda S et al. Radiographic picture of meconium peritonitis: an autopsy report. Jpn J Clin Radiol 1977; 22:509–12. Leonidas JC, Berdon WE, Baker DH et al. Meconium ileus and its complications. A reappraisal of plain ﬁlm roentgen diagnostic criteria. Am J Roentgenol Radium Ther Nucl Med 1970; 108:598–609. Marchese GS. Radiographic appearance of intestinal blockages in the newborn. Panminerva Med 1965; 7:300–2. Thompson RB, Rosen DI, Gross DM. Healed meconium peritonitis presenting as an inguinal mass. J Urol 1973; 110:364–5. Berdon WE, Baker DH, Becker J, De Sanctis P. Scrotal masses in healed meconium peritonitis. N Engl J Med 1967; 277:585–7. Heetderks DR Jr, Verbrugge GP. Healed meconium peritonitis presenting as a scrotal mass in an infant. J Pediatr Surg 1969; 4:363–5. Kalayoglu M, Sieber WK, Rodnan JB et al. Meconium ileus: critical review of treatment and eventual prognosis. J Pediatr Surg 1971; 61:290–300. Roscioli B, Bassetti D. A case of meconial peritonitis with favourable spontaneous evolution. Pathologica 1969; 61:255–9. Tibboel D, Gaillard JL, Molenaar JC. The ‘microscopic’ type of meconium peritonitis. Z Kinderchir 1981; 34:9–16. Olnick HM, Hatcher MB. Meconium peritonitis. J Am Med Assoc 1953; 152:582. Graziani M, Bergami GL, Fasanelli S. Fibroadhesive meconium peritonitis: ultrasonographic features. J Pediatr Gastroenterol Nutr 1994; 18:241–3. Smith B, Clatworthy HW. Meconium peritonitis: prognostic signiﬁcance. Pediatrics 1961; 27:967. Harris JH. Meconium peritonitis. Am J Roentgenol 1956; 76:555. Miller JP, Smith SD, Newman B et al. Neonatal abdominal calciﬁcation: is it always meconium peritonitis?. J Pediatr Surg 1988; 23:555–6. Faripor F. Origin of calciﬁcation in healed meconium peritonitis. Med Hypoth 1984; 14:51–6.

53. Brugman SM, Bjelland JJ, Thomasson JE et al. Sonographic ﬁndings with radiologic correlation in meconium peritonitis. J Clin Ultrasound 1979; 7:305–6. 54. Bowen A, Mazer J, Zarabi M et al. Cystic meconium peritonitis: ultrasonographic features. Pediatr Radiol 1984; 14:18–22. 55. Kenney PJ, Spirt BA, EIlis DA et al. Scrotal masses caused by meconium peritonitis: prenatal sonographic diagnosis. Radiology 1985; 154:362. 56. Blumental DH, Rushovich AM, WiIliams RK et al. Prenatal sonographic ﬁndings of meconium peritonitis with pathologic correlation. J Clin Ultrasound 1982; 10:350–2. 57. Dunne M, Haney P, Sun CCJ. Sonographic features of bowel perforation and calciﬁc meconium peritonitis in utero. Pediatr Radiol 1983; 13:231–3. 58. DeCurtis M, Martinelli P, Saitta F et al. Prenatal ultrasonic diagnosis of meconium peritonitis in a preterm infant. Eur J Pediatr 1983; 141:51–2. 59. Garb M, Riseborough J. Meconium peritonitis presenting as fetal ascites on ultrasound. Br J Radiol 1980; 53:602–4. 60. Hartung RW, Kilcheski T, Hreaney RB et al. Antenatal diagnosis of cystic meconium peritonitis. J Ultrasound Med 1983; 21:49–50. 61. Lauer JD, Cradock TV. Meconium pseudocyst: prenatal sonographic and antenatal radiologic correlation. J Ultrasound Med 1982; 1:333–5. 62. McGahan JP, Hanson F. Meconium peritonitis with accompanying pseudocyst: prenatal sonographic diagnosis. Radiology 1983; 148:125–6. 63. Nancarrow PA, Mattrey FR, Edwards DK et al. Fibroadhesive meconium peritonitis in utero: sonographic diagnosis. J Ultrasound Med 1985; 4:213–15. 64. Schwimer SR, Vanley GT, Reinke RT. Prenatal diagnosis of cystic meconium peritonitis. J Clin Ultrasound 1964; 12:37–9. 65. Williams J, Nathan RO, Worthen NJ. Sonographic demonstration of the progression of meconium peritonitis. Obstet Gynecol 1984; 64:822–6. 66. Diakoumakis EE, Weinberg B, Beck AR et al. A case of meconium peritonitis with ileal stenosis: prenatal sonographic ﬁndings with radiological correlation. Mt Sinai J Med 1986; 53:152–3. 67. Boureau M, Prot D. Valeur diagnostique des calciﬁcations intráperitonéales au cours de la peritonite meconiale. J Parisiennes Pediatr 1974; 149. 68. Kuffer F. Die meconiumperitonitis. Schweiz Med Wochschr 1968; 98:1109. 69. Finkel LI, Slovis TL. Meconium peritonitis, intraperitoneal calciﬁcations and cystic ﬁbrosis. Pediatr Radiol 1982; 12:92–3. 70. Estroff JA, Bromley B, Benacerraf BR. Fetal meconium peritonitis without sequelae. Pediatr Radiol 1992; 22:277–8. 71. Dirkes K, Crombleholm TM, Craigo SD et al. The natural history of meconium peritonitis diagnosed in utero. J Pediatr Surg 1995; 30:979–82.

References 477 72. Louw MB. Resection and end to end anastomosis in the management of atresia and stenosis of small bowel. Surgery 1967; 62:940. 73. Moore TC. Giant cystic meconium peritonitis. Ann Surg 1963; 556. 74. Coerper C, Daum R, Hecker W. Beitrag zur Klinik der Mekonium peritonitis. Bruns Beitr Klin Chir 1965; 211:160. 75. Rao YS, Murthy TV. Giant cystic meconium peritonitis. Indian Pediatr 1983; 20:773–5.

76. Careskey JM, Grosfeld JL, Weber TR et al. Giant cystic meconium peritonitis (GMCP): improved management based on clinical and laboratory observations. J Pediatr Surg 1982; 17:482–9. 77. Tanaka K, Hashizume K, Kawarasaki H et al. Elective surgery for cystic meconium peritonitis: report of two cases. J Pediatr Surg 1993; 28:960–1. 78. Reynolds E, Douglass B, Bleacher J. Meconium peritonitis. J Perinatology 2000; 3:193–5.

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51 Duplications of the alimentary tract PREM PURI

INTRODUCTION

Partial twinning

Duplications of the alimentary tract are rare spherical or tubular structures which can occur anywhere in the tract from mouth to anus.1–3 Ladd, in 1937, introduced the term ‘alimentary tract duplication’ in the hope of clarifying the nomenclature which had previously included descriptive terms such as enteric or enterogenous cysts; giant diverticula; ileal, jejunal or colonic duplex, an unusual Meckel’s diverticulum.4 Ladd proposed that the unifying term ‘alimentary tract duplications’ be applied to congenital anomalies that involved the mesenteric side of the associated alimentary tract and shared a common blood supply with native bowel.4 Most duplications might indeed be called simply ‘enterogenous cysts’, since in only very few cases there is an actual doubling of the alimentary tract and these are therefore deserving of the name ‘duplication’.

Certain duplications appear to represent partial twinning, particularly the tubular duplications of the terminal ileum and colon.6–10 There is a wide spectrum of abnormalities, from complete twinning of the lower trunk and extremities to mere doubling of the lumen of hindgut structures. These lesions are often associated with duplication of the lower urinary tracts.11–13 Many rare examples of abortive cephalic twinning have also been described.14 When there is complete doubling of the colon, one or both lumens may open as a ﬁstula into the perineum or into the genitourinary (GU) tract, and may be associated with an imperforate anus. Doubling of the anus, vagina, and bladder all have been detailed and often can be associated with other severe deformities, such as double spines or two heads.

Split notochord EMBRYOLOGY Numerous theories have been developed to account for the multitude of gastrointestinal (GI) tract duplications. Recently, Stern and Warner in an exciting review outlined the most widely held theories regarding GI duplication.1 Embryologically, duplications have been categorized into foregut, midgut and hindgut types.1 Foregut duplications include the pharynx, respiratory tract, esophagus, stomach, and the ﬁrst portion and proximal half of the second portion of the duodenum. Midgut duplications include the distal half of the second part of the duodenum, the jejunum, ileum, cecum, appendix, ascending colon, and proximal two-thirds of the transverse colon. The hindgut is composed of duplications of the distal third of transverse colon, the descending and sigmoid colon, the rectum, anus, and components of the urological system. In one series, 39% of duplications involved the foregut, whereas 61% represented duplications of both mid- and hindgut.5

The most satisfactory of several theories of the origin of GI duplications is that relating to the development of the neurenteric canal. Saunders, in 1943, noted that thoracic duplications are frequently associated with abnormalities of the cervical and thoracic vertebrae.15 These duplications may be attached to the vertebral bodies or connected to the spinal canal. These ﬁndings gave rise to the Bentley and Smith ‘split notochord theory’.16–18 The embryo initially has two layers: ecoderm and endoderm. Mesoderm forms between the two but for a short time these two layers remain adherent. A transient opening (the notochordal plate) appears, connecting the neural ectoderm with the intestinal endoderm. This notochordal plate normally migrates dorsally and becomes ‘pinched’ off from the endoderm by the ingrowth of mesodermal cells from each side. If the notochordal plate fails to migrate as a result of adhesions to the endodermal lining, the spinal canal cannot close ventrally and a tract resembling a diverticulum is established with the primitive gut. This tract may remain open, leaving a ﬁstula between the gut and the spinal canal, or close

480 Duplications of the alimentary tract

leaving only ﬁbrous tract. However, in the majority of cases it disappears completely, leaving only the duplication on the GI tract. This theory explains the formation of thoracic and caudal duplications, which may be associated with vertebral anomalies. However the absence of spinal defects in many alimentary tract duplications makes this theory less tenable as a unifying model of origin.

Peristalsis

Embryonic diverticula and recanalization defects Lewis and Thyng found in human embryos (4–23 mm), and in other animal embryos, tiny bands of intestinal epithelium protruding into the subepithelial connective tissue.19 The identiﬁcation of numerous diverticula in the intestines of embryos, led to the proposal of extension of the diverticula into duplications. The frequent ileal position of these diverticula is congruous with the frequent ileal location of human GI duplications. Although this theory could explain duplications in the absence of spinal anomalies, it fails to account for the variability of the mucosal lining and speciﬁcally for the frequency of heterotopic gastric mucosae. Furthermore, the diverticula identiﬁed in this pathological series were located throughout the bowel circumference as opposed to the general locations of duplications on the mesenteric side of the intestine. The occurrence of tubular duplications would also not be explained by this theory (Fig. 51.1). Bremer20 believed that abnormal recanalization of the intestinal lumen after the solid stage of development of the primlumen after the solid stage of development of the primitive gut in the sixth to seventh week of gestation resulted in duplications.21 Such duplications, however, would not be conﬁned to the mesenteric side of the bowel. Also opposing this theory is the ﬁnding that the solid stage of development in the human does not usually extend beyond the duodenum.21 In 1961, Mellish and Koop proposed an environmental theory, which held that trauma or hypoxia could induce duplications and twinning in lower orders.22 Based on the work of Louw, they concluded that vascular insufﬁciency could lead to the recognized GI duplications seen in humans.23 Additionally, intrauterine vascular accidents are known precipitators of the other congenital anomalies, such as GI atresias.

PATHOLOGY Duplications are hollow structures that involve the mesenteric side of the associated GI tract.24 They tend to share a common muscular wall and blood supply with its mature bowel, although each has its own separate lining.25 The lesions have a muscular coat in two layers and are

Figure 51.1 Various types of tubular duplications of the intestine

usually lined with epithelium similar to that found in the associated portion of alimentary tract. The duplications, however, occasionally are lined with heterotopic epithelium; the presence of colonic mucosae has been described to appear at the base of the tongue, and sinuses lined with gastric mucosae have been found near the anus.26 Duplications containing gastric mucosae are at risk of peptic ulceration, perforation and hemorrhage.27 Patches of ectopic gastric mucosa along the GI tract may represent the mildest manifestation of duplication abnormalities. Ectopic pancreatic tissue has been reported in duplications of the stomach, ileum and colon.28 The contents of a duplication vary with the type of epithelial lining of the structure, the presence or absence of a communication with the proximate part of the GI tract, and the absence or necrosis of the duplication wall. If an opening is present, the duplication contents will be similar to that of the adjacent intestinal tract. Communication between the two structures is rare and the cysts usually contain chyle or mucus. Multiple duplications can occur in the same patient.26,29–31 There is an increased incidence of other associated anomalies such as vertebral anomalies32,33 myelomeningocele,34,35 imperforate anus,36,37 exomphalos,33 malrotation of bowel,32,38 genital anomalies,33,37 polysplenic syndrome39 and duodenal atresia.40 No genetic tendency has been demonstrated.

Gastric duplication 481

INCIDENCE

Table 51.2 Location of duplications of stomach in 87 reported cases

Duplications of the alimentary tract are rare. Table 51.1 summarizes the larger published series of duplications. In many cases the numbers of patients reported represent up to 40 years’ work in these centers. Only a small percentage of the total cases reported actually present in the neonatal period.28,40–44

Location

No. of cases

Greater curvature Lesser curvature Anterior wall Posterior wall Others

55 7 9 9 7

GASTRIC DUPLICATION The stomach is one of the less common sites of duplications, accounting for only 3.8% of all GI duplications.34 Over 60% of cases are diagnosed during the ﬁrst year of life, with a signiﬁcant number (40%) appearing in the neonatal period by the ﬁnding of a palpable cystic mass in the upper abdomen accompanied by vomiting and weight loss.45,46 Rarely they undergo peptic ulceration and if the cyst communicates with the stomach, hematemesis and melena may be the presenting features. Rarely a carcinoma may arise within a gastric duplication cyst.47 Gastric outlet obstruction, which mimicks hypertrophic pyloric stenosis, also is a common presenting feature of this duplication.48 Gastric duplications occur twice as often in females as in males.24 It is often difﬁcult to make a preoperative diagnosis. Plain radiographs are usually negative. A barium meal may show compression of the stomach, usually along the greater curvature. Barium may demonstrate a connection between the stomach and duplication, but only in a small minority of cases. In these cases, barium may be retained in the duplication long after the remainder has passed from the GI tract. Ultrasonography has been shown to be useful in the diagnosis of gastric duplications. The vast majority of gastric duplications are located in the greater curvature (Table 51.2). Occasionally these are pedunculated,32,49 but most are closed spherical cysts or tubular structures.

Associated anomalies occur in 3% of gastric duplications.50 The most common is another cyst, usually of the esophagus.51 Dual duplications of the stomach and pancreas have been reported.52,53 These are thought to arise from an error in rotation of the ventral pancreatic anlage.

Treatment The management of gastric duplications is surgical because of the high incidence of complications due to obstruction, bleeding or peritonitis. As most duplications occur in the greater curvature, a wedge of stomach is excised together with the cyst and the gap closed with a single layer of horizontal inverted mattress sutures (Fig. 51.2). Partial gastrectomy should be avoided in children if possible, and if necessary only 25–30% of the stomach should be resected because of the associated long-term complications. When restriction of the adjoining stomach is impracticable, as with the long tubular duplications of the greater curvature (Fig. 51.3a), the main part of the duplication is excised and the mucosa stripped off (Fig. 51.3b). The remaining seromuscular cuff can be sutured over the denuded area (Fig. 51.3c) after checking that the common wall between the stomach and duplication has not been perforated, by insufﬂating the stomach with air. The use of a stapling gun to divide the common wall

Table 51.1 Incidence and locations of duplications Author Gross22 Sieber11 Grosﬁeld et al.23 Favara et al.12 Wrenn7 Lister & Vaos24 Holcomb et al.9

Total No. 68 25* 20 37† 22‡ 32 96§

No. of Cervical neonates 20 – – – – 24 36

1 – – 3 – – 1

Mediastinal 13 5 4 4 3 3 20

* One patient had two, one had three and one had ﬁve duplications; † One patient had three duplications; ‡ Two patients each had two duplications; § 96 patients had 106 atresias.

Thoraco- Gastric abdominal 3 – – 2 2 – 3

2 4 1 3 1 1 8

Duodenal Jejunal/ Colonic Rectal ileal 4 2 – 4 2 – 2

32 16 9 20 12 20 47

9 5 4 4 3 5 20

4 – – – 3 3 –

482 Duplications of the alimentary tract

along the length of the greater curvature has also been described.54

PYLORIC DUPLICATIONS

Figure 51.2 Gastric duplication located at the greater curvature. A wedge of stomach is excised together with the cyst and the gap closed with a single layer of horizontal inverted mattress sutures

True pyloric duplications are extremely rare; only ﬁve have been reported in the English literature,45,55–58 four of these presenting within the ﬁrst week of life. They simulate the symptoms and signs of hypertrophic pyloric stenosis.59 Vomiting, weight loss and a palpable abdominal mass are the main ﬁndings. There are certain physical features which are consistent with duplication: the mass is usually large and smooth, in contrast to the smaller and often more mobile ‘olive’ mass in hypertrophic pyloric stenosis.59 Because of the nonspeciﬁc physical examination, radiographic procedures are essential for diagnosis. Plain ﬁlm radiography may show signs of gastric outlet or

(a)

(b)

(c)

Figure 51.3 (a) Tubular duplication of the greater curvature of the stomach. (b) The mucosa is stripped from the entire length of the duplication. (c) The seromuscular cuff is closed over the denuded area

Duplications of the small intestine 483

duodenal obstruction with a lack of distal bowel gas,60 or rarely calciﬁcation within a cyst wall.61 Ultrasonography may demonstrate an inner echogenic mucosal layer and outer hypoechoic muscular layer differentiating the duplication from a mesenteric cyst. Barium contrast studies may help differentiate the duplication from pyloric stenosis.

Treatment Of the ﬁve cases of pyloric duplication reported, four underwent simple surgical excision after opening the pyloric canal longitudinally. The pylorus was then closed transversely and no complications occurred.45,54,57

DUODENAL DUPLICATIONS The duodenum is involved in only 5–6% of all duplications; they are often located behind the duodenum and do not communicate with the bowel lumen.62 Vomiting secondary to partial or complete duodenal obstruction and an upper abdominal mass are present in the majority of cases. They may present with hematemesis or perforation as gastric mucosae are present in 10–15% of cases.63 If the duplication is of sufﬁcient size, it may appear on plain radiography as a large opacity in the right side of the abdomen displaying the intestine (Fig. 51.4a). A barium meal will show the duodenum to be displaced upwards and a ‘beak-like’ projection due to compression of the duodenum lumen by the duplication (Fig. 51.4b).64 Ultrasonography may show a cystic lesion below the liver and a double-layered appearance (Fig. 51.5a).

(a)

Treatment In view of the occasional occurrence of a gastric mucosa in the duplication cyst, these lesions should if possible be dissected from the duodenum and excised, closing the resulting defect in the duodenum in two layers. Intraoperative cholangiography will help determine the relationship of the cyst to the bile and pancreatic ducts.65 If the lesion is extensive (Fig. 51.5b), or if eversion of the cyst may compromise the biliary system, then cystoduodenostomy may be performed.66 The cyst may also be only partially excised, stripping off all the lining mucosae and leaving the part of the cyst which is adherent to the duodenum or pancreas.65

DUPLICATIONS OF THE SMALL INTESTINE Small bowel duplications constitute 45% of all alimentary tract duplications.67 The vast majority of small bowel duplications are spherical cysts in the

(b) Figure 51.4 (a) Supine view in this 1-day-old baby showing a large soft tissue mass in the right upper and central abdomen displacing bowel loops to the left. (b) Barium study demonstrates beak-like projection of proximal duodenum superiolaterally characteristic of duodenal duplication cyst

terminal ileum. Jejunal and ileal cysts are found on the mesenteric side of the bowel, sharing a common muscularis with the adjacent bowel. They may cause obstruction by exerting external pressure on the lumen,68 by acting as a lead point for intussusception69 or occasionally by causing a volvulus.70 Tubular duplications have the same features as the cystic variety, but they communicate with the normal lumen of the intestine and are more likely to contain

484 Duplications of the alimentary tract

can differentiate between a mesenteric and a duplication cyst. A barium meal will demonstrate displacement of the bowel (Fig. 51.6). Intraoperative 99mTc scanning may prove useful during this procedure to assure complete removal of all involved mucosae.76

Treatment Cystic duplications are relatively straightforward to deal with. Resection of the cyst with adjacent bowel (Fig. 51.7a) is performed, the two ends of the bowel are anastomosed with one layer of horizontal inverting mattress sutures, and the mesenteric defects are closed (Fig. 51.7b). Tubular duplications, if very short, can be restricted as in a cystic lesion, but the majority involve a considerable length of small bowel, and much ingenuity and patience may be required to meet the needs of any one particular case. Wrenn suggested coring out the mucosal lining of a long tubular duplication through multiple seromuscular incisions in the wall of the duplication.77 The muscle and blood supply of the normal small bowel and duplication then need only be limited to the junction of the two. Norris et al.78 employed a technique ﬁrst described by Bianchi for bowel lengthening,79 to separate two leashes of blood vessels passing to each side of the small intestine (Fig. 51.8). Using this method, the entire mucosa and almost the entire muscle wall can be excised.

(a)

(b) Figure 51.5 Duodenal duplication. (a) Ultrasound shows the cystic lesion below the liver. (b) Large duodenal duplication cyst

gastric mucosae.71 The presence of pancreatic mucosae has also been described in these duplications. Tubular duplications can range in length from a few millimetres to the whole length of the small bowel.72,73 The communication may be at the cephalad end, which will cause the duplication to become grossly distended with intestinal contents, or at the caudal end, which will allow the duplication to drain freely. Communication at several different points may be present. Hemorrhage occurs most often in tubular duplications, but perforation has been reported as well.74,75 Plain abdominal radiographs may show nonspeciﬁc displacement of bowel gas shadows by the cyst or signs of intestinal obstruction or perforation. Ultrasonography

Figure 51.6 Barium study demonstrates a space-occupying lesion displacing bowel. At laparotomy a large ileal duplication cyst was found

Rectal duplications 485

COLONIC DUPLICATIONS

(a)

(b)

Figure 51.7 Cystic ileal duplication. (a) Resection of the cyst with adjacent bowel is performed. (b) The two ends of the bowel are anastomosed

(a)

Colonic duplications are among the rarest reported. They are frequently diagnosed in infancy and some reports suggest a female predilection. McPherson et al. proposed a simple classiﬁcation of colonic duplications: type I mesenteric cysts, type II diverticula and the more common type III tubular colonic duplication.82 A number of etiological factors may be involved in the development of the ‘double colon’. The most valid theory suggests division of the hindgut into two parts at a stage during which the anlage possessed a multi-organ developmental potential.82,83 The hindgut anlage normally forms the distal ileum, colon, rectum, bladder and urethra. Division of the anlage at the same initial stage could therefore be responsible for duplication of the lower urinary tract as well.82 Simple cysts (type I) and diverticula (type II) occasionally result. They can be identiﬁed by plain radiography or barium studies. Barium enema may demonstrate a communication between the colon and duplications in types II and III. Associated GU, and lumbosacral spinal abnormalities can also be demonstrated on the appropriate radiographic studies, particularly when dealing with type III duplications. Isotope scans are rarely of beneﬁt with colonic duplications, as they contain only colonic mucosae. Complete duplication of the colon is usually asymptomatic in the neonatal period unless duplication of the anus or an abnormal oriﬁce, in addition to the normal oriﬁce in the perineum, is present. One or both oriﬁces at the distal end of the colon may end as rectovaginal or recto-urethral ﬁstulas.83

Treatment

(b)

(c)

Figure 51.8 Tubular duplication of small bowel. (a) The main part of the tubular duplication is excised. (b) The mucosa is stripped from the entire length of the duplication. (c) The sermuscular cuff is closed over the denuded area

The remaining cuff of muscle wall can be oversewn, preserving the blood supply to the normal bowel. Bishop and Koop described the techniques of anastomosing the distal end of the duplication to adjacent normal intestine, allowing free drainage of the contents.80 Malignant change in the mucosa has, however, been described as a late complication of this procedure.81

Surgery for colonic duplication is rarely indicated in the neonatal period unless there are complications, e.g. obstruction or an associated imperforate anus. The principal aim of management is to end up with two colons draining through one anal oriﬁce. If one part of the colon has already reached the perineum, then the other colon is divided and anatomosed to its partner. The mucosa of the distal part of the divided colon is colonized and any ﬁstulas oversewn. If neither colon reaches the perineum, then a formal pull-through procedure will be required. Neonatal management in any of these situations is conﬁned to fashioning a transverse defunctioning colostomy to drain both colons.

RECTAL DUPLICATIONS Approximately 70 cases of rectal duplications have now been reported in the literature. More than 50% of these have been examples of hindgut twinning.84

486 Duplications of the alimentary tract

The embryogenesis of rectal duplication cysts is attributed to a ‘pinching off ’ of a diverticulum in the 20–30 mm embryo,85 in contrast to the ‘caudal twinning’ which occurs in the 10 mm embryo and is associated with complex hindgut anomalies.86,87 Presentation of the cysts depends on: (1) size and their mass effect, (2) ﬁstulas, (3) infection, (4) ulceration if they contain gastric mucosae, and (5) malignancy.88 The duplication cyst usually forms in the retrorectal space and contains colorless mucus, which can become infected. They frequently present in 20–45% of cases.84,85 No cases of a ﬁstula between the rectum and urinary tract have been described. Malignant degeneration has been reported in the rectal duplication from the fourth decade onwards.89,90

Treatment Treatment of the rectal duplication cyst is surgical excision or fenestration of the common wall. Depending on the anatomical variations, a transanal or transcoccygeal (Kraske) approach can be employed. For longer or more complicated cysts, a longer posterior sagittal incision will provide better exposure. As with other duplications, it is of prime importance to remove all mucosae in the duplication. The muscularis can be left in situ. It can be seen that duplications of the GI tract represent a diverse group of anomalies. Small duplications in readily accessible areas (i.e. the small intestine) may be excised with adjacent bowel. In other locations, where resection would endanger adjacent structures, simple anastomosis between the cyst and normal intestine can be performed, provided that there is no gastric mucosa in the cyst. If bleeding has been a persisting complaint, the presence of a gastric mucosa can be assumed. If resection is contraindicated, the lining mucosa may be stripped from the cyst, leaving the muscle wall in situ. Involvement of the anus may represent a signiﬁcant challenge for the surgeon.91 In 1969, Smith analyzed 32 cases of anal duplication and discovered three basic patterns:6 1 Two separate perineal anuses opened externally 2 Two anuses, with one or both ending in a ﬁstula to the GU tract 3 An external anus, with the other ending as a blind sac and without communication with the GU tract. Associated anomalies such as presacral tumors (16%) and anorectal malformations (21%) are frequently described in the literature.91 Management of these lesions may be difﬁcult and often requires preoperative evaluation of both the GI and GU tract. Continence of both systems is imperative, and, therefore treatment strategies must be individualized based on the ﬁndings of each patient.

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References 487 23. Louw JH. Congenital atresia and stenosis in the newborn. Ann Roy Coll Surg Engl 1959; 25:209. 24. Ladd WE, Gross RE. Surgical treatment of duplications of the alimentary tract. Surg Gynec Obstet 1940; 70:295–307. 25. Smith JR. Accessory enteric formations: classiﬁcation and nomenclature. Arch Dis Childh 1960; 35:87–9. 26. Wrenn E. Alimentary tract duplications. In: Holder T, Ashcraft K, editors. Pediatric Surgery. Philadelphia: W.B. Saunders, 1992; 455–6. 27. Rios-Dalenz JC, Kress JW, Montgomery CG. Duplication of small intestine with perforated ulcer in ectopic gastric mucosa. Arch Surg 1965; 91:863–8. 28. Holocomb GW, Gheisser A, O’Neill J et al. Surgical management of alimentary tract duplications. Ann Surg 1989; 209(2):167–74. 29. Sieber WK. Alimentary tract duplication. Arch Surg 1956; 73:383. 30. Basu R, Forshall I, Rickham PP. Duplications of the alimentary tract. Br J Surg 1960; 47:477. 31. Favara BE, Franciose RA, Akers DR. Enteric duplications: 37 cases – a vascular theory of pathogenesis. Am J Dis Child 1971; 122:501. 32. Kremer RM, Lepoff RB, Izamt RJ. Duplication of the stomach. J Pediatr Surg 1970; 5:360–4. 33. Dawn H, Schuler W, Tonnesen H et al. Duplication des Magen-Darm-Traktez Bertrag zum lleus im Neugeborenen. Z Kinder 1972; 11:64–76. 34. Carachi R. The split notochord syndrome: a case report on a mixed spinal enterogenous cyst in a child with spina biﬁda cystica. Z Kinder 1982; 35:32–4. 35. Hecker WC, Hollman G, Stuck B. Perristierender Canalis Neurenterious und Seine Beziehung zur Entwicklung von Steibbeinteratomen. Arch Klin Chir 1963; 309:662–75. 36. Lister J, Zachary RB. Cystic duplication of tongue. J Pediatr Surg 1968; 3:491–3. 37. Swartz DL, Procaccino A, Becker M et al. Segmented colonic duplication presenting as a sigmoid volvulus. Z Kinder 1983; 38:338–40. 38. Sherman NJ, Marrow D, Asch M. A triple duplication of the alimentary tract. J Pediatr Surg 1978; 13:187–8. 39. Paddock RJ, Arensman RM. Polysplenic syndrome: spectrum of gastro-intestinal anomalies. J Pediatr Surg 1982; 17:563–6. 40. Soon OC, Woo HP. Duodenal duplication cyst associated with duodenal atresia. Pediatr Surg Int 1995; 10:167–8. 41. Gross RE. The Surgery of Infancy and Childhood. Philadelphia: W.B. Saunders, 1953:221–45. 42. Grosfeld JL, O’Neill A, Clatworthy HW. Enteric duplications in infancy and childhood. Ann Surg 1970; 132:83–6. 43. Stringer MD, Spitz L, Abel R et al. Management of alimentary tract duplications in children. Br J Surg 1995; 82:74–8. 44. Iyer CP, Mahour GH. Duplications of the alimentary tract in infants and children. Pediatr Surg 1995; 30:1267–70. 45. Abrami G, Dennison WM. Duplication of the stomach. Surgery 1961; 49:794–801.

46. Silverman A, Ray CC, Cozetto FJ. Pediatric Clinical Gastroenterology. St. Louis: C.V. Mosby, 1971. 47. Pruksapong C, Donovan RJ, Pinit A et al. Gastric duplication. J Pediatr Surg 1979; 14:83–5. 48. Alschibaja T, Putram TC, Yabhin BA. Duplication of the stomach simulating hypertrophic pyloric stenosis. Am J Dis Child 1974; 127:120–2. 49. Shepphard MD, Gilmour JR. Torsion of a pedunculated gastric cyst. Br Med J 1945; 1:874–5. 50. Torma MJ. Of double stomachs. Arch Surg 1974; 109:555–6. 51. Soundararajan S, Subramaniam TK. Gastropancreatic duplications. Pediatr Surg Int 1988; 4:288–9. 52. Chontier R. Pseudocyst of pancreas secondary to gastric duplication. J Pediatr Surg 1973; 8:67. 53. Siddiqui AM, Shamberger RC, Filler RM et al. Enteric duplications of the pancreatic head: deﬁnitive management by local resection. J Pediatr Surg 1998; 33:1117–20. 54. Sammarai AI, Crankson SJ, Sadiq A. The use of mechanical sutures in the treatment of gastric duplications. Z Kinder 1989; 44:186–7. 55. Langer JC, Superina RF, Payton D. Pyloric duplication presenting with gastric outlet obstruction in the newborn period. Pediatr Surg Int 1988; 4:63–5. 56. Bamimen M, Singh MP. Pyloric duplications in a preterm neonate. J Pediatr Surg 1984; 19:158–9. 57. Grosfeld JC, Boles ET, Reiner C. Duplication of the pylorus in the newborn: a rare cause of gastric outlet obstruction. J Pediatr Surg 1970; 5:365–9. 58. Novak RW, Beckman CR. Pyloric duplication presenting with haemorrhagic ascites. Clin Pediatr 1983; 22:386–8. 59. Ramsey GS. Enterogenous cyst of the stomach simulating pyloric stenosis. Br J Surg 1957; 44:632. 60. Tihansky DP, Sukarochana K, Hanrahan JB. Pyloroduodenal duplication cyst. Ann J Gastroent 1986; 81:189–91. 61. Sieunarine K, Manmohansingh E. Gastric duplication cyst presenting as an acute abdomen in a child. J Pediatr Surg 1989; 24:1152. 62. Alfred BA, Armstrong P, Franken FA et al. Calciﬁcation associated with duodenal duplications in children. Radiology 1980; 134:647. 63. Bower RJ, Sieber WK, Kiesewetter WB. Alimentary tract duplication in children. Ann Surg 1978; 188:669–71. 64. Blake NS. Beak sign in duodenal duplication cyst. Pediatr Radiol 1984; 14:232–3. 65. Raffensperger JG. Alimentary tract duplication. In: Swenson’s Pediatric Surgery. 5th edn. CT: Appleton and Lange, 1990:579–85. 66. Gardner CK, Hart J. Enterogenous cysts of the duodenum. J Am Med Assoc 1935; 104:1809–12. 67. Stringer MD. Duplications of the alimentary tract. In: Spitz L, Coran AG, editors. Operative Surgery. 5th edn. London: Chapman and Hall, 1995: 383–95. 68. Ravitch MM. Duplications of the alimentary canal. In: Mustar WY, Ravitch MM, Snyder WH et al., editors. Pediatric Surgery. Chicago: Year Book.

488 Duplications of the alimentary tract 69. Daniss RK, Graviss ER. Jejunal intraluminal diverticular duplication with recurrent intussusception. J Pediatr Surg 1982; 17:84–5. 70. Howanietz C, Lachmann D, Remes I. Volvulus as a rare complication of enterogenous cyst in newborns. Z Kinderchir 1969; 6:48. 71. Wardell S, Vidican DE. lleal duplication causing massive bleeding in a child. J Clin Gastroenterol 1991; 12:681–4. 72. Javett TE, Walter AB, Cooney DR. A long-term follow-up on duplication of the entire small bowel treated by gastroduplication. J Pediatr Surg 1980; 18:186–8. 73. Schwartz BC, Becker JM, Schneider KM et al. Tubular duplication with autonomous blood supply: resection with preservation of adjacent bowel. J Pediatr Surg 1980; 15:341–2. 74. Balen EM, Hernandez-Lizvain JL, Pardo F, Longo JM. Giant jejunoileal duplication: prenatal diagnosis and complete excision without intestinal resection. J Pediatr Surg 1993; 28:1586–8. 75. Doyle SG, Doig CM. Perforation of the jejunum secondary to a duplication cyst lined with ectopic gastric mucosa. J Pediatr Surg 1988; 23:1025–6. 76. Dittrich JR, Spottswood SE, Jolles PR. Gastric duplication cyst: Scintigraphy and correlative imaging. Clin Nucl Med 1997; 22:93–6. 77. Wrenn E. Tubular duplication of the small intestine. Surgery 1962; 52:494. 78. Norris R, Bereton R, Wright V et al. A new surgical approach to duplications of the intestine. J Pediatr Surg 1986; 21:167.

79. Bianchi A. Intestinal loop lengthening – a technique for increasing small bowel length. J Pediatr Surg 1982; 15:145–51. 80. Bishop HE, Koop CE. Surgical management of duplication of the alimentary tract. Am J Surg 1964; 107:434–42. 81. Orr MM, Edwards AJ. Neoplastic change in duplications of the alimentary tract. Br J Surg 1975; 62:269–74. 82. McPherson AG, Trapnell JE, Airth GR. Duplications of the colon. Br J Surg 1969; 56:138. 83. Kettre JJ, Davido WT. Duplication of the large bowel. Am J Roentgenol 1971; 113:310–15. 84. La Quaglia MP, Fains W, Eraklis A et al. Rectal duplications. J Pediatr Surg 1990; 25:980–4. 85. Ravitch MM. Hindgent duplication – doubling of the colon and genitourinary tracts. Ann Surg 1953; 137:588–601. 86. Edwards H. Congenital duplication of the intestine. Br J Surg 1929; 17:7–21. 87. Van Zwalenburg RR. Double colon differentiation of cases into two groups. Am J Roentgenal 1956; 75:349–53. 88. Kroft RO. Duplication anomalies of the rectum. Ann Surg 1961; 155:230–2. 89. Ballantyne EW. Sacrococcygeal tumours. Adenocarcinoma of a cystic congenital embryonal remnant. Arch Pathol 1932; 14:1–9. 90. Crowley LW, Page HG. Adenocarcinoma arising in presacral enterogenous cyst. Arch Pathol 1960; 69:65–6. 91. Jasquier C, Dobremez E, Piolat C et al. Anal canal duplication in infants and children – a series of 6 cases. Eur J Pediatr Surg 2001; 11:186–91.

52 Mesenteric and omental cysts DANIEL L. MOLLITT

INTRODUCTION Mesenteric and omental cysts, although uncommon, represent signiﬁcant clinical pathology in infants and children. The age at diagnosis has gradually decreased over the years, with recent series reporting mean ages of 3–5 years at presentation.1–4 With the widespread use of routine prenatal ultrasonography at least one reported case has been diagnosed in utero.2 More than half of these children present with acute clinical problems.1–14 Although initially described in 1507, considerable confusion continues to surround the origin, clinical signiﬁcance, and classiﬁcation of mesenteric and omental cysts.15 Much of this confusion arises from the continued use of the terms ‘mesenteric’ and ‘omental’ in present day series. This terminology is purely descriptive of anatomic location, with no information as to the speciﬁc histology or pathology involved. In 1897 Moynihan attempted differentiation of these cysts on the basis of ﬂuid content.16 Serous cysts are characterized by a translucent, straw-colored ﬂuid of low speciﬁc gravity. Their chemical composition is similar to plasma. In contrast, chylous cysts contain an opaque ﬂuid of high speciﬁc gravity, with lipids and fat globules contributing to the ﬂuid content. Subsequent attempts at a more appropriate classiﬁcation of intraabdominal cysts have been based on suspected etiology initially proposed by Beahrs in 1950 (Box 52.1).17 Although still widely employed, the etiology of many intra-abdominal cysts is questionable, rendering classiﬁcations of this type of limited clinical usefulness. A more appropriate classiﬁcation, based on histologic ﬁndings, was proposed in 1987 by Ros et al. (Box 52.2).18 This differentiation is applicable to all operative cases and can provide the basis for a more uniform evaluation of the clinical and pathologic characteristics of these cysts. Approximately 90% of the mesenteric and omental cysts encountered in the neonate are lymphangiomas. These are characterized by multiple thin-walled cystic spaces with a distinct endothelial lining similar to that

Box 52.1 Classiﬁcation of abdominal cysts1,6,13 Embryonic/developmental Enteric Urogenital Dermoid Embryonic defects of lymphatics (retroperitoneal, mesenteric and omental cysts) Traumatic/acquired Hemorrhagic (sanguinous) Ruptured lacteal Chylous extravasation Neoplastic Benign (lymphangioma) Malignant (lymphangioendothelioma) Infectious Mycotic Parasitic Tuberculous Hydatid Cystic degeneration Box 52.2 Histologic classiﬁcation of mesenteric/omental cysts14 Enteric cyst:

Enteric lining No muscle layer

Enteric duplication:

Enteric lining Double muscle layer with neural elements

Lymphangioma:

Endothelial lining

Mesothelial cyst:

Mesothelial lining

Pseudocyst: (nonpancreatic)

No lining Fibrous wall

seen in the more common subcutaneous location (Fig. 52.1). They appear most frequently in the mesentery of the small bowel with a propensity for the ileum. When located centrally in the mesentery,

490 Mesenteric and omental cysts

Figure 52.1 Chylous mesenteric lymphangioma resected with adjacent small intestine

extension into the retroperitoneum has been reported.13,14 They may also be encountered in both the mesocolon and omentum. They present grossly as a solitary multiloculated, ﬂuid-containing cyst which can reach an enormous size (Fig. 52.2). The ﬂuid may be serous or chylous with chyle being characteristic of a small bowel location and the associated high lymphatic fat content. Hemorrhagic ﬂuid is not uncommon, particularly in an omental location, although pure blood is rare. These lesions are congenital in nature with an etiology presumed to be secondary to proliferating lymphatic tissue without access to adequate drainage. Mesothelial cysts are unusual, but represent the majority of those nonlymphangiomatous congenital cysts encountered in the omentum (Fig. 52.3). They may also occur within the mesentery. There are generally unilocular serous-containing cysts lined by mesothelium. They are thought to arise from incomplete fusion of the mesothelial leaves of omentum and/or mesentery. Those remaining lesions commonly referred

Figure 52.2 Chylous mesenteric lymphangioma

Figure 52.3 Typical omental mesothelial cyst containing serosanguinous ﬂuid

to as mesenteric and/or omental cysts are actually nonpancreatic pseudocysts with no distinct cellular lining; these are seldom encountered in the neonate and are secondary to inﬂammation or trauma. Because of this etiology, the contained ﬂuid is generally hemorrhagic or purulent. Enteric duplication cysts are not usually included under the heading of mesenteric cysts, but require mention due to their frequent neonatal presentation, mesenteric location, and occasional similarity in appearance (Fig. 52.4). Thus they need be included in the differential diagnosis of intra-abdominal cystic lesions in the neonate. These cysts may occur anywhere along the gastrointestinal tract as saccular or tubular unilocular lesions, usually within the mesentery adjacent to a

Figure 52.4 Saccular intestinal duplication simulating the appearance of a mesenteric cyst. Lesion distinguished grossly by common wall and blood supply shared with adjacent intestine

Diagnosis 491

normal intestine. Histologically, they are composed of all the layers seen in normal intestine. Intraoperative differentiation is necessary as, in contradistinction to the usual mesenteric cyst, they share a common blood supply with the adjacent intestine, precluding simple excision.

demonstrate a mass, ‘ascites,’ or evidence of intestinal obstruction (Fig. 52.5). Contrast radiography will usually evidence a mass effect with varying degrees of compression of normal bowel (Fig. 52.6). Sonography is the most useful diagnostic modality. These lesions appear as a welldeﬁned, hypoechoic to anechoic smooth-walled mass, with echogenicity related to the cyst contents. In lymph-

CLINICAL CHARACTERISTICS These cystic lesions are generally of isolated pathology with few reports of associated developmental anomalies. Large reviews have indicated a male predominance.13 Signs and symptoms of mesenteric and/or omental cysts are nonspeciﬁc and related to mechanical forces due to cyst location and size. As opposed to in the adult, in whom these lesions are frequently asymptomatic and/or incidental ﬁndings, the majority of children present with abdominal complaints. Several authors have suggested that this may be related to the higher incidence of lymphangiomas in individuals in this age group.13,14 Prominent symptoms commonly include pain, vomiting, and distention (Box 52.3). A palpable mass is the most common physical ﬁnding, but this may be apparent in only 60% of affected children due to the ﬂaccidity and mobility of the cyst itself. The mass, if present, is generally smooth, nontender and mobile in character. Of the affected children, 50% or more will present with complications. Intestinal obstruction, either partial or complete, is frequent and usually due to compression of the adjacent intestine. Volvulus can occur around the cyst and result in infarction of the bowel with perforation, peritonitis and shock.19 Hemorrhage within the cyst secondary to expansion or erosion may lead to rapid enlargement and pain.20 Torsion of the cyst itself, rupture, and urinary obstruction have also been reported.20,21

Figure 52.5 Plain abdominal radiograph of a child with a large mesenteric cyst, suggesting a nondiscrete mass

Box 52.3 Clinical presentation1–4, 5,6,8,11–14,19 (281 children) Pain Mass Obstruction Distension Miscellaneous *

41% 35% 32% 25% 23%

* Failure to thrive, nausea, gastrointestinal bleeding, diarrhea etc.

DIAGNOSIS A deﬁnitive preoperative diagnosis is seldom possible, but with the current modalities available, an accurate differential can usually be obtained. Laboratory evaluation is pertinent only to complications which may be associated with the cyst. A plain radiograph of the abdomen may

Figure 52.6 Barium enema in the same child conﬁrms displacement of bowel by a large intra-abdominal mass

492 Mesenteric and omental cysts

angiomas, the multiple thin septae are apparent (Fig. 52.7a,b).1,18,22–24 Computed tomography can be disappointing in the differential diagnosis of these lesions. Although it frequently demonstrates a ﬂuid-ﬁlled mass, this can easily be interpreted as ascites. The thin septae, diagnostic of lymphangioma, may not be apparent (Fig. 52.8). Sensitivity is, however, enhanced through the use of pre- and postcontrast views.18,22,25

DIFFERENTIAL DIAGNOSIS Other neonatal intra-abdominal lesions which may be difﬁcult to distinguish from a mesenteric or omental cyst include ovarian cysts, choledochal cysts, pancreatic cysts, and enteric duplication. The majority of these can only be differentiated intraoperatively, and therefore do not change the initial operative approach. Large cysts may mimic ascites in the neonate. Unless the ascites is loculated, however, shifting will occur with movement and the bowel will ﬂow centrally as opposed to in the lateral dislocation associated with mesenteric or omental

Figure 52.8 Abdominal CT of the same child conﬁrms a large ﬂuid-ﬁlled mass. Septae not visible

cysts. If ascites is suspected, paracentesis and urinary tract evaluation are indicated prior to exploration.

OPERATIVE PROCEDURE Preparation Preoperatively the diagnosis is frequently in doubt and management may require intestinal resection. Broadspectrum antibiotics should therefore be administered preoperatively. Mechanical bowel preparation is rarely necessary.

Technique (a)

(b) Figure 52.7 (a,b) Longitudinal and transverse abdominal ultrasound of a child with a large omental lymphangioma demonstrating a hypoechoic, septated mass immediately beneath the anterior abdominal wall

The infant is placed in the supine position on the operating table. Following induction of anesthesia and endotracheal intubation, the entire abdomen is prepped and draped. A transverse incision 1.5–2 cm superior to the umbilicus is employed (Fig. 52.9). This is carried across the area of the rectus muscles bilaterally. The underlying muscles are individually elevated and transected by electric cautery. The peritoneum is grasped, elevated and sharply incised lateral to the midline. Because of the usual associated abdominal distension, great care must be taken to avoid entry into loops of intestine or the cyst itself. In difﬁcult situations, entry into the peritoneal cavity may be facilitated through the use of traction clamps placed on the fascia. Prior to carrying the peritoneal incision across the midline, the falciform ligament and umbilical vein remnant are bluntly mobilized, ligated and transected. Omental cysts are generally immediately apparent upon entering the peritoneal cavity. They present as large, translucent, solitary ﬂuid-ﬁlled sacs overlying the bowel. The omentum and associated cyst is gently with-

Operative procedure 493

Figure 52.11 Removal of omental cyst by transection of the omentum at the transverse colon

Figure 52.9 Supraumbilical transverse incision utilized in the abdominal exploration of the neonate with a mesenteric and/or omental cyst

drawn from the abdomen and placed on the abdominal wall (Fig. 52.10). The cyst may then be easily removed by transection at the junction with normal omentum or transverse colon (Fig. 52.11). No effort should be made to remove the cyst from the overlying omentum. Care must be taken to ligate the numerous omental vessels at the level of the transection. Larger mesenteric cysts may also be apparent upon opening the peritoneal cavity, or if they are smaller, require careful exploration. Once localized, the area of involvement is mobilized, eviscerated and the remaining

Figure 52.10 Characteristic appearance of a large omental cyst hanging from the transverse colon

bowel packed away with sponges to facilitate exposure and resection (Fig. 52.12). Management options include enucleation or resection. Intraoperative aspiration of the cyst and subsequent analysis prior to removal is not indicated unless there is a question of biliary or pancreatic origin. Aspiration to reduce the size may actually render dissection more difﬁcult. If any obvious plane exists between the cyst and adjacent bowel wall, enucleation should be undertaken. The leaf of mesentery overlying the cyst is grasped, elevated and sharply incised in an avascular location. Care must be taken to avoid entry into the cyst wall itself. In larger cysts, enucleation may require incision on both sides of the mesentery. The mesentery is then carefully elevated from the underlying cyst utilizing blunt dissection. Generally a plane of loose areolar tissue is present, enabling mobilization. This may be facilitated

Figure 52.12 A mesenteric cyst amenable to removal without intestinal resection

494 Mesenteric and omental cysts

with a moistened cotton-tipped applicator or a gauze pledget and gentle downward traction on the cyst wall (Fig. 52.13). The mesentery itself is quite thin and it is necessary to avoid tearing it by administering direct traction or overzealous dissection. Similarly, it is necessary to avoid injury to the overlying mesenteric vessels and/or adjacent intestinal wall. Dissection in these areas may require sharp mobilization. Dissection is continued circumferentially until the cyst can be totally enucleated (Fig. 52.14).

Following enucleation, the mesenteric defect is closed, approximating both leaves of the mesentery in a single layer with ﬁne interrupted absorbable sutures (Fig. 52.15). In instances where a deﬁnite plane between the cyst and adjacent bowel cannot be identiﬁed, resection of the intestine in continuity with the cyst is required (Fig. 52.16). Dissection should be planned to remove as little bowel as possible. The mesentery immediately proximal and distal to the cyst wall is sequentially ligated and transected until the cyst is completely freed from the mesentery. The bowel is transected between noncrushing clamps at the proximal and distal extent of the mesenteric dissection, removing that section in continuity with the cyst itself (Fig. 52.17). The bowel is then re-approximated, end to end, with a single layer of interrupted absorbable sutures. The mesenteric defect is similarly closed (Fig. 52.18).

Figure 52.13 Gentle dissection of the mesenteric leaf overlying the cyst

Figure 52.15 Closure of the mesenteric dissection with ﬁne interrupted absorbable sutures

Figure 52.14 Removal of the mesenteric cyst from between the leaves of the mesentery

Figure 52.16 Mesenteric cyst impinging upon normal intestine requiring resection of adjacent bowel for removal

References 495

cautery, tincture of iodine, and/or 10% glucose. Although there have been no reports to date of its use in infants, laparoscopy has been successfully employed in the management of these cysts in older children.26

REFERENCES

Figure 52.17 Mesenteric cyst removed en bloc with adjacent bowel

Figure 52.18 Reapproximation of the intestine with a single layer of interrupted absorbable sutures

Following completion of cyst removal, the operative area is irrigated with warm normal saline and the bowel replaced. The abdominal wall is closed in anatomic layers utilizing running absorbable sutures for the anterior and posterior fascia and ﬁne intracuticular absorbable sutures for the skin edges. Marsupialization has been reported as an alternative where complete resection is deemed to be not possible;2,4,8 this should include sclerosis of the cyst lining to minimize the risk of recurrence. Agents suggested include electro-

1. Bliss DP,Cofﬁn CM,Bower RJ et al. Mesenteric cysts in children. Surgery 1994; 115:571–7. 2. Egozi EI, Ricketts RR. Mesenteric and omental cysts in children. Am Surg 1997; 63:287–90. 3. Hebra A, Brown MF, McGeehin KM et al. Mesenteric, omental, and retroperitoneal cysts in children: A clinical study of 22 cases. South Medl J 1993; 86:173–6. 4. Okur H, Kuchukaydin M, Ozokutan BH. Mesenteric, omental, and retroperitoneal cysts in children. Eur J Surg 1997; 163:673–7. 5. Caropreso PR. Mesenteric cysts – a review. Arch Surg 1974; 108:242–6. 6. Mollitt DL, Ballantine TVN, Grosfeld JL. Mesenteric cysts in infancy and childhood. Surg Gynecol Obstet 1978; 147:182–4. 7. Moore TC. Congenital cysts of the mesentery. Ann Surg 1957; 145:428–36. 8. Kurtz RJ, Heimann TM, Holt J et al. Mesenteric and retroperitoneal cysts. Ann Surg 1986; 203:109–12. 9. Takiff H, Calabria R,Yin L et al. Mesenteric cysts and intraabdominal cystic lymphangiomas. Arch Surg 1985; 120:1266–9. 10. Vanek VW, Phillips AK. Retroperitoneal, mesenteric and omental cysts. Arch Surg 1984; 119:838–42. 11. Walker AR, Putnam TC. Omental, mesenteric, and retroperitoneal cysts. Ann Surg 1975; 178:13–19. 12. Chung MA, Brandt ML, St-Vil D et al. Mesenteric cysts in children. J Pediatr Surg 1991; 26:1306–8. 13. Galifer RB, Pous JG, Juskiewenski S et al. Intra-abdominal cystic lymphangiomas in childhood. Prog Pediatr Surg 1978; 11:173–238. 14. Kosir MA, Sonnino RE, Gauderer MWL. Pediatric abdominal lymphangiomas: A plea for early recognition. J Pediatr Surg 1991; 26:1309–13. 15. Benevieni A. De abditis nonullis ac mirandis morborum e sanationum causis. Translated by Singer CJ.Springﬁeld, IL: Charles C. Thomas, 1954. 16. Moynihan BGA. Mesenteric cysts. Ann Surg 1897; 26:1–29. 17. Beahrs OH, Judd ES, Dockerty MB. Chylous cyst of the abdomen. Surg Clin North Am 1950; 30:1081–96. 18. Ros PR, Olmsted WW, Moser RP et al. Mesenteric and omental cysts-histologic classiﬁcation with imaging correlation. Radiology 1987; 164:327–32. 19. Colodny AH. Mesenteric and omental cysts. In: Welch KJ, Randolph JG, Ravitch MM et al.,editors. Surgery. Chicago: Yearbook Medical Publishers, 921–5. 20. Gross RE.Omental Cysts and Mesenteric Cysts. The Surgery of Infancy and Childhood. Philadelphia: W.B. Saunders, 1953:377–83.

496 Mesenteric and omental cysts 21. Parrish RA, Potts JM. Torsion of omental cyst – a rare complication of ventriculoperitoneal shunt. J Pediatr Surg 1973; 8:969–70. 22. Geer LL, Mittelstaedt CA, Staab EV et al. Mesenteric cyst: sonographic appearance with CT correlation. Pediatr Radiol 1984; 14:102–4. 23. Mittelstaedt CA. Ultrasonic diagnosis of omental cysts. Radiology 1975; 117:673–6.

24. Takeuchi S, Yamaguchi M, Sakurai M et al. A case of mesenteric cyst diagnosed by ultrasound examination and a review of Japanese literature. Jpn J Surg 1979; 9:359–65. 25. Rifkin MD, Jurtz AB, Pasto ME. Mesenteric chylous (lymphcontaining) cyst. Gastrointest Radiol 1983; 8:267–9. 26. Kenney B, Smith B, Bensoussan AL. Laparoscopic excision of a cystic lymphangioma. J Laparoendosc Surg 1996; (Suppl 1):S99–101.

53 Neonatal ascites PREM PURI

INTRODUCTION The relatively rare condition of ascites in the newborn may occur due to a wide range of medical and surgical causes.1 The surgical conditions most likely to result in accumulation of ﬂuid in the peritoneal cavity of the newborn are obstructive uropathy, spontaneous perforation of the extrahepatic biliary tree and chylous ascites.

URINARY ASCITES Urinary ascites, which occur almost exclusively in boys, is most commonly a complication of posterior uretharal valves.2,3 Other causes include pelvi-ureteral obstruction, ureterocele, lower ureteral atresia and neuropathic bladder.4 Rarely, urinary ascites may occur in the absence of a demonstratable urinary tract obstruction.5 The ascites usually results from extravasation of urine into the peritoneal cavity due to urinary tract perforation above a point of obstruction. The perforation may occur in the bladder,4 but most often occurs in the upper tracts.6 Rupture of renal parenchyma or a dilated renal pelvis results in perirenal collection of urine, and a ‘perforation in the extraperitoneal membrane’ allows the perirenal urine to accumulate in the peritoneal cavity. It is believed that if urinary leakage occurs from the highpressure, obstructed fetal urinary tract into peritoneal cavity, then this ‘safety valve’ may protect the fetal kidneys from further prenatal damage. Adzick et al. studied 12 fetal cases of urinary extravasation and showed that fetal urinary ascites appeared to ameliorate the high-pressure, obstructed fetal urinary system.6 The typical patient with neonatal urinary ascites is a male infant who presents with gross abdominal distension and ascites at birth. The abdominal distension may be severe enough to cause respiratory embarrassment. Abdominal paracentesis yields urine. Plain abdominal ﬁlms will show diffuse opacity. If the amount of intraperitoneal ﬂuid is large, abdominal

X-ray may show splaying of the lower rib cage and centrally located ﬂoating intestines. I.v. pyelography may show a characteristic ‘halo’ sign produced by extravasation of contrast material into the perirenal area. A voiding cystourethrogram will demonstrate extravasation of contrast material and may show the underlying cause (Fig. 53.1a,b). Ultrasonography may be used to demonstrate free intraperitoneal ﬂuid. Treatment of neonatal urinary ascites depends upon the general condition of the baby at diagnosis and also on the site of perforation. Murphy et al. have clearly described the management of these babies.5 It consists of four distinct phases: 1 Relief of respiratory embarrassment by aspiration of the ascitic ﬂuid 2 Correction of electrolyte and metabolic disturbances 3 Decompression of the urinary tract by nephrostomy or bladder catheter drainage upon the site of perforation 4 Correction of the underlying cause of urinary tract obstruction. Longterm outcome of bladder and kidney function is surprisingly good in cases of neonatal urinary ascites secondary to severe obstructive uropathy.4 Intrauterine pressure relief of the bladder through urinary extravasation protects renal function and this decompression of the urinary tract prevents severe secondary changes to bladder function.

BILE ASCITES Bile ascites in infancy is a rare condition usually resulting from spontaneous perforation of bile ducts. Typically biliary ascites occurs in infants between 1 and 12 weeks of age. Perforations occur most frequently between the ages of 4 and 12 weeks and the site of perforation is most often the junction of the cystic duct with the common bile duct. The etiology of these perforations is not known. Many etiological theories have been proposed,

498 Neonatal ascites

(a)

(b) Figure 53.1 Urinary ascites. This infant had severe respiratory distress at birth due to gross abdominal distension requiring abdominal paracentesis. (a) Supine ﬁlm immediately after removal of 650 ml of ﬂuid shows stomach and small bowel loops ﬂoating centerally in the peritoneal ﬂuid. Note splaying of ribs. (b) Cystogram shows leakage of contrast into the peritoneal cavity. Spontaneous perforation of the bladder was found at operation. There was no demonstrable anatomical obstruction in the urinary tract

but no one adequately explains this clinical entity. Congenital weakness at the junction of cystic and common bile ducts,7 viral infections8 and a malformation of the pancreaticobiliary system9 have been suggested as possible causes. Lilly et al. proposed that the perforation is secondary to a localized embryonic mural malformation of the wall of the common duct.10 In the majority of cases there is no apparent cause for the perforation. Occasionally, the perforation is secondary to bile duct obstruction.11–13 The disease usually follows a chronic course with persistant jaundice, acholic stools, progressive abdominal distention and ascites.14,15 In some cases, bile staining of hyroceles or inguinal hernias is present from distension of the tunica vaginalis by the bilious ascites.14 Rarely, biliary ascites may present an acute fulminating condition with jaundice, anorexia, vomiting, abominal distension, pyrexia and leucocytosis.16,17 The infant is acutely ill and may progress to cardiopulmonary collapse or septic shock. In the acute case, the initial diagnosis is usually that of peritonitis. The diagnosis may not be made before surgery, but should be suspected in the presence of jaundice and ascites. Abdominal paracentesis is the essential tool to make the diagnosis. Abdominal radiographs will show ascites and barium meal may demonstrate collection of ﬂuid between the liver and stomach (Fig. 53.2a,b). I.v. cholangiography has been used to conﬁrm the presence of a bile leak preoperatively. Hepatobiliary scintiscanning is an effective, rapid and non-invasive test in the preoperative diagnosis of bile ascites.18 This will show leakage of isotope into the peritoneal cavity. Surgical treatment of spontaneous perforation of the bile ducts has ranged from simple drainage to biliary diversion procedures. Simple external biliary drainage is usually sufﬁcient to allow the perforation to heal spontaneously. Most authors recommend that simple drainage should be accompanied by cholecystostomy.16 Cholecystostomy will provide excellent access for postoperative evaluation of the biliary tract. The drains should not be removed too early, since this can lead to reaccumulation of bile in the peritoneal cavity. The cholecystostomy tube should be kept in place until normal radiographic anatomy is demonstrated without obstruction. Some authors, in view of the possible existence of distal bile duct obstruction, recommended Roux-en-Y cholecystojejunostomy14 or cholecystojejunostomy with distal jejunojejunostomy.18,19

CHYLOUS ASCITES Chylous ascites is an uncommon form of ascites. This condition occurs more frequently in infants than children. The ascites is secondary to lymphatic obstruction

References 499

(a)

resulting from congenital malformations of lymphatics, physical distortion of the mesentery by obstructive lesions such as malrotation, peritoneal bands or incarcerated inguinal hernia and rarely it may be secondary to trauma. In neonates the cause is unknown in most cases.20,21 About 10% of all infants with chylous ascites have lymphedema of the limbs.22 Infants with chylous ascites present with abdominal distention at birth or it may develop in the ﬁrst few days or weeks of life. Abdominal paracentesis will yield clear ﬂuid in the newborn. After oral feedings have been started, the chylous ﬂuid is milky white with a high fat content. Plain abdominal ﬁlms show an opaque distended abdomen, indicating ascites. Diagnosis is conﬁrmed by determining high lipid content in the ascitic ﬂuid. Treatment of chylous ascites is usually conservative. The majority of patients respond to abdominal paracentesis and an enteral diet containing medium-chain triglycerides and high protein. In recent years, total parenteral nutrition has been successfully used in treating these infants by resting the gastrointestinal tract.23 Patients in whom chylous ascites recurs upon resumption of a regular oral diet should undergo surgical exploration.19,24 When no surgical remediable lesion is found, chylous ascites has been managed by inserting a peritoneovenous shunt.22,25,26

REFERENCES

(b) Figure 53.2 Biliary ascites. (a) Marked abdominal distention with opacity in upper and central abdomen and downward displacement of bowel loops. (b) Barium study shows compression with downward displacement of stomach and duodenum. At operation, perforation of common hepatic duct was found

1. Griscom NT, Colodny AH, Rosenberg HK et al. Diagnostic aspects of neonatal ascites: report of 27 cases. Am J Roentgenol 1977; 128:961–70. 2. Mitchell ME, Garrett RA. Perirenal urinary extravasation associated with urethral valves. J Urol 1980; 124:688–91. 3. Hoffer FA, Winters WD, Retik AB et al. Urinoma drainage for neonatal respiratory insufﬁciency. Pediatr Radiol 1990; 20:270–1. 4. De Vries SH, Klijn AJ, Lilien MR, De Jong TP. Development of renal function after neonatal urinary ascites due to obstructive uropathy. J Urol 2002, 168:675–8. 5. Murphy D, Simmons M, Guiney EJ. Neonatal urinary ascites in the absence of urinary tract obstruction. J Petiatr Surg 1978; 13:529–31. 6. Adzick NS, Harrison MR, Flake AW et al. Urinary extravation in fetus with obstructive uropathy. J Pediatr Surg 1985; 20:608–15. 7. Johnston JH. Spontaneous perforation of the common bile duct in infancy. Br J Surg 1961; 48:532–3. 8. Moore TC. Massive bile peritonitis in infancy due to sponaneous bile duct perforation with portal vein occlusion. J Pediatr Surg 1975; 10:537–8. 9. Ohkawa H, Takahashi H, Maie M. A malformation of the pancreatico-bilary system as a cause of perforation of the bilary tract in childhood. J Pediatr Surg 1977; 12:541–6.

500 Neonatal ascites 10. Lilly JR, Weintraub WH, Altman RP. Spontaneous perforation of the extrahepatic bile duct and bile peritonitis in surgery. Surgery 1974; 75:664–73. 11. Hanson RC, Wasnick RD, DeVries PA. Bile ascites in infancy: diagnosis with I-131 rose bengal. J Pediatr 1974; 84:719–21. 12. Pinter A, Pilazanovitch I, Schafer J. Membranous obstruction of the common bile duct. J Pediatr Surg 1975; 10:839–40. 13. Donahoe PK, Hendren WH. Bile duct perforation in a neonate with stenosis of the ampulla of Vater. J Pediatr Surg 1976; 1:823–5. 14. Howard ER, Johnston DI, Mowat AP. Spontaneous perforation of common bile duct in infants. Arch Dis Childh 1976; 51:883–6. 15. Prevot J, Babut M. Spontaneous perforation of the bilary tract in infancy. Progr Pediatr Surg 1971; 1:187–208. 16. Stringel G, Mercer S. Idiopathic perforation of the bile duct in infancy. J Pediatr Surg 1983; 18:546–50. 17. Hammoudi SM, Alauddin A. Idiopathic perforation of the bilary tract in infancy and childhood. J Pediatr Surg 1988; 23:185–7. 18. Saltzman DA, Snyder CL, Leonard A. Spontaneous

19.

20.

21. 22.

23.

24.

25. 26.

perforation of the extraheptic biliary tree in infancy. A case report. Clin Pediatr 1990; 29:322–4. Fitzgerald RJ, Parbhoo K, Guiney EJ. Spontaneous perforation of bile ducts in neonates. Surgery 1978; 83:303–5. Gryboski J, Walker WA. Chylous ascites. In: Gastrointestinal Problems in the Infant. Walker WA editor 2nd edn. Philadelphia: WB Saunders, 1983:264–5. Levine C. Primary disorders of the lymphatic vessels – a uniﬁed concept. J Pediatr Surg 1989; 24:233–40. Guttman FM, Montupet P, Bloss RS. Experience with peritovenous shunting for congenital chylous ascites in infants and children. J Pediatr Surg 1983; 17:368–72. Ash MJ, Sherman NJ. Management of refractory chylous ascites by total parenteral nutrition. J Pediatr 1979; 94:260–2. Pearl J, Joyner J, Collins D. Chylous ascites: the ﬁrst reported surgical cure by direct litigation. J Pediatr Surg 1977; 12:687–91. Man WK, Spitz L. The management of chylous ascites in children. J Pediatr Surg 1985; 20:72–5. Loiterman DL, Bleicher MA. Chylous ascites: an aetiology of peritonitis in infancy. J Pediatr Surg 1985; 20:538–40.

54 Necrotizing enterocolitis ANN M. KOSLOSKE

INTRODUCTION Necrotizing enterocolitis (NEC), a disease characterized by crepitant necrosis of the gut, is the most common surgical emergency in newborns in the USA, Canada and many countries of the world.1–3 NEC occurs chieﬂy among premature infants in neonatal intensive care units (NICUs). The overall incidence of NEC in the USA is 1–3 cases per 1000 live births, representing 1% to 7.7% of all admissions to NICUs.4 Although the disease entity was recognized in the 1950s5–7 and a few centers reported their surgical experience in the 1960s,8–10 it was not until NICUs were established in the 1970s that NEC became a disease of surgical signiﬁcance. These NICUs enabled the survival of small premature infants, who formerly died of pulmonary failure soon after birth, without developing intestinal disease. Great advances in neonatal respiratory care in the 1980s and 1990s, e.g. improved ventilators and surfactant therapy, allowed the survival of ‘micropremature’ infants, i.e. with a birth weight <1000 g and/or a gestational age < 28 weeks, who would have died in earlier decades, but have emerged as the group most susceptible to NEC.11,12 In countries that lack the technology of NICUs, NEC is not a neonatal problem; however, older infants and children in such countries may develop enteritis necroticans, a counterpart of NEC, following an episode of severe diarrhea and dehydration.13–15 The presence of clostridial toxins in the intestinal lumen may be a factor in pathogenesis of enteritis necroticans.13,16 The etiology and pathogenesis of NEC are imperfectly understood. Because premature infants account for approximately 90% of cases,17 their poorly developed gastrointestinal immune mechanisms are implicated. The feeding of human breast milk, which contains secretory immunoglobulin A and several other immunological factors, protects against NEC. In the multicentre study of Lucas and Cole, premature infants fed breast milk alone had a low incidence of NEC; those fed formula alone had a six- to tenfold increase in risk; those fed a combination of breast milk and formula had

a threefold increase in risk.18 Feeding of breast milk currently is the only documented and widely practised preventive measure. The two main theories of pathogenesis were proposed by Lawrence et al. from Brisbane19 and by Touloukian and Santulli et al. from New York.9,20 Lawrence emphasized the aberrant bacterial ﬂora selected out by the NICU environment, and the vulnerability of the premature gut to injury from bacterial toxins during the ﬁrst weeks of life. Touloukian and Santulli invoked a combination of the ‘three essential components’: (1) intestinal injury, primarily ischemia; (2) bacterial colonization of the gut; and (3) the presence of substrate, usually formula feedings, within the lumen of the bowel. Intramural gas is produced by the enteric bacteria, which proliferate in the presence of mucosal ischemia and ileus. The dominant pathological lesion is coagulation necrosis, indicating the importance of ischemia in the pathogenesis.21 NEC may occur postoperatively, after operation for unrelated neonatal conditions22,23 most commonly gastroschisis24 or myelomeningocele.25 Current theories of etiology and pathogenesis of NEC were reviewed elsewhere.26–28 This chapter addresses the surgical management of NEC.

DIAGNOSIS AND TREATMENT The clinical manifestations of NEC are those of intestinal ischemia, including abdominal distension, lethargy, feeding intolerance, bilious vomiting and rectal bleeding. The early signs of ileus may be indistinguishable from those of neonatal septicemia.17 X-rays of the abdomen show the pathognomonic ﬁnding of pneumatosis intestinalis, i.e. air within the bowel wall (Fig. 54.1). Pneumoperitoneum in an infant with NEC signiﬁes intestinal perforation and the need for immediate operation. The radiographic ﬁnding of portal venous gas occurs in the sickest infants, and is usually associated with extensive gangrene29–31 (Fig. 54.2).

502 Necrotizing enterocolitis Box 54.1 Medical supportive management of NEC

Figure 54.1 Abdominal X-ray showing pneumatosis intestinalis. Bubbly appearance of bowel loops throughout right side of abdomen, and a focus of linear pneumatosis intestinalis in the left upper quadrant

1 Cultures: blood culture is essential; CSF, urine, other sites are cultured as indicated 2 Gastric suction: for decompression of bowel, prevention of aspiration, and control of ileus 3 I.V. ﬂuids: 150–250 ml/kg/day of ﬂuid to restore tissue perfusion and urinary output 4 Antibiotics: a penicillin (penicillin or ampicillin), an aminoglycoside (gentamicin), and usually clindamycin or metronidazole for control of sepsis from gut pathogens 5 Blood and blood products: as needed for correction of anemia, coagulopathy 6 X-rays of abdomen: supine and left lateral decubitus views every 6–8 hours until infant is stable, then less frequently 7 Re-examination: every 6–8 hours until infant is stable, then less frequently

INDICATIONS FOR SURGERY

Figure 54.2 ‘Babygram’ showing portal venous gas (arrow). Pneumatosis intestinalis is also noted in right upper and lower quadrants and suprapubic area

When the diagnosis of NEC is suspected, medical supportive management (Box 54.1) is begun immediately. Approximately two-thirds of infants with NEC recover with medical treatment. Those who require operation are the sickest infants with advanced NEC, designated stage III by the clinical staging system of Bell et al.32

The indications for surgery in NEC are intestinal perforation or intestinal gangrene. Intestinal perforation is often suspected after an increase in the infant’s abdominal distension, and conﬁrmed by the ﬁnding of pneumoperitoneum on abdominal ﬁlms. In contrast, the clinical ﬁndings of intestinal gangrene prior to perforation are less precise, and some are controversial indications. The controversy stems from the patient population itself. NEC strikes tiny, premature infants, who typically are already ill with respiratory distress, sepsis and other ailments. They cannot complain of pain, rarely develop fever, and may lack abdominal tenderness or leucocytosis; the diagnosis of gangrene may thus be delayed until perforation and peritonitis have occurred, and the pathology is far advanced. The radiographic ﬁnding of pneumatosis intestinalis is not an indication for operation, because the majority of infants with this ﬁnding recover under medical management. Moreover, most pediatric surgeons are reluctant to operate without convincing evidence of intestinal gangrene, since negative exploratory laparotomy is not an acceptable procedure in critically ill premature infants. Ideally, operation should be timed to coincide with the advent of intestinal gangrene, rather than the occurrence of perforation. The mortality of NEC, however, correlates most strongly not with the event of perforation, but with the length of gangrenous intestine.33 A variety of clinical and radiographic criteria have been proposed as indications for operation in NEC. In a series from New Mexico, 12 such proposed criteria were evaluated.34 Sensitivity, speciﬁcity, positive predictive value, negative predictive value, and prevalence were calculated by standard epidemiological methods.35 The

Technique of paracentesis 503

end-point was the presence or absence of intestinal gangrene. The results are summarized in Table 54.1. In clinical decision making for or against operation, the most important measures are speciﬁcity (no false negatives) and positive predictive value (no false positives). The sensitivity, which is most valuable as a screening test, need not be high; in fact, as sensitivity approaches 100%, the positive predictive value usually falls. Pneumoperitoneum was a reliable criterion for intestinal gangrene after perforation. No false negatives were encountered in this series, although pneumoperitoneum may occasionally result from a pulmonary air leak in a ventilated infant. Several criteria were highly speciﬁc for the presence of intestinal gangrene prior to perforation: a positive paracentesis (described later), portal venous gas, a dilated loop on serial abdominal X-rays, a ﬁxed abdominal mass, and erythema of the abdominal wall. The latter three indicators were uncommon, however, occurring in less than 10% of cases. Severe pneumatosis intestinalis (according to a grading system in Reference 31) was present in 20% of cases and was also a good indication for operation. Other criteria which were not good indications for operation in NEC included: clinical deterioration (deﬁned in Reference 34), a falling platelet count (< 100 000/mm3), abdominal tenderness, severe gastrointestinal hemorrhage, and the radiographic ﬁnding of a gasless abdomen with ascites. These criteria had too many false positives (present in infants who proved not to have gangrene) or false negatives (absent in infants who proved to have gangrene) to be clinically useful.

TECHNIQUE OF PARACENTESIS Paracentesis is performed on infants in whom the diagnosis of intestinal gangrene is suspected. The procedure

is unnecessary in infants with suspected NEC, or those with deﬁnite NEC who are improving on non-operative therapy. Paracentesis is optimally carried out a few hours after the onset of symptoms because the evolution of intestinal gangrene may take several hours. Repeat paracenteses may be done in infants who fail to improve on medical therapy. Technique (Fig. 54.3) is of paramount importance. The abdomen is palpated for masses or enlarged viscera. After an antiseptic skin preparation, a small needle (22 or 25 gauge) is inserted into the ﬂank at a 45° angle. It is advanced slowly and aspirated gently until free ﬂow of 0.5 ml or more of peritoneal ﬂuid is obtained. A volume

Figure 54.3 Technique of paracentesis (see above) in a premature infant weighing 740 g with NEC. A 25-gauge needle was gently advanced and aspirated intermittently. The peritoneal ﬂuid in this infant was negative (not brown, no bacteria on Gram stain) and she recovered with medical therapy

Table 54.1 Indications for operation in acute NEC (%) (adapted from Reference 34) Indication Pneumoperitoneum Positive paracentesis* Portal venous gas Dilated loop on serial X-rays Fixed abdominal mass Erythema of abdominal wall Clinical deterioration† Platelet count < 100 000 /mm3 Persistent abdominal tenderness Severe gastrointestinal hemorrhage X-ray: gasless abdomen with ascites

Sensitivity 48 87 24 12.5 12.5 8 39 38 29 12 0

Speciﬁcity

PPV

NPV

Prevalence

100 100 100 100 100 100 89 83 72 83 94

100 97 100 100 100 100 78 73 58 50 0

52 60 43 46 46 45 59 54 43 42 41

31 72 16 7 7 5 25 28 29 14 2

PPV: positive predictive value; NPV = negative predictive value; *Positive paracentesis = brown ﬂuid and/or bacteria on Gram stain; †Clinical deterioration = deﬁned as two or more of the following: hypotension, oliguria, lethargy, increasing apnea, or persistent metabolic acidosis.

504 Necrotizing enterocolitis

(a)

Figure 54.4 (a–g) Operation for NEC. (a) Right transverse supraumbilical incision. (b) Mobilization and (c) resection of gangrenous gut. (d) Measurement of residual viable gut, when appropriate. (e) Formation of Mikulicz stoma, brought through separate site (f, g) on abdominal wall.

less than 0.5 ml is a ‘dry tap’ and cannot be interpreted. The color and appearance of the ﬂuid are noted; it is transported immediately to the laboratory for Gram stain and aerobic and anaerobic cultures. A positive paracentesis is deﬁned as brown ﬂuid and/or bacteria on Gram stain of the unspun ﬂuid.36 In the author’s experience with paracentesis on more than 175 infants with NEC, there were no instances of intestinal perforation which were attributable to the technique as described. One falsely positive paracentesis occurred in a premature infant weighing 1120 g with extensive pneumatosis intestinalis and brown peritoneal ﬂuid. His intestine proved to be viable at operation; he

Operative procedure – peritoneal drainage 505

made an uneventful postoperative recovery. Ricketts, using a similar technique, reported a 94% sensitivity and 100% speciﬁcity for paracentesis ﬁndings in 36 infants with intestinal gangrene from NEC.37

OPERATIVE PROCEDURE – LAPAROTOMY Figure 54.4 (a–g) depicts the author’s technique of laparotomy for NEC. The bowel is gently examined from stomach to rectum. The ileocecal area is usually the site of the most severe ischemia, including perforations. Involved segments are typically pale from ischemic necrosis or purple from hemorrhagic necrosis (Fig. 54.5), and may have bubbles of intramural air visible beneath the serosa. ‘Skip areas’ of viable intestine between ischemic segments are common. The cardinal principles of surgery for NEC are excision of the gangrenous bowel, exteriorization of the marginally viable ends, and preservation of as much intestinal length as possible.27,38 Segments which are obviously gangrenous should be resected. Dusky bowel is preserved, especially when there is extensive involvement. Such areas may have the potential for healing if protected by an enterostomy. Perforations generally should be exteriorized rather than closed. Gangrenous foci that have not yet perforated are usually located on the antimesenteric border of the bowel and may be inverted into the lumen by enteroplasty. Massive intestinal resection, which leaves less than 30 cm of viable intestine, should not be performed. Surgical options in such cases of extensive NEC will be discussed separately later. After the gangrenous segment(s) of intestine are resected, the ends are exteriorized as an enterostomy. Our preferred method of exteriorization has been the Mikulicz enterostomy, brought through a separate site adjacent to the laparotomy incision (Fig. 54.6).39 Others

Figure 54.5 Operative photograph showing gangrenous loops of bowel in foreground, viable bowel in background. (The drawing of Fig. 54.4b was based on this photograph)

Figure 54.6 Mikulicz enterostomy (technique of author). (a) Double-barrelled enterostomy. Stoma matures spontaneously, without a surgical ‘tumback’. (b) Application of spur-crushing clamp. (c) Septum divided by clamp, luminal continuity restored. (From Rosenman and Kosloske, Reference 39, with permission)

prefer to bring the two ends of bowel out through the laparotomy incision40 (Fig. 54.7). The distal limb of bowel should be exteriorized, rather than dropped back in the abdomen, to avoid enterocyst formation between two ischemic areas, which may subsequently become strictured.41,42 A comparative study of the two methods depicted in Figs 54.6 and 54.7 of 100 infants who underwent enterostomy formation and closure showed no difference in the rate of wound or stomal complications.43 The rate of stricture formation in the distal bowel was higher for separate stomas than for the Mikulicz enterostomy (36% vs 18%), which was attributed to earlier re-establishment of intestinal continuity in the Mikulicz group. Both methods exteriorized the bowel ends close to one another, which was advantageous because subsequent closure could be performed without a formal laparotomy. Closure of a Mikulicz enterostomy (Fig. 54.8) was a simpler procedure than closure of separate stomas, although there was no difference in complication rate between the two procedures. Precise technique and meticulous enterostomal care are clearly more important than the method of enterostomy chosen.

506 Necrotizing enterocolitis

Figure 54.8 Closure of Mikulicz enterostomy. (a) Stoma mobilized and margins trimmed. (b) Single layer closure. (c) Closure completed. (From Rosenman and Kosloske, Reference 39, with permission) Figure 54.7 Double enterostomy (technique of Dr Richard R. Ricketts). (a) Separate stomas brought through incision, secured with four ﬁne sutures through full thickness of abdominal wall and seromuscular layer of intestine. (b) Closure of abdomen with running absorbable sutures, leaving one-suture fascial bridge between stomas. (c) Skin closed with running ﬁne nonabsorbable suture. One-suture skin bridge between stomas. Stomas matured to skin with four quadrant ﬁne absorbable sutures. (Courtesy of Dr R.R. Ricketts)

OPERATIVE PROCEDURE – PERITONEAL DRAINAGE A drainage procedure of the peritoneal cavity was reported in 1977 by Ein et al. for severely ill premature infants with perforated NEC who were considered ‘too sick to be operated upon’.44,45 The procedure was performed in the NICU under local anesthesia. A small stab wound was made either in the right lower quadrant or above the umbilicus for evacuation of free gas, peritoneal exudate, pus and feces; a small Penrose drain was inserted. Others have used peritoneal drainage as an adjunctive procedure to resuscitation before laparotomy,46 or as primary therapy in very sick premature infants with bowel perforation.47 Ein et al. from the Hospital for Sick Children, Toronto, Ontario, Canada, continue to recommend peritoneal drainage for resuscitation of small, critically ill infants with NEC; however, they concede that

most of these infants will also require laparotomy.48 Drainage remains a controversial choice, as it violates the surgical principle of removal of necrotic bowel, which is a source of continuing sepsis. Moss et al. from Stanford University analyzed the conﬂicting data on the efﬁcacy of peritoneal drainage for NEC in infants of extremely low birth weight.49 Of their 17 infants who received primary peritoneal drainage, seven improved without further need for operation and ten worsened. All ten of the infants who worsened subsequently died, in spite of ‘salvage’ laparotomy in four of them. Moss has postulated that the peritoneal inﬂammatory response of the premature infant may be fundamentally different from that of older infants or children. His group of investigators is currently conducting a prospective, randomized, multicenter trial comparing peritoneal drainage to laparotomy in infants of extremely low birth weight with perforated NEC.

Peritoneal drainage and ileostomy A different approach was employed in a report from Belgium,50 in which 18 infants with acute NEC received a double-barrelled ileostomy via a McBumey-type incision and insertion of two or three peritoneal drains. Subsequent operations were done for ileostomy closure and resection of strictures, with only one death in the series. More experience is needed with this technique, by which necrotic bowel is left in situ, yet may be afforded some protection by the ileostomy.

Subcapsular hematoma of the liver 507

OTHER OPERATIONS FOR ACUTE NEC Resection and primary anastomosis Some pediatric surgeons advocate resection of gangrenous intestine and primary anastomosis for infants with NEC, including some infants with intestinal perforation and peritonitis.51–54 In these series, results were generally good; however, in spite of careful selection and operation by expert pediatric surgeons, a few deaths in each series could be attributed to intraabdominal sepsis from an anastomotic leak. In the 1970s, the author’s experience with primary anastomosis55 and that of others56,57 showed an unacceptable rate of anastomotic leakage and stricture, leading to the recommendation that primary anastomosis should not be carried out. An analysis of 173 infants with advanced (surgical) NEC at the Children’s Hospital of Philadelphia found no advantage for primary anastomosis in selected patients with NEC, and concluded that it may actually jeopardize the survival of an infant who should be expected to live.58 O’Neill commented that a decision to perform primary anastomosis may lead to unnecessarily extensive resection, in order to assure that the bowel ends are unequivocally viable.59 Although the subject is debated,33,54 consensus still favors resection and enterostomy as the safer and preferred procedure for acute NEC.1,58,60,61 In infants who require resection of more than one segment, primary anastomosis ‘downstream’ from an enterostomy is safe from the risk of an anastomotic leak, although stricture may occur.

viable bowel (about 30 cm) remains, the demarcated gangrenous bowel should be resected. Massive resection, however, which leaves crippling short-gut syndrome, should not be done. A group from Indiana performed a ‘clip and drop back’ procedure in ﬁve infants; necrotic intestine was excised between clips; delayed anastomosis was done at subsequent laparotomy.68 This approach avoided stomas and allowed preservation of maximal intestinal length. Schneider and Harrison reported a survivor with a similar technique, which they called ‘sausage resection,’ using ligatures instead of clips.69 Moore described a method of ‘patch, drain, and wait’ for preservation of intestinal length, which was successful in ﬁve infants.70 His technique included limited closure of major perforations, leaving necrotic bowel in situ, and placement of Penrose drains on both sides of the abdomen, extending from the diaphragm to lower quadrants. Moore’s ﬁve infants all formed enterocutaneous ﬁstulas, which were ‘captured’ by the drains. Two of his ﬁve infants required delayed anastomosis; the other three recovered spontaneously, with no need for a second operation. Lessin et al. reported two infants with extensive multisegmental NEC successfully treated by resection of necrotic bowel and placement of an intraluminal stent, without anastomosis.71 The intestine healed, with preservation of maximal bowel length. Salvage from extensive NEC might be further improved by earlier intervention based on the radiographic abnormalities of severe pneumatosis intestinalis or portal venous gas, which are highly correlated with extensive NEC.31

SUBCAPSULAR HEMATOMA OF THE LIVER EXTENSIVE NECROTIZING ENTEROCOLITIS Massive ischemic injury of the small and large intestine (pan-necrosis, NEC totalis) is found in 17–19% of operations for NEC.21,62 Typically, the ischemic change begins a few centimeters beyond the ligament of Treitz with dusky, pale-gray areas of ischemic necrosis, purple areas of hemorrhagic necrosis, black spots of frank gangrene and occasional transparent ‘serosal windows’, interspersed with ‘skip areas’ of viable intestine. Rarely even the stomach, duodenum or rectum is necrotic. In such patients mortality exceeds 80% and surgery has little to offer. Some cases of fulminant NEC, especially ones that occur in term infants, have been associated with bowel wall invasion with Clostridium perfringens; these cases may represent gas-gangrene of the bowel.63,64 A variety of heroic procedures has been tried; occasional successes tend to appear as case reports, since the majority of infants with extensive NEC die. Proximal enterostomy and a ‘second-look’ procedure has been suggested.65–67 The ‘second-look’ operation should be done 48–72 hours after proximal diversion; if sufﬁcient

Major hemorrhage from the liver is a rare but catastrophic complication which may occur during laparotomy for NEC. The hemorrhage is a manifestation of coagulopathy in the septic, very low birth weight (VLBW) infant. In the typical scenario, a ‘blood-blister’ appears beneath Glisson’s capsule after minimal or no retraction of the liver (Fig. 54.9). Within minutes, the hematoma expands and ruptures, leading to uncontrollable hemorrhage from the liver. In this situation, techniques for surgical hemostasis (e.g. pressure, suture, topical thrombin or other coagulants) are futile; the bleeding will not cease until either the coagulopathy is corrected, which may take hours, or the patient dies, which may take just a few minutes. The emergency management of this crisis is: (1) pack the liver, and (2) abandon the operation. Bowel which is obviously dead may be clipped out, with ligatures or clips above and below. The ends are dropped back into the abdomen; no stomas or anastomoses are carried out. The abdomen should be closed rapidly in one layer or covered with a sterile ‘vac-pac’ dressing.72 The surgeons can come back

508 Necrotizing enterocolitis

death from a leaking suture line. The outcome of operation for perforation is good, whether laparotomy or peritoneal drainage is carried out. Uceda et al., who performed laparotomy, reported a survival rate of 88% for ‘spontaneous’ perforation, 56% for NEC.77 Rovin et al. from Charlottesville utilized peritoneal drainage for intestinal perforation in 18 consecutive premature infants.79 They distinguished intestinal perforation with evidence of NEC (ten infants with pneumoperitoneum and pneumatosis intestinalis) from intestinal perforation without NEC (eight infants with pneumoperitoneum, but without pneumatosis intestinalis). The latter group, as might be predicted, had less severe bowel involvement and better outcomes.

Figure 54.9 Subcapsular hematoma (arrows) of left lobe of liver during laparotomy for NEC. Hemostat at left holds bowel end after resection. Ileostomy was done, and abdomen gently closed. The hematoma did not burst and the premature infant recovered

another day to ﬁnish the operation when the coagulopathy is corrected. This approach, recommended 2 decades ago for adults with major intraoperative hemorrhage by Stone et al.,73 is effective in neonates and has been used successfully by the author on several occasions.74 Speed is of the essence. Prevention is, of course, better than the most expert treatment of subcapsular hematoma. Blood products containing appropriate clotting factors should be given before and during laparotomy. A generous incision which obviates the need for retraction on the liver, i.e. the ‘no-touch’ technique, should be utilized.

OPERATION IN NICU Anveden-Hertzberg and Gauderer evaluated the inﬂuence of the operative event itself on the outcome of 34 very low birth weight (VLBW) infants (weighing < 1500 g) who underwent laparotomy for NEC.80 Intraoperative hypotension occurred in 42% of infants. Intraoperative hypothermia was also common, in spite of the employment of two or more warming devices in the operating room, e.g. radiant heater, heating mattress, or increased room temperature. Based on similar experiences, some pediatric surgeons, including the author, avoid transporting critically ill, VLBW infants with NEC to the operating room. Instead, the surgical team is brought to the infant’s bedside in the NICU; the operation is conducted with the infant in a radiant warmer bed. This approach decreases the risk of hypothermia or hypotension, minimizes the risk of dislodgment or slippage of the endotracheal tube, and eliminates the stress of additional handling during transport to the operating room.

‘IDIOPATHIC’ INTESTINAL PERFORATION Some authors have distinguished ‘spontaneous’ intestinal perforation as a pathologic process separate from NEC.75–77 Infants with ‘spontaneous’ perforation have pneumoperitoneum but no pneumatosis intestinalis on abdominal ﬁlms; typically they develop progressive distention with bluish discoloration of the abdomen. At laparotomy, a focal perforation is found, usually in the distal ileum. Since ‘spontaneous’ perforation occurs in the same population as NEC, and both conditions are characterized by histologic evidence of ischemia, ‘spontaneous’ perforation seems likely to represent a focal form of NEC, rather than a separate disease process. Even gastric perforation in the premature infant may have histologic evidence of ischemia, and may thus represent a variant of NEC.78 The optimal surgical management is exteriorization, rather than closure of the perforation. Exteriorization is the safer choice because it leaves no risk of sepsis and

POSTOPERATIVE MANAGEMENT After operation for acute NEC is completed, intensive medical care (Box 54.1) is continued. Crystalloid and colloid i.v. solutions are given to maintain perfusion and urinary output. Antibiotics for coverage of aerobic and anaerobic bacteria are continued for 7–10 days. Gastric suction is carried out until ileus has resolved, and the enterostomy begins to function. Inotropic medications may sometimes be helpful for cardiovascular support. Total parenteral nutrition (TPN) is given, either by a peripheral or a central venous line. In a follow-up study from Indiana, one-third of infants who required prolonged administration of TPN developed cholestatic jaundice following NEC;81 infants < 31 weeks’ gestational age or <1000 g birth weight were particularly prone to this complication, which occasionally progressed to cirrhosis and liver failure.

Outcome 509

After sepsis and ileus have subsided, usually in the second or third week after operation, oral feedings are cautiously resumed. An elemental formula is preferred because many infants have malabsorption following NEC. Excessive sodium and bicarbonate losses from the enterostomy may be anticipated,82,83 often leading to depletion of total body sodium, metabolic acidosis and failure to thrive. These problems may be deterred by oral administration of sodium and bicarbonate supplements, or by early closure of the enterostomy.84 A review of 100 infants who underwent enterostomy and closure found no difference in the complication rate between early (before the age of 3 months or under 2.5 kg in weight) vs late closure, and concluded that enterostomies should be closed early, as long as good anesthesia and special care facilities for premature infants are available.43

loop and the abdominal incision). Late obstruction from inﬂammatory pseudopolyps at an ischemic focus has been reported.91 Abscess formation is not common,55 probably because bacterial colonization of the gut may be incomplete at the time of NEC or because the ﬂimsy neonatal omentum is incapable of walling off an inﬂammatory process. Severe ischemia occasionally results in dissolution and disappearance of the affected segment of intestine, analogous to the embryogenesis of intestinal atresia. Jona reported an infant with intestinal obstruction from acquired ileal atresia with a 20 mm gap following NEC; at operation the infant had redeveloped intestinal continuity via an enteroenteric ﬁstula.92

INTESTINAL STRICTURE

The operative survival rate in large series of NEC has improved over the past 3 decades.93 The series of Santulli et al. (1955–74) consisted of far-advanced cases; only 30% of the infants survived.20 In the 1970s O’Neill et al. reported a 60% survival of surgical infants.56,94 Beasley et al. attributed a 72% survival rate for operated infants (1979–84) to reﬁnements in the indications for surgery without obvious perforation, as well as energetic supportive measures.60 In Grosfeld et al.’s study, an improved operative survival rate (51% in 1972–82; 75% in 1983–90) was credited to early operation and resection of necrotic bowel, plus improvements in neonatal care, e.g. surfactant therapy and jet ventilators.61 Ricketts and Jerles’ series (1980–87) correlated hospital survival rates with birth weight: the survival rate was 54% for the group weighing < 1000 g, 74% for infants weighing from 1001–1500 g and 79% for the group weighing >1500.95 A recent report from the Institute of Child Health, Great Ormond Street, London, analyzed the results of surgical treatment of 83 infants with NEC, according to the extent of disease and to determine if resection of the ileocecal valve represented a poor prognostic factor.33 Not surprisingly, the survival rate varied inversely with the extent of disease: 88% for isolated disease, 69.5% for multifocal disease, and 33% for pan-intestinal involvement. Good outcomes were documented in infants who underwent resection and primary anastomosis, their preferred technique over resection and double enterostomy. These investigators and others96 observed that neonates with NEC adapt rapidly to the loss of the ileocecal valve. The majority of infants who survive acute NEC eventually recover normal gastrointestinal function. In a follow-up study from Stanford University of 40 survivors of NEC,97 10% of infants had gastrointestinal symptoms associated with short-gut syndrome or colonic strictures, but none suffered permanent failure to thrive. Serious neurological problems nonetheless were prevalent in this

Stricture formation occurs in 15–25% of the survivors of acute NEC.85 The pathogenesis is cicatricial healing of a segment of intestine injured by ischemia. Usually the stricture is located in the colon and can be identiﬁed by barium enema. Schwartz et al. reported a higher incidence of post-NEC stricture (36%); their series included asymptomatic radiographic strictures which resolved spontaneously.86 Barium enema has been recommended as a screening procedure85,86 for infants after recovery from NEC, although some investigators cite the low yield (14–23%) and are reluctant to subject asymptomatic infants to barium enema.87 The risk of stricture, however, is not trivial; Hartman et al. reported four infants with a sudden onset of life-threatening sepsis or perforation due to stricture following NEC.88 Contrast enemas were advised, as well as close clinical observation. Many strictures are located distally to an enterostomy and are discovered on barium enema prior to enterostomy closure. Strictures which are composed of heavy scar tissue must be resected prior to enterostomy closure. Less severe strictures which are focal may not require resection. Ball et al. successfully employed a technique of dilatation under ﬂuoroscopy, using the Gruntzig balloon catheter.89,90 The technique is recommended for focal strictures located distally to an enterostomy (which are asymptomatic), but not for symptomatic strictures. Infants with clinical evidence of intestinal obstruction should be treated by urgent operation.

OTHER LATE COMPLICATIONS The healing process after severe intestinal ischemia may result in ﬁstula formation, either enteroenteric (between affected loops) or enterocutaneous (between an affected

OUTCOME

510 Necrotizing enterocolitis

population. Of the Stanford survivors of NEC tested at 1–3 years of age, 50% were completely normal children, but 35% had various mild neurological sequelae, e.g. an abnormal EEG, and 15% had moderate to severe neurological impairment, e.g. spasticity, blindness, or deafness. These sequelae occurred at the same rate in a matched group of premature infants without NEC, and were attributed to prematurity and perinatal stress, rather than NEC. Others have conﬁrmed a generally encouraging follow-up for infants surviving NEC,81,98 although the surgical survivors are at an increased risk for late sepsis from Gram-negative bacilli,99 cholestatic jaundice, and growth retardation and neurodevelopmental impairment.100

REFERENCES 1. Albanese C, Rowe MI. Necrotizing enterocolitis. In: O’Neill JA Jr et aI. editors. Pediatric Surgery. Vol. 2. 5th edn. St Louis: Mosby, 1998:1297–1320. 2. Kosloske AM. Necrotizing enterocolitis in the neonate: collective review. Surg Gynecol Obstet 1979; 148:259–69. 3. Kosloske AM. Epidemiology of necrotizing enterocolitis. Acta Pediatr Suppl 1994; 396:2–7. 4. Holman RC, Stehr-Green JK, Zelasky MT. Necrotizing enterocolitis mortality in the United States. Am J Publ Health 1989; 79:987–9. 5. Schmid KO, Quaiser K. Uber eine besonders schwer Verlaufende From von Enteritis beim saugling. Oesterr Z Kinderh 1953; 8:114–20. 6. Pouyanne MM, Triassac M, Lassere J et al. Enterite necrosante du grele chez un nouveaune. J Med de Bordeaux 1956; 133:610. 7. Rossier A, Sarrot S, Delplanque J. L’entercolite ulcero necrotique du premature. Sem Hop Paris 1959; 35:1428–36. 8. Waldhausen JA, Herendeen T, King HA. Necrotizing colitis of the newborn; common cause of perforation of the colon. Surgery 1963; 54:365–72. 9. Touloukian RJ, Berdon WG, Amoury RA et al. Surgical experience with necrotizing enterocolitis in the infant. J Pediatr Surg 1967; 2:389–401. 10. Stevenson JK, Graham CB, Oliver TK Jr et al. Neonatal necrotizing enterocolitis; a report of 21 cases with 14 survivors. Am Surg 1969; 118:260–72. 11. Rowe MI, Reblock KK, Kurkchubasche AG et al. Necrotizing enterocolitis in the extremely low birth weight infant. J Pediatr Surg 1994; 29:987–91. 12. Snyder CL, Gittes GK, Murphy JP et al. Survival after necrotizing enterocolitis in infants weighing less than 1000 grams: 25 years’ experience at a single institution. J Pediatr Surg 1997; 32:434–7. 13. Lawrence G, Walker PD. Pathogenesis of enteritis necroticans in Papua New Guinea. Lancet 1976; 1:125–6.

14. Shann F, Lawrence G, Jun-Di P. Enteritis necroticans in China. Lancet 1979; 1:1083–4. 15. Johnson S, Echeverria P, Taylor DN et al. Enteritis necroticans among Khmer children at an evacuation site in Thailand. Lancet 1987; 2:496–500. 16. Arseculeratne SN, Panabokke RG, Navaratnam C. Pathogenesis of necrotising enterocolitis with special reference to intestinal hypersensitivity reactions. Gut 1980; 21:265–78. 17. Kliegman RM, Fanaroff AA. Necrotizing enterocolitis. N Engl J Med 1984; 310:1093–1103. 18. Lucas A, Cole T. Breast milk and neonatal necrotizing enterocolitis. Lancet 1990; 336:1519–23. 19. Lawrence G, Bates J, Gaul A. Pathogenesis of neonatal necrotizing enterocolitis. Lancet 1982; 1:137–9. 20. Santulli TV, Schullinger JN, Heird WC et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975; 55:376–87. 21. Ballance WA, Dahms BB, Shenker N et al. Pathology of neonatal necrotizing enterocolitis. J Pediatr 1991; 117:S6–13. 22. Amoury RA, Goodwin CD, McGill CW et al. Necrotizing enterocolitis following operation in the neonatal period. J Pediatr Surg 1980; 15:1–8. 23. Mollitt DL, Golladay ES. Postoperative neonatal necrotizing enterocolitis. J Pediatr Surg 1982; 17:757–63. 24. Oldham KT, Coran AG, Drongowski RA et al. The development of necrotizing enterocolitis following repair of gastroschisis: A surprisingly high incidence. J Pediatr Surg 1988; 23:945. 25. Costello S, Hellmann J, Lui K. Myelomeningocele: a risk factor for NEC in term infants. J Pediatr 1988; 113:1041–44. 26. Kosloske AM. The epidemiology and pathogenesis of necrotizing enterocolitis. Semin Neonatol 1997; 2:231–8. 27. Kosloske AM. Necrotizing enterocolitis. In: Oldham KT et al., editors. Surgery of Infants and Children: Scientiﬁc Principles and Practice. Philadelphia: Lippincott-Raven, 1997:1201–13. 28. Kliegman RM. Models of the pathogenesis of necrotizing enterocolitis. J Pediatr Suppl 1991; 117:S2–5. 29. Cikrit D, Mastandrea J, Grosfeld JL et al. Signiﬁcance of portal vein air in necrotizing entercolitis: analysis of 53 cases. J Pediatr Surg 1985; 20:425–30. 30. Buras R, Guzzetta P, Avery G et al. Acidosis and portal venous gas: indications for surgery in necrotizing enterocolitis. Pediatrics 1986; 78:273–7. 31. Kosloske AM, Musemeche CA, Ball WS Jr et al. Necrotizing enterocolitis: value of radiographic ﬁndings to predict outcome. AJR Am J Roentgenol 1988; 151:771–4. 32. Bell MJ, Ternberg JL, Feigin RD et al. Neonatal necrotizing enterocolitis; therapeutic decisions based upon clinical staging. Ann Surg 1978; 187:1–7. 33. Fasoli L, Turi RA, Spitz L et al. Necrotizing enterocolitis: Extent of disease and surgical treatment. J Pediatr Surg 1999; 34:1096–9.

References 511 34. Kosloske AM. The indications for operation in necrotizing enterocolitis revisited. J Pediatr Surg 1994; 29:663–6. 35. Gordis L. Epidemiology. 2nd edn. Philadelphia: Saunders, 2000:63–81. 36. Kosloske AM, Lilly JR. Paracentesis and lavage for diagnosis of intestinal gangrene in neonatal necrotizing enterocolitis. J Pediatr Surg 1978; 13:315–20. 37. Ricketts RR. The role of paracentesis in the management of infants with necrotizing enterocolitis. Ann Surg 1986; 52:61–5. 38. Kosloske AM. Surgery of necrotizing enterocolitis. World J Surg 1985; 9:277–84. 39. Rosenman JE, Kosloske AM. A reappraisal of the Mikulicz enterostomy in infants and children. Surgery 1982; 91:34–7. 40. Ricketts RR. Surgical therapy for necrotizing enterocolitis. Ann Surg 1984; 200:653–7. 41. Lloyd DA, Cywes S. Intestinal stenosis and enterocyst formation as late complications of neonatal necrotizing enterocolitis. J Pediatr Surg 1973; 8:479–86. 42. Ladin DA, Campbell DP, Crowe CP. Perforated enterocyst: a late complication of neonatal necrotizing enterocolitis. Pediatr Surg Int 1992; 7:394–5. 43. Musemeche CA, Kosloske AM, Ricketts RR. Enterostomy in necrotizing enterocolitis: an analysis of techniques and timing of closure. J Pediatr Surg 1987; 22:479–83. 44. Ein SH, Marshall DG, Girvan D. Peritoneal drainage under local anesthesia for perforations from necrotizing enterocolitis. J Pediatr Surg 1977; 12:963–7. 45. Janik JS, Ein SH. Peritoneal drainage under local anesthesia for necrotizing enterocolitis (NEC) perforation: a second look. J Pediatr Surg 1980; 15:565–8. 46. Cheu HW, Sukarochana K, Lloyd DA. Peritoneal drainage for necrotizing enterocolitis. J Pediatr Surg 1988; 23:557–61. 47. Morgan LJ, Shochat SJ, Hartman GE. Peritoneal drainage as deﬁnitive management of perforated NEC in the very low birthweight infant. J Pediatr Surg 1994; 29:310–15. 48. Ahmed T, Ein S, Moore A. The role of peritoneal drains in treatment of perforated necrotizing enterocolitis: Recommendations from recent experience. J Pediatr Surg 1998; 33:1468–70. 49. Dimmitt RA, Meier AH, Skarsgard ED et al. Salvage laparotomy for failure of peritoneal drainage in necrotizing enterocolitis in infants with extremely low birth weight. J Pediatr Surg 2000; 35:856–9. 50. Legat C, Latour JP. Peritoneal drainage and ileostomy as a treatment for the acute necrotizing enterocolitis. Z Kinderchir 1989; 44:315–17. 51. Harberg FJ, McGill CW, Saleem MM et al. Resection with primary anastomosis for necrotizing enterocolitis. J Pediatr Surg 1983; 18:743–6. 52. Pokorny WJ, Garcia-Prats JA, Barry YN. Necrotizing enterocolitis: incidence, operative care, and outcome. J Pediatr Surg 1986; 21:1149–54. 53. Sparnon AL, Kiely BM. Resection and primary anastomosis for necrotizing enterocolitis. Pediatr Surg Int 1987; 2:101–4.

54. Stringer MD, Spitz L. Surgical management of neonatal necrotizing enterocolitis. Arch Dis Child 1993; 69:269. 55. Kosloske AM, Martin LW. Surgical complications of neonatal necrotizing enterocolitis. Arch Surg 1973; 107:223–8. 56. O’Neill JA Jr, Stahlman MT, Meng HC. Necrotizing enterocolitis in the newborn: operative indications. Ann Surg 1975; 182:274–9. 57. Touloukian RJ. Neonatal necrotizing enterocolitis: an update on etiology, diagnosis, and treatment. Surg Clin N Am 1976; 56:281–98. 58. Cooper A, Ross AJ III, O’Neill JA Jr et aI. Resection with primary anastomosis for necrotizing enterocolitis: a contrasting view. J Pediatr Surg 1988; 23:64–8. 59. O’Neill JA Jr. Discussion of Harberg FJ et al. Resection with primary anastomosis for necrotizing enterocolitis. J Pediatr Surg 1983; 18:743–6. 60. Beasley SW, Auldist AW, Ramanujan TM et al. The surgical management of neonatal necrotizing enterocolitis, 1975–1984. Pediatr Surg Int 1986; 1:210–17. 61. Grosfeld JL, Cheu H, Schlatter M et aI. Changing trends in necrotizing enterocolitis:experience with 302 cases in two decades. Ann Surg 1991; 214:300–7. 62. Kurkchubasche AG, Smith SD, Rowe MI. Portal venous air – an old sign and new operative indication for necrotizing enterocolitis. Proceedings of the BAPS XXXVIII Annual International Congress, Budapest, Hungary, July 1991 (Abstract). 63. Kosloske AM, Ulrich JA, Hoffman H. Fulminant necrotizing enterocolitis associated with clostridia. Lancet 1978; 2:1014–16. 64. Kosloske AM, Ball WS Jr, Umland E et al. Clostridial necrotizing enterocolitis. J Pediatr Surg 1985; 20:155–9. 65. Martin LW, Neblett WW. Early operation with intestinal diversion for necrotizing enterocolitis. J Pediatr Surg 1981; 16:252–5. 66. Firor HV. Use of high jejunostomy in extensive NEC. J Pediatr Surg 1982; 17:771–2. 67. Weber TR, Lewis EJ. The role of second-look laparotomy in necrotizing enterocolitis. J Pediatr Surg 1986; 21:232–5. 68. Vaughan WG, Grosfeld JL, West K et al. Avoidance of stomas and delayed anastomosis for bowel necrosis: the ‘clip and drop-back’ technique. J Pediatr Surg 1996; 31:542–5. 69. Schneider PA, Harrison MR. Sausage resection of ischemic intestine. J Pediatr Surg 1987; 22:1011–12. 70. Moore TC. The management of necrotizing enterocolitis by ‘patch, drain, and wait.’ Pediatr Surg Int 1989; 4:110–13. 71. Lessin MS, Schwartz DL, Wesselhoeft CW Jr. Multiple spontaneous small bowel anastomosis in premature infants with multisegmental necrotizing enterocolitis. J Pediatr Surg 2000; 35:170–2. 72. Markley M, Letton R, Mantor PC, Tuggle D. The pediatric ‘vac-pac’ wound closure for damage control laparotomy. Presented at the Meeting of the American Pediatric Surgical Association. Naples: Florida, May, 2001.

512 Necrotizing enterocolitis 73. Stone HH, Strom PR, Mullins RJ. Management of the major coagulopathy with onset during laparotomy. Ann Surg 1983; 197:532. 74. Kosloske AM. Management of subcapsular hematoma of the liver during neonatal laparotomy. Presented at the Meeting of the Paciﬁc Association of Pediatric Surgeons, Oaxaca, Mexico, May, 1995. 75. Mintz AC, Applebaum H. Focal gastrointestinal perforations not associated with necrotizing enterocolitis in very low birth weight neonates. J Pediatr Surg 1993; 28:857–60. 76. Bucheit JQ, Stewart DL. Clinical comparison of localized intestinal perforation and necrotizing enterocolitis in neonates. Pediatrics 1994; 93:32–6. 77. Uceda JE, Laos CA, Kolni HW et al. Intestinal perforations in infants with a very low birth weight: A disease of increasing survival? J Pediatr Surg 1995; 30:1314–16. 78. Goldthorn JF, Kosloske AM. The pathogenesis of neonatal gastric rupture. Controversies in Pediatric Surgery. Austin: University of Texas Press, 1984:98–106. 79. Rovin JD, Rodgers BM, Burns RC, McGahren ED. The role of peritoneal drainage for intestinal perforation in infants with and without necrotizing enterocolitis. J Pediatr Surg 1999; 34:143–7. 80. Anveden-Hertzberg A, Gauderer MWL. Surgery is safe in very low birth weight infants with necrotizing enterocolitis. Acta Paediatr 2000; 89:242–5. 81. Cikrit D, West KW, Schreiner R et al. Long term follow up after surgical management of necrotizing enterocolitis: 63 cases. J Pediatr Surg 1986; 21:533–5. 82. Schwartz KB, Ternberg JL, Bell MJ et al. Sodium needs of infants and children with ileostomy. J Pediatr 1983; 102:509–13. 83. Bower TR, Pringle KC, Soper RT. Sodium deﬁcit causing decreased weight gain and metabolic acidosis in infants with ileostomy. J Pediatr Surg 1988; 23:567–72. 84. Rothstein FC, Halpin TC Jr, Kliegman RJ et al. Importance of early ileostomy closure to prevent chronic salt and water losses after necrotizing enterocolitis. Pediatrics 1982; 70:249–53. 85. Kosloske AM, Burstein J, Bartow SA. Intestinal obstruction due to colonic structure following neonatal necrotizing enterocolitis. Ann Surg 1980; 192:202–7. 86. Schwartz MZ, Hayden CK, Richardson CJ et al. A prospective evaluation of intestinal stenosis following necrotizing enterocolitis. J Pediatr Surg 1982; 17:764–70.

87. Born M, Holgersen LO, Shahrivar F et al. Routine contrast enemas for diagnosing and managing strictures following nonoperative treatment of necrotizing enterocolitis. J Pediatr Surg 1985; 20:461–3. 88. Hartman GB, Drugas GT, Shochat SJ. Post-necrotizing enterocolitis strictures presenting with sepsis or perforation: risk of clinical observation. J Pediatr Surg 1988; 23:562–6. 89. Ball WS Jr, Seigel RS, Goldthorn JF et al. Colonic strictures in infants following intestinal ischemia. Radiology 1983; 149:469–72. 90. Ball WS Jr, Kosloske AM, Jewell PF et al. Balloon catheter dilatation of focal intestinal strictures following necrotizing enterocolitis. J Pediatr Surg 1985; 20:637–9. 91. Iofel E, Kahn E, Lee TK, Chawla A. Inﬂammatory polyps after necrotizing enterocolitis. J Pediatr Surg 2000; 35:1246–7. 92. Jona JZ. Acquired ileal atresia and spontaneous reconstitution of intestinal continuity in a premature infant with necrotizing enterocolitis. J Pediatr Surg 2000; 35:505–7. 93. Horwitz JR, Lally KP, Cheu HW et al. Complications after surgical intervention for necrotizing enterocolitis: a multicentre review. J Pediatr Surg 1995; 30:994–9. 94. O’Neill JA Jr, Holcomb GW Jr. Surgical experience with neonatal necrotizing enterocolitis. Ann Surg 1979; 189:612–19. 95. Ricketts RR, Jerles ML. Neonatal necrotizing enterocolitis: experience with 100 consecutive surgical patients. Wld J Surg 1990; 14:600–15. 96. Rescorla FJ, Ladd AP. Necrotizing enterocolitis. In: Stringer MD et al., editors. Pediatric Surgery and Urology: Long Term Outcomes. London: Saunders, 1998; 289–299. 97. Stevenson DK, Kerner JA, Malachowski N et al. Late morbidity among survivors of necrotizing enterocolitis. Pediatrics 1980; 66:925–7. 98. Hack M, Gordon D, Jones P et al. Necrotizing enterocolitis in the VLBW: an encouraging follow-up report. Pediatr Res 1981; 15:534. 99. Walsh MC, Simpser EF, Kliegman RM. Late onset of sepsis in infants with bowel resection in the neonatal period. J Pediatr 1988; 112:468–71. 100. Walsh MC, Kliegman RM. Severity of necrotizing enterocolitis: inﬂuence on outcome at 2 years of age. Pediatrics 1989; 84:808–14.

55 Hirschsprung’s disease PREM PURI

INTRODUCTION Hirschsprung’s disease (HD) is a relatively common cause of intestinal obstruction in the newborn. It is characterized by absence of ganglionic cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The aganglionosis is conﬁned to rectosigmoid in 75% of patients, the sigmoid, splenic ﬂexure or transverse colon in 17% and total colon along with a short segment of terminal ileum in 8% of patients.1,2 Total intestinal aganglionosis with absence of ganglionic cells from the duodenum to the rectum is the most rare form of HD.3–7 The incidence of HD is estimated to be one in 5000 live births8-10 (Table 55.1). Spouge and Baird studied the incidence of HD in 689 118 consecutive live births in British Columbia and reported an incidence rate for this disease to be one in 4417 live births.9 The disease is more common in boys, with a male-to-female ratio of 4:1.10–12 The male preponderance is less evident in long-segment HD, where the male-to-female ratio is 1.5–2:1.8–10 Table 55.1 Incidence of Hirschsprung’s disease Author

Incidence

Area

Passarge8 Orr and Scobie10 Goldberg59 Spouge and Baird9

1 in 5000 1 in 4500 1 in 5682 1 in 4417

Cincinnati Scotland Baltimore British Columbia

ETIOLOGY Neural crest cell migration The enteric nervous system (ENS) is the largest and the most complex division of the peripheral nervous system.13 The ENS contains more neurons than the spinal cord and is responsible for the coordination of

normal bowel motility and secretory activities. It is generally accepted that the enteric ganglion cells are derived primarily from the vagal neural crest cells.14–18 During normal development neuroblasts migrate from the vagal neural crest along the bowel wall in a craniocaudal direction from esophagus to anus. The embryonic neural crest arises in the neural tube, originating with the central nervous system, but neural crest cells detach from this tissue via reduction of cell–cell and cell–matrix adhesion. The epithelio-mesenchymal transformation allows crest cells to migrate along pathways. Pathway selection is most likely achieved by balanced combinations of molecules that promote and reduce adhesion. In the human fetus, neural crest-derived neuroblasts ﬁrst appear in the developing esophagus at 5 weeks, and then migrate down to the anal canal in a cranio-caudal direction during the ﬁfth to 12th weeks of gestation. The neural crest cells ﬁrst form the myenteric plexus just outside the circular muscle layer. The mesenchymally derived longitudinal muscle layer then forms, sandwiching the myenteric plexus after it has been formed in the 12th week of gestation. In addition, after the craniocaudal mitration has ended, the submucous plexus is formed by the neuroblasts, which migrate from the myenteric plexus across the circular muscle layer and into the submucosa; this progresses in a cranio-caudal direction during the 12th to 16th weeks of gestation.19 The absence of ganglion cells in HD has been attributed to a failure of migration of neural crest cells. The earlier the arrest of migration, the longer the aganglionic segment is. Several investigators have suggested that the enteric neurons follow a dual gradient of development from each end of the gut toward the middle, with vagal neural crest cells providing the main source of enteric neurons and sacral–neural crest cells innervating the hindgut.20–22 Results of a recent study indicated that less than 20% of neurons in the hindgut are derived from the sacral crest; the remainder are vagal crest derivates.23 However, a dual origin of enteric neurons has been questioned by several studies on chick embryos as well as human embryos.24–27

514 Hirschsprung’s disease

Altered extracellular matrix For normal innervation of the gut to occur, the neural crest cells must be able to migrate, differentiate, and survive. All these processes depend not only on the competence of the cells but also on the microenvironment in which they ﬁnd themselves.28,29 Extracellular matrix proteins have been recognized as important microenvironmental factors of the neural processing pathway in the early embryonal stage and as an important matrix for cell adhesion and movement.30–32 Extracellular matrices provide important signals that are critical for neural crest cell differentation.33,34 Fujimoto et al. studied the distribution of extracellular matrix interactions in the migration pathway of neural crest cells in the gut in early human embryos using a panel of anti-extracellular matrix protein antibodies such as ﬁbronectin, laminin, collagen type IV and hyaluronic acid.29 It was observed that enteric neurogenesis is dependent on extracellular matrices; ﬁbronectin and hyaluronic acid provide a migration pathway for neural crest-derived cells in the developing gut, and laminin and collagen type IV promote outgrowth and maturation of neuritis from settled neural crest-derived cells. Alteration of extracellular matrices in the early embryonal stage may either cause the arrest of migration of neural crest-derived cells to their ﬁnal destination, thus producing HD or result in the abnormal development of enteric ganglia, thereby producing HD-related disorders (e.g. neuronal intestinal dysplasia). Studies of bowel in HD have demonstrated an abnormal distribution of extracellular matrix components, laminin and collagen type IV, thus supporting the hypothesis that an abnormal microenvironment may play a role in the pathogenesis of HD.35,36

Neurotrophic factors It has been suggested that neurotrophic factors play an essential role in the normal development and survival of neurons in the peripheral and central nervous system.37 Nerve growth factor (NGF) and neurotrophic factor-3 (NT-3) are well characterized neurotrophic factors that have been suggested to be crucial in the development and survival of enteric neurons.38–40 NGF is demonstrated to function as a trophic and chemotactic agent for developing nerves, promoting the outgrowth of axons and the establishment of synapses.41 NT-3 is reported to be essential for the development of enteric neurons and glia in vitro, having a mitotic effect on neural crest cells.40 Ohshiro and Puri42 investigated the levels of NGF and NT-3 in circular muscle layers of both aganglionic and normoganglionic colon. They reported that protein levels of NGF and NT-3 were signiﬁcantly lower in the circular muscle layer of aganglionic colon than in the aganglionic colon, suggesting that the intestinal muscle in HD is less favorable for the normal development of

enteric neurons. Glial cell line-derived neurotrophic factor (GDNF) is a ligand of RET, which is a major gene causing HD. The number of GDNF immunoreactive epithelial cells in the mucosa of aganglionic bowel, as well as the protein levels of GDNF, were signiﬁcantly decreased compared to those in normoganglionic bowel.43

Cell adhesion molecules Cell adhesion molecules play an important role in cell–cell interactions, which regulate development and maintenance of multicellular organisms. In the nervous system, there are unique cell adhesion molecules that are essential for elaborate neural network formation.44 Neural cell adhesion molecule (NCAM) is a cell surface glycoprotein involved in adhesion between several types of neural cells and their processes, and in the formation of initial contact between nerve and muscle cells.45 It has been reported that myoﬁbers transiently express NCAM in the development of skeletal and cardiac muscle both in vitro and in vivo.46,47 In mature tissue, this expression is reduced substantially, and NCAM is restricted to the neuromuscular junction.48 Romanska et al. demonstrated markedly increased NCAM expression in smooth muscle cells of aganglionic bowel, particularly those of muscularis mucosae, suggesting that these ﬁndings reﬂect the degree of immaturity in smooth muscle cells.49 On the other hand, Kobayashi et al.50 demonstrated a lack of NCAM expression on nerve ﬁbers within the muscle of HD patients, suggesting a developmental abnormality of innervation of the aganglionic bowel. Furthermore Ikawa et al.51 reported the lack of L1CAM expression in hypertrophic nerve trunks of aganglionic segments despite the positive expression of other neural cell adhesion molecules, which suggests that these molecules perturb neural crest migration and adequate neurite outgrowth, with the resulting aganglionic segment and abnormal hypertrophic nerve trunks of extrinsic ﬁbers in HD.

Major histocompatibility complex class II antigen and intercellular adhesion molecule-1 abnormalities Kuroda et al.52 and Hirobe et al.53 demonstrated marked elevation of major histocompatibility complex (MHC) class II antigens throughout the intestinal wall of aganglionic colon, with abnormal localization in the mucosa and lamina propria. MHC class II antigen is a cell surface glycoprotein involved in the immune recognition of foreign tissue and in the regulation of the immune response. The ectopic expression of MHC class II antigens was not seen in any portion of bowel of patients who did not have HD. These authors suggested that ectopic expression of class II antigen might indicate

Etiology 515

that an underlying immunologic mechanism is responsible for HD. Intercellular adhesion molecule-1 (ICAM-1) is pivotal in many inﬂammatory and immune paracrine interactions, playing a major role in the process of leukocyte adhesion and regulation of leukocyte extravasation and inﬁltration into inﬂammatory tissues. Kobayashi et al.54 reported strong expression of ICAM-1 and MHC class II antigens on hypertrophic nerve trunks in both the submucous and myenteric plexuses of aganglionic colon and small ganglia in the transition zone without histological evidence of inﬂammation. The expression of both antigens in hypertrophic nerve trunks suggests the presence of an immunologic response in the pathogenesis of HD.

Genetic factors Genetic factors have been implicated in the etiology of HD. HD is known to occur in families. The reported incidence of familial cases varied from 3.6% to 7.8% in different series.55 A familial incidence of 15–21% has been reported in total colonic aganglionosis and 50% in the rare total intestinal aganglionosis.7,56 Schiller et al.57 reported 22 infants belonging to four families from Gaza, who had either documented or clinically suspected HD. Of these infants, 13 underwent laparotomy and multiple intestinal biopsies, ten had total intestinal aganglionosis, one had total colonic aganglionosis, one had near-total colonic aganglionosis and only one had rectosigmoid HD. Engum et al.58 reported 20 cases of HD in 12 kindreds. The level of aganglionosis was rectal or rectosigmoid in eight cases, left colon in two, transverse or right colon in two and total colonic ganglionosis with variable small bowel involvement in eight. The relationship with Down syndrome also tends to suggest a probable genetic component in the etiology of HD. Down syndrome is the most common chromosomal abnormality associated with aganglionosis and has been reported to occur in 4.5–16% of all cases of HD.59–61 Other chromosomal abnormalities that have been described in association with HD include: interstitial deletion of distal 13q, partial deletion of 2p and reciprocal translocation, and trisomy 18 mosiac.55 A number of unusual hereditary syndromes have been reported in patients with HD. These include: Waardenburg syndrome, Von Recklinghausen’s syndrome, type D brachydactyly and Smith–Lemli–Opitz syndrome.55 Recurrence risk to siblings is dependent upon the sex of the person affected and the extent of aganglionosis. Badner et al.62 calculated the risk of HD transmission to relatives and found that the recurrence risk to siblings increases as the aganglionosis becomes more extensive (Table 55.2). The brothers of patients with rectosigmoid HD have a higher risk (4%) than sisters (1%). Much

Table 55.2 Recurrence risk to siblings Relative

Recurrence risk (%)

Brothers of patients with rectosigmoid HD Sisters of patients with rectosigmoid HD Brothers of females with long-segment HD Sons of females with long-segment HD

4 1 24 29

higher risks are observed in cases of long-segment HD. The brothers and sons of affected females have a 24% and 29% risk of being affected, respectively. Recently, several receptors have been identiﬁed which control morphogenesis and differentiation of the ENS.63 One of these receptors, Ret with tyrosine kinase activity is involved in the development of enteric ganglia derived from vagal–neural crest cells.64 The importance of RET in mammalian organogenesis has been further illustrated by the generation of RET knockout mice.65 These mice exhibit total intestinal aganglionosis and renal agenesis. The RET proto-oncogene has been demonstrated to be a major gene causing HD.66–69 Mutations of RET account for 50% of familial and 15–20% of sporadic cases of HD.70,71 Mutation screening of this gene in familial and sporadic HD patients resulted in the detection of over 90 mutations, including missense, nonsense, and deletion/ insertion mutations. These mutations are scattered throughout the gene, and have no other particular hot spots. In addition, mutations occur at higher incidence in long-segment HD, compared with short-segment HD in both familial and sporadic patients.72,73 Total aganglionosis occurring throughout the digestive tract observed in RET knockout mice appears to reﬂect a close association between RET mutations and long-segment HD in humans.74,75 The development of the enteric nervous system is dependent upon the actions of GDNF, which stimulates the proliferation and survival of neural crest-derived precursor cells in the embryonic gut.76–79 It has been reported that GDNF is the ligand of RET.80 Mice carrying the homozygous null mutation in GDNF have been generated, and these mice demonstrate the lack of kidneys and ENS, conﬁrming the crucial role of GDNF in the development of the ENS.81,82 Although a causative role for GDNF mutations in some patients with HD has been suggested, the occurrence of such cases is uncommon, and it is more likely that the GDNF mutations are involved in modulation of the HD phenotype via its interaction with other susceptibility loci such as RET.43,83 Endothelin-3 (EDN-3) and endothelin-B receptors (EDNRBs) also have a role to play in the migration and development of the ENS.84–86 In mice in whom the EDN-3 or EDNRB gene was disrupted, intestinal aganglionosis was demonstrated experimentally. Furthermore, in natural mutants exhibiting aganglionic colon (piebald lethal and lethal spotting mice), a deletion of the entire

516 Hirschsprung’s disease

ENRB gene and a point mutation of the EDN-3 gene have been conﬁrmed respectively.86,87 In the case of humans, mutation of EDN-3 or the EDNRB gene have been detected in sporadic as well as familial HD cases. Mutations of these genes were observed only in limited cases.88–94 HOX11L1 is a homebox gene involved in peripheral nervous system development and is reported to play a role in the proliferation or differentiation of neural crest lines.95 Two different HOX11L1 knockout mouse models have been generated.96,97 In both cases homozygous mutant mice were viable but developed megacolon at the age of 3–5 weeks. Histological and immunohistochemical analysis showed hyperplasia of myenteric ganglia, a phenotype similar to that observed in a human congenital intestinal disorder named intestinal neuronal dysplasia (IND).98 The sex determining region Y-box (SOX10) gene is expressed in neuronal crest derivates that contribute to the formation of the peripheral nervous system during embryogenesis.99,100 Mutations in SOX10 have been identiﬁed as a cause of the dominant megacolon mouse and Waardenberg–Shah syndrome in humans, both of which include defects in the enteric nervous system and pigmentation.101,102 For the production of mature and active endothelins, the cleavage of precursor peptides by a speciﬁc metalloprotease called endothelin-converting enzyme-1 (ECE-1) is necessary.103 Yanagisawa et al. recently reported that null mutation of the ECE-1 gene produced mice with aganglionic colon as well as cranio-facial and cardiac defects.104 So far a wide range of mutations of the RET protooncogene have been found in 30–50% of familial and sporadic Hirschsprung’s disease cases while other genes like EDN-3, EDNRB, GDNF, SOX10 and ECE-1 are responsible for a total of 5–10% of cases (Table 55.3). Table 55.3 Genes involved in the morphogenesis and differentiation of the ENS Genes

Chromosomal assignment

RET GDNF EDNRB EDN-3 HOX11L1 SOX 10 ECE-1

10q11.2 5p12-13.1 13q22 20q13.2-13.3 2p12-p13 22q13.1 1p36

PATHOPHYSIOLOGY The pathophysiology of HD is not fully understood. There is no clear explanation for the occurrence of the spastic or tonically contracted aganglionic segment of bowel. The most important ﬁnding in aganglionic colon

is the absence of ganglion cells, which normally coordinate muscular activity by balancing the motor effects of the preganglionic cholinergic ﬁbers and inhibitory inﬂuence of postganglionic adrenergic ﬁbers.

Adrenergic innervation abnormalities Ehrenpreis,105 using ﬂuorescent microscopy, demonstrated a lack of adrenergic nerve ﬁbers in the aganglionic segment and suggested that a state of denervation hypersensitivity (based on Canon’s law), induced permanent contraction of smooth muscle in the aganglionic segment. Other investigators, however, have shown that the adrenergic innervation of the aganglionic bowel is increased relative to that of normal bowel.106,107 The tissue concentration of norepinephrine (noradrenaline), the neurotransmitter of adrenergic nerves, is two to three times higher in the aganglionic bowel than in the normal colon; there is also a corresponding increase in tyrosine hyroxylase, an enzyme which regulates norepin biosynthesis.108–110 It is proposed that adrenergic hyperactivity of the ganglionic segment contributes to the increased muscle tone and abnormal peristaltic activity observed in HD. Because adrenergic nerves normally act to relax the bowel, it is unlikely that adrenergic hyperactivity would be responsible for increased tone in the aganglionic colon.

Cholinergic hyperinnervation Cholinergic nerve hyperplasia has been proposed as the cause of spasticity of the aganglionic segment.111,112 In the absence of ganglion cells, there exists an overabundance of acetylcholine, which in turn stimulates excessive production of the enzyme acetylcholinesterase. In the aganglionic segment, therefore, an excessive accumulation of the enzyme acetylcholinesterase occurs, resulting from a continuous acetylcholine release from the axons of the extramural parasympathetic ganglion. Pharmacological investigations of the colon in HD have demonstrated higher acetylcholine release in the aganglionic segment at rest and after stimulation compared with the proximal ganglionic bowel.113,114 It has been suggested that in HD the increased acetylcholine release, enhanced sensitivity of smooth muscle cells to acetylcholine and lack of α2-adrenoreceptor release from cholinergic interneurons might be responsible for the spasm of the aganglionic segment. Histochemical staining techniques demonstrate a marked increase in acetylcholinesterase activity in the aganglionic segment compared to in the ganglionic colon.115,116

Abnormal peptidergic innervation Strong evidence has emerged concerning the existence of non-adrenergic non-cholinergic autonomic nerves,

Pathophysiology 517

which contain different peptides, and that these peptides act as neurotransmitters and/or neuromodulators. These nerves have been termed peptidergic nerves.117 Several authors have reported that the contracted state of the aganglionic segments may be due to abnormal peptidergic patterns of innervation. They noted a decrease of vasoactive intestinal polypeptide (VIP) containing ﬁbers in the aganglionic bowel.55,118 Other investigators have reported the absence or reduction of nerve ﬁbers containing substance P, metenkephalin and gastrin-releasing peptide, and peptide histidine ioleucine, in aganglionic segments in HD.55 The density of nerve ﬁbers containing galanin or calcitonin gene-related peptide (CGRP) is not overtly changed in the aganglionic bowel compared with the ganglion bowel, whereas ﬁbers containing neuropeptide-Y (NPY) are increased in number in the aganglionic segment.119–121 The peptidergic nerves play an important role in the neural regulation of gut function, but the precise functional signiﬁcance of defects in peptidergic innervation in HD has yet to be deﬁned.

strong NADPH diaphorase staining of the submucous and myenteric plexuses and a large number of NADPH diaphorase-positive ﬁbers in the circular and longitudinal muscle in the normal colon and ganglionic segment of HD patients. The most striking difference between the aganglionic and normal colon was the absence or marked reduction of NADPH diaphorase-positive nerve ﬁbers in the circular as well as the longitudinal muscles of aganglionic bowel. The hypertrophic nerve trunks in the aganglionic segment stained weakly with NADPH diaphorase. Kusafuka and Puri138 examined the expression of the neural NOS gene at the mRNA level in the intestinal specimens from seven patients who had Hirschsprung’s disease using the reverse transcription polymerase chain reaction (RT-PCR) technique. Neuronal NOS mRNA expression in aganglionic bowel was decreased at least 1/50 to 1/100th of the level expressed in ganglionic bowel. These ﬁndings indicate that there is impaired NO synthesis in the aganglionic bowel, which is most likely responsible for motility dysfunction in HD.

Abnormalities of nerve-supporting cells Interstitial cells in Cajal The ENS is composed of two distinct neural components, extrinsic and intrinsic. The intrinsic innervation has two major divisions: the myenteric plexus, which is concerned primarily with motor activity; and the submucous plexus, which receives sensory input from the lumen of the intestine and controls secretomotor function. The supporting nerve cells of the intrinsic ENS are often referred to as enteric glia.122,123 These glia have been reported to express various markers for both astrocytes and Schwann cells, such as: 1 Glial ﬁbrillary acidic protein, a speciﬁc marker for astrocytes within the central nervous system124,125 2 S-100, a marker for astrocytes and Schwann cells126,127 3 D7, a marker of Schwann cells and oligodendrocytes.128,129 The nerve-supporting cells permit cell bodies and processes of neurons to be arranged and maintained in a proper special arrangement and are essential in the maintenance of basic physiologic functions of neurons. Abnormalities of nerve-supporting cells have been reported in the aganglionic colon by many investigators.130–132

Nitergic innervation Several investigators have studied nitric oxide synthase (NOS) distribution in the ganglionic and aganglionic bowel of patients with HD using NOS immunohistochemistry or nicotine adenine dinucleotide phosphate (NADPH) diaphorase histochemistry.133–137 There was

Interstitial cells in Cajal (ICCs) are pacemaker cells which generate slow waves and facilitate active propagation of electrical events and neurotransmission in the bowel wall. ICCs can be recognized either by their unique ultrastructure on electron microscopy or with the immunohistochemical demonstration of their surface receptor tyrosine kinase KIT (C-KIT).139 Recent studies demonstrated that the C-KIT receptor is essential for the development of ICCs. Mesenchymal ICC precursors that carry the C-KIT receptor require the KIT ligand (KL), which can be provided by neuronal or smooth muscle cells. According to the inﬂuence of the KL from either neuronal or smooth muscle cells the ICCs develop as either myenteric ICCs (ICCmys) or muscular ICCs (ICCmuss).140 Altered distribution of ICCs have been described in several disorders of human intestinal motility, including hypertrophic pyloric stenosis,141 Hirschsprung’s disease,142–145 intestinal pseudo-obstruction,146–148 slowtransit constipation149 and ulcerative colitis.150 Vanderwinden et al.142 described scarce ICCs with a disrupted network in the aganglionic bowel whereas the distribution of ICCs in the ganglionic bowel of HD was similar to controls. These ICCs did not form a network and showed no clear relationship to the hypertrophic nerve trunks. Yamataka et al.143,144 found few C-KIT+ cells in the muscle layers in HD and a moderate number around the thick nerve bundles in the space between the two muscle layers in the aganglionic bowel. Horisawa et al. reported no differences in C-KIT immunopositive cells in aganglionic segments compared with the corresponding area of ganglionic bowel.151

518 Hirschsprung’s disease

Pathology The characteristic gross pathological feature in HD is dilation and hypertrophy of the proximal colon with abrupt or gradual transition to normal or narrow distal bowel (Fig. 55.1). Although the degree of dilation and hypertrophy increases with age, the cone-shaped transitional zone from dilated to narrow bowel is usually evident in the newborn. Histologically, HD is characterized by the absence of ganglionic cells in the myenteric and submucous plexuses and the presence of hypertrophied nonmyelinated nerve trunks in the space normally occupied by the ganglionic cells (Fig. 55.2). The aganglionic segment of bowel is followed proximally by a hypoganglionic segment of varying length. This hypoganglionic zone is characterized by a reduced number of ganglionic cells and nerve ﬁbers in myenteric and submucous plexuses.

(a)

Clinical features Of all cases of HD, 80–90% produce clinical symptoms and are diagnosed during the neonatal period.152 Delayed passage of meconium is the cardinal symptom in neonates with HD. Over 90% of affected patients fail to pass meconium in the ﬁrst 24 hours of life. The usual presentation of HD in the neonatal period is with constipation, abdominal distension (Fig. 55.3) and vomiting during the ﬁrst few days of life. In many cases a rectal examination or rectal irrigation causes passage of meconium and relief of acute intestinal obstruction.

Figure 55.1 Typical gross pathology in Hirschsprung’s disease, with transitional zone at rectosigmoid level

(b) Figure 55.2 (a) Auerbach’s plexus, containing ganglion cells. (b) Hypertrophied nerve trunks in rectal biopsy from a patient with Hirschsprung’s disease

These babies may have normal bowel movements for a few days or weeks and then present again with signs and symptoms of intestinal obstruction. Some babies may have normal health for several months or years in response to changes in feeds, laxatives, suppositories or enemas and develop a chronic form of congenital megacolon manifested by chronic constipation with or without abdominal distension. About one-third of the babies with HD present with diarrhea.153 Diarrhea in HD is always a symptom of enterocolitis, which remains the commonest cause of death in those with this disease.1,2,153 Enterocolitis may resolve with adequate therapy or it may develop into a lifethreatening condition, the toxic megacolon, characterized by the sudden onset of marked abdominal distension, bile-stained vomiting, fever and signs of dehydration, and shock. Rectal examination or introduction of a rectal tube results in the explosive expulsion of gas and foul-smelling stools.

Pathophysiology 519

Figure 55.3 A 2-day-old infant with marked abdominal distention and failure to pass meconium. Suction rectal biopsy conﬁrmed Hirschsprung’s disease

(a)

Diagnosis The diagnosis of HD is usually based on clinical history, radiological studies, anorectal manometry and in particular on histological examination of the rectal wall biopsy specimens.

Radiological diagnosis Plain abdominal ﬁlms in a neonate with HD will show dilated loops of bowel with ﬂuid levels. Occasionally, one may be able to see a small amount of air in the undistended rectum and dilated colon above it (Fig. 55.4a). This should raise the suspicion of HD. Within the institution of the author, they ﬁnd the prone lateral view with buttocks elevated and using a horizontal beam invaluable in demonstrating gas in the undilated rectum in HD. The main advantage of this view is the lack of discomfort to the baby who can be kept in this position for 10 minutes or longer to allow gas to ascend from the colon into the rectum. In patients with enterocolitis complicating HD, plain abdominal radiography may show thickening of the bowel wall with mucosal irregularity or a grossly dilated colon loop, indicating toxic megacolon. Pneumoperitoneum may be found in those with perforation. Spontaneous perforation of the intestinal tract has been reported in 3% of patients with HD.153 A strong correlation was noted between the length of aganglionic bowel and spontaneous perforations which occurred in patients with long-segment HD.

(b) Figure 55.4 Hirschsprung’s disease. (a) Abdominal radiograph in a 4-day-old infant showing marked dilation of large and small bowel loops. Note gas in undilated rectum. (b) Barium enema in this patient reveals transitional zone at sigmoid level

Barium enema performed by an experienced radiologist, using careful technique, should achieve a high degree of reliability in diagnosing HD in the newborn. It is important that the infant should not have rectal washouts or even digital examinations prior to barium

520 Hirschsprung’s disease

enema, as such interference may distort the transitional zone appearance and give a false-negative diagnosis. A soft rubber catheter is inserted into the lower rectum and held in position with ﬁrm strapping across the buttocks. A balloon catheter should not be used due to the risk of perforation and the possibility of distorting a transitional zone by distension. The barium should be injected slowly in small amounts under ﬂuoroscopic control with the baby in the lateral position. A typical case of HD will demonstrate ﬂow of barium from the undilated rectum through a cone-shaped transitional zone into dilated colon (Fig. 55.4b). Some cases may show an abrupt transition between the dilated proximal colon and the distal aganglionic segment, leaving the diagnosis in little doubt. In some cases, the ﬁndings on the barium enema are uncertain and a delayed ﬁlm at 24 hours may conﬁrm the diagnosis by demonstrating the retained barium and often accentuating the appearance of the transitional zone (Fig. 55.5). In the presence of enterocolitis complicating HD, barium enema may demonstrate spasm, mucosal edema and ulceration (Fig. 55.6). The characteristic ﬁnding of the transitional zone of HD is not present due to impairment of muscular function by inﬂammation.

Figure 55.6 Enterocolitis complicating Hirschsprung’s disease. Spasm in rectosigmoid shown in barium enema, with ﬁne mucosal ulceration and mucosal edema giving cobblestone appearance

Anorectal manometry In the normally innervated bowel, distension of the rectum produces relaxation of the internal sphincter.154

Figure 55.5 Delayed 24-hour ﬁlm in lateral position showing barium retention with accentuated transition at splenic ﬁxture in a 10-day-old baby

In 1964, Callaghan and Nixon155 reported the absence of internal sphincter response to rectal distension in HD. The absence of internal sphincter relaxation is the basis for the manometric differential diagnosis of HD from other causes of constipation.156–159 Different investigators use different materials (air or water) for recording anorectal motor activity and rectal sensation. It has been shown that there are no signiﬁcant differences in anorectal manometry between the results of rectal balloon inﬂation with water or air. We perform anorectal manometric studies in our hospital in Dublin using a simpliﬁed air-ﬁlled balloon system, as described by Aaronson and Nixon.158 The probe consists of two rubber-covered chambers, each 1 cm long, which are placed in the anal canal and a thin latex balloon mounted 4 cm above the upper chamber, which is placed inside the rectum and is distended by graduated inﬂations of air. The air lines are connected via three pressure transducers to a paper recorder. The probe is calibrated before each test in cmH2O from 0 to 100. The tests are carried out in conscious patients and no sedation is used. With the patient in the left lateral position, the probe is inserted into the rectum and steadied so that the lower chamber lies just within the anal canal. Thus, the upper chamber records from the internal sphincter and the lower chamber predominantly from the external sphincter. In normal persons, upon distending the rectal balloon with air, the rectum immediately responds with a transient rise in pressure,

Pathophysiology 521

lasting 15–20 seconds; at the same time the internal sphincter rhythmic activity is depressed or abolished and its pressure falls by 15–20 cm, the duration of relaxation coinciding with the rectal wave. In patients with HD, the rectum often shows spontaneous waves of varying amplitude and frequency in the resting phase. The internal sphincter rhythmic activity is more pronounced. On rectal distension, with an increment of air, there is complete absence of internal sphincter relaxation.160 Although in older children anorectal manometry has proved to be a reliable method for diagnosing HD, considerable controversy exists as to the diagnostic accuracy of manometry in neonates.161,162 Holschneider et al.163 have reported that the development of the normal rectosphincteric reﬂex is completed on the 14th day of life and therefore absence of the reﬂex could be diagnostic only after that. Ito et al.164 reported that the normal reﬂex does not occur in the premature infant or in infants in whom maturational age (gestational plus postnatal age) has not reached 39 weeks and who weigh less that 2.7 kg. The absent or atypical rectosphincteric reﬂex is thought to be related to immaturity of ganglion cells, as demonstrated by Smith165 as well as by Bughaighes and Emery.166 Little is known of the state of anatomical maturity at which the neurons become effective. In an experimental study, Puri et al.167 showed that function can precede anatomical maturity of the ganglion cells. Other investigators have demonstrated anorectal manometry to be accurate in the newborn for the diagnosis of HD.168–172 Tamate et al.170 reported manometry ﬁndings in 60 normal neonates and 17 neonates with symptoms of gastrointestinal obstruction. They showed that all 60 healthy neonates had normal rectosphincteric reﬂexes regardless of postnatal age and birth weight. Among the 17 patients, ﬁve were diagnosed as having HD based on absence of the rectosphincteric reﬂex regardless of postnatal age and birth weight. There were no false-negative or false-positive results among the cases. They suggested that the failure to detect the retrosphicteric reﬂex in premature and term neonates is probably due to technical difﬁculties and not to immaturity of ganglion cells. We have found anorectal manometry to be an excellent screening method for the exclusion of HD.

Rectal biopsy The diagnosis of HD is conﬁrmed on examination of rectal biopsy specimens. Prior to the use of suction rectal biopsies, a full-thickness rectal biopsy specimen that included both muscle coats and submucosa provided enough tissue to make a relatively easy diagnosis. However, the introduction of suction rectal biopsy, while making the procedure less traumatic for the patient, has made the diagnosis more difﬁcult for the pathologist.

Many histopathologists are reluctant to make a positive diagnosis of HD on the basis of suction rectal biopsies using conventional hematoxylin–eosin stains. This is due both to doubt as to the amount of submucosa that must be scanned before absence of ganglion cells by comparison with the more compact and familiar ganglion cells of the intermuscular plexus. The development of histochemical and immunohistochemical staining techniques using suction rectal biopsies for the diagnosis of HD represents a considerable advance in the investigation of this disease, particularly in the newborn. Meier-Ruge and colleagues described a histochemical staining technique of Karnovsky and Roots for the detection of acetylcholinesterase in rectal suction biopsies.173 Lake et al.174 reported an improved method of staining using Hanker’s modiﬁcation of Karnovsky and Roots’s method, which stains cholinergic ﬁbers almost black, making them easily noticeable. In normal persons, barely detectable acetylcholinesterase activity is observed within the lamina propria and muscularis mucosa, and submucosal ganglion cells stain strongly for acetylcholinesterase. In HD, there is a marked increase in acetylcholinesterase activity in lamina propria and muscularis which is evident as coarse, discrete cholinergic nerve ﬁbers stained brown to black (Fig. 55.7 a,b). At our hospital we usually take three biopsy specimens at 3 cm, 5 cm and 7 cm above the dentate line. One specimen is stained by conventional hematoxylin–eosin staining to ascertain the presence or absence of ganglion cells, one specimen is stained histochemically for the detection of acetylcholinesterase, and the third specimen is processed for NADPH diaphorase histochemistry. Most investigators have found the histochemical staining technique for the detection of acetycholinesterase in rectal suction biopsies to be a reliable and simple method for diagnosing HD.175–177 Occasionally, false-negative results have been reported in newborns and patients with total colonic aganglionosis.177 Using a supplemental oxidation step, we have recently modiﬁed the acetylcholinesterase histochemistry technique of Karnovsky and Roots to produce staining of cholinergic ﬁbers in 10 minutes rather than 2 hours as required with conventional acetylcholinesterase techniques.178,179 The rapid acetylcholinesterase technique is a simple and reliable method for the diagnosis of HD and for intraoperative evaluation of the extent of the aganglionic segment. We have used NADPH diaphorase histochemistry to stain suction rectal biopsy sections and found it a valuable additional technique in the diagnosis of HD.180 Normal suction rectal biopsy specimens showed strong NADPH diaphorase reactivity in the submucosal ganglia and a large number of NADPH diaphorase-positive ﬁbers in the muscularis mucosa. In contrast, there were no NADPH diaphorase-positive ﬁbers in the muscularis mucosae in patients with HD, no submucosal ganglia, and the presence of weakly stained hypertrophic nerve trunks.

522 Hirschsprung’s disease

(a)

(b) Figure 55.7 Acetylcholinesterase staining of suction rectal biopsy. (a) Normal rectum showing minimal acetylcholinesterase staining in mucosa, lamina propria and muscularis mucosae (×4). (b) Hirschsprung’s disease characterized by marked staining of cholinesterase-positive nerves in the lamina propria and muscularis mucosae (×40)

Management Once the diagnosis of HD has been conﬁrmed by rectal biopsy examination, the infant should be prepared for surgery. Biopsies for frozen sections are taken to determine the extent of aganglionosis and level of transition zone. If the newborn has enterocolitis complicating HD, correction of dehydration and electrolyte imbalance by infusion of appropriate ﬂuids will be required. Thomas

et al.181 have demonstrated a relationship to Clostridium difﬁcile and its toxin in about 30% of patients with enterocolitis in HD, and suggested treating these patients with vancomycin during acute episodes. It is essential to decompress the bowel as early as possible in these babies. Deﬂation of the intestine may be carried out initially by rectal irrigations, and when the baby is clinically stable a colostomy could be performed. Traditionally, a deﬁnitive pull-through operation for HD has been performed when the infant is 6–12 months old. This approach evolved during the 1950s, when major operations on neonates were considered unsafe and neonatal HD was associated with a high mortality rate. Advances in neonatal anesthesia, monitoring and surgical care together with parenteral nutrition and effective antibiotics have allowed primary prolonged reparative procedures to be undertaken safely in the neonate. In recent years, the vast majority of cases of HD are diagnosed in the neonatal period. Many centers are now performing one-stage pull-through operations in the newborn with minimal morbidity rates and encouraging results.182–187 The advantages of operating on the newborn are that the colonic dilatation can be quickly controlled by washouts and at operation the caliber of the pull-through bowel is near normal, allowing for an accurate anastomosis that minimizes leakage and cuff infection. Recently, a number of investigators have described and advocated a variety of one-stage pullthrough procedures in the newborn using minimally invasive laparoscopic techniques.188–190 More recently, a transanal endorectal pull-through operation performed without opening the abdomen has been used with excellent results in rectosigmoid HD.191–192 A number of different operations have been described for the treatment of HD. The three most commonly used operations are the rectosigmoidectomy developed by Swenson and Bill,193 the retrorectal transanal approach developed by Duhamel194 and the endorectal procedure developed by Soave.195 The basic principle in all these procedures is to bring the ganglionic bowel down to the anus. The long-term results of any of these operations are very satisfactory if they are performed correctly.

Colostomy Many surgeons prefer right transverse colostomy; others advocate performing colostomy just above the transition to ganglionic bowel. Ileostomy is indicated in patients who have total colonic aganglionosis. The abdomen is opened via a left paramedian incision. The biopsy site is selected by observing the apparent transitional zone. In the usual case of rectosigmoid aganglionosis, three seromuscular biopsies are taken along the antimesenteric surface without entering the lumen (Fig. 55.8). One biopsy is taken from the narrowed segment of bowel, a second biopsy from the transition zone and a third

Pathophysiology 523

Figure 55.8 Biopsy sites

biopsy from the dilated portion above the transition zone. Biopsies are assessed intraoperatively by frozen section, to determine the level of ganglionic bowel. A right transverse colostomy is very convenient in usual cases. We perform a loop colostomy over a skin bridge. A V-shaped incision is made in the right upper

quadrant (Fig. 55.9a). The V-skin ﬂap is reﬂected upwards. The external oblique is split and the internal oblique and transverse abdominis muscles are divided with diathermy. The peritoneum is opened. An opening is made in the mesocolon of the selected segment of transverse colon (Fig. 55.9b). The skin ﬂap is pulled through the opening in the mesocolon and sutured to the opposite skin margin (Fig. 55.9c). A few interrupted sutures of 4-0 or 5-0 silk are placed between the peritoneum, the muscle layers of abdominal wall and the seromuscular layer of colon. The colon is opened longitudinally along the antimesenteric border using diathermy (Fig. 55.9d). The bowel is sutured to the skin using interrupted 4-0 silk sutures (Fig. 55.9e).

Primary pull-through operation Many surgeons have reported good results with the primary neonatal pull-through operation for HD.182–192 The current author prefers the one-stage transanal

Figure 55.9 (a) V-shaped incision. (b) An opening is made in the mesocolon of the selected segment of transverse colon. (c) The Vskin ﬂap is pulled through the opening in the mesocolon. (d) Colon opened longitudinally along the antimesenteric border using diathermy. (e) The bowel is sutured to skin margins

524 Hirschsprung’s disease

endorectal pull-through operation for classical rectosigmoid HD and Swenson’s pull-through operation for long-segment HD because of their simplicity and lack of complications. We have not used diversionary colostomy for usual cases. Once the diagnosis of HD is conﬁrmed, rectal irrigations are carried out twice a day for 3 days before surgery. I.v. gentamicin and metronidazole are started on the morning of operation.

Swenson’s pull-through operation OPERATIVE TECHNIQUE The patient is positioned on the operating table to provide simultaneous exposure of the perineum and abdomen. The pelvis is allowed to drop back over the lower end of the table and the legs are strapped over sandbags. A Foley catheter is inserted into the bladder. The abdomen is opened via a paramedian incision

(a)

(c)

(Fig. 55.10a). Some surgeons prefer a Pfannenstiel incision when performing a Swenson’s pull-through operation in the neonate. A Denis-Browne retractor is applied and the urinary bladder is lifted forward out of the abdomen by stay sutures. Extramucosal biopsies are taken at intervals along the antimesenteric border and assessed by frozen section to determine the level of ganglionated bowel. The sigmoid colon is mobilized by dividing the sigmoid vessels and retaining the marginal vessels. It may be necessary to mobilize the splenix ﬂexure to obtain adequate length. The proximal level of resection above the ganglionated level previously determined by frozen section is selected and the bowel is divided between intestinal clamps or staples (Fig. 55.10b,c). The peritoneum is divided around its lateral and anterior reﬂection from the rectum, exposing the muscle coat of the rectum. At this point, the bowel is divided at the rectosigmoid junction and removed (Fig. 55.10b). Dissection extends around the rectum, keeping very

(b)

(d)

Figure 55.10 (continued on page 515) (a) Incision. (b) Proximal and distal level of resection of colon to provide more room for dissection in the pelvis. (c) It is essential to maintain dissection close to rectal wall in order to prevent damage to splanchnic nerves. (d) The mobilized rectum is intussuscepted through the anus.

Pathophysiology 525

close to the bowel wall. It is essential to maintain the dissection close to the muscular wall in order to prevent damage to the pelvic splanchnic innervation. All vessels are electro-coagulated under direct vision. Sufﬁcient tension-free length is obtained by dividing the inferior mesenteric pedicle, carefully preserving the marginal vessels. Dissection is carried down to the level of the external sphincter posteriorly and laterally, but does not

extend as deeply anteriorly, leaving around 1.5 cm of intact rectal wall abutting against the vagina or urethra. The extent of dissection can be conﬁrmed by putting a second glove over that on the left hand and by manual palpation with a ﬁnger in the anus. The mobilized rectum is intussuscepted through the anus by passing a curved clamp or a Babcock forceps through the anal canal; an assistant places the closed

(e)

(f)

(g)

(h)

(i)

Figure 55.10 (continued from page 514) (e) A clamp is inserted through the incision in the anterior rectal wall to grasp the proximal colon. (f) Pulled-through colon. (g) Outer layer of sutures. (h) Inner layer of sutures. (i) Anastomosis retracted within the anus

526 Hirschsprung’s disease

rectal stump within the jaws of the clamp (Fig. 55.10d). The mucosal surface is cleaned with betadine. When the dissection has been completed, it should be possible to evert the anal canal completely when traction is applied to the rectum. An incision is made anteriorly through the rectal wall about 102 cm from the dentate line, extending halfway through the rectal circumference. A clamp is inserted through this incision to grasp multiple sutures placed through the cut end of the proximal colon (Fig. 55.10e). An outer layer of interrupted 4-0 Vicryl sutures is placed through the cut muscular edge of the rectum and the muscular wall of the pull-through colon (Fig. 55.10f,g). When the outer layer has been completed, the proximal bowel is opened and an inner layer of interrupted 4-0 Vicryl sutures is placed (Fig. 55.10h). When anastomosis is completed, the sutures are cut, allowing the anastomosis to retract within the anus (Fig. 55.10i).

Transanal one-stage endorectal pull-through operation

When the submucosal dissection has extended proximally to a point above the peritoneal reﬂection, the rectal muscle is divided circumferentially, and the full thickness of the rectum and sigmoid colon is mobilized out through the anus. This requires division of rectal and sigmoid vessels, which can be done under direct vision using cautery or ligatures. When the transition zone is encountered, fullthickness biopsy sections are taken, and frozen section conﬁrmation of ganglion cells is obtained. The rectal muscular cuff is split longitudinally either anteriorly or posteriorly. The colon is then divided several centimeters above the most proximal normal biopsy site (Fig. 55.11b), and a standard Soave-Boley anastomosis is performed (Fig. 55.11c). No drains are placed. The patient is started on oral feeds after 24 hours and discharged home on the third postoperative day. Digital rectal examination is performed 2 weeks after the operation. Routine rectal dilatation is not performed unless there is evidence of a stricture.

Of patients with HD, 75–80% have rectosigmoid aganglionosis. A one-stage pull-through operation can be successfully performed in these patients using a transanal endorectal approach without opening the abdomen. This procedure is associated with excellent clinical results and permits early postoperative feeding, early hospital discharge and no visible scars.191,192

Preoperative management A good barium enema study is essential for this technique. A typical case of rectosigmoid HD will demonstrate ﬂow of barium from undilated rectum through a cone-shaped transition zone into dilated sigmoid colon (Fig. 55.4b). Once the diagnosis of HD is conﬁrmed by suction rectal biopsy, the newborn is prepared for surgery. Rectal irrigations are carried out twice a day for 2–3 days prior to surgery. I.v. gentamicin and metronidazole are started on the morning of operation.

(a)

Operative technique The patient is positioned on the operating table in the lithotomy position. The legs are strapped over sandbags. A Foley catheter is inserted into the bladder. A DenisBrowne retractor or anal retractor is placed to retract perianal skin. The rectal mucosa is circumferentially incised using the cautery, approximately 5 mm from the dentate line, and the submucosal plane is developed. The proximal cut edge of the mucosal cuff is held with multiple 4-0 silk sutures, which are used for traction (Fig. 55.11a). The endorectal dissection is then carried proximally, staying in the submucosal plane.

(b)

References 527

(c) Figure 55.11 Transanal endorectal pull-through operation. (a) Rectal mucosa is incised about 5 mm above the dentate line and staying in the submucosal plane, the endorectal dissection is carried to a point above the peritoneal reﬂection. (b) After conﬁrmation of ganglion cells by frozen section, the colon is ready to be divided several centimetres above the transitional zone. (c) A standard Soave-Boley anastomosis is completed using interrupted 5-0 Vicryl sutures

Long-term outcome The vast majority of patients treated with any one of the standard pull-through procedures achieve satisfactory continence and function with time.55,196 The attainment of normal continence is dependent on the intensity of bowel training, social background and respective intelligence of patients. Mental handicap, including Down syndrome, is invariably associated with long-term incontinence.

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110. Touloukian RJ, Morgenroth VH, Roth RH. Sympathetic neurotransmitter metabolism in Hirschsprung’s disease. J Pediatr Surg 1975; 10:593. 111. Kamijo K, Hiatt RB, Koelle B. Congenital megacolon: a comparison of the spastic and hypertrophic segments with respect to cholinesterase activities and sensitivities to acetylcholine, DFP and barium ion. Gastroenterology 1953; 24:173. 112. Meier-Ruge W. Das Megacolon: Seine Diagnose and Pathophysiologie. Virchows Arch 1968; 344:67. 113. Frigo GM, Del Tacca M, Lecchini S et al. Some observations on the intrinsic nervous mechanism in Hirschsprung’s disease. Gut 1973; 14:35. 114. Vizi ES, Zseli J, Kontor E et al. Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprung’s disease. Gut 1990; 31:1046. 115. Meier-Ruge W, Lutterbeck PM, Herzog B et al. Acetylcholinesterase activity in suction rectal biopsies of the rectum in the diagnosis of Hirschsprung’s disease. J Pediatr Surg 1972; 7:11. 116. Lake BD, Puri P, Nixon HH et al. Hirschsprung’s disease: an appraisal of histochemically demonstrated acetylcholine estrase in suction rectal biopsy specimens as an aid to diagnosis. Arch Pathol Lab Med 1978; 102:244. 117. Polak JM, Path MRC, Bloom SR. Neuropeptides of the gut: a newly discovered major control system. World J Surg 1979; 3:393. 118. Bishop AE, Polak JM, Lake BD et al. Abnormality of the colonic regulatory peptides in Hirschsprung’s disease. Histopathology 1981; 5:679. 119. Larsson LT, Malmfors G, Sundler F. Neuropeptide Y, calcitonin generelated peptide, and galanin in Hirschsprung’s disease: an immunocytochemical study. J Pediatr Surg 1988; 23:342. 120. Hamada Y, Bishop AE, Federici G. Increased neuropeptide Y-immunoreactive innervation of aganglionic bowel in Hirschsprung’s disease. Virchows Arch A 1987; 411:369. 121. Kawana T, Nada O, Hirose R. et al. Distribution of neuropeptide Y-like immunoreactivity in the normoganglionic and aganglionic segments of human colon. Acta Neuropathol 1990; 80:469. 122. Gabella G. Glial cells in the myenteric plexus. Z Naturforsch 1971; 266:244. 123. Gabella G. Ultrastructure of the nerve plexuses of the mammalian intestine: the enteric glaial cells. Neuroscience 1981; 6:425. 124. Jessen KR, Mirsky R. Glial cells in the enteric nervous system contain glial ﬁbrillary acidic protein. Nature 1980; 286:736. 125. Eng LF. The glial ﬁbrillary acidic (GFA) protein. In: Bradshaw R, Schneider D, editors. Proteins of the Nervous System. New York: Raven, 1980:85. 126. Ferri GL, Probert L, Cocchia D et al. Evidence for the presence of S-100 protein in the glial component of the human enteric nervous system. Nature 1982; 297:409.

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532 Hirschsprung’s disease 159. Loening-Baucke VA. Anorectal manometry: experience with strain gauge pressure transducers for the diagnosis of Hirschsprung’s disease. J Pediatr Surg 1983; 18:595–600. 160. Sun WM, Read NW, Prior A et al. Sensory and motor responses to rectal distension vary according to rate and pattern of balloon inﬂation. Gastroneterol 1990; 99:1008–15. 161. Iwai N, Yanagihara J, Tokiwa K et al. Reliability of anorectal manometry in the diagnosis of Hirschsprung’s disease. Z Kinderchis 1998; 43:405–7. 162. Holschneider AM. Functional diagnosis in Hirschsprung’s disease. In: Holschneider AM, Puri P. Hirschsprung’s Disease and Allied Disorders. Singapore: Harwood Publishers, 2000:230–51. 163. Holschneider AM, Kellner E, Streibl P et al. The development of anorectal continence and its signiﬁcance in the diagnosis of Hirschsprung’s disease. J Pediatr Surg 1976; 11:151–6. 164. Ito Y, Donahoe PK, Hendren WH. Maturation of the rectoanal response in premature and perinatal infants. J Pediatr Surg 1977; 12:477–82. 165. Smith B. Pre and postnatal development of ganglion cells of the rectum and its surgical implications. J Pediatr Surg 1968; 3:386–92. 166. Bughaighis AG, Emery JL. Functional obstruction of the intestine due to neurological immaturity. Progr Pediatr Surg 1971; 3:37–52. 167. Puri P, Blake N, Carroll R et al. Relationship between functional and histologic appearances of developing ganglion cells in the guinea pig rectum. J Pediatr Surg 1980; 15:42–7. 168. Boston VE, Scott JES. anorectal manometry as a diagnostic method in the neonatal period. J Pediatr Surg 1976; 1:9–16. 169. Loening-Baucke V, Pringle KC, Ekiro GG. Anorectal manometry for the exclusion of Hirschsprung’s disease in neonates. J Pediatr Gastroenterol Nutr 1985; 4:596–603. 170. Tamate S, Shiokawa C, Yamada C et al. Manometric diagnosis of Hirschsprung’s disease in the neonatal period. J Pediatr Surg 1984; 19:285–8. 171. Verder H, Peterson W, Mauritzen K. Anal tonometry in the neonatal period for the diagnosis of Hirschsprung’s disease. Acta Paediatr Scand 1991; 80:45–50. 172. Nunez R, Vargas I, Rubio I et al. Anorectal manometry in newborns. Pediatr Surg Int 1995; 10:105–7. 173. Meier-Ruge W, Lutterbeck PM, Herzog B et al. Acetylcholinesterase activity in suction rectal biopsies of the rectum in the diagnosis of Hirschsprung’s disease. J Pediatr Surg 1972; 7:11–17. 174. Lake BD, Puri P, Nixon HH et al. Hirschsprung’s disease. An appraisal of histochemically demonstrated acetylcholine esterase in suction rectal biopsy specimens as an aid to diagnosis. Arch Path Lab Med 1978; 102:244–7. 175. Lake BD, Malone MT, Risdon RA. Acetylcholinesterase in the diagnosis of Hirschsprung’s disease, including a

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56 Anorectal anomalies ALBERTO PEÑA

Anorectal anomalies present with a spectrum of defects. At one end of the spectrum these include minor malformations that require minimal treatment and which usually render excellent results. At the other end of the spectrum, one can have a very sick baby with a very complex defect, which usually represents a very serious technical challenge in which the results in terms of bowel, urinary and sexual function are not good, in spite of the best efforts of a specialist. A newborn with anorectal malformation may represent a surgical emergency mainly because the baby may suffer from intestinal obstruction or, in addition, from severe associated urologic, gastrointestinal or cardiac defects which may require aggressive and efﬁcient management to save the baby’s life. Other patients with these defects do not represent an emergency because they have a ﬁstula that allows intestinal decompression; in these cases, the repair of the defect becomes an elective procedure.

Table 56.1 Classiﬁcation of anorectal anomalies Male defects Low defects: cutaneous ﬁstula, anal stenosis, anal membrane, and ‘bucket handle’ malformation Recto-urethral bulbar ﬁstula Recto-urethral prostatic ﬁstula Rectovesical (bladder neck) ﬁstula Imperforate anus without ﬁstula Rectal atresia and stenosis Female defects Cutaneous (perineal) ﬁstula Vestibular ﬁstula Imperforate anus without ﬁstula Rectal atresia and stenosis Persistent cloaca Complex and rare defects

Frequency This defect occurs with a frequency of approximately 1 to 4000 or 5000 newborns.1–3

Classiﬁcation There are several classiﬁcations4,5 for these defects. Table 56.1 gives a practical classiﬁcation used by the author.

CLINICAL FEATURES AND DIAGNOSIS Male defects LOW DEFECTS These defects include cutaneous ﬁstulas (Fig. 56.1), anal stenosis, anal membrane (very unusual), and ‘buckethandle’ malformation (Fig. 56.2) The common denominator of these defects is the fact that the intestinal

opening is located anterior to the center of the external sphincter, as demonstrated by electrical stimulation during the repair (Fig. 56.3). These are the only defects that the author speciﬁcally recommends to treat surgically in a primary way without a protective colostomy. Most of the time, the patient is able to pass even tiny amounts of meconium through a mini oriﬁce in the perineum. Sometimes it takes a few hours before the baby passes meconium. The presence of a prominent midline epithelial tag below which one can pass an instrument (‘bucket-handle’ malformation) is considered pathognomonic of this defect (Fig. 56.2). Many times one sees a midline raphe subepithelial ﬁstula that looks like a black ribbon which is also a pathognomonic evidence of this type of defect (Fig. 56.1). An anal membrane has also been described in this type of defect but it is very unusual. Otherwise, the patients have a normal-looking perineum. The diagnosis is made on a clinical basis and usually no radiologic studies are necessary. The chances of having an associated genitourinary defect are extremely low.

536 Anorectal anomalies

Figure 56.3 Perineal ﬁstula – sagittal view

Figure 56.1 Cutaneous (subepithelial) ﬁstula

Figure 56.4 ‘Good-looking’ perineum Figure 56.2 ‘Bucket-handle’ malformation

RECTO-URETHRAL BULBAR AND RECTOURETHRAL PROSTATIC FISTULAS These two types of defects are indistinguishable from a clinical point of view. However, the patient has more chances of having a ‘good-looking’ perineum in a case of recto-urethral bulbar ﬁstula (Fig. 56.4); this means having a prominent midline groove and anal dimple. In cases of prostatic ﬁstula, the chances of having a short sacrum and a ﬂat perineum (Fig. 56.5) increase. The rectum opens into the bulbar urethra (Fig. 56.6) or else into the prostatic urethra (Fig. 56.7). Both rectum and urethra have a common wall located above the ﬁstula site which is longer in the case of bulbar ﬁstula and shorter in

Figure 56.5 Flat bottom

Clinical features and diagnosis 537

Figure 56.6 Recto-urethral bulbar ﬁstula – sagittal view

Figure 56.8 Invertogram showing a bubble inside the bowel located more than 1 cm above the perineal skin

Figure 56.7 Recto-urethral prostatic ﬁstula – sagittal view

colostomy. Recto-urethral bulbar ﬁstula is the most common type of defect seen in male babies by the author,10 with prostatic ﬁstula being the next most frequently seen.

RECTOVESICAL BLADDER NECK FISTULA the prostatic type. The rectum passes through the levator mechanism partially (Figs 56.6 & 56.7). The neonatal nurses may notice that the baby is passing meconium through the urethra. The chances of seeing a bubble inside the bladder in an X-ray ﬁlm of the abdomen is rather remote, since the rectum opens into the urethra, below the bladder neck. An invertogram, as described by Wangensteen and Rice,6 may show intestinal air below the pubococcygeus line but still more than 1 cm away from the perineum (Fig. 56.8). More recently,7,8 a cross-table lateral ﬁlm, with the patient in the prone position and the pelvis elevated, has demonstrated the same radiological image obtained with an invertogram, but without the risks of bronchial aspiration and respiratory distress seen in cases of invertograms. Unfortunately, these studies are not reliable; the contraction of the muscle mechanism compresses the distal bowel, and therefore the intestinal air can be seen above the pubococcygeus line, erroneously indicating the presence of a much higher defect. The chances of these defects being associated with urological anomalies in the author’s experience9 vary from 25% in cases of urethral bulbar ﬁstula, to 66% in cases of urethral prostatic ﬁstula. These patients need a diverting

This defect accounts for approximately 10% of all anorectal defects in males and is the highest that we have seen in male patients. The rectum opens into the bladder neck in a ‘T’ fashion (Fig. 56.9). In addition, the distance from the pubic bone to the sacrum is usually decreased. The entire pelvis of these babies seems to be

Figure 56.9 Rectovesical (bladder neck) ﬁstula – sagittal view

538 Anorectal anomalies

hypotrophic. It is frequently associated with poor muscle development and the perineum looks rather ﬂat in most patients (Fig. 56.5); although, some patients with these defects may have a ‘good-looking’ perineum (Fig. 56.4) with a marked midline groove and a prominent anal dimple. The frequency of associated urological anomalies in this speciﬁc defect is very high (up to 92%),9 and therefore a urologic work-up is mandatory and represents a priority. An invertogram or a cross-table lateral ﬁlm, with the patient in the prone position and with the pelvis elevated, shows an image consistent with air much higher than the pubococcygeus line (Fig. 56.10). Sometimes, a plain ﬁlm of the abdomen shows air in the bladder. The neonatal nurses will often inform us that the baby is urinating meconium. Manifestations of intestinal obstruction will become evident during the ﬁrst 12 h. In addition to these symptoms, the baby may show symptoms consistent with acidosis and sepsis secondary to the association with some sort of obstructive uropathy. These patients of course, require a decompressing colostomy. They also require an abdominal approach during the deﬁnitive repair, in addition to the posterior sagittal approach.

IMPERFORATE ANUS WITHOUT FISTULA In this type of defect, the blind rectum is usually located at the level of the bulbar urethra. Even when there is no communication between rectum and urethra, the wall

that separates both of them is very thin and has no surgical plane of separation. This must be taken into consideration for technical reasons. This defect is rather unusual, but it has good muscle development, and therefore most of the time the perineum is a ‘good-looking’ one. The frequency of this defect is approximately 5% of male defects in the current author’s experience.10 It is the author’s conviction that the incidence of these defects that are reported in the literature is higher than actually occurs. This is due to the fact that most of these statistics were based on different diagnostic and clinical criteria, but in most cases the authors were not able to visualize the ﬁstula site directly. Distal colostograms done with the aim of demonstrating a recto-urethral ﬁstula are frequently unsuccessful if they are not done properly. A successful colostogram requires the injection of contrast material under enough hydrostatic pressure into the blind rectal pouch as to demonstrate the passage of contrast material into the urethra.11 The rectum is surrounded by voluntary muscle (Figs 56.3, 56.6, 56.7 & 56.9) and the hydrostatic pressure must be high enough to overcome the muscle action. The lack of pressure represents a frequent error that may explain the reporting of very high numbers of anorectal atresias without ﬁstula when actually this is a rather unusual defect. It is interesting to note that out of all our cases of imperforate anus with no ﬁstula, approximately half of them have Down syndrome. The other half is predominantly made up of patients with other syndromes that frequently cause mental retardation. Also, in all of our Down syndrome patients with imperforate anus, 19 out of 20 had imperforate anus with no ﬁstula.12 These patients also require a protective diverting colostomy. The chances of these patients having an associated defect is very low.

RECTAL ATRESIA AND STENOSIS

Figure 56.10 Invertogram showing intraluminal air above pubococcygeus line

This is the type of defect classically described as the one that is diagnosed by the nurse while passing the thermometer during the initial physical examination of the newborn. The reason for this is that these babies are born with a normal anal canal and an atresia located about 1–2 cm above the anal verge. Above that, there is a dilated rectal pouch. The atresia site is always located at the natural limit of the anal canal and rectum. Sometimes, the patient actually has a stenosis. The separation between the blind pouch and the anal canal may be constituted by a very thin membrane, but more frequently is represented by a thick ﬁbrous septum of 3–7 mm length. These patients need a protective colostomy. The perineum looks normal. The sacrum is usually normal and the chances of associated defects are extremely low. These patients have all the necessary anatomical elements to become totally continent; the muscles are intact and the anal canal has normal sensation.

Clinical features and diagnosis 539

Female defects CUTANEOUS (PERINEAL) FISTULA This is the lowest defect seen in females and it is equivalent to the same defect already described in males. The ﬁstula site is located in these patients anywhere between the vestibule and the center of the anal dimple (Fig. 56.11). The entire ﬁstula site is surrounded by skin epithelium, and therefore it is also given the name of cutaneous ﬁstula. The oriﬁce is also variable in size, and therefore it may be sufﬁcient for a full-bowel evacuation or else it may require dilations to provide good bowel movements. These patients do not require a protective colostomy as part of their treatment. The most prominent anatomical feature in this type of defect is that rectum and vagina do not share a common wall (Fig. 56.11). Thus, the technical implication is that the rectum can be mobilized easily without risking injury to the vagina. Patients have otherwise normal muscle structures and a normal sacrum. The incidence of associated defects of the urinary tract or spine is almost nil. The patients may require a small operation for the repair of this defect, but usually it does not represent an emergency, since anal dilations are usually enough to decompress the bowel.

VESTIBULAR FISTULA This is the most frequent defect seen in female babies. The intestine opens into the vestibule of the baby which is the space located immediately outside the hymen (Fig. 56.12). The most notable anatomical feature in this defect is the presence of a very long common wall between rectum and vagina located above the ﬁstula site (Fig. 56.12). The vagina must be completely separated from the rectum in order to achieve good mobilization and a good repair of this defect. One must remember that there is no surgical plane of separation between these two structures. The ﬁstula is usually represented by a short (5–15 mm) narrow rectal opening which sometimes is not wide enough to decompress the bowel and

Figure 56.11 Perineal ﬁstula in a female patient

Figure 56.12 Vestibular ﬁstula

may require dilatations. Above that, one ﬁnds a completely normal rectum. Sometimes, the oriﬁce is wide enough to allow a satisfactory decompression, and therefore the baby does not need an emergency colostomy. The opening of a colostomy is the safest way to manage these girls and guarantees the best results. However, a modern trend is observed at the present time, among pediatric surgeons, to operate on babies with anorectal malformations, primarily without a colostomy. If this is to be practised, perhaps vestibular ﬁstula should be one of the ﬁrst defects that should be treated in this way; however, this should be done by surgeons with demonstrated experience in the management of these malformations. In fact, at our institution, we operate on otherwise healthy newborn babies who were born with vestibular ﬁstulas, primarily without a colostomy. Newborn babies with these defects do not need bowel preparation and can be fed within the ﬁrst few days after the operation. On the other hand, sometimes patients who did not receive a colostomy at birth come for a consultation later in life with vestibular ﬁstula. They usually suffer from severe constipation and megacolon. These patients have more chances of suffering complications when operated on without a protective colostomy. They can receive a protective colostomy, or if the surgeon decides to repair the malformation without it, it is advisable to clean the bowel in a scrupulous manner preoperatively. These patients must then receive parenteral nutrition and nothing by mouth for ten days. Although these patients have a signiﬁcantly dilated rectum, a tapering is not required, mainly because the rectum is always located within the muscle structures, and therefore there is a natural space through which the rectum can be pulled down. The incidence of associated urogenital malformations is 30% in the author’s experience.9 The sacrum is usually normal. The perineum of these babies shows a very prominent midline groove and a very obvious anal dimple. Once in a while, we see a ‘poor-looking’ perineum as well as short or very abnormal sacrum in this type of defect.

540 Anorectal anomalies

VAGINAL FISTULA Vaginal ﬁstula is a very unusual defect in female patients. Less than 1% of the current author’s cases suffer from this malformation. On the other hand, vaginal ﬁstula is presented in the traditional literature as a relatively common defect. A recent review of the author’s own experience with re-operations in female patients showed 80 female patients operated on at other institutions with a diagnosis of recto-vaginal ﬁstula. During our reoperations the author found objective evidence indicating that none of these patients actually had recto-vaginal ﬁstulas. In fact, two-thirds of them had cloacas. The surgeons were unaware of the correct diagnosis; they repaired the rectal component of the malformation and left the patient with a persistent urogenital sinus. The remaining one-third of the patients actually had vestibular ﬁstulas and that diagnosis was also missed by the surgeon. The importance of this observation is not only semantic; the group of patients that were born with cloacas were mislabeled as having recto-vaginal ﬁstulas and the patients missed a great opportunity to have their entire malformation repaired during the ﬁrst operation. The results of a second procedure are never as good as the ﬁrst one. Furthermore, the patients with vestibular

ﬁstulas were born with a malformation that carries an excellent functional prognosis, and yet more erroneously subjected to an unnecessary abdominal perineal procedure and as a result suffer from fecal incontinence. Therefore, it is very important to increase the index of suspicion for malformations such as cloaca and vestibular ﬁstula, and to recognize that vaginal ﬁstulas are almost non-existent defects. To make the diagnosis of a real recto-vaginal ﬁstula, it is necessary to perform a meticulous inspection of the genitalia of female babies; this sometimes is not easy to perform in the newborn period due to edema. Patients with recto-vaginal ﬁstulas must show meconium coming from inside the vagina through the hymen. These babies may have a signiﬁcant incidence of associated urological defects (around 70%),9 and they need to have a protective colostomy prior to the main repair.

IMPERFORATE ANUS WITHOUT FISTULA All that was written regarding this defect in males is valid regarding females.

RECTAL ATRESIA AND STENOSIS This type of defect is identical to the one described in males, except that its frequency in females seems to be higher.

PERSISTENT CLOACA

(a)

This is the most serious anorectal malformation seen in females. It represents approximately 10% of the total number of anorectal defects. A cloaca is deﬁned as the junction of rectum, vagina and urethra into a single common channel or cloaca (Fig. 56.14). Cloacas represent another spectrum by themselves. In other words, at one end of the spectrum one may ﬁnd a rather benign, short common channel type of cloaca with good prognosis and no associated defect (Fig. 56.15). At the other end of the spectrum, one can ﬁnd a very complex defect with a common channel of about 7 cm length, with a

(b)

Figure 56.13 Vaginal ﬁstula (a) low; (b) high

Figure 56.14 Persistent cloaca

Preoperative care 541

Figure 56.15 Low cloaca

very short vagina, severe associated obstructive uropathy as well as very poor sacrum and poor muscles. Therefore, the prognosis for this last type of case will be very poor for bowel, and urinary control as well as sexual function. The spectrum of cloacas include many different types. One may see patients with a very dilated vagina which becomes evident as a palpable abdominal mass and is called hydrocolpos. The dilated vagina usually causes urinary obstruction. Also, a frequent ﬁnding is a double vagina and double uterus; the rectum may open at different levels in the mid-vaginal septum. About 30% of these patients require an abdominal approach during the deﬁnitive repair, in addition to the perineal operation. The most important fact to remember in this type of defect is the high incidence of associated urinary tract obstruction (70%–90%). Obstructive uropathy is the main cause of death in these patients. The diagnosis of a cloaca is a clinical one. General practitioners, pediatricians and neonatologists, as well as pediatric surgeons, must suspect this defect if they want to detect it early enough. A baby girl with absent anus and small-looking genitalia must arouse the suspicion for the presence of a persistent cloaca (Fig. 56.16). If one separates the labia minora of their genitalia, a single oriﬁce becomes evident. These ﬁndings are pathognomonic of a cloaca. At that point the most important priority in a newborn is the evaluation and treatment of the associated defects of the urinary tract. The external appearance of the perineum in these babies may vary, but more frequently a ‘poor-looking’ perineum is found, which means a ﬂat one with a very poor midline groove and almost absent anal dimple. However, one may be pleasantly surprised to ﬁnd a cloaca with good muscles and a good sacrum. These patients always need a completely diverting colostomy and often some sort of urinary diversion, which may include a vesicostomy as well as a vaginostomy. Except for the urinary evaluation, mandatory in cases of cloacas, X-ray ﬁlms done during the newborn period in females with anorectal malformations are seldom useful, since most of these patients have a visible ﬁstula

Figure 56.16 Cloaca, perineal appearance

opening, which allows the defect to be classiﬁed. An invertogram, therefore, would be only useful in cases of anorectal atresia without ﬁstula.

PREOPERATIVE CARE Figures 56.17 and 56.18 show decision-making algorithms for the initial management of newborn babies with anorectal malformations. In approximately 90% of the male babies, the physical examination (perineal inspection) as well as the urinalysis produce enough information to determine whether the patient needs a colostomy or not. The presence of a perineal subepithelial midline raphe ﬁstula, a ‘bucket-handle’ defect, and anal stenosis all of the group of defects traditionally known as ‘low’ that can be treated during the newborn period, with a simple anoplasty and without a protective colostomy. In cases of very sick babies, a series of anal dilatations may be enough to allow bowel decompression, leaving the anoplasty to be done later as an elective procedure. The author speciﬁcally suggests a ‘minimal’ posterior sagittal anoplasty for these types of defects. On the other hand, a ﬂat bottom, or else the evidence of meconium in the urine, very abnormal sacrum or spine the presence of tethered cord or other severe associated defects are considered enough information to determine whether a patient requires a protective colostomy prior to the deﬁnitive treatment of these defects. These babies receive

542 Anorectal anomalies Newborn with anorectal malformation Male

16–24 hours

{

Perineal inspection Urinalysis Kidney Spinal Ultrasound X-ray of sacrum and spine Watch for associated defects

Diagnostic evidence 90%

Perineal ﬁstula ‘Bucket handle’ Midline raphe ﬁstula Meconium in perineum Normal sacrum No associated defects

Questionable evidence 10%

Flat bottom Meconium in urine Very abnormal sacrum and spine Tethered cord Severe associated defects

COLOSTOMY

Minimal PSAP No colostomy

PSARP

Cross-table lateral ﬁlm

> 1 cm Bowel-skin distance

< 1 cm Bowel-skin distance

Look again at the perineum for a tiny missed perineal ﬁstula

Minimal PSAP No colostomy

Figure 56.17 Decision-making algorithm for the management of male neonates with anorectal malformations

an emergency colostomy and, 4–8 weeks after the colostomy is done and provided that the patient is growing well, a posterior sagittal anorectoplasty is performed. All these defects together represent approximately 90% of the entire group of anorectal defects in males (Fig. 56.17). The remaining 10% are considered to have ‘questionable clinical evidence’. In these cases, we recommend the cross-table lateral ﬁlm with the patient in the prone position.6–8 An intraluminal bubble located more than 1 cm from the skin is considered an indication for a colostomy. Since the patient did not have signs of a recto-urinary ﬁstula, most likely, the case is one of imperforate anus with no ﬁstula. If the patient has Down syndrome, it is more likely that there will be no ﬁstula. On the other hand, if the rectum is located closer than 1 cm from the skin, most likely the patient was born with a perineal ﬁstula. The surgeon should look into the perineum again and may ﬁnd a tiny oriﬁce, so narrow that it does not allow the passage of meconium in the ﬁrst hours of life. The baby can then be treated with a minimal posterior sagittal anoplasty and without a colostomy. Figure 56.18 shows a decision-making algorithm used for the initial management of female babies with anorectal defects. The process of decision making in females is easier than in males, mainly because approximately

90% of the female patients have some form of ﬁstula either to the perineum, vestibule or genitalia which, per se, indicates the type of defect that one is dealing with. The presence of a cloaca (single perineal oriﬁce), as was previously discussed, represents an indication for an emergency urological evaluation. In addition, the patient will require a colostomy and sometimes a vesicostomy, vaginostomy, or any other kind of urinary diversion, to be done at the same time that the colostomy is performed. Provided the baby is growing well, the patient must undergo a complete repair of her defect 3–6 months after this procedure. In the cases in which the meconium comes from inside the vagina or else from the vestibule, a protective colostomy is recommended. Many times, the ﬁstula opening is big enough to decompress the bowel, and therefore there is no need for an emergency colostomy. Still, the baby will require the colostomy 2 weeks prior to her main repair. Sometimes, the ﬁstula is not big enough to decompress the baby’s bowel and we still have to perform a diverting colostomy on an emergency basis. Once the baby reaches 4–8 weeks old, and provided that it is growing normally, it can undergo the posterior sagittal anorectoplasty (PSARP). The presence of a cutaneous (perineal) ﬁstula indicates that the baby has the most benign congenital anorectal

Preoperative care 543 Newborn with anorectal malformation Female

16–24 hours

{

Perineal inspection Kidney Spinal Ultrasound Pelvic X-ray of sacrum and spine Watch for associated defects

Evidence of ﬁstula 95%

Single oriﬁce (CLOACA) Potential urologic emergency

COLOSTOMY . . . if necessary Vaginostomy Urinary diversion

VESTIBULAR

PERINEAL

COLOSTOMY

4–8 weeks

COLOSTOMY

4–8 weeks

3 months

PSARVUP

No ﬁstula 5%

PSARP

Minimal PSAP No colostomy

PSARP

Figure 56.18 Decision-making algorithm for the management of female neonates with anorectal malformations

defect. This can be treated with a ‘minimal’ posterior sagittal anoplasty without a protective colostomy. If the perineal ﬁstula is big enough to decompress the intestine, then the anoplasty can be postponed and done on an elective basis. The remaining 5% of patients that have no ﬁstula still need a colostomy followed by a PSARP 4–8 weeks later. Every surgeon must develop their own learning curve in the surgical management of these defects. Thus, if the surgeon has no experience with this type of technique, it is advisable to perform the main repair of the defect when the patients are 1 year old. As one gains conﬁdence with this technique, one can do the main repair earlier and earlier. There are both theoretical and practical advantages in doing these repairs early in life. From the theoretical point of view, placing the rectum in its normal position early may allow the creation of new nerve synapses which may have advantages in terms of bowel control, as suggested by Freeman and colleagues.13 From the practical point of view, it is much easier for the mother to dilate the anus of a small baby than trying to do it in an older patient. It is also always better to ﬁnish the entire treatment before the baby becomes conscious of him/herself, thus avoiding unpleasant memories. The modern trend is to operate on newborns with anorectal malformations, primarily without a protective colostomy.14 Even more ambitious and bold is the tendency to repair these babies primarily without a

protective colostomy and laparoscopically.15 It is, of course, desirable to try to inﬂict as little trauma as possible on these little babies. It is therefore, understandable that a single procedure is highly attractive when compared to the alternative of three operations (colostomy, main repair and colostomy closure). In fact, it has been demonstrated that this novel approach is feasible. However, what remains to be seen is whether or not a new treatment will result in better or worse functional results for these babies. In general, this should be the aim, but it should always be kept in mind that the supreme goal is the beneﬁt of the children. Those who embrace the new bold treatment modality are morally obligated to report their results, including complications. Concerning the laparoscopic approach of these malformations, it must be kept in mind that at the present time, 90% of the male cases can be repaired via the posterior sagittal route without opening the abdomen; these patients experience minimal pain, eat the same day of surgery and literally could go home the same day of the operation. Laparoscopy was created and conceived as minimally invasive surgery and it is difﬁcult to accept that repair of malformations must be done through the peritoneal cavity that are currently repaired in an extra-abdominal and extra-peritoneal way. There is one particular defect (recto-bladder neck ﬁstula), that represents 10% of all malformations in males and currently requires repair by a laparotomy in addition to the posterior sagittal approach. It is perhaps, in repairing

544 Anorectal anomalies

this particular malformation, that laparoscopy could be justiﬁed at the present time. In general, babies with anorectal malformations look healthy unless they have a severe associated defect, mainly urologic, cardiac or in another site of the gastrointestinal tract. The frequency of associated urologic defects in babies with anorectal malformation varies according to the statistics that one consults.22–27 In this author’s series,9 48% of the patients with anorectal defects had a signiﬁcant associated urologic defect, and this frequency changes depending on the level of the ﬁstula site. This, we believe, may help neonatologists and pediatricians to suspect, detect and treat those defects early. Before the performance of the colostomy, every baby must at least have an abdominal ultrasound done to rule out the presence of obstructive uropathy. Concerning the passage of meconium, decisions should not be made during the ﬁrst 16 h of life, since meconium often appears after that period of time. Abdominal distension does not become a serious problem during the ﬁrst 16 h of life.

COLOSTOMY Once a decision has been taken to perform a colostomy, a nasogastric tube is placed in the stomach and intravenous ﬂuids started. Prophylactic antibiotics are recommended and we usually administer ampicillin and gentamicin. Figure 56.19(a) shows the type of colostomy that the author recommends in the management of anorectal malformations. The advantages of this colostomy over other types are as follows:28

(a)

Figure 56.19 (a) Ideal colostomy. (b) Too distal colostomy

• defunctionalizes only a small portion of distal intestine, allowing better water absorption • is completely diverting • allows decompression of urine that may pass from the urinary tract back into the rectum • simpliﬁes preparation of the distal intestine prior to the main repair • makes the distal colostograms easier than when dealing with a more proximal colostomy • the incidence of prolapse is virtually zero. Loop colostomies are speciﬁcally condemned because of the possibilities of allowing feces to pass into the distal stoma, provoking fecal impaction, megarectum and urinary tract infection. Also, there is a risk of contamination and infection after the main repair. The recommended incision measures approximately 6 cm, is made in the left lower quadrant and is oblique. The proximal functional stoma is located in the upper and lateral portion of the incision and the mucous ﬁstula (non-functional) distal stoma is placed in the lower and medial portion of the incision. The distal bowel must be irrigated with saline solution at the end of the operation to empty it of all the meconium. In this way, the bowel remains completely clean, does not get distended and the patient does not need any preparation prior to the main repair. Colostomy must be considered a serious, delicate procedure. The surgeon must carefully identify the piece of intestine that he is going to exteriorize to avoid serious mistakes. The most frequent errors in performing colostomies seen by the author include: 1 Too distal a colostomy (Fig. 56.19b) 2 Opening of a right upper sigmoidostomy. The surgeon thought that he was opening a transverse

(b)

Colostomy 545

colostomy and actually grabbed the sigmoid colon and exteriorized it in the right upper quadrant. This interferes with the pull-through. 3 Retracting colostomies. In these cases the bowel was probably handled poorly and may suffer from ischemia and retraction. In addition, the bowel is poorly ﬁxed to the abdominal wall. To avoid this, the author’s suggestion is to ﬁx the bowel in two layers of interrupted non-absorbable ﬁne sutures. The ﬁrst layer is the peritoneum and the second the aponeurosis. 4 Prolapsed colostomies. This is most often seen in loop transverse colostomies. After the operation, we keep the child on nasogastric suction for approximately 48–72 h. After that period of time and provided that we have evidence that the baby’s bowel is working well, the nasogastric tube is removed and oral feedings are started. At the time of colostomy, a urinary diversion can be performed when necessary; this is particularly frequent in those cases of very high defects or cloacas. After the colostomy is opened, the baby can go home and be observed by the pediatrician to rule out other associated defects and to conﬁrm that the baby is growing well. Four weeks after this, the main repair can be performed. Prior to the ﬁnal repair, it is mandatory to perform a distal colostogram in order to determine the precise type of anatomical defect that one is dealing with. This has important prognostic and therapeutic implications. This study must be done under ﬂuoroscopy with the patient in the lateral position. A Foley catheter is introduced into the distal stoma, its balloon is inﬂated and water-soluble contrast material (never barium) is injected under enough hydrostatic pressure to overcome the contraction of the funnel-like muscle structure that surrounds the lowest part of the rectum. The dye injection is done with a hypodermic syringe by hand. Failure to observe these principles will most likely show the dye staying above the pubococcygeus line, erroneously indicating the presence of a very high defect, simply because of lack of hydrostatic pressure.11 Figures 56.20–56.22 show distal colostograms in a case of rectourethral bulbar ﬁstula, rectoprostatic ﬁstula and rectovesical (bladder neck) ﬁstula. Having this information, the surgeon will be able to plan the ﬁnal procedure in an adequate way. Hence, when dealing with a case of rectovesical (bladder neck) ﬁstula, the surgeon will be able to predict that the prognosis in terms of bowel function is not going to be as good as in other types of defects. In addition, the main repair will take approximately 5 h. Also, a laparotomy will be necessary in order to mobilize the rectum. most importantly, the surgeon will avoid looking for the rectum through a posterior sagittal incision because that would risk injury of the urinary tract, vas deferens, seminal vesicles and ectopic ureters. The posterior sagittal approach in this case will be used

Figure 56.20 Distal colostogram in a recto-urethral bulbar ﬁstula

Figure 56.21 Distal colostogram in a recto-urethral prostatic ﬁstula

546 Anorectal anomalies

Figure 56.22 Distal colostogram in a rectovesical (bladder neck) ﬁstula

(a)

only to place a rubber tube along the trajectory of a normal rectum, which will serve the purpose of guiding the rectum during the pull-through, after its mobilization through a laparotomy.

FINAL REPAIR Since 1980, the author has been using the posterior sagittal approach for the treatment of all anorectal defects. Following the concept of the learning curve, many patients were operated on after they were 1 year of age at the beginning of the author’s series. As time went by, these procedures were done in younger patients. At the present time, this repair is done when the patient is 4–8 weeks old, except in cloacas in which it is preferable to do it when the patient is 6 months old.29

(b)

Minimal posterior anoplasty This operation is done in all the so-called ‘low’ defects, including perineal and cutaneous ﬁstulas in both males and females. In cases of male babies it is important to place a Foley catheter in the bladder during the operation. The rectum and urethra are very close together in spite of not having a real communication. The incision is very small and divides the external sphincter and continues around the ﬁstula in a ‘racketlike’ fashion (Fig. 56.23a). Multiple 6-0 sutures are placed, taking the mucocutaneous junction of the ﬁstula. This serves the purpose of exerting uniform traction which helps in these dissections. The anal canal is mobilized, as well as part of the rectum, sufﬁciently to be relocated comfortably within the limits of the external sphincter (Fig. 56.23b). The rectum is anchored to the muscle complex and then a 16-stitch anoplasty is done, as shown in Fig. 56.23(c).

(c)

Figure 56.23 Perineal ﬁstula repair: (a) incision; (b) reconstruction; (c) anoplasty

Final repair 547

Limited posterior sagittal anorectoplasty This procedure is performed in cases of rectovestibular ﬁstula in female babies. The incision is very similar to the one just described but it is extended more cephalad as far as necessary to achieve enough bowel mobilization. The main difference in comparison with the previous defect lies in the fact that the rectum and vagina share a rather long common wall. The most important part of the operation consists in separating the rectum and vagina by creating a plane of separation without injuring either one (Fig. 56.24). The separation is carried out all the way up until both structures have a full-thickness normal wall. Lack of mobilization is the main cause of recurrences and dehiscence after this repair. The separation of the rectum from the vagina requires a meticulous and delicate technique and is performed with a needle-tip cautery, changing from cutting to coagulation where

Figure 56.24 Vestibular ﬁstula repair. Separation of rectum from vagina

(a)

(b)

(c)

(d)

Figure 56.25 Vestibular ﬁstula repair: (a) perineal reconstruction; (b) anchoring rectum to muscle complex; (c) anoplasty; (d) operation completed

548 Anorectal anomalies

necessary to provide meticulous hemostasis (Fig. 56.24). Once the rectum has been completely separated, the limits of the external sphincter are determined by electrical stimulation. This will indicate where the rectum should be located. The perineal body is then reconstructed with interrupted stitches of long-term absorbable sutures (Fig. 56.25a). The rectum is anchored to the posterior edge of the muscle complex (Fig. 56.25b) and then a 16-stitch anoplasty is performed in the same way as previously (Fig. 56.25c,d). The suture recommended is a 5-0 long-term absorbable one. These patients can have oral feedings the same day of surgery and can go home the following day. Bacitracin ointment is applied to the wound three times a day for 1 week.

Posterior sagittal anorectoplasty This technique is used for the repair of a recto-urethral ﬁstula or a rectovaginal ﬁstula. The patient is placed as previously described in the prone position, with the pelvis elevated and with a Foley catheter in the bladder. Electrical stimulation of the perineum will allow the surgeon to identify the anal dimple in a rather precise manner. The incision runs from the middle portion of the sacrum down and through the external sphincter. The electrical stimulation allows the incision to be exactly maintained in the midline, leaving equal amounts of muscle on both sides. One would expect the same intensity in muscle contraction on both sides of the midline as well as a symmetrical appearance. After opening of the skin, one can identify subcutaneous tissue and then the presence of parasagittal ﬁbers. The incision is deepened and after another area of subcutaneous fat, one ﬁnds the levator muscle. Levator muscle continues with the muscle complex down to the skin of the anal dimple, forming a single structure. Parasagittal ﬁbers run on both sides of the midline and will serve the purpose of closing the lumen of the anus once this is reconstructed. Muscle complex ﬁbers run perpendicular to the parasagittal ones and also medially. The muscle complex and parasagittal ﬁbers cross perpendicularly, forming the posterior and anterior limits of the new anus (Fig. 56.26). The contraction of the muscle complex elevates the anus. Levator muscle contraction pulls the rectum forward. The levator muscle is opened exactly in the midline and the rectum is opened between two traction sutures (Fig. 56.26). Once the rectum is opened, one can visualize the ﬁstula site. One must remember that the rectum and urethra or vagina share a common wall immediately above the ﬁstula. Accordingly, a submucosal dissection must be carried out above the ﬁstula site (Fig. 56.27). After approximately 1 cm of submucosal dissection, the dissection continues taking the full thickness of rectal wall. Once the rectum has been separated from the urethra or vagina, the ﬁstula is closed with interrupted long-term absorbable sutures.

Figure 56.26 Anatomy exposed. Parasagittal ﬁbers, muscle complex and levator muscle have been split in the midline. The rectum is open in the midline

Figure 56.27 Separation of rectum from urethra

The rectum is then dissected in a circumferential manner, so as to gain enough length to reach the perineum without tension (Fig. 56.28). At this point, a decision must be reached concerning the need for tapering (Fig. 56.29). This is not always necessary and the amount of resected bowel varies from one patient to another. If the tapering is necessary, this must be carried out in the posterior aspect of the rectum. The bowel must then be closed in two layers of interrupted sutures. The rectum is then placed in front of the levator muscle within the limits of the muscle complex and external sphincter. The rectum is also anchored to the muscle complex with interrupted sutures to prevent prolapse (Fig. 56.30). The anoplasty is done as previously described (Figs 56.31 & 56.32). Following the operation, the Foley catheter must remain in place for approximately 5 days in males. If the catheter comes out accidentally, it is better to leave it out

Final repair 549

Figure 56.31 Anoplasty Figure 56.28 Rectum separated from urethra

Figure 56.32 Anoplasty – operation completed

Figure 56.29 Tapering the rectum

rather than trying to pass it back into the bladder and thus risking a urethral perforation at the urethral suture site. Most of the time, babies will be able to void with no difﬁculty. If this is not so, then a suprapubic cystostomy is recommended. This is rather unusual.

Posterior sagittal anorectoplasty and laparotomy (bladder neck ﬁstula)

Figure 56.30 Rectum placed in front of the levator. Anchoring sutures from muscle complex to the rectum

This technique is used in cases of very high defects, mainly the bladder neck type of ﬁstulas in males. The operation is started with the patient in the prone position and a Foley catheter placed in the bladder. The incision is the same as previously described for the posterior sagittal anoplasty. All the muscle structures are divided in the midline until we ﬁnd the urethra. A rubber tube is placed following the location of a normal rectum. The wound is closed meticulously, reconstructing all the necessary layers. The rubber tube is anchored to the skin of the buttocks with heavy silk (Fig. 56.33). The patient is then turned to a supine position and the entire body from the axilla down to and including both

550 Anorectal anomalies

Figure 56.33 Posterior sagittal anorectoplasty and laparotomy. Tube in place – sagittal view

feet are prepared with antiseptic solution. The abdomen is entered, the peritoneal reﬂection is opened and the sigmoid colon is dissected down to the ﬁstula site where it is ligated and divided. The rectum in these cases opens into the bladder neck in a ‘T’ fashion with no common wall, and therefore the separation from the bladder is easy. One must be careful to avoid damage to the vasa deferentia which open very close by. The rubber tube which was previously located in the presacral space is seen, and the rectum is tapered to the size of the tube. Then the rectum is anchored to the tube and the pullthrough is performed by pulling the rubber tube through the perineum (Fig. 56.34). The anoplasty is done as previously described. The peritoneal ﬂoor is reconstructed and the abdomen is closed. These patients require the nasogastric tube for 48–72 h, until there is evidence that the bowel is working normally. The Foley catheter remains in the bladder for 5 days. The posterior sagittal approach has also been used since 1982 to repair cloacas. Since cloacas represent a spectrum, the operations to repair these defects may last from 3–14 hours and should be carried out by surgeons

Figure 56.34 Posterior sagittal anorectoplasty and laparotomy – operation completed

with signiﬁcant experience on the subject. During the last few years, a new technical maneuver was introduced in the repair of cloacas and that is called ‘total urogenital mobilization’.30 Traditionally, through the posterior sagittal approach, the goal of the operation consisted of separating the rectum from the vagina and vagina from the urinary tract. Both the rectum and vagina were then mobilized, pulled down and placed in normal locations. It was necessary to open the abdomen 30–40% of the time to reach a very high rectum or a very high vagina. Using total urogenital mobilization, the rectum is separated from the vagina and then both the urethra and vagina are mobilized together, down to the perineum. The surgical time has decreased by about 70%. This new maneuver also avoids the formation of urethro-vaginal ﬁstulas as well as vaginal stenosis. Two weeks after the operation, the mid-sagittal suture is removed and anal dilatations are started following this protocol. Two weeks postoperatively Remove sutures, calibrate; teach the mother to dilate. Pass only the dilator that ﬁts snugly. Give the dilator to the mother and instruct her to dilate the child twice a day faithfully. Every week Have the child come back to the clinic and pass the next sized dilator. Give it to the mother, who must pass it twice a day. Once the desired size is reached, the colostomy may be closed, but keep passing the dilator (after the closure) until the dilator goes easily with no pain (usually 3–4 weeks after the last size dilator was reached). Once the mother says that the dilator goes in easily with no pain (twice a day), one may start tapering the frequency of the dilatation: • • • • • •

once a day for a month every other day for a month every third day for a month twice a week for a month once a week for a month once a month for 3 months.

A speciﬁc indication to dilate twice a day again and restart the process is if the dilatation becomes difﬁcult, painful or bloody at any time during the process of tapering. Usually the dilatation becomes painful during the passing of the last 2–3 sizes. At that particular time the surgeon is pressed by the family to avoid pain to the child. The surgeon may then decide to dilate only once a week. This is not recommended. By doing this, a laceration may form and then heal and then be opened again, which in turn provokes severe ﬁbrosis. Also, staying in a single dilator size for prolonged periods of time (more than a week) will allow the healing process to ﬁnish while being in a rather small caliber, and it will

References 551

then be extremely difﬁcult to dilate more. Anal dilatations are difﬁcult in cases where ischemic bowel has been anastomosed to the skin. The ideal size of dilator for dilatations is no. 12 for 1–4 months old, no. 13 for 4–8 months, no. 14 for 8–12 months, no. 15 for 1–3 years old, and no. 16 for 3–12 years.

Results The posterior sagittal approach was used by the author to treat 792 patients with anorectal malformations.31 From these, 387 cases were evaluated 6 months to 13 years later. Volunteer bowel movements were present in 74.3% of the entire series. When distributed by diagnosis, the percentages varied: 100% in patients with rectal atresia and perineal ﬁstula; 93.2% in those with vestibular ﬁstula; 80.9% in those with bulbar ﬁstula; 71.1% in those with cloacas; 66.7% in those with prostatic ﬁstula; and 15.8% in those with bladder neck ﬁstula. Soiling was present in 57% of all cases. Patients with voluntary bowel movements and no soiling were classiﬁed as totally continent; 40.8% of the series belong to this group. Distributed by diagnosis, it varied from 100% in cases with rectal atresia or perineal ﬁstula, 65.9% in those with vestibular ﬁstula, 34% in those with bulbar ﬁstula, 31.6% in those with cloacas, 26.3% in those with prostatic ﬁstula; none of the patients with vaginal ﬁstula or bladder neck ﬁstula was totally continent. Constipation was detected in 43.1% of all patients, and was more frequent in those with simple defects. Urinary incontinence was found in 1% of patients with cloacas who had a common channel shorter than 3 cm, and in 68.8% of the patients who had longer common channels. Other patients suffered from urinary incontinence only when they had an absent sacrum or other severe bladder or urethral congenital defects. An accurate diagnosis and evaluation of the sacrum allows us to establish, with reasonable accuracy, functional prognosis in most children. Those with functional disorders must be treated properly medically, to improve their quality of life. For patients suffering fecal incontinence as a sequelae from the treatment of anorectal malformations (25% of patients), the current author implemented a bowel management program that is used after the child reaches 3 years of age. The goal is to send these children to school with normal underwear so they can adapt to their social environment. The program is implemented by trial and error over a period of 1 week. It consists of teaching the family to clean the patient’s colon once a day by use of an enema. This implementation is radiologically monitored every day during the period of 1 week until the speciﬁc type of enema capable of cleaning the colon is found and the patients’ colons are kept completely clean for 24 hours.32 Every year, during summer vacation, the patient is subjected to a laxative test; the enemas are suspended

and the capacity of the patient to become toilet-trained without enemas is evaluated. If the patient is not ready to become toilet-trained, the bowel management system is re-installed for another year. The patient over 10 years of age sometimes expresses dissatisfaction with the application of enemas, wants more privacy, and doesn’t want his mother or father to give enemas to him. In order to further improve his quality of life, the family is offered a procedure called ‘continent appendicostomy’ (Malone procedure).33 A few modiﬁcations have been made to the original Malone procedure that the current author thinks are beneﬁcial for the patient.34

REFERENCES 1. Brenner EC. Congenital defects of the anus and rectum. Surg Gynecol Obstet 1915; 20:579–88. 2. Santulli TV. Treatment of imperforate anus and associated ﬁstulas. Surg Gynecol Obstet 1952; 95:601–14. 3. Trusler GA, Wilkinson RH. Imperforate anus: a review of 147 cases. Can J Surg 1962; 5:169–77. 4. Stephens FD, Smith ED (editors). Proposed international classiﬁcation. In Anorectal Malformations in Children, Year Book, Chicago, 1971. 5. Stephens FD, Smith ED. Classiﬁcation, identiﬁcation and assessment of surgical treatment of anorectal anomalies. Pediatr Surg Int 1986; 1:200–5. 6. Wangensteen OH, Rice CV. Imperforate anus: a method of determining the surgical approach. Ann Surg 1930; 92:77–81. 7. Narasimharao KL, Prasad GR, Katariya S. Prone crosstable lateral view: an alternative to the invertogram in imperforate anus. Am J Roentgenol 1983; 140:227. 8. Goon HK. Repair of anorectal anomalies in the neonatal period. Pediatr Surg Int 1990; 5:246–9. 9. Rich MA, Brock WA, Peña A. Spectrum of genitourinary malformations in patients with imperforate anus. Pediatr Surg Int 1988; 3:110–13. 10. Peña A. Posterior sagittal anorectoplasty: results in the management of 332 cases of anorectal malformations. Pediatr Surg Int 1988; 3:94–104. 11. Gross GW, Wolfson PJ, Peña A. Augmented-pressure colostogram in imperforate anus with ﬁstula. Pediatr Radiol 1991; 21:560–2. 12. Torres P, Levitt MA, Tovilla JM, Rodriguez G, Peña A. Anorectal malformations and Down’s syndrome. J Ped Surg 1998; 33:1–5. 13. Freeman NV, Burge DM, Soar JS et al. Anal evoked potentials. Z Kinderchir 1980; 31:22–30. 14. Moore TC. Advantages of performing the sagittal anoplasty operation for imperforate anus at birth. J Pediatr Surg 1990; 25:276. 15. Georgeson KE, Inge TH, Albanese CT. Laparoscopically assisted anorectal pull-through for high imperforate anus – a new technique. J Ped Surg 2000; 35:927–31.

552 Anorectal anomalies 16. Sachs TM, Applebaum H, Touran T et al. Use of MRI in evaluation of anorectal anomalies. J Pediatr Surg 1990; 25:817. 17. Panuel M, Guys JM, Devred P et al. Imagerie par resonance magnetique des malformations ano-rectales hautes. Chir Pediatr 1988; 29:243. 18. Pomeranz AJ, Altman N, Sheldon JJ et al. Magnetic resonance of congenital anorectal malformations. Magnet Reson Imag 1986; 4:69. 19. Krasna IH, Nosher JL, Amorosa J et al. Localization of the blind rectal pouch in imperforate anus with the CT scanner. Pediatr Surg Int 1988; 3:114. 20. Tam PKH, Chan FL, Saing H. Direct sagittal CT scan: a new diagnostic approach for surgical neonates. J Pediatr Surg 1987; 22:397. 21. Donaldson JS, Black CT, Reynolds M et al. Ultrasound of the distal pouch in infants with imperforate anus. J Pediatr Surg 1989; 24:465. 22. Belman BA, King LR. Urinary tract abnormalities associated with imperforate anus. J Urol 1972; 108:823–4. 23. Hoekstra WJ, Scholtmeijer RJ, Molenar JC et al. Urogenital tract abnormalities associated with congenital anorectal anomalies. J Urol 1983; 130:962–3. 24. Munn R, Schillinger JF. Urologic abnormalities found with imperforate anus. Urology 1983; 21:260–4.

25. Parrott TS. Urologic implications of anorectal malformations. Urol Clin N Am 1985; 12:13–21. 26. Wiener ES, Kiesewetter WB. Urologic abnormalities associated with imperforate anus. J Pediatr Surg 1973; 8:151–7. 27. Williams DI, Grant J. Urological complications of imperforate anus. Br J Urol 1969; 41:660–5. 28. Wilkins S, Peña A. The role of colostomy in the management of anorectal malformations. Pediatr Surg Int 1988; 3:105–9. 29. Peña A. Atlas of Surgical Management of Anorectal Malformations. New York: Springer-Verlag, 1989. 30. Peña A. Total urogenital mobilization – an easier way to repair cloacas. J Ped Surg 1997; 32:263–8. 31. Peña A. Anorectal malformations. Sem Pediatr Surg 1995; 4:35–47. 32. Peña A, Guardino K, Tovilla JM, Levitt MA et al. Bowel management for fecal incontinence in patients with anorectal malformations. J Ped Surg 1988; 33:133–7. 33. Malone PS, Ransley PG, Kiely EM. Preliminary report: The anterograde continence enema. Lancet 1990; 336:1217–18. 34. Levitt MA, Soffer SZ, Peña A. Continent appendicostomy in the bowel management of fecally incontinent children. J Ped Surg 1997; 32:1630–3.

57 Congenital segmental dilatation of the intestine HIROO TAKEHARA AND HIROKI ISHIBASHI

HISTORY Congenital segmental dilatation of the intestine is a rare lesion that is complicated by obstruction of the intestines or chronic constipation from birth. Since Swenson and Rathauser ﬁrst described three patients with segmental dilatation of the colon in 1959,1 59 cases (30 newborns, 25 children and four adults) with this condition (41 in the small intestine and 18 in the colon) had been collected from previously reported world literature in 1996.2 In addition, seven neonatal cases (eight in the small intestine and one in the colon) had been collected afterwards.3–10 In 39 neonates, 19 were conﬁrmed to be males and 17 females, and their ages ranged from 4 hours to 20 days. Of them, two with segmental dilatation of the jejunum or the ileum were discovered by antenatal ultrasonography at 29 or 30 weeks’ gestation, respectively.8,10 The dilated segment was the small intestine in 32 cases (one duodenum, seven jejunum, 12 ileum and 12 undetected small intestine) and the colon in seven cases (Box 57.1). Box 57.1 Summary of 39 neonates with segmental dilatation of the intestine Age Sex

Dilated segment

Antenatal to 20 days Male Female Undetected Duodenum Jejunum Ileum Undetected small intestine Colon

19 (cases) 17 3 1 7 12 12 7

ETIOLOGY AND MORPHOLOGY The etiology of segmental dilatation of the intestine remains unknown. Some etiologic hypotheses have been proposed:

1 An obstructive insult to the developing bowel11 2 Presence of heteroplastic tissue in the bowel wall may result in primary dysplasia of the intestinal segment or may interrupt the myenteric plexus3,6,11–15 3 Anomalous tortuous vessels on the mesenteric side of the dilated segment16,17 4 Unequal proliferation or vacuoles in smooth muscle at the epitherial stage.9,14 The common morphological feature of congenital segmental dilatation of the intestine is the presence of a single, well-deﬁned segment of dilated intestine with a more or less abrupt transition to normal bowel both proximally and distally, with no evidence of intrinsic obstruction or deﬁcient innervation. These cases can be divided into two groups according to histopathologic ﬁndings. One group had a hypertrophic muscular layer within the dilated segment and the other had a very thin or absent muscular layer. From the review of 39 neonatal cases,3–16,18–35 ﬁve with hypertrophic muscular layer were reported,10,16,21,27,35 but eight with hypotrophic or atrophic muscular layer were collected.5,6,8,11,13,29 Abnormal prominent, tortuous vessels on the mesenteric side of the dilated segment were reported in 11 cases.10,11,16,24,27,30,35 Heteroplastic foci were found in the resected segment in ﬁve cases.6,12,13,26,30 The congenital segmental dilatation of the intestine is associated with numerous other malformations. In these series, one or more malformations were reported in 28 cases (71.8%).3–16,18–31 These included intestinal malrotation (14 cases), omphalocele (six cases), vertebral anomalies (six cases), anorectal malformation (four cases), atresia of the intestine (three cases), short intestine (two cases), extrophy of the bladder (two cases), diverticulum (two cases), lymphoangioma (two cases), annular pancreas (one case), trisomy 21 (one case), Bochdalek hernia (one case), ganglionic dysplasia (one case), vacuoles in smooth muscle (one case), duplication of appendix (one case), and miscellaneous malformations (six cases).

554 Congenital segmental dilatation of the intestine

CLINICAL FEATURES AND DIAGNOSIS Many cases of congenital segmental dilatation of the intestine localized in the small intestines often present intestinal obstructions during the neonatal period.1,4,11,14,16–18,27,36 Consequently, they had a diagnosis of this condition during the early period after birth.

Neonates with missed and accordingly delayed diagnosis appear with abdominal pain, vomiting and intermittent attacks of diarrhea. Chronic constipation and abdominal distension, similar to the presentation of Hirschsprung’s disease, is more common when the colon is involved.1,4,11,26,27,30,36,37 In segment dilatation of the colon, the ﬁndings on contrast enema are very similar to those

Segmental dilated jejunum

(c)

Endo GIA stapler

(a)

(d)

Excise

(b)

Figure 57.1 Laparoscopic surgery for congenital segmental dilatation of the jejunum (a). Following devascularization of the mesenterium of the dilated jejunum laparoscopically, the dilated segment is pulled out via the umbilical wound of the port site for an endoscope (b). The dilated segment is divided using Endo GIA staples and a primary end-to-end anastomosis is performed extracorporeally (c). The jejunum is replaced into the abdominal cavity after anastomosis (d)

Surgical treatment 555

in Hirschsprung’s disease, but the two conditions can be differentiated by anorectal manometry.37 Additionally, histochemical studies demonstrate no proliferation of cholinergic nerve ﬁbers of the rectal mucosa.37 Rarely, the patient may present with peritonitis due to perforation of the dilated segment.5

SURGICAL TREATMENT The surgeon must make every effort to establish the diagnosis as precisely as possible prior to initiating surgery. Congenital segmental dilatation is often confused with mechanical intestinal obstruction or Hirschsprung’s disease. A thorough preoperative radiological evaluation is necessary to distinguish the two, as well as to determine the site of the dilated segment. Surgery for segmental dilatation of the small intestine

or the colon should be performed with a laparoscopic procedure. The main advantage of laparoscopic surgery in children is that it is a minimally invasive procedure that provides safe and superior cosmetic results. Following devascularization of the mesenterium of the dilated jejunal or ileal segment laparoscopically, the dilated segment is pulled out via the umbilical wound of the port site for a endoscope. The dilated segment is divided and a primary end-to-end anastomosis is performed extracorporeally (Fig. 57.1). Segmental dilatation of the colon is treated similarly. For cases complicated by the segmental dilated rectum, the rectum is inverted using a venous stripper and divided on the normal colon of the oral side transanally. An end-to-end anastomosis between the colon and the rectum is performed laparoscopically with an autosuture instrument after setting an anvil head into the oral side (Fig. 57.2).

Excise Venous stripper (a)

(b)

(d)

(c)

(e)

Figure 57.2 Laparoscopic surgery for congenital segmental dilatation of the rectum. The mesenterial vessels of the segmental dilated rectum and the sigmoid colon are dissected laparoscopically (a). The rectum is inverted transanally using a venous stripper and divided on the normal colon of the oral side (b). An end-to-end anastomosis between the colon and the rectum is performed with an autosuture instrument after setting an anvil head into the colon on the oral side (c,d,e)

556 Congenital segmental dilatation of the intestine

PROGNOSIS Most patients experience an uncomplicated postoperative course following cosmetic and minimally invasive intervention with laparoscopic surgery for congenital segmental dilatation of the intestine. The survival rate is excellent unless other serious complications or anomalies exist.

REFERENCES 1. Swenson O, Rathauser F. Segmental dilatation of the colon. Am J Surg 1959; 97:734–9. 2. Takehara H, Komi N. Congenital segmental dilatation of the intestine. In: Puri P, editor. Newborn Surgery. 1st edn. Oxford: Butterworth-Heinemann, 1996:399–403. 3. Waag LK, Joppich I. Beitrag zur kongenitalen segmentalen Darmdilatation. Z Kinderchir 1982; 36:34–6. 4. Sehiralti V, Bulut M. Intraperitoneal anomalilerin eslik ettigi bir ileal segmental dilatasyon olgusu. Pediatrik Cer Der 1988; 2:178–80. 5. Kuint J, Avigat I, Husar M et al. Segmental dilatation of the ileum: an uncommon cause of neonatal intestinal obstruction. J Pediatr Surg 1993; 28:1637–9. 6. Esposito C. Segmental dilatation of the ileum in a newborn with Bochdaleck’s hernia. Eur J Pediatr Surg 1994; 4:182–3. 7. Rizalar R, Sarac A, Gork AS et al. Duplication of appendix with segmental dilatation of the colon, myeloschisis and anal atresia. Eur J Pediatr Surg 1996; 6:112–13. 8. Mboyo A, Aubert D, Massicot R et al. Antenatal ﬁnding of intestinal obstruction caused by isolated segmental jejunal dilatation: A case report. J Pediatr Surg 1996; 31:1454–6. 9. Cheng W, Lui VCH, Tam PKH. Enteric nervous system, intestinal cells of Cajal and smooth muscle vacuolization in segmental dilatation of jejunum. J Pediatr Surg 2001; 36:930–5. 10. Hosie S, Lorenz C, Schaible T et al. Segmental dilatation of the jejunum resembling prenatal volvulus. J Pediatr Surg 2001; 36:927–9. 11. Irving IM, Lister J. Segmental dilatation of the ileum. J Pediatr Surg 1977; 12:103–12. 12. Marsden HB, Gilchrist W. Pulmonary heteroplasia in the terminal ileum. J Path Bact 1963; 86:532–4. 13. Aterman K, Abaci F. Heterotopic gastric and esophageal tissue in the colon. Am J Dis Child 1967; 113:552–9. 14. Rovira J, Morales L, Parri FJ et al. Segmental dilatation of the duodenum. J Pediatr Surg 1989; 24:1155–7. 15. Mathe JC, Khairallah S, Phat Vuoung N et al. Dilatation segmentaire du grele a revelation neonatale. Presse Med 1982; 11:265–6. 16. Komi N, Kohyama Y. Congenital segmental dilatation of the jejunum. J Pediatr Surg 1974; 9:409–10. 17. Rossi R, Giacomoni MA. Segmental dilatation of the jejunum. J Pediatr Surg 1973; 8:355–6.

18. Rehbein F. Kinderchirurgische Operation. Stuttgart: Hippokrates, 1976. 19. Aboulola M, Boukheloua B, Asselah F. Dilatations segmentaires ileales associees a une omphalocele et a un mesentere commun. Chir Pediatr 1979; 20:197–202. 20. Bell MJ, Ternberg JL, Bower RJ. Ileal dysgenesis in infants and children. J Pediatr Surg 1982; 17:395–9. 21. El Shaﬁe M. Congenital short intestine and cystic dilatation of the colon associated with ectopic anus. J Pediatr Surg 1971; 6:70–6. 22. Graft AW, Watson AJ, Scott JES ‘Giant Meckel’s diverticulum’ causing intestinal obstruction in the newborn. J Pediatr Surg 1976; 11:1037–8. 23. Babut J M, Bracq H, Riciur C et al. Les dilatation segmentaires congeniyales de l’intestin: presentation de 3 nouveaux cas et revue de la literature. Ann Chir Infant 1977; 18:11–19. 24. Miyoshi S, Sakaguchi H, Yamashita S et al. A case report of segmental dilatation of the jejunum in a newborn associated with annular pancreas and heterotopic hepatic tissue. J Jpn Soc Pediatr Surg 1979; 15:127–31. 25. Brown A, Carty H. Segmental dilatation of the ileum. Br J Radiol 1984; 57:371–3. 26. Chiba T, Kokubo T. Congenital segmental dilatation of the colon. Arch Jap Chir 1976; 45:45–7. 27. Helikson MA, Shapiro MB, Garﬁnkel DJ et al. Congenital segmental dilatation of the colon. J Pediatr Surg 1982; 17:201–2. 28. Doody D, Nguyen LT. Congenital atresia of the colon combined with segmental dilatation of the ileum: a case report. J Pediatr Surg 1987; 22:804–5. 29. Ziv Y, Lombrozo R, Mor C et al. Congenital dilatation of small intestine with oesophageal atresia and duodenal atresia in a premature infant. Z Kinderchir 1987; 42:317–18. 30. Senocak ME, Bulut M, Caglar M et al. Congenital segmental dilatation of the colon with heterotopic esophageal mucosa. Turk J Pediatr 1987; 29:51–60. 31. Ngai RLC, Chan AKH, Lee JPK et al. Segmental colonic dilatation in a neonate. J Pediatr Surg 1992; 27:506–8. 32. Gross VF, Wendth AJ, Phelan JJ et al. Giant Meckel’s diverticulum in a premature infant. Am J Roentgenol 1970; 108:591–7. 33. Wallon P, Mitrofanoff P, Borde J. Une forme rare d’occlusion neonatale par dilatation segmentaire du grele. Ann Chir Infant 1975; 16:181–8. 34. Itoh S, Nakata T, Uchida T et al. A perforated case of segmental dilatation of the intestine. J Jpn Soc Pediatr Surg 1978; 14:485–6. 35. Ratcliffe J, Tait J, Lisle D et al. Segmental dilatation of the small bowel: report of three cases and literature review. Radiology 1989; 171:827–30. 36. Heller K, Waag LK, Beyersdorf F. Intestinal duplication – Segmental dilatation of intestine: a common genetic complex. Pediatr Surg Int 1989; 4:249–53. 37. Takehara H, Komi N, Hino M. Congenital dilatation of the colon: report of a case and review of the literature. Pediatr Surg Int 1988; 4:66–8.

58 Intussusception SPENCER W. BEASLEY

PRENATAL INTUSSUSCEPTION Prenatal intussusception is a recognized cause of intestinal atresia.1 The presentation is that of a bowel obstruction at birth. Preoperative evaluation usually fails to yield a deﬁnite diagnosis1 and the diagnosis is made at laparotomy.2 Prenatal intussusception may be associated with fetal ascites.2 Some cases are due to a Meckel’s diverticulum.3

In the older infant, vomiting, lethargy, pallor and colic are the most common symptoms.7 In longstanding cases, the infant may appear shocked and septicemic, with abdominal distension. Where abdominal distension and tenderness are not pronounced, an abdominal mass may be palpable and there may be evidence of blood mixed with the stool on rectal examination.

NON-OPERATIVE TREATMENT

NEONATAL INTUSSUSCEPTION

Indication for enema

Although intussusception is common in the ﬁrst year of life, it is rare in neonates and premature infants,2 accounting for fewer than 1% of cases. When it does occur, the possibility of a pathological lesion at the lead point must be entertained, and of these, a duplication cyst, inverted Meckel’s diverticulum or an ileal polyp are the most likely.4 It is now well recognized that in the neonate and infant under 3 months of age the likelihood of a pathological lesion at the lead point is signiﬁcantly greater than in intussusception later in the ﬁrst year of life.1,5

When a diagnosis of intussusception is suspected and there is no clinical evidence of necrotic bowel (i.e. peritonitis or septicemia), reduction of the intussusception by gas enema should be attempted.8 As an alternative, in institutions where gas enemas are not available, a barium enema may be employed. Duration of symptoms, radiological evidence of small bowel obstruction9 and the position of the apex10 per se are not contraindications to attempted enema reduction. Unfortunately, in the neonate contrast enema is diagnostic in relatively few cases, mainly because the intussusception may not extend through the ileocecal valve, which may remain competent. Abdominal ultrasonography may assist in the early diagnosis, when performed.

CLINICAL ASSESSMENT When intussusception occurs in premature infants its presentation may mimic neonatal necrotizing enterocolitis: the infant develops bile-stained vomiting, increased nasogastric aspirates, blood in the stools, and intestinal dilatation but without intramural gas (pneumotosis intestinalis).6 It is not surprising that diagnostic confusion with necrotizing enterocolitis can lead to delay in appropriate treatment. Similarly, in the neonate, the combination of bowel obstruction and rectal bleeding may lead to confusion with malrotation and volvulus; given the rarity of the condition in this age group, the diagnosis is often made only at operation.

Preparation for gas enema There is increasing evidence that the gas enema is more effective and safer than the barium enema for reduction of intussusception that extends beyond the ileocecal valve11–13 (Fig. 58.1). A gas enema should be performed in a pediatric surgical center by an experienced pediatric radiologist in the presence of a pediatric surgeon.11 An i.v. line should be inserted and rehydration commenced before undertaking the enema. The child should be placed on a warming blanket during the procedure to prevent heat loss.

558 Intussusception Height adjuster Air vent Mercury manometer

300

Oxygen inlet Oxygen flow meter 4

80

120 100 80

To patient Silastic tubing

20

Hg

3 2

Reservoir

1

Manifold

Figure 58.1 Schematic representation of the apparatus used to achieve gas (oxygen) reduction of intussusception

Technique of enema reduction

Cessation of gas enema

Gas (usually oxygen from a wall supply) is pressure controlled and run into the colon through a Foley catheter, which is inserted through the anal canal, as with a conventional barium enema reduction.11 The infant lies prone with buttocks tapped and squeezed tightly together by the radiologist to avoid air leakage. The upper limit of pressure can be controlled by a manometer and the entire procedure is performed under continuous ﬂuoroscopic control (Fig. 58.2).

Flooding of the small bowel with gas signiﬁes a complete reduction of the intussusception (Fig. 58.3). If free intraperitoneal gas is observed, the enema should be ceased immediately. If the initial attempt at reduction is unsuccessful and the infant remains in good condition, repetition of the gas enema after 2–3 hours is likely to be successful in about 50% of cases.14 It is now our standard practice to repeat the enema after several hours if there has been partial reduction of the intussusception (as far as the cecum) in an infant whose clinical condition remains satisfactory.14 Gas reduction tends to occur more rapidly than barium reduction. Both techniques have a

Figure 58.2 Gas reduction of intussusception: the pressurecontrolled oxygen runs through the anus and outlines the intussusceptum in the transverse colon

Figure 58.3 Sudden ﬂooding of the small bowel signiﬁes complete reduction of the intussusception

Surgical technique 559

similar recurrence rate15 but the perforation rate may be more common after a gas enema than a barium enema.16,17

INDICATION FOR SURGERY Clinical evidence of peritonitis or septicemia is an absolute indication for surgery, as it signiﬁes that dead bowel is likely and resection is required (Box 58.1). Other indications for surgery include failure of gas reduction or early recurrence of intussusception after a successful enema (suggesting the presence of a pathological lesion at the lead point). Occasionally, a pathological lesion at the lead point may be seen during attempted enema reduction, but usually when a pathological lesion is present the intussusception cannot be reduced by enema. In the neonate who presents with an established bowel obstruction, the diagnosis is made when the intussusception is discovered at the time of laparotomy. Surgical management involves resection of non-viable bowel, and primary anastomosis. Until recent years the mortality rate was over 20%6 largely because of delay in diagnosis. Recurrence is rare. Box 58.1 Indications for surgery • Clinical evidence for dead bowel, i.e. peritonitis, septicemia • Failure of enema reduction • Early or multiple recurrences (relative indication) • Evidence of pathological lesion at the lead point

Preparation for surgery Prior to the general anesthetic, a nasogastric tube is inserted to empty the stomach. Prophylactic antibiotics are given intravenously at induction. The infant is paralyzed and intubated. A warming blanket must be used to prevent excessive heat loss, and temperature is monitored with a rectal or mid-esophageal probe. An oximeter monitors oxygen saturation.

Figure 58.4 Right supra-umbilical transverse incision

Manual reduction The intussusception is carefully reduced by manipulation of the intussusceptum within the intussuscipiens in a proximal direction (Fig. 58.5). This is performed by gently squeezing the bowel between the ﬁngers and in the cup of the hand. Time must be allowed to enable edema to dissipate. The intussusception is most difﬁcult to reduce in the region of the ileocecal valve. Care must be taken to avoid splitting the serosa.

Check for pathological lead point After full reduction of the intussusception, a dimple at the lead point is a common sight. Look for evidence of a duplication cyst, inverted Meckel’s diverticulum or another lesion at the lead point, because if these are present they should be resected.

Technique of resection The indicators for resection are shown in Box 58.2. The aim should be to remove as little viable bowel as possible

SURGICAL TECHNIQUE Approach A right, supra-umbilical transverse incision is made, dividing the ventral abdominal wall muscles in the line of the incision (Fig. 58.4). This gives good exposure, irrespective of the length of intussusception. Free peritoneal ﬂuid is aspirated and the bowel is delivered into the wound.

Figure 58.5 Gentle pressure on the distal limit of the intussusception coerces the intussusceptum proximally. Pulling on the bowel as it enters the intussuscipiens is not advised, as it tends to be more traumatic and less efﬁcient at reducing the intussusception

560 Intussusception Box 58.2 Indications for resection • Inability to reduce intussusception manually • Necrosis or gangrene of the bowel • A pathological lesion at the lead point

(Fig. 58.6). The small bowel mesentery is ligated and divided, and the bowel at the edges of resection is divided with scissors. A one-layer 4-0 Vicryl interrupted suture end-to-end anastomosis is performed. The defect in the mesentery is closed to prevent internal herniation.

Closure The peritoneal cavity is irrigated with warm saline. The peritoneum and posterior rectus sheath and anterior rectus sheath are closed with continuous 3-0 sutures. The skin is closed with 5-0 subcuticular Monocryl. No drainage is required.

Preoperative instructions A nasogastric tube is usually not necessary unless there has been severe obstruction or a prolonged ileus is anticipated. Oral ﬂuids are resumed when the infant appears to be hungry and the abdomen is becoming soft to palpation.

Figure 58.6 Line of resection of an irreducible intussusception

REFERENCES 1. Wang Nl, Chang PY, Sheu JC, Chen CC, Lee HC, Hung HY, Hsu CH. Prenatal and neonatal intussusception. Pediatr Surg Int 1998; 13(4):232–6.

2. Reguerre Y, de Dreuzy O, Boithias C, Lacaze-Masmonteil T, Andre P, Dehan M. An unknown etiology of fetal ascites: acute intestinal intussusception. Arch de Pediatr 1997; 4(12):1197–9. 3. Guandogdu HZ, Senacak ME. Intrauterine intussusception due to Meckel’s Diverticulum as a cause of ileal atresia: analysis of 2 cases. Eur J Pediatr Surg 1996; 6(1):52–4. 4. Ong NT, Beasley SW. The lead point in intussusception. J Pediatr Surg 1990; 25:640–3. 5. Blakelock RT, Beasley SW. The clinical implications of non-idiopathic intussusception. Pediatr Surg Int 1998; 14(3):163–7. 6. Mooney DP, Steinthorsson G, Shorter NA. Perinatal intussusception in premature infants. J Pediatr Surg 1996; 31(5):695–7. 7. Beasley SW, Auldist AW, Stokes KB. The diagnostically difﬁcult intussusception: its characteristics and consequences. Pediatr Surg Int 1988; 3:135–8. 8. Beasley SW. Can the outcome of intussusception be improved? Aust Paediatr J 1988; 24:99–100. 9. Beasley SW, de Campo JF. Radiological evidence of small bowel obstruction in intussusception: is it a contraindication to attempted barium reduction? Pediatr Surg Int 1987; 2:291–3. 10. Ong NT, Beasley SW. Progression of intussusception. J Pediatr Surg 1990; 25:644–6. 11. Phelan E, de Campo JF, Maleckey G. Comparison of oxygen and barium reduction of ileocolic intussusception. Am J Radiol 1988; 150:1349–52. 12. Beasley SW, Glover J. Intussusception: prediction of outcome of gas enema. J Pediatr Surg 1992; 27:474–5. 13. Guo JZ, Ma XY, Zhou QH. Results of air pressure enema reduction of intussusception: 6396 cases in 13 years. J Pediatr Surg 1986; 21:1201–3. 14. Saxton V, Katz M, Phelan E, Beasley SW. Intussusception: a repeat delayed gas enema increases the non-operative reduction rate. J Pediatr Surg 1994; 29:1–3. 15. Renwick AA, Beasley SW, Phelan E. Intussusception: recurrence following gas (oxygen) enema reduction. Pediatr Surg Int 1992; 7:362–3. 16. Maoate K, Beasley SW. Perforation during gas reduction of intussusception. Pediatr Surg Int 1998; 14:168–70. 17. Daneman A, Alton DJ, Ein S et al. Perforation during attempted intussusception reduction in children – a comparison of perforation with barium and air. Pediatr Radiol 1995; 25:81–8.

59 Inguinal hernia JUAN A. TOVAR

Inguinal hernia is one of the most common surgical conditions in infancy, with a peak incidence during the ﬁrst 3 months of life. The diagnosis of inguinal hernia is made with increasing frequency in newborns; this period carries a particularly high risk of incarceration. On the other hand, the incidence of hernia is much higher in premature infants who survive in growing numbers after sophisticated intensive care management. As a consequence more and more indications for early surgical repair are proposed in a population in which there are additional surgical and anesthetic risks. These issues are discussed in this chapter.

hernia in preterm infants is considerably higher and ranges from 9–11%.4 The incidence approaches 60% as birth weight decreases from 500 g to 750 g.2 Inguinal hernia is more common in males than in females. Most series report a male preponderance over females ranging from 5:1 to 10:1.5 Of all inguinal hernias, 60% occur on the right side, 25–30% on the left, and 10–15% are bilateral.2,6 Bilateral hernias are more common in premature infants and are reported to occur in 44–55% of patients.4,7,8 The risk of a metachronous contralateral hernia is 7%.9 There is a higher familial incidence and inguinal hernia has been observed with increasing frequence in twins and siblings of patients.10 There is no geographic or racial predominance reported in the literature.

ETIOLOGY

ASSOCIATED CONDITIONS

Direct hernia is exceedingly rare at this age1 and practically all congenital indirect inguinal herniae develop because the processus vaginalis remains patent after birth. This processus is an outpouching of the peritoneum through the inguinal canal that is ﬁrst seen during the third month of intrauterine life. It accompanies the gubernaculum and the testis during their descent through the inguinal canal and reaches the scrotum by the seventh month of gestation. In the female, the processus extends along the round ligament. Obliteration of the processus vaginalis commences soon after the descent of the testis is completed and continues after birth. Most infants have a patent processus vaginalis several months after birth. Patency has been reported to be 80–94% in the newborn period, 57% in the 4–12-month age group and 20% in adulthood2;this patency is not equivalent to an inguinal hernia and most times it has no clinical relevance.

There is an increased incidence of inguinal hernia in patients with the following conditions:

INTRODUCTION

EPIDEMIOLOGY The incidence of congenital indirect inguinal hernia in full-term neonates is 3.5–5%.3 The incidence of inguinal

• • • • •

Undescended testis Ventriculoperitoneal shunts11,12 Peritoneal dialysis13,14 Cystic ﬁbrosis Increased abdominal pressure15 secondary to meconium ileus, necrotizing enterocolitis, chylous ascites, tight closure of gastroschisis, omphalocele • Bladder exstrophy16,17 • Connective tissue disorders such as cutis laxa,18 Ehlers–Danlos and Marfan syndromes or Hurler–Hunter mucopolysaccharidoses.19

CLINICAL FEATURES Inguino-scrotal hernia can be diagnosed prenatally by ultrasonographic screening.20 In the newborn, the presenting feature is a bulge in the groin which increases in size with crying and which is usually noticed by the mother. This bulge may disappear spontaneously when the patient

562 Inguinal hernia

is quiet and relaxed but sometimes it remains visible and palpable for hours causing crying, obvious discomfort and sometimes vomiting. When the lump in the groin is reduced, it is usually possible to feel thickening of the structures of the cord due to a hernial sac. A reliable clinical history along with palpation of a thickened cord is highly suggestive of inguinal hernia. In girls, the lump intermittently felt in the groin is usually less obvious and often a tender, nonreducible, ovoid-shaped mass corresponding to the ovary slided within the sac, can be palpated. Some premature infants with previous apneic episodes stopped having them after inguinal hernia repair. The obvious interpretation is that there can be some association between both clinical conditions.21 Although this eventuality is exceedingly rare, acute inﬂammation of the appendix within the hernial sac has been reported in premature and full-term newborns.22–25

INCARCERATED INGUINAL HERNIA Incarceration occurs when the contents of the sac is blocked at its neck and cannot be easily reduced into the abdominal cavity. Strangulation occurs when there is vascular compromise of the contents of the sac because of the persistent constriction at its neck. The contents of the hernial sac may consist of small bowel, appendix, omentum or ovary and fallopian tube. If there is delay in treatment, incarceration rapidly progresses to strangulation and can lead to intestinal necrosis and even fecal ﬁstula.26 The incidence of incarceration in neonates and young infants is reported to vary between 24% and 40%.3,27,28 The incarceration rate is much higher in premature infants compared with full-term infants. Testicular infarction has been reported in up to 30% of infants younger than 3 months of age with incarcerated inguinal hernia29 and testicular atrophy following emergency operation for incarceration ranges between 10% and 15%. However, testicular volume in a group of children who had incarcerated inguinal hernia reduced by taxis during infancy and subsequently had elective herniotomy was not signiﬁcantly different from agematched controls, suggesting that this risk has been overemphasized.27 Ovarian infarction is also possible after incarceration in females4 and vaginal bleeding has been reported in an infant after uterine incarceration in the hernial sac.30 The risks of gonadal damage when the slided ovary cannot be reduced justify the fact that most surgeons advise prompt operation in these cases.31

DIAGNOSIS A newborn with incarcerated inguinal hernia usually presents with irritability, vomiting, a moderately distended abdomen and a tender groin lump (Fig. 59.1). Occasion-

Figure 59.1 Large incarcerated right inguinal hernia in a 1-day-old infant. The hernia was reduced by taxis and herniotomy performed 2 days later

ally, the infant may pass blood per rectum. Local examination reveals a tense, tender lump in the groin, the upper margin of which is not well deﬁned. The homolateral testis may be normal or swollen and hard due to vascular compromise. Rectal examination usually is not necessary but, if done, the contents of the hernia can be palpated at the internal ring. The diagnosis of incarcerated inguinal hernia is usually made on clinical grounds. Abdominal radiographs may occasionally show bowel gas within the lump in the groin and conﬁrm the diagnosis (Fig. 59.2). If intestinal obstruction is present, plain abdominal ﬁlms will show dilated loops of bowel with ﬂuid levels. Ultrasonography can help diagnosis in some cases.32

DIFFERENTIAL DIAGNOSIS Clinical diagnosis of incarcerated inguinal hernia is usually easy but it may be difﬁcult to differentiate from the following conditions.

Hydrocele It is possible to get above the swelling, which is nontender. Transillumination is not a reliable sign in infants, as bowel can be transilluminant because of its thin wall. Hydrocele of the cord or cyst of canal of Nuck is difﬁcult to differentiate from incarcerated hernia. There is no previous history of reducible groin lump in these

Operation 563

of premature infants with inguinal hernias improve after repair.35 Nowadays, most inguinal hernia operations are done as day-case procedures,31 although premature infants and children with cardiac, respiratory or other conditions have an increased risk of anesthetic complications. However, most authors consider it reasonably safe to operate on these patients on a day-case basis,36 even when they have bronchopulmonary dysplasia.37

ANESTHESIA General anesthesia with endotracheal intubation is preferred in small infants. Premature infants undergoing surgery have an increased risk of life-threatening postoperative apnea.36 The use of spinal anesthesia in LBW infants undergoing inguinal hernia repair is associated with a lower incidence of postoperative apnea38,39 and caffeine can be used for preventing this complication.40 Figure 59.2 Supine abdominal ﬁlm in a 10-day-old infant who presented with an irreducible lump in the right groin shows distended bowel loops extending into the right inguinal hernia

patients. Since the lower half of the abdomen is accessible to digital palpation through the rectum, rectal examination may be useful in excluding incarcerated hernia.

OPERATION Inguinal herniotomy is the procedure employed in the treatment of congenital persistence of processus vaginalis. The operation consists of simple ligation of the hernial sac without opening the external ring.

Position Inguinal lymphadenitis The examination of the area of drainage will at most times reveal the source of infection. The cord and testes are found to be normal.

Torsion of the testes In a scrotal testicular torsion, it is possible to get above the swelling. The testis is tender and slightly higher than on the other side, while the torsion of the testes, which is situated in the superﬁcial inguinal pouch, will be associated with an empty scrotum on the same side.

MANAGEMENT OF INGUINAL HERNIA The treatment of inguinal hernia is surgery and, in our opinion, there is no place for the use of trusses or other so-called conservative procedures, even in low birth weight (LBW) infants.33 The ideal time for surgery is as soon as possible after the diagnosis has been made not only because of the high risk of incarceration34 but also because it has been shown that comfort and weight gain

The infant is placed in the supine position on a heating blanket.

Incision A 1.5 cm transverse inguinal skin crease incision is placed above and lateral to the pubic tubercle (Fig. 59.3a).

Exposure of external ring Hemostats are placed on subcutaneous tissue, which is cut or spread until the cord is seen to emerge from the external ring (Fig. 59.3b,c).

Separation of sac The external spermatic fascia and cremaster are separated along the length of the cord by blunt dissection. The hernial sac is seen and gently separated from the vas and vessels (Fig. 59.3e). A hemostat is placed on the fundus of the sac.

564 Inguinal hernia

(a)

(b)

(c)

(d)

(f)

(e)

(g)

(h)

Figure 59.3 (a) Skin incision. (b,c) Exposure of external inguinal ring. (d) Isolation of the spermatic cord. (e) Separation of the hernial sac. (f) Transﬁxation of the hernial sac. (g) Closure of subcutaneous tissue. (h) Subcuticular closure of skin

Herniotomy The sac is twisted so as to reduce its content into the abdominal cavity. The spoon can be used to keep vas and vessels away from the neck of the sac. The sac is transﬁxed with a 4-0 stitch at the level of internal ring, which is marked by an extraperitoneal pad of fat (Fig. 59.3b). The part of the sac beyond the stitch is usually excised but there are no obvious advantages of removing the distal part of the sac after its division and closure, particularly if there is complete persistence of the perito-

neovaginal duct, and therefore the operation should remain as simple as possible.41 In girls the operation is even more straightforward since there is no risk for the vas or the vessels and the external oriﬁce can be closed after excising the sac.

Closure Subcutaneous tissues are approximated using two or three 4-0 absorbable interrupted stitches (Fig. 59.3g) and the skin is closed with a 5-0 absorbable continuous

Management of incarcerated hernia 565

subcuticular suture (Fig. 59.3h). A recent alternative is the use of cyano-acrylate adhesives for approximating the skin edges. A small dressing can be applied over the wound if necessary. At the end of the operation, the testis, always tractioned upwards during operative maneuvers, must be routinely pulled back into the scrotum to avoid iatrogenic ascent.42

Alternative approaches In some difﬁcult cases, and particularly after incarceration, simple closure of the hernial oriﬁce through the sac has been advocated as a simpler procedure.43 In the very rare instances of direct inguinal hernia diagnosed in the newborn, reconstruction of the posterior wall of the inguinal canal should be performed.44

Contralateral exploration Contralateral exploration is often performed in premature babies because of the high incidence of bilateral hernia in them, which ranges from 11.5%45 to 28%46 according to different authors. Otherwise contralateral exploration is not necessary as only around 10% of these children will subsequently proceed to develop a clinically apparent inguinal hernia on the other side.47–49

POSTOPERATIVE MANAGEMENT Adequate postoperative analgesia is achieved by regional anesthesia, ilio-inguinal and ilio-hypogastric nerve block, which is administered either before or at the end of operation. Feeding is resumed as soon as the infant is awake. Most patients can be discharged home the same day. Postoperative apnea is a well-known risk of inguinal hernia operation in premature infants.50 Although most episodes of postoperative apnea in these babies occur in the ﬁrst 4 hours following the end of the procedure,51 they are often admitted for 24–48 hours for observation in order to prevent this complication.52 Postoperative apnea is inversely correlated with gestational and postconceptual ages53 but absolute weight at operation and previous respiratory dysfunction are apparently the best independent variables to be correlated with such risks.54

MANAGEMENT OF INCARCERATED HERNIA In a stable patient, there is no doubt that the preferred treatment for incarcerated hernia is reduction. This policy of non-operative reduction is based on the following facts: the likelihood of reducing strangulated bowel in infants is extremely rare and the complication rates are higher with emergency operations for irreducible hernia.55

The infant is placed in the Trendelenburg position, which helps to relieve the edema and allows mild traction of the hernial contents. Adequate sedation is given to the infant so as to relax the abdominal muscles. If the hernia is not reduced within 1 hour with these measures, an attempt is made to reduce it with gentle taxis, where constant gentle pressure is applied on the fundus of the sac in the direction of the cord. The vast majority of incarcerated hernias reduce with these nonoperative techniques. After the hernia is reduced, the infant is kept in the hospital and observed. Elective operation is carried out after 24–48 hours, when edema and swelling have subsided.

Operative management Failure to reduce the hernia and strangulation are indications for emergency operation. In girls, when the ovary is nonreducible, at least half of the surgeons in a recent US survey advise emergency operation.31

Preoperative support Infants need to be stabilized prior to surgery. Nasogastric suction, and correction of ﬂuid and electrolyte imbalance are undertaken, and antibiotics are given but this period should be kept to a minimum.

Operation The patient is anesthetized. If the hernia is spontaneously reduced, the sac is opened and the intestine inspected. Herniotomy is performed if there is no evidence of intestinal ischemia. The bowel should be examined through the same incision or through right lower quadrant laparotomy on suspicion of reduction of nonviable bowel, as indicated by blood-stained ﬂuid in the sac or if blue bowel is seen in the abdomen through the opened sac. If the bowel does not reduce spontaneously when the patient is anesthetized, no attempts are made to reduce the hernia. The sac is opened and the contents are examined. If the bowel is viable, it is reduced. In case of difﬁculty in reducing the contents, the internal ring is either dilated or split superiorly. On the other hand, if viability of the bowel is questionable, it is delivered out and warm saline soaks are applied. The intestine is examined after 5–10 minutes. If its color returns to normal with adequate perfusion, peristalsis is visible and mesenteric arterial pulsations are seen, the intestine is returned to the abdomen and herniotomy is completed. If the bowel is nonviable, resection and anastomosis are performed, either through the same incision or through laparotomy. Testes are put in the scrotum irrespective of

566 Inguinal hernia

whether they are normal or ischemic. Only frankly necrotic gonads may be removed.

• Mortality. In a present-day situation, the mortality rate of inguinal hernia operation should be zero.

Postoperative care REFERENCES If resection and anastomosis are carried out, nasogastric aspiration and i.v. ﬂuids are continued in the infant until peristalsis returns and feeds are established. Antibiotics are continued for 5 days.

COMPLICATIONS The overall complication rates after elective hernia repair are low at about 2%,56 while these are increased to 8–33% for the incarcerated hernias requiring emergency operations. 4,55 Complications of inguinal hernia repair include: • Hematoma – can be avoided with meticulous attention to hemostasis. It is rarely necessary to evacuate wound, cord or scrotal hematoma. • Wound infection – low risk and should not exceed 1%. 3,57,58 • Gonadal complications – occur due to compression of the vessels by incarcerated viscera. Though large numbers of testes look nonviable in patients with incarcerated hernia, the actual incidence of testicular atrophy is low27 and therefore, unless the testis is frankly necrotic, it should not be removed. • Intestinal resection. This is necessary in about 3–7% of patients in whom the hernia is not reduced and it may cause some additional morbidity corresponding to resection itself and contamination of the ﬁeld. 4 • Iatrogenic ascent of the testes. This event is relatively rare since slightly more than 1% of patients operated upon for inguinal hernia during infancy required subsequently orchidopexy.48 This complication is probably due to entrapment of the testis in the scar tissue or failure to pull it down into the scrotum at the end of the operation and to maintain it there.42 • Recurrence. The acceptable recurrence rate for inguinal hernia repair is less than 1%56 but when operation is performed in the neonatal period this complication can occur in up to 8%.58 The factors which predispose to recurrence are ventriculoperitoneal shunts, sliding hernia, incarceration and connective tissue disorders.59 Recurrence may be indirect or direct. Indirect recurrence is due to either failure to ligate the sac at high level, tearing of a friable sac, a slipped ligature at the neck of the sac, missed sac, or wound infection. Direct hernia may be due to inherent muscle weakness or injury to the posterior wall of the inguinal canal.

1. Wright JE. Direct inguinal hernia in infancy and childhood. Pediat Surg Int 1994; 9:161–3. 2. Nakayama DK, Rowe MI. Inguinal hernia and the acute scrotum in infants and children. Pediatr Rev 1989; 11:87–93. 3. Grosfeld JL. Current concepts in inguinal hernia in infants and children. World J Surg 1989; 13:506–15. 4. Rescorla FJ, Grosfeld JL. Inguinal hernia repair in the perinatal period and early infancy: clinical considerations. J Pediatr Surg 1984; 19:832–7. 5. Given JP, Rubin SZ. Occurence of contralateral inguinal hernia following unilateral repair in a pediatric hospital. J Pediatr Surg 1989; 24:963–5. 6. Czeizel A. Epidemiologic characteristics of congenital inguinal hernia. Helv Paediatr Acta 1980; 35:57–67. 7. Harper RG, Garcia A, Sia C. Inguinal hernia: a common problem of premature infants weighing 1,000 grams or less at birth. Pediatrics 1975; 56:112–15. 8. Boocock GR, Todd PJ. Inguinal hernias are common in preterm infants. Arch Dis Child 1985; 60:669–70. 9. Miltenburg DM, Nuchtern JG, Jaksic T et al. Meta-analysis of the risk of metachronous hernia in infants and children. Am J Surg 1997; 174:741–4. 10. Czeizel A, Gardonyi J. A family study of congenital inguinal hernia. Am J Med Genet 1979; 4:247–54. 11. Grosfeld JL, Cooney DR. Inguinal hernia after ventriculoperitoneal shunt for hydrocephalus. J Pediatr Surg 1974; 9:311–15. 12. Moazam F, Glenn JD, Kaplan BJ et al. Inguinal hernias after ventriculoperitoneal shunt procedures in pediatric patients. Surg Gynecol Obstet 1984; 159:570–2. 13. Modi KB, Grant AC, Garret A et al. Indirect inguinal hernia in CAPD patients with polycystic kidney disease. Adv Perit Dial 1989; 5:84–6. 14. Matthews DE, West KW, Rescorla FJ et al. Peritoneal dialysis in the ﬁrst 60 days of life. J Pediatr Surg 1990; 25:110–15. 15. Powell TG, Hallows JA, Cooke RW et al. Why do so many small infants develop an inguinal hernia? Arch Dis Child 1986; 61:991–5. 16. Husmann DA, McLorie GA, Churchill BM et al. Inguinal pathology and its association with classical bladder exstrophy. J Pediatr Surg 1990; 25:332–4. 17. Connolly JA, Peppas DS, Jeffs RD et al. Prevalence and repair of inguinal hernias in children with bladder exstrophy. J Urol 1995; 154:1900–1. 18. Mehregan AH, Lee SC, Nabai H. Cutis laxa (generalized elastolysis). A report of four cases with autopsy ﬁndings. J Cutan Pathol 1978; 5:116–26.

References 567 19. Coran AG, Eraklis AJ. Inguinal hernia in the Hurler–Hunter syndrome. Surgery 1967; 61:302–4. 20. Shipp TD, Benacerraf BR. Scrotal inguinal hernia in a fetus: sonographic diagnosis. AJR Am J Roentgenol 1995; 165:1494–5. 21. Yeaton HL, Mellish RW. Resolution of prolonged neonatal apnea with hernia repair. J Pediatr Surg 1983; 18:158–9. 22. Srouji MN, Buck BE. Neonatal appendicitis: ischemic infarction in incarcerated inguinal hernia. J Pediatr Surg 1978; 13:177–9. 23. Bar-Maor JA, Zeltzer M. (1978) Acute appendicitis located in a scrotal hernia of a premature infant. J Pediatr Surg 13:181–2. 24. Dessanti A, Porcu A, Scanu A et al. Neonatal acute appendicitis in an inguinal hernia. Pediat Surg Int 1995; 10:561–2. 25. Iuchtman M, Kirshon M, Feldman M. Neonatal pyoscrotum and perforated appendicitis. J Perinatol 1999; 19:536–7. 26. Rattan KN, Garg P. Neonatal scrotal faecal ﬁstula. Pediatr Surg Int 1998; 13:440–1. 27. Puri P, Guiney EJ, O’Donnell B. Inguinal hernia in infants: the fate of the testis following incarceration. J Pediatr Surg 1984; 19:44–6. 28. Misra D, Hewitt G, Potts SR et al. Inguinal herniotomy in young infants, with emphasis on premature neonates. J Pediatr Surg 1994; 29:1496–8. 29. Schmitt M, Peiffert B, de Miscault G et al. Complications des hernies inguinales chez l’enfant. Chir Pediatr 1987; 28:193–6. 30. Zitsman JL, Cirincione E, Margossian H. Vaginal bleeding in an infant secondary to sliding inguinal hernia. Obstet Gynecol 1997; 89:840–2. 31. Wiener ES, Touloukian RJ, Rodgers BM et al. Hernia survey of the Section on Surgery of the American Academy of Pediatrics. J Pediatr Surg 1996; 31:1166–9. 32. Munden M, McEniff N, Mulvihill D. Sonographic investigation of female infants with inguinal masses. Clin Radiol 1995; 50:696–8. 33. Ruderman JW, Schick JB, Sherman M et al. Use of a truss to maintain inguinal hernia reduction in a very low birth weight infant. J Perinatol 1995; 15:143–5. 34. Uemura S, Woodward AA, Amerena R et al. Early repair of inguinal hernia in premature babies. Pediatr Surg Int 1999; 15:36–9. 35. Desch LW, DeJonge MH. Weight gain: a possible factor in deciding timing for inguinal hernia repair in premature infants. Clin Pediatr (Phila) 1996; 35:251–5. 36. Melone JH, Schwartz MZ, Tyson KR et al. Outpatient inguinal herniorrhaphy in premature infants: is it safe? J Pediatr Surg 1992; 27:203–7. 37. Emberton M, Patel L, Zideman DA et al. Early repair of inguinal hernia in preterm infants with oxygendependent bronchopulmonary dysplasia. Acta Paediatr 1996; 85:96–9. 38. Webster AC, McKishnie JD, Kenyon CF et al. Spinal anaesthesia for inguinal hernia repair in high-risk neonates. Can J Anaesth 1991; 38:281–6.

39. Somri M, Gaitini L, Vaida S et al. Postoperative outcome in high-risk infants undergoing herniorrhaphy: comparison between spinal and general anaesthesia. Anaesthesia 1998; 53:762–6. 40. Welborn LG, Hannallah RS, Fink R et al. High-dose caffeine suppresses postoperative apnea in former preterm infants. Anesthesiology 1989; 71:347–9. 41. Gahukamble DB, Khamage AS. Prospective randomized controlled study of excision versus distal splitting of hernial sac and processus vaginalis in the repair of inguinal hernias and communicating hydroceles. J Pediatr Surg 1995; 30:624–5. 42. Kaplan GW. Iatrogenic cryptorchidism resulting from hernia repair. Surg Gynecol Obstet 1976; 142:671–2. 43. Applebaum H, Bautista N, Cymerman J. Alternative method for repair of the difﬁcult infant hernia. J Pediatr Surg 2000; 35:331–3. 44. Wright JE, Gill AW. Direct inguinal hernias in the newborn. Aust N Z J Surg 1991; 61:78–81. 45. Schwobel MG, Schramm H, Gitzelmann CA. The infantile inguinal hernia – a bilateral disease? Pediatr Surg Int 1999; 15:115–18. 46. Tackett LD, Breuer CK, Luks FI et al. Incidence of contralateral inguinal hernia: a prospective analysis. J Pediatr Surg 1999; 34:684–7. 47. Salaman R, Foster M. Ingested foreign body presenting as an irreducible inguinal hernia in a baby. J Pediatr Surg 1993; 28:262–3. 48. Surana R, Puri P. Iatrogenic ascent of the testis: an underrecognized complication of inguinal hernia operation in children. Br J Urol 1994; 73:580–1. 49. Kemmotsu H, Oshima Y, Joe K et al. The features of contralateral manifestations after the repair of unilateral inguinal hernia. J Pediatr Surg 1998; 33:1099–102. 50. Warner LO, Teitelbaum DH, Caniano DA et al. Inguinal herniorrhaphy in young infants: perianesthetic complications and associated preanesthetic risk factors. J Clin Anesth 1992; 4:455–61. 51. Allen GS, Cox CS Jr, White N et al. Postoperative respiratory complications in ex-premature infants after inguinal herniorrhaphy. J Pediatr Surg 1998; 33:1095–8. 52. Bell C, Dubose R, Seashore J et al. Infant apnea detection after herniorrhaphy. J Clin Anesth 1995; 7:219–23. 53. Cote CJ, Zaslavsky A, Downes JJ et al. Postoperative apnea in former preterm infants after inguinal herniorrhaphy. A combined analysis. Anesthesiology 1995; 82:809–22. 54. Gollin G, Bell C, Dubose R et al. Predictors of postoperative respiratory complications in premature infants after inguinal herniorrhaphy. J Pediatr Surg 1993; 28:244–7. 55. Rowe MI, Clatworthy HW. Incarcerated and strangulated hernias in children. A statistical study of high-risk factors. Arch Surg 1970; 101:136–9. 56. Rowe MI, Marchildon MB. Inguinal hernia and hydrocele in infants and children. Surg Clin North Am 1981; 61:1137–45.

568 Inguinal hernia 57. Audry G, Johanet S, Achraﬁ H et al. The risk of wound infection after inguinal incision in pediatric outpatient surgery. Eur J Pediatr Surg 1994; 4: 87–9. 58. Phelps S, Agrawal M. Morbidity after neonatal inguinal herniotomy. J Pediatr Surg 1997; 32:445–7.

59. Grosfeld JL, Minnick K, Shedd F et al. Inguinal hernia in children: factors affecting recurrence in 62 cases. J Pediatr Surg 1991; 26:283–7.

60 Short bowel syndrome and surgical techniques for the baby with short intestines MICHAEL E. HÖLLWARTH

INTRODUCTION Short bowel syndrome (SBS) in term neonates was deﬁned by Rickham, in 1967, as an extensive resection of all but a maximum of 75 cm of the small gut.1 This corresponds to 30% of the total jejuno-ileal length in term newborns. SBS in the premature newborn also corresponds to 30% of the calculated intestinal length for the given gestational age.2 In the past, extensive loss of small bowel in newborns and babies used to be a catastrophic event nearly always followed by malnutrition and death. Reviewing the literature in 1965, Kuffer found only nine surviving children with SBS.3 In 1972, Wilmore reviewed 50 babies younger than 2 months with SBS and found survival was possible with 15 cm jejuno-ileum without the ileocecal valve, or with 38 cm jejuno-ileum with ileocecal valve.4 Recently, Dorney and colleagues reported that long-term nutritional support today allows survival in infants with as little as 11 cm of jejuno-ileum with the ileocecal valve (5% of the total), or with 25 cm of jejuno-ileum without the ileocecal valve (10% of the total).5 Intestinal adaptation is the term which characterizes the pathophysiology which follows intensive intestinal resection, and by which more than 80% of babies with SBS do ﬁnally reach a normal life with entirely oral nutrition. Adaptation is characterized by an early increase of blood ﬂow to the intestinal remnants6 and by long-term stimulation of intestinal growth which enormously enlarges the absorptive surface area.7 The latter includes an increase of villus height, crypt depth, intestinal length, thickness and diameter. Additionally, water and solute absorption is enhanced in the colon, colonic bacteria ferment undigested carbohydrates and proteins into short-chain fatty acids, which act as important energy providers and apparently, as additional promoters of adaptation.8,9 The precise mechanisms of adaptation are not clear,

but intraluminal nutrients and endogenous intestinal secretions stimulate growth.10–12 In general, the higher the workload required for digestion and absorption, the more potent is the stimulus for adaptation.13 In response to the nutrients and secretions a large number of trophic polypeptides and other mediators are secreted. Over the years, some of them have attracted attention regarding their possible clinical value in promoting adaptation in SBS patients. First, Gastrin was demonstrated to exhibit trophic effects on the small bowel.14 Later, enteroglucagon has been shown to stimulate the adaptive response on the intestinal tract in animal experiments and humans.15 Since monoclonal antibodies failed to block this trophic effect, recently precursors of enteroglucagon such as glucagon-like peptide 2 are considered to be responsible for the intestinal effects.16,17 Lately, human growth hormone (GH) in combination with epidermal growth factor, or with insulin-like growth factor-I (IGF-I) have been shown to regulate small intestinal growth and adaptation.18–22 IGF-I receptors have been identiﬁed in all segments of the gastrointestinal tract, and IGF-I stimulates DNA and RNA synthesis and cellular amino acid uptake.23 The endogenous GH-IGF-I system is an important regulator of small intestinal growth and adaptation.21 Among the amino acids, glutamine (GL) plays an important role in the maintenance of intestinal structure and function by providing the energy required by cells with a rapid turnover, such as macrophages and enterocytes. Patients after major trauma or in chronic catabolic states beneﬁt from GL supplementation.24 In addition, Ziegler et al. have shown that human growth hormone increases glutamine uptake after intestinal resection, supporting the evidence that glutamine exerts trophic effects in the small intestine and colon of patients with SBS.19,25 More research however is needed, since studies by Vanderhoof et al. could not conﬁrm a role for GL or GH as trophic agents for the intestinal tract.26 Prostaglandin (Pg) E2 and polyamines have also been shown to stimulate cell

570 Short bowel syndrome and surgical techniques for the baby with short intestines

proliferation in animal experiments by increasing blood ﬂow and DNA synthesis.27,28 Experimental evidence exists that testosterone enhances adaptation after small bowel resection in cats.29 Within 1 year in more than 80% of the patients, adequate intestinal adaptation occurs and they can be weaned off parenteral nutritional support.29,30,31 However, this process can cause signiﬁcant embarrassment and psychological stress to the child and its family, as well as complications such as septicemia, cholecystitis and chronic liver ﬁbrosis.32 While intestinal transplantation has still limited clinical applicability with long-term survivors,33 ongoing interest exists in surgical methods to enhance nutrient absorption. This chapter reviews current surgical techniques for patients with SBS, with special emphasis on their clinical applicability.

SURGICAL TACTIC IN SITUATIONS REQUIRING EXTENSIVE INTESTINAL RESECTION Malformations such as multiple intestinal atresias or gastroschisis with atresia can cause a congenital SBS in the newborn. Acquired conditions such as intestinal strangulation by midgut volvulus or necrotizing enterocolitis may require extensive intestinal resection. For patients at risk of SBS, surgery must be adapted to preserve as much small bowel as possible. In intestinal atresias, dilated intestinal loops should be preserved instead of resected in the usual way. In volvulus, second-look procedures can help the surgeon decide which parts of the intestine are deﬁnitely lost. In extensive necrotizing enterocolitis, intestinal loops of questionable viability should be decompressed by an enterostomy, not resected. The ileum is more important than the jejunum, since it is the site of vitamin B12 and bile acid absorption. Also, the ileum has a much greater capacity for intestinal adaptation. When resection has been completed, the remaining jejunum and ileum should be measured from the ligament of Treitz all the way down to the ileocecal valve, with a thread laid along the antimesenteric border. Intestinal loops shrink considerably during manipulation, and the real intestinal length is difﬁcult to measure in vivo. This may be one reason that survival does not seem strictly related to the length of the remaining bowel.

SURGICAL TECHNIQUES IN SBS PATIENTS General agreement exists that the therapeutic priorities in patients with SBS consist of the stabilization of the patients’ conditions, the evaluation of the adaptive capacities of the intestinal remnants, and the clariﬁcation of the patients’ special needs. Therefore, the primary surgical aim is restoration of the bowel continuity as soon as possible in order to allow all remaining intestinal segments to take part in the adaptation process. Additional surgical strategies come into play only if: 1 The absorptive area is deﬁnitely too small to allow enteral feeding 2 Dysmotility in grossly dilated loops entails stagnation of chyme 3 Intestinal transit is too fast to allow sufﬁcient absorption of nutrients (Table 60.1). Intestinal transplantation (TPX) is, of course, the most effective method to increase intestinal absorptive area immediately. Indications for TPX are patients after a catastrophic abdominal event with little or no small bowel remaining, and patients with SBS and irreversible liver failure due to progressive TPN-associated hepatic dysfunction. Until recently the results of intestinal TPX had been poor, mainly due to a high rejection rate. With the introduction of new immunosuppressive drugs, such as Tacrolism and OKT3 in addition to steroids, signiﬁcant progress has been achieved with a 1-year transplant survival rate approaching 75% in recent series.34 However, the adverse effects including lymphoproliferative diseases related to EBV infections are reaching an incidence of 20%, and therefore much progress is still needed before transplantation can be recommended as a routine treatment in a larger number of patients.33,35 Augmentation of the absorptive surface area has been attempted – almost exclusively in animal experiments – by autologous mucosal transplantation into demucosized intestinal loops and by patching surgically created intestinal defects with adjacent serosal surfaces causing new intestinal mucosa to grow over the exposed serosal surface.36–38 Digestive and absorptive function of this neomucosa is considerably lower compared to native mucosa and, clinical experience with intestinal patching has not been reported.39,40

Table 60.1 Surgical strategies in SBS patients To increase passage time

To increase absorptive surface area

To improve peristalsis

Antiperistaltic segment Colon interposition Intestinal valves Artiﬁcial invagination

Serosa patching Mucosa transplantation Small bowel TPX

Tapering Tapering and lengthening

Inefﬁcient peristalsis 571

Therefore, current surgical procedures usually support only one or two of the above factors. The predominant problem in a given patient has to be evaluated carefully to choose the method most likely to enhance the absorptive capacity of the intestinal remnants. General agreement exists that most of such techniques are not indicated as a primary procedure. The priorities are: (a) stabilization of the patient’s condition, (b) evaluation of the adaptive capacity of the intestinal remnants, and (c) clariﬁcation of the patient’s special needs.

INEFFICIENT PERISTALSIS Tapering In a newborn with multiple intestinal atresias resulting in SBS, bowel which is congenitally enlarged due to chronic obstruction should be preserved. However, the low contraction pressure in such bowel segments results in inefﬁcient to-and-fro peristalsis easily demonstrated by radiological studies. Inefﬁcient peristalsis can lead to stasis of the chyme, symptoms of obstruction, and a contaminated bowel syndrome caused by bacterial overgrowth. Tapering of dilated loops can be accomplished by triangular resection of an antimesenteric segment (Fig. 60.1). The disadvantage of this type of tapering is that it reduces the available intestinal surface area. Thus, the technique can be recommended only for patients with sufﬁcient intestinal length and absorptive area in whom inadequate peristalsis is the main problem.

Figure 60.1 Tapering can be performed either by resection of a triangular antimesenteric segment or by turning in the redundant tissue. The latter method saves all the available resorptive surface area

Tapering can also be accomplished simply by turning in the redundant tissue (Fig. 60.1). This technique avoids reduction of intestinal surface area and results in normal bowel function.41–43 Whichever method is used, effective and propulsive peristalsis takes at least 3 weeks to return.

Tapering and lengthening In 1980, Bianchi reported an experimental procedure combining the tapering of dilated loops with use of the redundant tissue for lengthening the bowel.44 Anatomically, the mesenteric vessels from the last parallel arcade divide into anterior and posterior branches entering the bowel from either side of the midline. Especially in dilated segments, a relatively broad avascular plane in the midline can be used to divide the vascular layers. Longitudinal division can be accomplished this way, while preserving sufﬁcient nutrient vessels to either half of the intestine. Longitudinal closure of each intestinal segment and isoperistaltic end-to-end anastomosis doubles the ﬁnal intestinal length. Bianchi in his experimental reports and Boeckmann and Traylor in the ﬁrst clinical report used a GIA stapler to divide the intestinal parts.45,46 Although the procedure using the GIA stapler is fast, it increases blood loss, produces two rigid intestinal segments and consumes absorptive surface area. Aigrain et al. recommend division with scissors and a manually sutured anastomosis.47 Seromuscular stitches guarantee a maximum of preserved mucosa (Fig. 60.2a). Since both sections of the bowel hang on the same mesenteric segment, a helix-like isoperistaltic anastomosis is easier to perform than an anastomosis with the two segments sliding one on the other. The helix technique avoids traction on the nutrient vessels, which is critical because necrosis of the divided segments has been reported48 (Fig. 60.2b). Recent experimental studies in dogs showed that intestinal tapering and lengthening may impair nutritional status as well as intestinal adaptation and absorption.49 Bianchi’s method has been used in more than 50 infants.50 Necrosis of half of the segments occurred in only one baby.48 In some of these infants the primary length of the intestinal segments was as long as 40–80 cm, which would question the indication of some of these procedures. According to Bianchi’s own experience, the method has proved successful when performed not in the newborn or early phase of a short bowel problem, but in a later stage of the disease on so called ‘self-selected survivors’, i.e. patients in stable general conditions and free of severe complications, such as liver failure.50 This statement can be conﬁrmed by the author’s experience with two SBS-newborn babies with 15 cm and 20 cm small bowel remnants, no ileocecal valve, and 40% of the normal colonic length. Although Bianchi’s procedure was performed uneventfully and nearly doubled the intestinal length, both babies suffered from poor peristalsis and died at the age of 1 year with progressive liver failure.

572 Short bowel syndrome and surgical techniques for the baby with short intestines

A1 B1

A2 B2

(a)

in patients with SBS has been challenged. A review from Dorney showed that the presence of an intact ileocecal valve is crucial to survival of newborns after extensive loss of small bowel.5 These ﬁndings have been conﬁrmed by the authors experience: all babies with SBS and preserved ileocecal valve survived while all patients with fatal outcome did not have the valve.53 In contrast, Coran and Vanderhoof have not shown a difference in outcome of SBS patients with regard to the presence or absence of the valve.54,55 Furthermore, experimental evidence exists that bacterial translocation in SBS-rats without ileocecal valves is signiﬁcantly lower when compared with animals with preserved ileocecal valves.56,57 While deﬁnite evidence of a beneﬁcial role of the ileocecal valves in SBS patients is lacking, nevertheless the valve should be preserved whenever possible, and it probably plays a role in regard to the prolongation of the intestinal transit time. Recently, Kosloske and Jewell published a technique of appendiceal interposition that allowed preservation of a very short ileal stump with the ileocecal valve.58

Antiperistaltic small intestinal segment A1 B1 A2

B2 (b)

Figure 60.2 (a) Bianchi’s tapering and lengthening is critical for the intestinal circulation. A Penrose drain facilitates the division of the segments. Seromuscular stitches save as much mucosal surface area as possible. (b) The helix-like arrangement of the two separated parts allows the anastomoses to be performed with minimal traction on the vessels

Reversal of distal small bowel loops has been studied experimentally for years. Since Gibson and colleagues’ original report of the use of reversal of small intestine in an adult,59 this has been the most commonly used method for patients with SBS (Fig. 60.3). The antiperistaltic small bowel segment acts as a physiological valve by causing retrograde peristalsis; therefore, it should always be located at the end of the intestinal remnants. The ideal length of the reversed segment appears to be 10 cm in adults and 3 cm in infants.30,48,59,60 This may explain why the method has not consistently resulted in clinical improvement.59,61 In a 3-month-old patient in the author’s department, a 3 cm antiperistaltic segment (out of a total of 11 cm of small bowel) was

Another method of bowel tapering and elongation has been published by Kimura. This procedure consists of an initial coaptation of the small bowel remnant to a host organ (liver, abdominal wall), and after collaterals have been developed a secondary longitudinal split of the bowel is done to provide two loops, one from its antimesenteric half and the other from its mesenteric half. This procedure has been successfully used in two infants.51,52

INADEQUATE INTESTINAL TRANSIT TIME For a long time, the ileocecal valve was supposed to prolong intestinal transit time. Today, its beneﬁcial role

Figure 60.3 The antiperistaltic intestinal segment should be interposed close to the ileocecal valve or at the end of the small bowel. The optimal length in newborns is around 3.0 cm

Inadequate intestinal transit time 573

helpful for intestinal adaptation. At 4 years of age, when the child was nourished completely orally, the total radiological small bowel length had reached 1 m, with a swinging of the opaque meal at the probable location of the antiperistaltic segment.30

The clinical results of colonic interposition are conﬂicting. Of nine reported infants with isoperistaltic interposition, only four survived.65,66 In two, the length of the intestinal remnants was not reported; in the other two they were 39 and 63 cm. The sole reported infant with a reversed colonic interposition died.68

Colonic interposition Intestinal valves and pouches Isoperistaltic or antiperistaltic interposition of colon has the advantage of using none of the small intestinal remnants. The method was developed by Hutcher et al.62,63 Isoperistaltic colonic interposition slows down the rate at which nutrients are delivered to the distal intestine by slowing peristaltic activity.64 The isoperistaltic segment should thus be interposed proximally either between the jejunum and ileum if the jejunal segment is short and the ileal segment is long, or between the duodenum and jejunum if the latter is long and the ileum is short64 (Fig. 60.4). The optimal length of an interposed colon has not been deﬁned. Glick et al. used 10–15 cm long segments in small babies, while Garcia et al. used a 24 cm segment in a 14-month-old infant.65,66 A reversed colonic interposition primarily causes a partial functional obstruction by delaying the emptying of the proximal bowel. It should therefore always be placed distally to the small bowel remnants.64 Besides the beneﬁcial effect of slowing peristaltic activity, the interposed colonic segment increases the bowel length between the duodenum and cecum. Furthermore, colonic loops adapt to the function of the small bowel and can absorb water, electrolytes and nutrients by active transport mechanism.67 However, the interposed colonic segment can cause a D-lactic acidemia, which may contribute to non-hepatic encephalopathy.

Figure 60.4 The isoperistaltic colonic interposition should be interposed proximally (while the reversed colonic interposition should be used distally). The length of an isoperistaltic interposition recommended is within 10–20 cm

As mentioned earlier, while the beneﬁts of the ileocecal junction on long-term outcome of babies with SBS has been questioned, there exists a large body of evidence as to its powerful impact on intestinal transit time by slowing the passage of intraluminal nutrients into the colon.69 Therefore a variety of experimental surgical procedures have been devised to slow down the intestinal transit time by creation of artiﬁcial valves. Constriction of the bowel by sutures and artiﬁcial sphincters,70 mechanical or chemical denervation of segments61,71 and intussusception techniques have been studied extensively.72–74 Clinical experience with intussuscepted valves is very limited. Waddell et al. performed a reversed intussusception of the colon into the jejunum in three adults, one of whom subsequently developed an obstruction.75 Ricotta et al. constructed a 4-cm long nipple-like ileocecal valve (Fig. 60.5) in a 15-year-old boy, which appeared to be helpful.73 Cywes created a duodenojejunal pouch in a 21-month-old child who

Figure 60.5 Nipple-like ileocecal valve according to Ricotta. The optimal length in newborns is not deﬁned, but will be around 1–2 cm. In a 15-year-old boy, a 4-cm long valve worked well. Seromuscular stitches allow the precise adaptation of the mucosal layers

574 Short bowel syndrome and surgical techniques for the baby with short intestines

previously had 4 cm of jejunum reversed. The mid-segment of the pouch acted as a reversed segment. While the transit time was prolonged at 3 months, the late results were not encouraging.38

CONCLUSION Despite the variety of surgical techniques designed to support intestinal adaptation after extensive loss of small bowel, none can be recommended unequivocally.76,77 In the past, the overwhelming majority of babies with SBS have been treated exclusively by parenteral nutritional support until intestinal adaptation allowed entirely oral nutrition. Full enteral feeding has ultimately been attained in infants with originally as little as 15 cm of the small bowel with the ileocecal valve preserved, or 25 cm of jejuno-ileum when it was missing.5,30,78 Survival rates of 75–83% are being reached in newborns, and 100% in children at or above 2 years of age.53,79,80 Surgery is indicated only in selected patients either to achieve effective propulsive peristalsis or to prolong intestinal transit time. However, adjunctive surgical procedures should be postponed until the special needs of individual patients are evident. Approximately 10% will beneﬁt from surgical interventions, either by prolongation of transit time or by remodelling parts of the intestine.81 Patients with total loss of small bowel or progressive liver failure may beneﬁt from the progress made by intestinal TPX, although the 3-year survival rate does not reach far above 50%.34 Survival rates after intestinal TPX as well as quality of life will hopefully signiﬁcantly improve in the future. Most importantly, a reduction in adverse effects or ﬁnding new forms of immunosuppressive therapy would be beneﬁcial.

REFERENCES 1. Rickham PP. Massive small intestinal resection in newborn infants. Ann Roy Coll Surg Engl 1967; 41:480–5. 2. Touloukian RJ, Smith GJ. Normal intestinal length in preterm infants. J Pediatr Surg 1983; 18:720–3. 3. Kuffer F. Zum Problem der subtotalen Dünndarmresektion beim Säugling. Z Kinderchir 1965; 2:39–55. 4. Wilmore D. Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. J Pediatr 1973; 80:88–95. 5. Dorney St FA, Ament ME, Berquist WE et al. Improved survival in very short small bowel of infancy with use of long term parenteral nutrition. J Pediatr 1985; 107:521–5. 6. Höllwarth ME, Urich-Baker MG, Kvietys PR et al. Blood ﬂow in experimental short bowel syndrome. Pediatr Surg Int 1988; 4:242–6.

7. Bristol JB, Williamson RCN. Mechanisms of intestinal adaptation. Pediatr Surg Int 1988; 4:233–41. 8. Briet F, Flourie B, Achour L et al. Bacterial adaptation in patients with short bowel and colon in continuity. Gastroenterology 1995; 109:1446–53. 9. Tappenden KA, Thomson ABR, Wild GE. Short-chain fatty acid-supplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats. Gastroenterology 1997; 112:792–802. 10. Altmann GG. Inﬂuence of bile and pancreatic secretions on the size of the intestinal villi in the rat. Am J Anat 1971; 132:167–78. 11. Bestermann HS, Adrian TE, Mallinson CN et al. Gut hormone release after intestinal resection. Gut 1982; 23:855–61. 12. Dowling RH, Booth CC. Structural and functional changes following small bowel resection in rat. Clin Sci (Lond) 1967; 32:139–49. 13. Weser E, Babitt J, Hoban M et al. Intestinal adaptation. Different growth responses to disaccharides compared with monosaccharides in rat small bowel. Gastroenterology 1986; 91:1521–7. 14. Johnson JR. The trophic action of gastrointestinal hormones. Gastroenterology 1976; 70:278–88. 15. Bloom SR, Polak JM. The hormonal pattern of intestinal adaptation. A major role for enteroglucagon. Scand J Gastroenterol 1982; 74:93–103. 16. Vanderhoof JA, Mataya SM. Enteral and parenteral nutrition in patients with short-bowel syndrome. Eur J Paediatr Surg 1999; 9:214–19. 17. Fuller PJ, Beveridge DJ, Taylor RG. Ileal proglucagon gene expression in rat: characterization in intestinal adaptation using in situ hybridisation. Gastroenterology 1993; 104:459–66. 18. Inoue Y, Copeland EM, Souba WW. Growth hormone enhances amino acid uptake by the human small intestine. Ann Surg 1994; 219:715–24. 19. Byrne TA, Morissey TB, Nattakorn TV et al. Growth hormone, glutamine, and a modiﬁed diet enhance nutrient absorption in patients with severe short bowel syndrome. JPEN 1995; 19:296–302. 20. Ianolli P, Miller JH, Ryan CK et al. Epidermal growth factor and human growth hormone accelerate adaptation after massive enterectomy in an additive, nutrient dependent, and site-speciﬁc fashion. Surgery 1997; 122:721–9. 21. Winesett DE, Ulshen DM, Hoyt EC et al. Regulation and localization of the insulin-like growth factor system in small bowel during altered nutrition status. Am J Physiol 1995; 268:G631–40. 22. Uhlsen MH, Dowling RH, Fuller CR et al. Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone. Gastroenterology 1993; 104:993–80. 23. Clemmons DR, Underwood LE. Nutritional regulation of IGF-I and IGF binding protein. Ann Rev Nutr 1991; 11:393–412. 24. Wilmore DW. Glutamine and the gut. Gastroenterology 1994; 107:1818–901.

References 575 25. Ziegler TR, Mantell MP, Chow JC et al. Gut adaptation and the insulin-like growth factor system: regulation by glutamine and IGF-I administration. Am J Physiol 1996; 271:G866–75. 26. Vanderhoof JA, Kollmann KA, Grifﬁn SK et al. Growth hormone and glutamine do not stimulate intestinal adaptation following massive small bowel resection in rat. J Pediatr Gastroenterol Nutr 1997; 25:327–31. 27. Vanderhoof JA, Park JH, Grandjean CJ. Morphological and functional effects of 16,16 dimethyl-prostaglandin-E2 on mucosal adaptation after massive distal small bowel resection. Am J Physiol 1988; 254:G373–7. 28. Höllwarth ME, Granger DN, Ulrich-Baker MG et al. Pharmacologic enhancement of adaptive growth after extensive small bowel resection. Pediatr Surg Int 1988; 3:55–61. 29. Pul M, Yilmaz N, Gürses N et al. Enhancement by testosterone of adaptive growth after small bowel resection. Isr J Med Sci 1991; 27:339–42. 30. Kurz R, Sauer H. Treatment and metabolic ﬁndings in extreme short bowel syndrome with 11 cm jejunal remnant. J Pediatr Surg 1983; 18:257–63. 31. Postuma R, Moroz S, Friesen F. Extreme short bowel syndrome in an infant. J Pediatr Surg 1983; 18:264–8. 32. Grosﬁeld JL, Rescona FJ, West KW. Short bowel syndrome in infancy and childhood: analysis of survival in 60 patients. Am J Surg 1986; 151:41–6. 33. Schwartz MZ. Small bowel transplantation. Pediatr Surg Int 1988; 3:318–25. 34. Vanderhoof JA, Langnas AN. Short-bowel syndrome in children and adults. Gastroenterology 1997; 113:1767–78. 35. Abu-Elmagd K, Reyes J, Todo S et al. Clinical intestinal transplantation: new perspectives and immunological considerations. J Am Coll Surg 1998; 186:512–27. 36. Binnington HB, Siegel BA, Kissane JM et al. A technique to increase jejunal mucosal surface area. J Pediatr Surg 1973; 8:765–9. 37. Zachariou Z, Daum R, Beiler HA et al. Autogeneic allotropic small-bowel mucosa transplantation in beagles. A new perspective for treatment of short-bowel syndrome. Eur J Paediatr Surg 1998; 8:230–3. 38. Cywes S. The surgical management of massive bowel resection. J Pediatr Surg 1968; 3:740–8. 39. Bragg LE, Thompson JS. Serosal patching impairs intestinal adaptation following enterectomy. J Surg Res 1992; 52:118–22. 40. Thompson JS, Harty RJ, Saigh JA et al. Morphological nutritional responses to intestinal patching following intestinal resection. Surgery 1988; 103:79–86. 41. Thomas CG Jr. Jejunoplasty for the correction of jejunal atresia. Surg Gynecol Obstet 1969; 129:545–6. 42. Weber TR, Vone DW, Grosﬁeld JL. Tapering enteroplasty in infants with bowel atresia and short gut. Arch Surg 1982; 117:684–8. 43. Ramanujan TM. Functional capability of blind small loops after intestinal remodelling techniques. Aust NZ J Surg 1986; 54:145–50.

44. Bianchi A. Intestinal loop lengthening – a technique for increasing small intestinal length. J Pediatr Surg 1980; 15:145–51. 45. Bianchi A. Intestinal lengthening: an experimental and clinical review. J Roy Soc Med 1984; 77:35–41. 46. Boeckmann CR, Traylor R. Bowel lengthening for short gut syndrome. J Pediatr Surg 1981; 16:996–7. 47. Aigrain Y, Cornet D, Cezard JP et al. Longitudinal division of small intestine: a surgical possibility for children with very short bowel syndrome. Z Kinderchir 1985; 40:233–6. 48. Thompson JS, Pinch LW, Muorey N et al. Experience with intestinal lengthening for the short bowel syndrome. J Pediatr Surg 1991; 26:721–4. 49. Thompson JS, Quigley EM, Adrian T. Effect of intestinal tapering and lengthening on intestinal structure and function. Am J Surg 1995; 169:111–19. 50. Bianchi A. Experience with longitudinal intestinal lengthening and tailoring. Eur J Paediatr Surg 1999; 9:256–9. 51. Kimura K, Soper RT. A new bowel elongation technique for the short bowel syndrome using the isolated bowel segment Iowa models. J Pediatr Surg 1993; 26:792–4. 52. Georgeson KE, Halpin D, Figueroa R et al. Sequential intestinal lengthening procedure for refractory short bowel syndrome. J Pediatr Surg 1994; 29:316–21. 53. Mayr J, Schober PH, Weissensteiner U et al. Morbidity and mortality of the short bowel syndrome. Eur J Paediatr Surg 1999; 9:231–5. 54. Coran AG, Spivak D, Teitelbaum DH. An analysis of the morbidity and mortality of short-bowel syndrome in the pediatric age group. Eur J Paediatr Surg 1999; 9:228–30. 55. Kaufman SS, Loseke CA, Lupo JV et al. Inﬂuence of bacterial overgrowth and intestinal inﬂammation on duration of parenteral nutrition in children with short bowel syndrome. J Pediatr 1997; 131:356–61. 56. Schimpl G, Feierl G, Linni K et al. Bacterial translocation in short-bowel syndrome in rats. Eur J Paediatr Surg 1999; 9:224–7. 57. Eizaguirre I, Aldazabal P, Barrena P et al. Bacterial translocation is favoured by the preservation of the ileocecal valve in experimental short bowel with total parenteral nutrition. Eur J Paediatr Surg 1999; 9:220–3. 58. Kosloske AM, Jewell PF. A technique for preservation of the ileocecal valve in the neonatal short intestine. J Pediatr Surg 1989; 24:369–70. 59. Gibson LD, Carter R, Hinshaw DB. Segmental reversal of small intestine after massive bowel resection. J Am Med Assoc 1962; 182:952–4. 60. Warden MJ, Weseley JR. Small bowel reversal procedure for treatment of the short gut baby. J Pediatr Surg 1978; 13:321–3. 61. Hidalgo F, Cortes ML, Salas SJ et al. Intestinal muscle layer ablation in short bowel syndrome. Arch Surg 1973; 106:188–90.

576 Short bowel syndrome and surgical techniques for the baby with short intestines 62. Hutcher NE, Salzberg AM. Pre-ileal transposition of colon to prevent the development of the short bowel syndrome in puppies with 90 percent small intestine resection. Surgery 1971; 70:189–97. 63. Hutcher NE, Mendez-Picon G, Salzberg AM. Prejejunal transposition of colon to prevent the development of the short bowel in puppies with 90 percent small intestine resection. J Pediatr Surg 1973; 8:771–7. 64. Lloyd DA. Colonic interposition between the jejunum and ileum after massive small bowel resection in rats. Progr Pediatr Surg 1978; 12:51–106. 65. Glick PL, de Lorimier AA, Adzick NS et al. Colon interposition: an adjuvant operation for short gut syndrome. J Pediatr Surg 1984; 19:719–25. 66. Garcia VF, Templeton JM, Eichelberger MR et al. Colon interposition for short bowel syndrome. J Pediatr Surg 1981; 16:994–5. 67. Sidhu GS, Narasimharao KL, Usha Rani V et al. Morphological and functional changes in the gut after massive small bowel resection and colon interposition in rhesus monkeys. Digestion 1984; 29:47–54. 68. Trinkle JK, Bryant LR. Reversed colon segment in an infant with massive bowel resection. A case report. J Ky Med Assoc 1967; 65:1090–91. 69. Gazet JC, Koop J. The surgical signiﬁcance of the ileocecal function. Surgery 1964; 56:565–73. 70. Stacchini A, Dido LJ, Primo ML et al. Artiﬁcial sphincter as a surgical treatment for experimental massive resection of small intestine. Am J Surg 1982; 143:721–6. 71. Sawchuk A, Goto S, Yount J et al. Chemically induced

72. 73.

74.

75. 76. 77. 78.

79.

80.

81.

bowel denervation improves survival in short bowel syndrome. J Pediatr Surg 1987; 22:492–6. Grier RL, Nelson AW, Lumb WV. Experimental sphincter for short bowel syndrome. Arch Surg 1971; 102:203–8. Ricotta J, Zuidema GD, Gadacz TR et al. Construction of an ileocecal valve and its role in massive resection of the small intestine. Surg Gynecol Obstet 1981; 152:310–14. Vinograd IL, Merguerian P, Udassin R et al. An experimental model of a submucosally tunnelled valve for the replacement of the ileo-cecal valve. J Pediatr Surg 1984; 19:726–31. Waddell WR, Kern F, Halgrimson CG et al. A simple jejunocolic valve. Arch Surg 1979; 100:438–44. Collins JB, Georgeson KE, Vicente Y. Short bowel syndrome. Sem Pediatr Surg 1995; 4:60–72. Stringer MD, Puntis JWL. Short bowel syndrome. Arch Dis Childh 1995; 73:170–3. Galea MH, Holliday H, Carachi R et al. Short-bowel syndrome: a collective review. Enteral and parenteral nutrition in short-bowel syndrome in children. J Pediatr Surg 1992; 27:592–6. Georgeson KE, Breaux CW. Outcome and intestinal adaptation in neonatal short-bowel syndrome. J Pediatr Surg 1992; 27:344–50. Ricour C, Duhamel JF, Arnaud-Battandier F et al. Enteral and parenteral nutrition in the short bowel syndrome in children. World J Surg 1985; 9:310–15. Georgeson Jr KE. Short bowel syndrome. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, editors. Pediatric Surgery. Vol. 2. Mosby, St Louis, USA 1998:1223–32.

6 Liver and biliary tract

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61 Biliary atresia KEN KIMURA

INTRODUCTION Biliary atresia is a neonatal cholestatic disease caused by complete organic obstruction of the extrahepatic biliary system, probably of congenital origin. The intrahepatic biliary system is simultaneously involved with pericholangeal ﬁbrosis. The etiology of this disease is unknown. The pathologic changes of the biliary systems are sequelae of inﬂammatory changes which might have occurred during fetal life. It does not appear to be a developmental anomaly. The overall incidence is one out of 10 000 live births. There is no racial signiﬁcance in incidence. Female infants are more commonly affected than males (f:m ratio 1.27:1). Patients initially present with acholic stools and jaundice persisting beyond the age of 2 weeks.1,2 In 1928, Ladd reported successful operations in selected patients with biliary atresia in whom a large duct containing bile was present at the porta hepatis proximal to the atretic portion.3 In this situation, a lumen-to-lumen anastomosis could be performed between the bile duct and bowel. The lesion observed in these patients was regarded as the ‘correctable form’ of biliary atresia, allowing the surgeon to perform reconstruction of the biliary tract. However, such a large bilecontaining duct is not available in more than 80% of patients.1,2 In the majority of patients, the extrahepatic biliary system has been totally involved in ﬁbrotic changes with absence of a bile duct with a visible lumen. Such a lesion was previously called the ‘incorrectable form’, because a surgical reunion of the bile duct to the bowel was impossible. Since Ladd’s report, the classiﬁcation dividing the lesions into two forms – correctable and incorrectable – has been used. In 1955, Kasai et al. observed the fact that microscopic bile ducts included in the portal ﬁbrous tissue have the potential to form a biliary ﬁstula to the bowel and function as a biliary tract when the portal ﬁbrosis tissue is appropriately transected and anastomosed to bowel.4 In a jaundiced infant Kasai explored the porta hepatis hoping to ﬁnd a large bile duct of the correctable form;

his effort failed and the portal dissection was complicated by substantial hemorrhage. To control hemorrhage from the denuded portal tissue, the ﬁrst portion of the duodenum was mobilized and sutured to the porta hepatis as a patch to cover the bleeding area. Several months later, the patient visited the clinic in a completely anicteric state. The mechanism by which the jaundice resolved was puzzling at the time. Unfortunately, the patient died of cholangitis several months later. At the autopsy table, Kasai found that a biliary ﬁstula had formed between the porta hepatis and the duodenum. The observations in this patient motivated Kasai to develop hepatic portoenterostomy.5 Since Kasai’s contribution made the ‘incorrectable form’ correctable, the classiﬁcation had to be revised. The classiﬁcation proposed by the Japanese Society of Pediatric Surgery is currently used in most centers (Fig. 61.1).1,6 Unless the surgical treatment promotes successful bile excretion, the ultimate prognosis is poor. Death usually occurs within 2 years. When the patient is operated on after the age of 90 days, achievement of disease-free status is difﬁcult because of advanced liver damage.1,2 Therefore, hepatic portoenterostomy must be carried out as soon as the diagnosis is established. However, there are a few exceptional patients aged 120–150 days at operation who did well after operation with a long disease-free status. This encourages us to perform hepatic portoenterostomy even in relatively older patients. Reﬁnements in the technique of portal dissection have achieved successful bile excretion in 70–90% of patients after hepatic portoenterostomy. About one-half of these patients can expect a long-term disease-free status.7 When hepatic portoenterostomy is unsuccessful or the postoperative course is complicated by cholangitis, several centers advocate the re-exploration at the porta hepatis.8,9 However, today liver transplantation is available as a more reliable technique to salvage patients who fail to respond to portoenterostomy. Liver transplantation is rendered safer and easier in children who have had fewer previous surgical interventions.10,11 For

580 Biliary atresia

1 Principal types

2 Subtypes according to the patterns of distal bile ducts

TYPE I: Atresia of common bile duct

a: patent common bile duct

I cyst

a1 patent common bile duct and atretic hepatic duct a1

a2 patent common bile duct and aplasia of hepatic duct

b1 fibrous common bile duct and patent or atretic hepatic duct b1

α. dilated hepatic radicles (internal diameter > 1 mm)

a2 β. hypoplastic hepatic radicles (internal diameter < 1 mm)

b: fibrous common bile duct TYPE II: Atresia of hepatic duct

3 Subtypes according to the patterns of hepatic radicles at the porta hepatis

b2 fibrous common bile duct and aplasia or hepatic duct

γ. bile lake (no epithelial lining)

b2 m. fibrous hepatic radicles

c: aplasia of common bile duct TYPE III: Atresia of bile duct at the porta hepatis

c1 aplasia of common bile duct and patent or atretic hepatic duct c1

c2 aplasia of common bile duct and common hepatic duct c2

n. fibrous mass

a. aplasia of hepatic radicles

d: miscellaneous

Figure 61.1 Classiﬁcation of types of biliary atresia proposed by the Japanese Society of Pediatric Surgeons6 (From Hays and Kimura,1 by permission)

this reason, we do not favor re-exploration of the porta hepatis in patients with unsuccessful portoenterostomies. Liver transplantation as the primary treatment for biliary atresia is not realistic because of the relative paucity of infant donors, the technical difﬁculties in the procedure of liver transplantation, and the need for multiple drug administrations to discourage rejection. In most centers of the world, hepatic portoenterostomy is the initial operation of choice for biliary atresia, with liver transplantation as the salvage procedure.12

PREOPERATIVE MANAGEMENT Physical examination often detects jaundice, abdominal distention and hepatosplenomegaly. By palpation, the liver surface is ﬁrm and irregular, and its margin is rounded rather than sharp, which is not seen in other nonsurgical hepatic disorders. In older patients, ascites, venous engorgement of the abdominal wall, malnutrition, palmar erythema, and drumstick ﬁngers are observed. The diagnostic strategy is to differentiate biliary atresia from nonsurgical icterus-producing hepatic disorders of infancy, such as infantile hepatitis, viral infections, alpha-l-antitrypsin deﬁciency, etc.1,2 Current diagnostic procedures consist of:

1 Laboratory studies of blood components (see later) 2 Histologic evaluation of the liver by percutaneous needle biopsy 3 Tests for bile excretion into the duodenum 4 Radiographic imaging of the biliary system. Studies of the blood components are mandatory for an overall evaluation of hepatic disease, but they are not usually signiﬁcant in the differential diagnosis of biliary atresia from other nonsurgical causes of infantile jaundice. They include serum bilirubin, plasma protein fractions, coagulation screen, serum enzymes, bile acid proﬁle, hepatitis B-surface antigen, serum colloidal reactions (CF, ZT, TT, etc.), and serological studies for perinatal infections (‘TORCH’ screen; [TO] toxoplasmosis, [R] rubella, [C] cytomegalovirus, and [H] herpes, etc.). Percutaneous liver biopsy helps to establish the diagnosis of biliary atresia in relatively older infants who have prominent hepatic ﬁbrosis with proliferation of bile ducts. However, this procedure is not useful in younger infants for differentiating biliary atresia from other nonsurgical hepatic disorders. Ultrasonography is the ﬁrst choice of diagnostic study, which is non-invasive, less technically difﬁcult and less expensive. In biliary atresia patients, absence of a gallbladder and visualization of the potal ﬁbrous mass are characteristic in the ultrasonographic image.13,14

Intraoperative studies 581

Direct tests for bile excretion by duodenal intubation or radiographic imaging studies are the most reliable preoperative diagnostic procedures.15,16 In biliary atresia, bile excretion is always completely absent. We have employed duodenal intubation to test for bile excretion with satisfactory results; this procedure is simple, quick and inexpensive.17,18 By this test, 100% of biliary atresia patients showed absence of bile in the duodenal content. However, it is not speciﬁc, since approximately 10–25% of infants with nonsurgical hepatic disorders yield the same result (Table 61.1). These patients with nonsurgical hepatic disorders were explored. In these patients, bile excretion was resumed several weeks after operation and liver function completely recovered in several years. In the past, the risk of surgical exploration in patients with infantile hepatitis has been excessively emphasized, which contributed to slow acceptance of surgical therapy for biliary atresia.19 Surgical exploration should be encouraged for jaundiced infants in whom the differential diagnosis between biliary atresia and nonsurgical hepatic disorders is unclear, before they grow out of the golden (or optimal) time of operation (within 90 days of age).20 The patient is admitted to the hospital on the day of operation. Before admission, preoperative laboratory studies are completed, including complete blood counts, urinalysis, liver proﬁle, blood coagulation studies, electrolytes, blood sugar, BUN and creatinine levels. Blood typing and cross-matching on a quantity of 200 ml is routinely performed. Vitamin K (1 mg/kg body weight) is parenterally given. No oral antibiotics are used. The patient is fasted for 6 hours before induction of anesthesia.

Table 61.1 Duodenal Intubation (KCH 1970–86) Bile excretion Positive Negative Bile atresia Infantile hepatitis

0 28

86 7

Under ﬂuoroscopic control, an 8 Fr. gauge feeding tube is placed at the second portion of the duodenum. A small amount of 25% magnesium sulfate (5–10 ml) is injected into the duodenal lumen. Several minutes later, the duodenal content is aspirated and checked for the bile. Seven out of 28 patients with infantile hepatitis (25%) were incorrectly diagnosed and underwent laparotomy.

OPERATION In the past, the surgical therapy of biliary atresia has employed a variety of approaches with different operative techniques. In this chapter, the only approach and technique which the current author employs today is described.

After successful induction of general endotracheal anesthesia, the patient is placed in the supine position on the operating table, which is specially designed to allow operative X-rays to be taken. I.v. lines are secured in the veins of the upper extremities. Arterial cannulation in the radial artery is connected to the appropriate monitoring system.

Incision for laparotomy The skin incision is made about 1 cm below the right costal margin, extending from the xiphoid process to the right anterior axillary line. The muscle layers and the peritoneum are incised with electrocautery in the same fashion to enter the abdomen. The falciform ligament is ligated with 4-0 silk sutures and divided. After exploration of the entire abdomen, the intestines are retracted into the lower abdomen using intraperitoneal pads. The liver is ﬁrm, enlarged and irregular, a dark brown discoloration reﬂecting the degree and duration of jaundice. The margin of the liver is retracted superiorly to expose the hepatoduodenal ligament.

INTRAOPERATIVE STUDIES Operative cholangiography (providing that there is a gallbladder) and liver biopsy are performed prior to the start of portal dissection.21 The fundus of the gallbladder is mobilized from the liver bed; a 4–6 Fr. gauge feeding catheter is passed into the gallbladder through a small stab incision inside a pursestring suture to secure water tightness and to anchor the catheter into place. A small amount (2–3 ml) of 36% urografﬁn is injected through the catheter, and operative cholangiography is performed by portable X-ray equipment on the table. Cholangiography is important to conﬁrm the differentiation from hepatitis and determine the form of the ducts. However, this procedure can be performed in only one-third of patients with biliary atresia, because the gallbladder does not have a lumen for catheter insertion in the rest of patients. In these patients, portoenterostomy is begun with portal dissection. In some patients the cholangiogram will show the contrast material diffusely inﬁltrating from the gallbladder into the liver substance (Fig. 61.2); this has been incorrectly interpreted to demonstrate a communication between the intrahepatic biliary system and the hepatic ducts, which are connected to the gallbladder. Based on this incorrect interpretation, cholecystoduodenostomy has been performed for reconstruction of the biliary tract, with miserable results.19 Diffuse intrahepatic inﬁltration represents cholangiolymphatic communications, which are commonly seen in liver diseases. Unless the normal anatomy of the intrahepatic biliary system is observed (Fig. 61.3), a hepatic portoenterostomy should be performed instead of cholecystoenterostomy.

582 Biliary atresia

Figure 61.2 Contrast material injected into the gallbladder ﬂowed effortlessly into the intrahepatic lymphatic network. There is no visualization of the bilateral hepatic ducts (compare with Figure 61.3)

Figure 61.3 Cholangiogram in an infant with infantile hepatitis. The large cystic, hepatic and common bile ducts are clearly visualized

In about 5–10% of patients with biliary atresia, a communication is observed from the gallbladder to the duodenum through narrowed cystic and common bile ducts (Fig. 61.4). In such a patient, it is tempting to perform a hepatic portocholecystostomy because of the potential advantage of eliminating the possibility of postoperative ascending cholangitis.22 However, the common bile duct is frequently hypoplastic and ﬁbrosed, and does not function as a normal biliary conduit after portocholecystostomy.23 For this reason, today we prefer to perform a hepatic portoenterostomy in such a patient. During hepatic portal dissection, a cystic structure is frequently detected in the hepatoduodenal ligament. Contrast material injected into the cyst is observed to inﬁltrate into the liver (Fig. 61.5). Such a ﬁnding might be misinterpreted to represent a ‘correctable form’ of biliary atresia, favoring the option to perform a cysto-

Figure 61.4 There is no visualization of the hepatic ducts. The common bile duct is visualized but the size is small (compare with Figure 61.3)

Figure 61.5 A round cyst was found in the hepatoduodenal ligament which was cannulated for contrast study. The contrast material ﬁlling the cyst inﬁltrates the liver substance representing the intrahepatic lymphatic system (compare with Figure 61.3)

enterostomy. However, the cyst is merely a lymphocele which communicates with the intrahepatic lymphatic system, and again for this patient, a portoenterostomy should be performed. Liver biopsy is usually carried out on the anterior margin of the right lobe. The pathologic ﬁndings of the liver specimen are important only to predict the prognosis of the patient.

HEPATIC PORTOENTEROSTOMY Hepatic portoenterostomy consists of two procedures: (1) portal dissection with transection of the portal ﬁbrous mass, and (2) reconstruction of the biliary drainage into the intestine.

Portal dissection 583

For portal dissection, special care is required to transect the portal ﬁbrous mass in the proper plane where the hepatic ducts terminate. Successful bile excretion, which is the ﬁrst milestone to the ﬁnal goal of therapy, can be achieved only when a proper transection is performed.24,25 Reconstruction of the biliary tract is achieved by an anastomosis between the transected porta hepatis and a part of the gastrointestinal tract. The stomach, duodenum, jejunum, ileocecum and appendix have been used for this purpose. The ultimate purpose of these various techniques is to reconstruct a biliary tract which functions and avoids cholangitis. A variety of techniques, such as complete isolation of the bile conduit from the functional intestine (Sawaguchi)26 or creation of an external stoma or an antireﬂux valve in the jejunal loop of the Roux-en-Y, or ileocolic conduit have been attempted.27,28 We have been using a long jejunal loop (80 cm) with satisfactory results.29,30 The technique we use is described.

PORTAL DISSECTION A vessel loop is passed into the foramen of Winslow and placed around the hepatoduodenal ligament to secure hemostasis if the portal vein is inadvertently injured during the procedure (Fig. 61.6). The gallbladder or its ﬁbrosed remnant is freed from the liver using needle tip electrocautery. The cystic artery is ligated and divided. A longitudinal serosal incision is made along the lateral margin of the hepatoduodenal ligament. By dissecting along the cystic duct (or its remnant), the common bile duct is usually detected as a ﬁbrous remnant, which is divided between 4-0 silk ties at the upper margin of the duodenum (Fig. 61.7). Using the tie on the distal end of the divided common duct remnant for traction, the ﬁbrous tissue is thoroughly dissected away from the adventitia of the portal vein. As the dissection advances

Portal fibrous mass Hepatic artery Portal vein

Figure 61.7 The ﬁbrous tissue (common duct) located anteriorly to the portal vein is divided

toward the porta hepatis along the portal vein, the common hepatic artery is found in the ﬁbrous tissue. This artery immediately branches into the right and left hepatic arteries; they are completely skeletonized by sharp and blunt dissection and individually encircled by vessel loops (Fig. 61.8). After the dissection reaches the portal venous bifurcation, further dissection is continued bilaterally along the rim of the right and left portal vein branches. In some patients, protrusion of the quadrate lobe of the liver is prominent, and obscures the entire porta hepatis. In such a situation, the liver tissue in the quadrate lobe is excised using electrocautery to expose the porta hepatis in the visible ﬁeld. With the portal venous fork clearly exposed, the ﬁbrous tissue is observed to form a portal ﬁbrous mass which is pyramidal in shape with its base located at the portal venous bifurcation. While applying moderate traction,

Portal fibrous mass Left hepatic artery Right hepatic artery Proper hepatic artery Common hepatic artery Gastroduodenal artery Portal vein

Hepatoduodenal ligament Cholecystic artery

Figure 61.6 The hepatoduodenal ligament is taped

Figure 61.8 The hepatic arteries are completely skeletonized

584 Biliary atresia

the portal ﬁbrous mass is lifted and the portal venous bifurcation retracted inferiorly to show the base of the ﬁbrous mass attached to the liver. At the base of the portal ﬁbrous mass there are several ﬁne veins extending to the portal venous bifurcation (Fig. 61.9). These are ligated or cauterized and divided (Fig. 61.10). Dissection along the rim of the portal venous fork is bilaterally extended until the portal veins are seen to enter the liver parenchyma. With complete skeletonization of the right and left hepatic arteries located anteriorly to the portal veins, the ﬁrst branch of each of those arteries is seen immediately before it enters the liver. These ﬁrst branches are the landmark identifying the extent of lateral dissection (Fig. 61.10).

Transection of the portal ﬁbrous mass is performed using ﬁne-tip scissors with blades placed perpendicular to each corner of the portal ﬁbrous mass (Fig. 61.11a,b).21 The transecting plane should be on the border between the liver and portal ﬁbrous mass. Moderate bleeding from small vessels is usual, which can be controlled by packing with gauze. Electrocautery should be avoided at this juncture because of the damage it might inﬂict to the ﬁne bile ducts on the cut surface.

First branchright hepatic artery (a)

(b)

Figure 61.11 (a,b) Both corners of the portal ﬁbrous mass are transected where the hepatic duct is located

RECONSTRUCTION OF BILIARY TRACT Figure 61.9 Fine veins are observed extending between the base of the portal ﬁbrous mass and the portal vein by retraction of the portal venous bifurcation

Figure 61.10 The ﬁne veins are divided

The proximal jejunum is divided between intestinal clamps 10–15 cm downstream from the ligament of Treitz (Fig. 61.12). The proximal 80 cm of jejunum is used for the Roux-en-Y loop. With caution to preserve the marginal vessels, the mesentery is incised to allow mobilization of this jejunal loop. The proximal end of the loop is brought to the xiphoid process to test for tension. If it reaches the xiphoid process, the length is adequate. At 80 cm from the transected end, a half circumference on the antimesenteric surface of the jejunum is incised to form an enterostomy; the end of the proximal jejunum is anastomosed to this enterostomy in an end-to-side fashion to restore intestinal continuity. The anastomosis is achieved by a 5-0 chromic catgut continuous suture on the inner layer and 5-0 silk interrupted Lembert sutures on the outer layer. The mesenteric defects are closed by 5-0 silk interrupted sutures (Fig. 61.13). The jejunal loop of Roux-en-Y is brought to the porta hepatis anteriorly to the transverse colon (Fig. 61.13). Antecolic positioning of the bile conduit will avoid extrinsic compression, which may be a cause of bile stasis.

Reconstruction of biliary tract 585 Treitz ligament 10–15 cm CT

Jejunum CT

Figure 61.12 The jejunum is divided 10–15 cm from the ligament of Treitz

Figure 61.14 The interrupted sutures of 5–0 coated Dexon are placed from the posterior margins of the porta hepatis to the proximal end of the jejunal loop. Traction sutures are placed on the connective tissue (CT) at the entrance of the vessels into the liver

Figure 61.13 The end-to-side jejunojejunal anastomosis. The proximal end of the jejunal loop of Roux-en-Y (80 cm) is brought to the porta hepatis in an antecolic position

The packing gauze applied to the transected surface of the porta hepatis is gently removed. At this point, hemostasis has usually been achieved. If not, electrocautery with a needle tip is used with low voltage to coagulate precisely the bleeding vessels. Hepatic portoenterostomy is performed in an end-toend fashion. As the ﬁrst step in this procedure, traction sutures of 5-0 coated Dexon are placed between the connective tissue that forms the entrance of the portal vein and hepatic artery into the liver and the seromuscular layer of the jejunal loop. Using interrupted stitches (usually 5-0 coated Dexon on 11 mm atraumatic needles, the sutures are placed in the liver tissue at the posterior margin of the transected portal ﬁbrous mass and the end of the jejunal loop (Fig. 61.14). The jejunal stitches are placed in an inverting Lembert fashion so that the end of the bowel will be inverted. When all

stitches are placed on the posterior margin, the intestinal clamp on the jejunal loop is released. Bleeders from the transected bowel margin are controlled by electrocautery. The sutures are gently tied because the liver tissue at the margin of the portal tissue is easily torn by the suture material (Fig. 61.15). Little effort is needed to use many stitches or to tie the sutures tightly in this anastomosis. Because the Roux-en-Y loop is 80 cm long, the portoenterostomy is protected from intestinal gas and succus entericus. The anterior margin of the jejunal end is then sutured to the surface of the quadrate lobe of the liver, which forms the anterior margin of the transected portal tissue. A running suture with 5-0 coated Dexon is used to invert the jejunal end of this anastomosis (Fig. 61.16). A 12 mm Penrose drain is placed in the foramen of Winslow through a separate

Figure 61.15 The sutures on the posterior margins of the porta hepatis and jejunal end are tied. The illustration on the right is the sagittal section of the anastomosis. The margin of the jejunal end is inverted

586 Biliary atresia

Figure 61.16 The anterior margins of the porta hepatis and jejunal end are approximated by continuous sutures with 5–0 coated Dexon. The sagittal section of the completed portoenterostomy is illustrated on the right

stab wound through the abdominal wall. The omentum is used to cover the site of liver biopsy and the porta hepatis. The wound is closed by 4-0 interrupted silk stitches for the muscle layers, 5-0 silk for the Scarpa’s fascia and the skin by 4-0 Dexon continuous subcuticular sutures.

bile in the intestine. Antibiotics (Keﬂin 100 mg and gentamicin 7.5 mg/kg/day) are intravenously administered using the central venous catheter continuously for 1 month. Complete blood count, coagulation studies and liver proﬁles are obtained weekly. If the patient excretes bile in the stools with improvement of jaundice and has no episodes of cholangitis during the ﬁrst postoperative month, the prognosis is usually favorable. The venous catheter can then be removed and no further administration of antibiotics is necessary. A signiﬁcant reduction is seen in the incidence of early cholangitis in patients who have been treated by this routine (Table 61.2).30 If there is an absence or cessation of bile excretion in the stools, a percutaneous transhepatic cholangiodrainage (PTCD) is indicated to decompress the intrabiliary system and allow cholangiograms to be performed. Successful PTCD can be achieved in about one-half of patients. Employing this technique, patients can be managed for several months, until liver transplantation becomes available.32,33 Patients in whom serum bilirubin level falls rapidly for 6 months can expect a long survival. In these patients, the serum enzyme levels will reduce gradually over a period of several years. When jaundice persists at the age of 1 year, recovery is unlikely and liver transplantation should be planned.

Table 61.2 Operative procedure and cholangitis (KCH 1970–86)

CENTRAL VENOUS ACCESS Cholangitis is the most serious postoperative complication of hepatic portoenterostomy; paradoxically, it occurs only in patients with successful bile excretion. Cholangitis occurring within 1 month after operation is called ‘early cholangitis’, while cholangitis which develops later is called ‘late cholangitis’. The prognosis of early cholangitis is extremely poor, with a mortality rate of 70–90%.31 We found a combination of a long jejunal Roux-en-Y loop (80 cm) and continuous administration of i.v. antibiotics for the ﬁrst month after operation to be extremely effective in preventing early cholangitis.29,30 To administer the i.v. antibiotics for 1 month after operation, we favor the placing of a Broviac singlelumen catheter (4.2 Fr. gauge) into the external jugular vein using conventional techniques.

POSTOPERATIVE MANAGEMENT The general principle of postoperative management is identical to the care of infants undergoing laparotomy for other reasons. Early postoperative feeding is encouraged considering its favorable effect on liver function. Daily stool specimens are collected to test for

80 cm loop Others

Cholangitis Late None

Patients

Early

15 25

2 (1) 11 (8)

8 (1) 2 (3)

5 2

40

13 (9)

20 (4)

(0) 7 (0)

(): death. J Jpn Societ Pediatr Surg 1988; 24:1254–8. Seven patients underwent laparotomy for the diagnosis of biliary atresia, which was determined by the duodenal tubing procedure. Six of these patients completely recovered from cholestasis several weeks later. One patient who was operated on at the age of one-and-a-half regained bile excretion but failed to recover from persistent jaundice. She died at the age of 9 of hepatic failure.

LONG-TERM FOLLOW-UP AFTER SURGERY FOR PATIENTS WITH BILIARY ATRESIA In 1991, a nationwide registry of biliary atresia patients by Chiba et al.34 collected 98 patients in Japan who underwent surgical treatment. Out of 98 patients, 89 (91%) had bile ﬂow after Kasai procedure and 52 (53%) became subsequently free of jaundice. In 1994, Ibrahim et al.35 reported the result of a prospective study carried out over the following 5 years. Of 629 patients collected in this series, 603 patients (96%) underwent a Kasai

References 587

procedure, and 346 (57%) became free of jaundice after operation. A total of 131 patients were persistently jaundiced, and 120 of them died before the end of study. Of 67 patients followed up for 5 years after operation, 39 (58%) were free of jaundice but 28 patients died. Ohi36,37 reviewed 274 patients who underwent surgical treatment for biliary atresia at Tohoku University between 1953 and 1991. A total of 124 patients (45%) were alive and 100 of them were free of jaundice. The 10-year survival rate was 10% in the patients treated in 1953–67, 27% in 1968–72, 54% in 1973–79, and 71% in 1980–81, indicating that the surgical result improves with the advancement of time. The biliary atresia registry in the USA and Canada collected 670 patients (from 1976–89)38 and reported that the 5- and 10-year actuarial survival rates were 48% and 30%, respectively. The results of these series suggest that approximately 50% of patients who have undergone a Kasai procedure have the chance to survive in a disease-free status for a long time.34–38 For the patients with a failed Kasai procedure, a liver transplantation is the choice procedure, with an expected 80% chance of survival. Controversy exists as to whether a primary liver transplantation should be indicated.39–40 Today’s consensus among pediatric surgeons is to perform a Kasai procedure as a primary operation and a liver transplantation as a secondary back-up procedure when the Kasai procedure fails.41,42 The reasons to choose a Kasai procedure for the primary procedure are: (1) 50% chance of survival after a Kasai procedure, (2) difﬁculty in obtaining a donor for infants, and (3) high cost of liver transplantation.

REFERENCES 1. Hays DM, Kimura K. Biliary atresia: The Japanese experience. Cambridge, MA: Harvard University Press, 1980. 2. Hays DM, Kimura K. Biliary atresia: New concepts of management. Curr Prob Surg 1981; 18:541–608. 3. Ladd WE. Congenital atresia and stenosis of the bile ducts. J Am Med Assoc 1928; 91:1082–5. 4. Kasai M, Watanabe K, Yamagata A et al. Surgical treatment of biliary atresia. Nihon-iji-shinpo 1957; 1730:15–23. 5. Kasai M. Personal communication. 6. Kasai M, Sawaguchi S, Akiyama H et al. A proposal of new classiﬁcation of biliary atresia. J Jpn Soc Pediatr Surg 1976; 12:327–31. 7. Kasai M, Ohi R, Chiba T. Long-term survivors after surgery for biliary atresia. In: Ohi R, editor. Biliary Atresia. Tokyo: Professional Postgraduate Services, 1987:277–80. 8. Suruga K, Miyano T, Kimura K et al. Reoperation in the treatment of biliary atresia. In: Ohi R, editor. Biliary Atresia. Tokyo: Professional Postgraduate Services, 1987:184–7.

9. Altman RP. Results of reoperations for correction of extrahepatic biliary atresia. J Pediatr Surg 1979; 14:305–9. 10. Gartner JR Jr, Zitelli BJ, Malatack JJ et al. Orthotopic liver transplantation in children: Two-year experience with 47 patients. Pediatrics 1984; 74:140–5. 11. Iwatsuki S, Shaw BW Jr, Starzl TE. Liver transplantation for biliary atresia. Wld J Surg 1984; 8:51–6. 12. Cubervas-Monsa V, Rimola A, Van Thiel DH et al. Does previous abdominal surgery alter the outcome of pediatric patients subjected to orthotopic liver transplantation? Gastroenterology 1986; 90:853–7. 13. Park WH, Choi SO, Lee HJ et al. A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy and liver needle biopsy in the evaluation of infantile cholestasis. J Pediatr Surg 1997; 32:1555–9. 14. Sera Y, Ikeda S, Akagi M. Ultrasonographic studies for the diagnosis of infatile cholestatic disease. In: Ohi R, editor. Biliary Atresia. Tokyo: Professional Services, 1987:106–9. 15. Miller JH, Sinatra FR, Thomas DW. Biliary excretion disorders in infants: Evaluation using 99mTC PIPIDA. Am J Roentgenol 1980; 135:47–52. 16. Majd M, Reba RC, Altman RP. Hepatobiliary scintigraphy with 99mTC-PIPIDA in the evaluation of neonatal jaundice. Pediatrics 1981; 67:140–5. 17. Hashimoto S, Tsugawa C, Kimura K et al. Diagnosis of biliary atresia by duodenal tubing. J Jpn Societ Pediatr Surg 1978; 14:889–92. 18. Greene HL, Helinek GL, Moran R et al. A diagnostic approach to prolonged obstructive jaundice by 24-hour collection of duodenal ﬂuid. J Pediatr 1979; 95:412–14. 19. Thaler MM, Gellis SS. Studies in neonatal hepatitis and biliary atresia. Am J Dis Child 1968; 116:257–84. 20. Kasai M, Suzuki H, Ohashi E et al. Technique and results of operative management of biliary atresia. Wld J Surg 1978; 2:571–9. 21. Kimura K, Tsugawa C, Matsumoto Y et al. The surgical management of the unusual forms of biliary atresia. J Pediatr Surg 1979; 14:653–60. 22. Lilly JR. Hepatic portocholecystostomy for biliary atresia. J Pediatr Surg 1979; 14:301–4. 23. Altman RP. Invited commentary. Wld J Surg 1978; 2:557–9. 24. Kasai M, Kimura S, Asakura S et al. Surgical treatment of biliary atresia. J Pediatr Surg 1968; 3:665–75. 25. Kimura K, Tsugawa C, Kubo M et al. Technical aspects of hepatic portal dissection in biliary atresia. J Pediatr Surg 1979; 14:27–32. 26. Sawaguchi S, Nakajo N. Reconstruction of the biliary (Sawaguchi procedure) tract in biliary atresia using jejunal conduit. J Jpn Surg Societ 1968; 69:1317–20. 27. Tanaka K, Shirahase I, Utsunomiya H et al. A valved hepatic portoduodenal intestinal conduit for biliary atresia. Ann Surg 1991; 213:230.

588 Biliary atresia 28. Kaufman BH, Luck SR, Raffensperger J. The evaluation of a valved hepatoduodenal intestinal conduit. J Pediatr Surg 1981; 16:279–83. 29. Kimura K, Tsugawa C, Matsumoto Y. Recent advances in the technique of portoenterostomy for biliary atresia. In: Kassai M, editor. Biliary Atresia and Its Related Disorders. Amsterdam: Excerpta Medica, 1983:174–6. 30. Yamazato M, Kimura K, Nishijima E et al. Biliary atresia: Reconstruction of the biliary tract and cholangitis. J Jpn Societ Pediatr Surg 1988; 24:1254–8. 31. Akiyama H, Saeki M, Ogata T et al. Ascending cholangitis after hepatic portenterostomy (original Roux-en-Y) for biliary atresia. In: Ohi R, editor. Biliary Atresia. Tokyo: Professional Postgraduate Services, 1987:156–60. 32. Kimura K, Hashimoto S, Nishijima E et al. Percutaneous transhepatic cholangio drainage after hepatic portoenterostomy for biliary atresia. J Pediatr Surg 1980; 15:811–16. 33. Kimura K, Muraji T, Ueoka E et al. Percutaneous transhepatic cholangio drainage for patients with biliary atresia. In: Ohi R, editor. Biliary Atresia. Tokyo: Professional Postgraduate Services, 1987:211–15.

34. Chiba T, Ohi R, Kamiyama T et al. Japanese Biliary Atresia Registry. In: Ohi R, editor. Biliary Atresia. Tokyo: Icom Associates, 1991:79–86. 35. Ibrahim M, Miyano T, Ohi R et al. Japanese Biliary Atresia Registry, 1989 to 1994. Tohoku J Exp Med 1997; 181:85–95. 36. Ohi R, Nio M, Chiba T et al. Long term follow-up after surgery for patients with biliary atresia. J Pediatr Surg 1990; 25:442–5. 37. Ohi R, Ibrahim M. Biliary atresia. Semin Pediatr Surg 1992; 1:115–24. 38. Karrer FM, Lilly JR, Stewart BA et al. Biliary Atresia Registry 1976 to 1989. J Pediatri Surg 1990; 25:1076–81. 39. Wood RP, Langnas AN, Stratta RJ et al. Optional therapy for patients with biliary atresia: portoenterostomy (Kasai procedure) versus primary transplantation. J Pediatr Surg 1990; 25:153–62. 40. Azarow KS, Phialips MJ, Sandler AD et al. Biliary atresia: should all patients undergo a portoenterostomy? J Pediatr Surg 1997; 32:168–74. 41. Carceller A, Blanchard H, Alverez F et al. Past and future of biliary atresia. J Pediatr Surg 2000; 35:717–20. 42. Ohi R. Surgery for biliary atresia. Liver 2001; 21:175–82.

62 Congenital biliary dilatation (choledochal cyst) TAKESHI MIYANO AND ATSUYUKI YAMATAKA

INTRODUCTION Congenital biliary dilatation (CBD) is also known as cystic or fusiform dilatation of the common bile duct. CBD is an uncommon anomaly of the biliary tract in Caucasians. There is little doubt that CBD is a congenital lesion with a strong hereditary component, which may explain the higher incidence seen in Asia, and its familial occurrence in siblings and twin.1–3 Approximately half of the affected patients become symptomatic in infancy, and neonatal cases have been uncommon. However, incidence in the newborn is increasing due to advances in diagnostic imaging techniques.4–12 In our series, about 20% of patients were detected either neonatally or antenatally.13 The treatment of CBD in early infancy has unique aspects that must be considered in relation to the risks of surgery itself and the size, and physiological/immunological immaturity of the patient. Because CBD is commonly associated with pancreaticobiliary malunion (PBMU) involving concurrent abnormalities of the common channel, pancreatic duct and intrahepatic ducts, the importance of cholangiography both preoperatively and intraoperatively cannot be overemphasized. If these anomalies go unnoticed by surgeons, they may be damaged during surgery and cause serious postoperative morbidity. Primary cyst excision with biliary reconstruction to avoid two-way reﬂux of bile and pancreatic secretions is now the standard procedure of choice.

ETIOLOGY Various theories have been proposed for the etiology of CBD, but two factors are known to be causal – weakness of the wall of the common bile duct, and obstruction distal to it. Spitz14 stressed an obstructive factor that appears early in development based on his experimental study in sheep, in which cystic dilatation of the common

bile duct could be induced by ligation of the distal end of the choledochus only in neonatal lambs and at no other stages of development. The current authors’ research using different animals also conﬁrms this hypothesis.15–20 Similarly, our radiological and histological studies on patients with CBD clearly demonstrate that distal stenosis is closely associated with cystic dilatation of the common bile duct, and that the site of stenosis is related to an abnormal choledochopancreatic ductal junction16,18,20 In recent years, cholangiography has identiﬁed anomalies of the pancreaticobiliary ductal system in association with CBD, which may allow reﬂux of pancreatic enzymes and subsequent dissolution of duct walls. This is known as the long common channel theory and was ﬁrst proposed by Babbit in 1969.21 Since then, numerous abnormal arrangements of the pancreaticobiliary junction associated with CBD have been reported by others based on the results of endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and intraoperative cholangiography. This theory is further supported by the high amylase content of ﬂuid aspirated from dilated ducts in patients with CBD. A dilated common channel and anomalous pancreatic duct are also frequently observed, which may be responsible for the formation of protein plugs or pancreatic stones, often associated with pancreatitis. In spite of these ﬁndings, controversy surrounds the cause of the stenosis distal to the dilated common bile duct. Babbit21 stressed that pancreatic ﬂuid is the most likely factor causing edema and eventual ﬁbrosis of the distal common bile duct as well as weakness of the choledochal wall. However, the chemical reaction of reﬂuxed pancreatic ﬂuid in the bile duct is extremely mild, according to our animal experiments in which choledochopancreatostomy was performed in puppies to allow regurgitation of pancreatic ﬂuid into the bile duct.22 Interestingly, in this animal model, fusiform rather than cystic dilatation of the common bile duct was induced. Also, it is generally recognized that a number of patients with an anomalous long common channel and high

590 Congenital biliary dilatation (choledochal cyst)

amylase level in the gallbladder, show no dilatation of the choledochus, although some had gallbladder carcinoma.23 The chemical effect of pancreatic ﬂuid on the bile duct has not been clariﬁed in the antenatal period. Although a diagnosis of CBD can be made antenatally as early as 15–20 weeks’ gestation,7,10–12 pancreatic acini are only just beginning to appear at this stage, zymogen granules are immature, and there is no evidence of secretion seen on electron microscopy.24 Even in the newborn, the pancreas has not matured enough to produce functional enzymes,25 so the role of pancreatic ﬂuid in CBD formation may be over-rated. Jona et al.26 purported that the pathogenesis of CBDassociated PBMU may be related to faulty budding of the primitive ventral pancreas. Tanaka27,28 proposed that regression of the terminal choledochus and canalization of the ventral pancreatic duct (W1) caused by sinistral dislocation of the ventral pancreas are responsible for PBMU. From research on human fetuses, Wong and Lister29 demonstrated that the choledopancreatic junction lies outside the duodenal wall before the eighth week of gestation, whereupon it moves inward toward the duodenal lumen, suggesting that an anomalous junction may be caused by arrest of this migration. Based on these radiological and experimental studies, the current authors believe that an anomalous choledochopancreatic duct junction combined with congenital stenosis are the basic causative factors of CBD at least in perinatal and young infants rather than weakness

of the duct wall caused by reﬂux of pancreatic ﬂuid. Both PBMU and stenosis are associated with abnormal development of the ventral pancreatic duct and biliary ductal system.

CLASSIFICATION Alonso-Lej et al.,30 Todani et al.,31 and Komi et al.32 have described classiﬁcations for CBD based on anatomy and cholangiography of the hepatobiliary ductal system or PBMU. Figure 62.1 presents the classiﬁcation used by the current authors.

CLINICAL SIGNS AND SYMPTOMS Clinical manifestations of CBD differ according to age. Neonates and young infants usually present with an abdominal mass, jaundice, and acholic stools. Some present with a huge upper abdominal mass with or without jaundice. Some cases can resemble correctable biliary atresia except that with CBD, there is a patent communication with the duodenum and a welldeveloped intrahepatic bile duct tree. In older children, the classical triad of pain, mass and jaundice may be present. Fever and vomiting may also occur. The pattern of pain has been described as being similar to that of

(a)

(b)

(c)

(d)

(e)

(f)

Figure 62.1 Classiﬁcation of choledochal cyst. With PBMU: (a) Cystic dilatation of the extrahepatic bile duct. (b) Fusiform dilatation of the extrahepatic bile duct. (c) PBMU without biliary dilatation. Without PBMU: (d) Cystic diverticulum of the common bile duct. (e) Choledochocele (diverticulum of the distal common bile duct). (f) Intrahepatic bile duct dilatation alone (Caroli’s disease)

Surgery 591

recurrent pancreatitis, in which a high serum amylase level is often present. However, in our series, there was little clinical evidence of pancreatitis in the newborn, because amylase levels were not found to be elevated. The signs and symptoms of incidental CBD differ somewhat from those seen in symptomatic older children, but the essentials of their management are the same.

DIAGNOSIS Currently, abdominal ultrasonography is the best method for detecting CBD, even though it does not permit visualization of the entire ductal system and it is not clear enough to demonstrate an undilated common channel and pancreatic duct. However, routine antenatal ultrasound performed mainly for dating purposes has been of increasing value for detecting fetal anomalies,4–13 and the number of neonates detected as having incidental CBD has increased signiﬁcantly (Fig. 62.2). For a complete diagnosis of CBD, it is also important to investigate for coexisting PBMU, abnormalities of the pancreatic duct, intrahepatic ducts and extrahepatic duct. ERCP can accurately visualize the conﬁguration of the pancreaticobiliary ductal system in detail, and is unlikely to be replaced by other investigations, especially in cases where ﬁne detail is required preoperatively. ERCP is routinely performed in the diagnosis of biliary malformations in infants and the newborn in many centers in Japan, with a reasonable success rate.33 However, it is an invasive procedure and therefore is unsuitable for repeated use, and is contraindicated during acute pancreatitis. The current authors and others34,35 have shown that magnetic resonance cholangiopancreatography (MRCP) can provide excellent visualization of the pancreaticobiliary ducts in patients with CBD allowing narrowing,

dilatation and ﬁlling defects of the ducts to be detected with medium to high degrees of accuracy (Fig. 62.3). Because MRCP is non-invasive, it can partially replace ERCP as a diagnostic tool for the evaluation of anatomical anomalies of the pancreaticobiliary tract, where it is available, but there are limitations of patient size, weight and age for the use of MRCP. Another advantage of MRCP over ERCP is that the pancreatic duct can be visualized upstream to an obstruction or area of stenosis. Once the quality of MRCP improves, ERCP may become optional. If preoperative imaging can allow clear visualization of the entire biliopancreatic ductal system, including the intra- and extrahepatic bile ducts, and pancreatic duct in detail, intraoperative cholangiography is unnecessary; however, if sufﬁcient information is not obtained, it must be performed. Furthermore, if the cyst is too large, intraoperative cholangiography via the gallbladder or directly via the common bile duct is useless. In such cases, intraoperative cholangiography should be performed separately for the intrahepatic bile duct and distal common bile duct by a selective technique during excision of the cyst.

Figure 62.3 Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatogram (MRCP) performed on the same patient showing dilatation of the extrahepatic duct and pancreaticobiliary malunion

SURGERY Choice of operative procedure

Figure 62.2 Antenatal ultrasound at 32 weeks’ gestation. Sagittal view. A cystic structure is seen to be connected to the liver via a short duct (arrow). BI: bladder

Cyst excision with Roux-en-Y hepatoenterostomy is currently the deﬁnitive treatment for CBD regardless of age or symptomatology because of the high rate of morbidity and high risk of carcinoma after internal drainage, a commonly used treatment in the past. The only differences in treatment are the types of biliary reconstruction used. Although most surgeons use a Roux-en-Y hepaticojejunostomy, some36,37 recommend a wide anastomosis at the level of the hepatic hilum to allow free drainage of bile in order to prevent postoperative anastomotic stricture and stone formation. Based on the current authors’ wealth of experience,38 they recommend conventional hepaticoenterostomy as the treatment of choice. Hepaticoenterostomy at the hepatic

592 Congenital biliary dilatation (choledochal cyst)

hilum is indicated in speciﬁc cases only, such as in patients with dilated intrahepatic bile ducts with stenosis in the common hepatic duct, or adolescent patients with severe inﬂammation of the common hepatic duct.

Cystoscope

Timing of surgery Neonates with choledochal cysts should receive standard medical management and nutritional support pre- and postoperatively; the importance of thorough preoperative assessment cannot be overemphasized. There are very few reports on the management of asymptomatic CBD detected in the antenatal or neonatal period. Some pediatric surgeons recommend primary cyst excision soon after diagnosis.6,9,11,39,40 In the current authors’ experience,13,41,42 cyst excision need not be performed hastily in these young infants; rather they should be thoroughly assessed and surgery should be planned and performed by experienced, well-trained pediatric surgeons. In cases of bile peritonitis following perforation, severe cholangitis, poor general condition, or huge dilated CBD in neonates, external biliary drainage is recommended by either percutaneous transhepatic cholangio drainage or direct percutaneous cyst drainage. Subsequently, delayed primary excision may be carried out 3–6 months later.

Complete excision According to the current authors’ investigations,13 the ratio of cystic to fusiform-type CBD antenatally or neonatally is 20:1, in contrast to an overall ratio of 5:3. Complete (full-thickness) excision of the cyst is much easier in young infants, because the wall of the dilated common bile duct is generally thin and there are few adhesions to surrounding structures, such as the portal vein.43,44 Aspiration of the cyst prior to dissection makes surgery easier if the cyst is large. The cyst should be incised in the middle portion close to the duodenum, because there is often an anomalous opening of the hepatic duct, i.e. a separate opening or opening into the distal part of the cyst. The cyst is then transected after careful circumferential dissection from the hepatic artery and portal vein. Subsequently, the distal portion is dissected and excised, taking care to completely remove the dilated segment at the level of the caliber change in order to prevent malignant transformation of the remaining cyst epithelium. If there is no distinct caliber change (i.e. fusiform type), the cyst should be excised just above the choledochopancreatic junction, and the stump double-sutured, ligated, and transected (Fig. 62.4). If a protein plug is found in the common channel, it must be washed out toward the duodenum to avoid postoperative stone formation and pancreatitis. Finally, the common hepatic duct is transected at the level of

Pancreatic duct 1 2 3

Common channel Debris, protein plug

Figure 62.4 Diagram of intraoperative endoscopy of the bile duct distal to a cyst with debris and a protein plug. After identiﬁcation of the oriﬁce of the pancreatic duct, the cyst is excised at level ‘2’. If excised at level ‘1’, there is likelihood of leaving residual cyst, level ‘2’ is the appropriate level for excision, and if excised at level ‘3’ there is likelihood of injuring the pancreatic duct

distinct caliber change to leave an adequate length for the hepatoenterostomy.

Mucosectomy When complete excision of the distal portion is difﬁcult, mucosectomy40,42 of the distal portion of the cyst is recommended, in order to avoid damage to the pancreatic duct, hepatic artery and portal vein, and also to prevent the residual epithelium of the distal portion of the cyst from undergoing malignant transformation. However, in neonates, mucosectomy is rarely indicated because there is little inﬂammation around the cyst wall.

Biliary reconstruction Biliary reconstruction in neonates and young infants is technically involved because anastomoses are often small and so should only be undertaken by experienced pediatric surgeons. Some surgeons overcome this problem by partially incising the mouth of the stoma of the anastomosis to widen it. On occasions, the current authors have encountered luminal stenosis of macroscopically normal common hepatic ducts at the time of cyst excision, which was considered to be secondary to ﬁbrosis, probably as a consequence of inﬂammation associated with previous perforation.

Associated anomalies requiring treatment 593

Although an end-to-side anastomosis was initially used, the current authors now prefer end-to-end, because the drainage is smoother and more direct, with less possibility of bile stasis (Fig. 62.5). With an end-toside anastomosis, the current authors have experienced overgrowth of the blind end, causing bowel obstruction in one case, and bile stasis in the blind pouch causing bowel obstruction in another.38 Bile stasis in the blind pouch can also cause stone formation in the pouch or dilatation of the intrahepatic bile ducts. However, the current authors’ results do not compel them to resort to other procedures such as hepaticoenterostomy at the hilum and valved jejunal interposition hepaticoduodenostomy to prevent reﬂux of digested food into the intrahepatic bile duct.36 Although these operations appeal theoretically, there is no signiﬁcant difference in morbidity if any of these procedures are performed. Hepaticoenterostomy at the hepatic hilum is more difﬁcult than conventional hepaticoenterostomy, particularly in neonates and young infants without intra-hepatic bile duct (IHBD) dilatation, and valved jejunal interposition hepaticoduodenostomy is a complicated procedure.

ASSOCIATED ANOMALIES REQUIRING TREATMENT Intrahepatic bile duct dilatation Recently, more attention has been paid to the treatment of intrahepatic ductal anomalies such as intrahepatic duct dilatation with downstream stenosis, which is strongly associated with late postoperative complications.38,45–52 In our series,13 eight of 21 neonatal patients (38.1%) had intrahepatic bile duct dilatation (in one it was severe, and was still persistent at follow-up 14 years later). This incidence of intrahepatic duct dilation is remarkably lower than that in older children (53.3%).38 Dilatation of the intrahepatic bile duct can be treated by segmentectomy of the liver, intrahepatic cystoenterostomy or balloon dilatation of the stenosis at the time of cyst excision.48–50 The current authors have treated stricture of the intrahepatic bile duct at the hepatic hilum by intrahepatic ductoplasty and cystojejunostomy or hepaticojejunostomy at the hepatic hilum in three

(a)

(b)

(c)

Figure 62.5 (a) Conventional hepaticoenterostomy. (b) Intrahepatic cystoenterostomy after excision of the stenosed portion of the common hepatic duct. (c) Hepaticoenterostomy at the hepatic hilum, with a wide stoma created by incising the lateral walls of the hepatic ducts

594 Congenital biliary dilatation (choledochal cyst)

cases,38,51 creating a wide stoma by incising along the lateral wall of the hepatic ducts following excision of the narrowed segment of the common hepatic duct (Fig. 62.5). By using intraoperative endoscopy, the ideal level of resection of the common hepatic duct can be safely determined without injuring the oriﬁces of the hepatic duct or leaving a redundant duct.

Disorders of pancreatic duct and common channel Disorders of the pancreatic duct and common channel are only rarely symptomatic in neonates and young infants, and can include pathology such as stenosis of the papilla of Vater, stricture of the pancreatic ducts, protein plugs, or even a septate common channel.32,52–54 Stone debris in the common channel and intrahepatic ducts can also be responsible for postoperative abdominal pain, pancreatitis, stone formation, or jaundice and should be removed at the time of radical surgery. The current authors have found intraoperative endoscopic examination of the common channel and intrahepatic duct to be of enough value to include it as a routine procedure during standard surgical treatment of CBD, because it is extremely efﬁcient for examination and irrigation, and allows all distal pancreatic duct stone debris and stone debris in the common channel to be removed. If stenosis of the major papilla with a dilated common channel is found, a transduodenal papilloplasty or endoscopic papilloplasty should be performed.52

INTRAOPERATIVE ENDOSCOPY Since 1986, the current authors have routinely performed intraoperative endoscopy of the common channel, pancreatic duct and intrahepatic duct to examine the duct system directly for stone debris and duct stenosis, and to remove stone debris by irrigation with normal saline38(Fig. 62.4). They use a pediatric cystoscope or ﬁne ﬁberscope with a ﬂush channel to view the pancreatic and biliary duct systems directly at the time of cyst excision.52,55 In other cases, a neonatal cystoscope, a ﬁne ﬂexible scope (1.9–2.0 mm) with a ﬂush channel is required.

time and higher costs, which, however, may be offset by a shorter hospital stay.

POSTOPERATIVE COMPLICATIONS AND MANAGEMENT The surgical outcome is better and early morbidity lower in younger children than in older children. The current authors58 reviewed 200 children and 40 adults who underwent cyst excision and hepatico-enterostomy (CEHE) and found that 18 out of 200 (9.0%) of children developed complications post-CEHE. No stone formation was seen in the 145 children who had CEHE before the age of 5 years in our series. The 18 children had 25 episodes of complications post-CEHE including cholangitis, intrahepatic bile duct stone formation, pancreatitis, stone formation in the intrapancreatic terminal choledochus or pancreatic duct, and bowel obstruction. There were no complications in the 70 children who had intraoperative cyst endoscopy in our series.58 Stones developed in seven (12.7%) of the 55 children who had CEHE over the age of 5. For management of complications, reoperation was required in 15 children – revision of hepaticoenterostomy in four, percutaneous transhepatic cholangioscopic lithotomy in one, excision of intrapancreatic terminal choledochus in two, endoscopic sphincterotomy of the papilla of Vater in one, pancreaticojejunostomy in one, and laparotomy for bowel obstruction in six. Careful long-term follow-up is required, particularly in patients with intrahepatic bile duct dilatation and also dilatation of the remaining distal bile duct, pancreatic duct and common channel, because there is a risk of chronic inﬂammation, stone formation, as well as the possibility of carcinoma arising at a later stage.

ACKNOWLEDGEMENT The authors deeply thank Dr Long Li for preparation of the ﬁgures.

REFERENCES LAPAROSCOPIC/VIDEO-ASSISTED CYST EXCISION Recent advances in laparoscopy technology have enabled pediatric/hepatobiliary surgeons to perform minimally invasive surgery for CBD.56,57 Although the procedure is technically demanding and the long-term follow-up results remain unknown, experienced laparoscopic surgeons can obtain results as good as those for open surgery. The disadvantages are mainly the longer surgical

1. Iwafuchi M, Ohsawa Y, Naito S. Familial occurrence of congenital bile duct dilatation. J Pediatr Surg 1990; 25:353–5. 2. Ando K, Miyano T, Fujimoto T et al. Sibling occurrence of biliary atresia and biliary dilatation. J Pediatr Surg 1996; 31:1302–4. 3. Lane GJ, Yamataka A, Kobayashi H, Segawa O, Miyano T. Different types of congenital biliary dilatation in dizygotic twins. Pediatr Surg Int 1999; 15:403–4.

References 595 4. Dewbury KC, Aluwihare APR, Birch SJ et al. Prenatal ultrasound demonstration of a choledochal cyst. Br J Radiol 1980; 53:906–7. 5. Frank JL, Chirathivat S, Sfakianakis GN et al. Antenatal observation of a choledochal cyst by sonography. Am J Roentgenol 1981; 137:166–8. 6. Howell CG, Templeton JM, Weiner S et al. Antenatal diagnosis and early surgery for choledochal cyst. J Pediatr Surg 1983; 18:387–93. 7. Marchildon MB. Antenatal diagnosis of choledochal cyst: the ﬁrst four cases. Pediatr Surg Int 1988; 3:431–6. 8. Wiedman MA, Tan AA, Martinez CJ. Fetal sonography and neonatal scintigraphy of a choledochal cyst. J Nucl Med 1985; 26:893–6. 9. Elrad H, Mayden KL, Ahart S. Prenatal ultrasound diagnosis of choledochal cyst. J Ultrasound Med 1985; 4:893–6. 10. Schroeder D, Smith L, Prain HC. Antenatal diagnosis of choledochal cyst at 15 weeks gestation: Etiologic implications and management. J Pediatr Surg 1989; 24:936–8. 11. Bancroft JD, Buncuvalas JC, Ryckman FC. Antenatal diagnosis of choledochal cyst. J Pediatr Gastroenterol Nutr 1994; 18:142–5. 12. Galliran EK, Crombleholme TM, D’Alton ME. Early prenatal diagnosis of choledochal cyst. Prenat Diagn 1996; 16:934–7. 13. Lane GJ, Yamataka A, Kohno S, Fujiwara T, Fujimoto T, Sunagawa M, Miyano T. Choledochal cyst in the newborn. Asian J Surg 1999; 22:310–312. 14. Spitz L. Experimental production of cystic dilatation of the common bile duct in neonatal lambs. J Pediatr Surg 1977; 12:39–42. 15. Miyano T, Suruga K, Kimura K, Suda K. A histopathologic study of the region of the ampulla of Vater in congenital biliary atresia. Jpn J Surg 1980; 10:34–328. 16. Suda K, Matsumoto Y, Miyano T et al. A narrow duct segment distal to choledochal cyst. Am J Gastroenterol 1991; 86:1259–63. 17. Miyano T, Suruga K, Chen SC. A clinicopathological study of choledochal cyst. World J Surg 1980; 4:231–8. 18. Miyano T, Suruga K, Suda K. Abnormal choledochopancreaticoductal junction related to the etiology of infantile obstructive jaundice. J Pediatr Surg 1979; 14:16–25. 19. Suda K, Miyano T. An abnormal pancreatico-choledochalductal junction in cases of biliary tract carcinoma. Cancer 1983; 52:2086–8. 20. Miyano T, Takahashi A, Suruga K. Congenital stenosis associated with abnormal choledocho-pancreatico-ductal junction in concerning the pathogenesis of congenital dilatation of biliary tract. Jpn J Pediatr Surg 1978; 10:539–54. 21. Babbit DP. Congenital choledochal cyst: new etiological concept based on anomalous relationships of common bile duct and pancreatic bulb. Ann Radiol 1969; 12:231–41.

22. Miyano T, Suruga K, Kuda K. The choledocho-pancreatic long common channel disorders in relation to the etiology of congenital biliary dilatation and other biliary tract disease. Ann Acad Med 1981; 10:419–26. 23. Tanaka K, Nishimura A, Yamada K, Ishibe R, Ishizaki N, Yoshimine M, Hamada N, Taira A. Cancer of the gallbladder associated with anomalous junction of the pancreatobiliary duct system without bile duct dilation. Br J Surg 1993; 80:622–4. 24. Laitio M, Lev R, Orlic D. The developing human fetal pancreas: An ultrastructural and histochemical study with special reference to exocrine cells. J Anat 1974; 117:619–34. 25. Lebenthal E, Lee PC. Development of functional response in the human exocrine pancreas. Pediatrics 1980; 66:556–60. 26. Jona JZ, Babbit DP, Starshak RJ et al. Anatomic observations and etiologic and surgical considerations in choledochal cyst. J Pediatr Surg 1979; 14:315–20. 27. Tanaka T. Embryological development of the duodenal papilla and related diseases: primitive ampulla theory. Am J Gastroenterol 1993; 88:1980–1. 28. Tanaka T. Pathogenesis of choledochal cyst. Am J Gastroenterol 1995; 90:685. 29. Wong KC, Lister J. Human fetal development of the hepato-pancreatic duct junction; a possible explanation of congenital dilatation of the biliary tract. J Pediatr Surg 1981; 16:139–45. 30. Alonso-Lej F, Rever WB, Pessagno GJ et al. Congenital choledochal cyst, with a report of 2, and an analysis of 94 cases. Int Abstr Surg 1959; 108:1–30. 31. Todani T, Narusue M, Tabuchi K, Okajima K. Management of congenital choledochal cyst with intrahepatic involvement. Ann Surg 1977; 187:272–80. 32. Komi N, Takehara H, Kunitomo K, Miyoshi Y, Yagi T. Does the type of anomalous arrangement of pancreaticobiliary ducts inﬂuence the surgery and prognosis of choledochal cyst? J Pediatr Surg 1992; 27:728–31. 33. Iinuma Y, Narisawa R, Iwafuchi M et al. The role of endoscopic retrograde cholangiopancreatography in infants with cholestasis. J Pediatr Surg 2000; 35:545–9. 34. Yamataka A, Kuwatsuru R, Shima H et al. Initial experience with non-breath-hold magnetic resonance cholangiopancreatography: A new noninvasive technique for the diagnosis of choledochal cyst in children. J Pediatr Surg 1997; 32:1560–2. 35. Shimizu T, Suzuki R, Yamashiro Y, Segawa O, Yamataka A, Miyano T. Progressive dilatation of the main pancreatic duct using magnetic resonance cholangiopancreatography in a boy with chronic pancreatitis. J Pediatr Gastroenterol Nutr 2000; 30:102–4. 36. Todani T, Watanabe Y, Mizuguchi T, Fujii T, Toki A. Hepaticoduodenostomy at the hepatic hilum after excision of choledochal cyst. Am J Surg 1981; 142:584–7. 37. Todani T, Watanabe Y, Toki A et al. Reoperation for congenital choledochal cyst. Ann Surg 1988; 207:142–7.

596 Congenital biliary dilatation (choledochal cyst) 38. Miyano T, Yamataka A, Kato Y, Segawa O, Lane GJ, Takamizawa S, Kohno S, Fujiwara T. Hepaticoenterostomy after excision of choledochal cyst in children: A 30-year experience with 180 cases. J Pediatr Surg 1996; 31:1417–21. 39. Burnweit CA, Birken GA, Heiss K. The management of choledochal cysts in the newborn. Pediatr Surg Int 1996; 11:130–3. 40. Suita S, Shono K, Kinugasa Y, Kubota M, Matsuo S. Inﬂuence of age on the presentation and outcome of choledochal cyst. J Pediatr Surg 1999; 34:1765–8. 41. Miyano T. Congenital biliary dilatation. In: Puri P, editor. Newborn Surgery. Oxford: Butterworth-Heinemann 1996; 433–9. 42. Miyano T, Yamataka A. Choledochal cysts. Curr Opin Pediatr 1997; 9:283–8. 43. Filler RM, Stringel G. Treatment of choledochal cyst by excision. J Pediatr Surg 1980; 15:437–42. 44. Somasundaram K, Wong TJ, Tan KC. Choledochal cyst: a review of 25 cases. Aust NZ J Surg 1985; 55:443–6. 45. Todani T, Watanabe Y, Toki A et al. Reoperation for congenital choledochal cyst. Ann Surg 1988; 207:142–7. 46. Ohi R, Yaoita S, Kamiyama T, Ibrahim M, Hayashi Y, Chiba T. Surgical treatment of congenital dilatation of the bile duct with special reference to late complications after total excision operation. J Pediatr Surg 1990; 25:613–17. 47. Ando H, Ito T, Kaneko K, Seo T, Ito F. Intrahepatic bile duct stenosis causing intrahepatic calculi formation following excision of a choledochal cyst. J Am Coll Surg 1996; 183:56–60. 48. Engle J, Salmon PA. Multiple choledochal cysts. Arch Surg 1964; 88:345–9. 49. Todani T, Narusue M, Watanabe Y, Tabuchi K, Okajima K. Management of congenital choledochal cyst with intrahepatic involvement. Ann Surg 1977; 187:272–80.

50. Tsuchida Y, Taniguchi F, Nakahara S, Uno K, Kawarasaki H, Inoue Y, Nishikawa J. Excision of a choledochal cyst and simultaneous hepatic lateral segmentectomy. Pediatr Surg Int 1996; 11:496–7. 51. Miyano T, Yamataka A, Kato S, Kohno S, Fujiwara T. Choledochal cyst: special emphasis on the usefulness of intraoperative endoscopy. J Pediatr Surg 1995; 30:482–4. 52. Yamataka A, Segawa O, Kobayashi H, Kato Y, Miyano T. Intraoperative pancreatoscopy for pancreatic duct stone debris distal to the common channel in choledochal cyst. J Pediatr Surg 2000; 35:1–4. 53. Miyano T, Suruga K, Shimomura H. Choledochopancreatic elongated common channel disorders. J Pediatr Surg 1984; 19:165–70. 54. Kaneko K, Ando H, Ito T. Protein plugs cause symptoms in patients with choledochal cysts. Am J Gastroenterol 1997; 92:1018–21. 55. Miyano T, Yamataka A, Kato Y. Choledochal cysts: special emphasis on the usefulness of intraoperative endoscopy. J Pediatr Surg 1995; 30:482–4. 56. Shimura H, Tanaka M, Shimizu S, Mizumoto K. Laparoscopic treatment of congenital choledochal cyst. Surg Endosc 1998; 12:1268–71. 57. Farello GA, Cerofolini A, Rebonato M, Bergamaschi G, Ferrari C, Chiappetta A. Congenital choledochal cyst: video-guided laparoscopic treatment. Surg Laparosc Endosc 1995; 5:354–8. 58. Yamataka A, Ohshiro K, Okada Y, Hosoda Y, Fujiwara T, Kohno S, Sunagawa M, Futagawa S, Sakakibara N, Miyano T. Complications after cyst excision with hepaticoenterostomy for choledochal cysts and their surgical management in children versus adults. J Pediatr Surg 1997; 32:1097–102.

63 Hepatic cysts and abscesses DAVID A. PARTRICK AND FREDERICK M. KARRER

INTRODUCTION Cysts and abscesses of the liver in the neonatal period are uncommon. Hepatic cysts presenting in infants are usually simple, unilocular cysts, with polycystic liver diseases presenting later in childhood or in adulthood. Most abscesses in infants are pyogenic with parasitic infections occurring in older children or adults. Crosssectional imaging studies (ultrasound, computed tomography, magnetic resonance imaging) now make work-up and localization straightforward. Treatment however still requires experience and judgment to prevent recurrences and complications.

Presentation Most congenital cysts do not have any clinical manifestations in infancy and are not diagnosed until the patient is an older age (in the fourth or ﬁfth decades of life). Some are discovered prenatally or incidentally during work-up of unrelated problems.5 When they are symptomatic in infancy, it is usually because of an upper abdominal mass.6–8 They rarely cause symptoms from compression of other structures, e.g. vomiting. Hemorrhage, secondary infection, rupture or torsion can lead to an acute abdominal condition but such complications are extremely rare.9

Diagnosis SIMPLE HEPATIC CYSTS Simple or solitary cysts in infants can be congenital or acquired in origin. Parasitic cysts (from hydatid disease) are rare in children and have never been reported in infancy. Congenital cysts probably arise from defective fusion or obstruction in intrahepatic bile ducts during development.1 These cysts are usually single and unilocular but septation has been reported.2 They are well encapsulated with a smooth surface. Most common in the right lobe, they abut or hang down from the liver edge.3 The liver almost never completely covers the cyst, especially the pedunculated cysts, so the presenting portion has a bluish hue. The internal cyst wall is lined by simple cuboidal or columnar epithelium.4 Most contain clear ﬂuid, but it may be brownish because of remote hemorrhage. If the cyst ﬂuid is bilious (rare), that indicates communication with a biliary radical. Acquired or post-traumatic cysts may result from blunt trauma or birth trauma causing an intrahepatic hematoma. The hematoma reabsorbs leaving behind a cyst cavity. These cysts are lined by granulation tissue and ﬁbrosis and rarely communicate with the biliary tree.

Cysts large enough to be detected on physical examination are easily distinguished from solid tumors by ultrasonography. Liver function is typically normal in spite of the impressive size of these cysts. Plain radiographs may show diaphragmatic elevation or a soft tissue mass displacing the gas pattern in the abdomen. Computed tomography (CT) is useful to identify the exact location and number of cysts. Other preoperative imaging techniques (cholangiography, angiography, nuclear scans) may provide additional information but are usually unnecessary.

Treatment Small asymptomatic cysts (<5 cm) discovered incidentally should be left alone. Large or symptomatic cysts should be treated surgically. Percutaneous cyst aspiration may rule out biliary communication or abscess, but is not deﬁnitive therapy because of a high recurrence rate.10 Complete resection is optimal and can be accomplished easily when the cyst is pedunculated. If complete excision cannot be accomplished by simple enucleation, formal lobectomy is not indicated. These are benign lesions, therefore the risk of treatment should not exceed the risk

598 Hepatic cysts and abscesses

of the disease. Under these circumstances, partial excision is preferred. By unrooﬁng at least one-third of the cyst cavity, any serous drainage will be reabsorbed by the peritoneal cavity.11 The edges of the cyst can be managed by oversewing with a running absorbable suture or by electrocautery. If the cyst contains bile and cholangiography conﬁrms communication of the cyst with the biliary tree, then internal drainage via Roux-en-Y cystojejunostomy is indicated. Infected cysts should be drained externally (infra vide).

Prognosis The prognosis for infants with simple hepatic cysts is excellent. The rate of mortality and cyst recurrence should approach zero. 5,12,13

endoscopic treatment or portosystemic shunting is preferred. Hepatic synthetic function is usually preserved and the portal hypertension may improve in adolescence as other collaterals develop. Therefore, liver transplantation is usually not needed. Rarely, ﬁbrosis is accompanied by cystic dilation of intrahepatic biliary ducts like in Caroli’s disease. This rare variant does not require treatment in infancy.17 The named sub-groups of ARPKD aid discussion but are far from distinct. There is, in fact, considerable overlap among individuals and within families. In infancy, the treatment of ARPKD only addresses the renal and consequent pulmonary insufﬁciency. No treatment is required for the hepatic lesion.

HEPATIC ABSCESSES POLYCYSTIC LIVER DISEASE When liver cysts develop throughout the liver in high number, it is usually in association with an inherited polycystic disease. The two main variants of polycystic disease are autosomal dominant (adult type) and autosomal recessive (child type).14 Both are associated with polycystic disease of the kidney. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form (90%). Symptoms of renal involvement (pain, hypertension, renal failure, urinary tract infection) usually don’t develop until adulthood. Liver cysts in ADPKD are exceptionally rare in childhood and have not been seen in infancy. Autosomal-recessive polycystic kidney disease (ARPKD) presents in childhood. There are four subgroups (perinatal, neonatal, infantile, juvenile), with varying degrees of involvement of the kidneys and liver.15 The most severe cases present perinatally with oligohydramnios, Potter’s syndrome, pulmonary hypoplasia and usually die shortly after birth. Patients with lesser degrees of renal involvement present at an older age with renal failure and hypertension. In some children, renal involvement is minor and they don’t present until adolescence with symptoms of portal hypertension such as variceal bleeding.16 In all forms of ARPKD, the liver is not usually grossly cystic. The liver abnormality is called congenital hepatic ﬁbrosis. Microscopically there is bile duct proliferation with irregular broad bands of ﬁbrous tissue containing multiple microscopic cysts formed by disordered terminal bile ducts, chieﬂy in the portal areas. The incidence of portal hypertension in ARPKD increases with longevity and appears to be inversely related to the severity of the renal disease. Treatment for portal hypertension is not required in infancy since it takes time for esophageal varices with the tendency to bleed to develop. If portal hypertension leads to esophageal bleeding,

Incidence and etiology The most common source of hepatic abscess in children has historically been perforated appendicitis, but the incidence in this population has decreased since the introduction of antibiotics. It is now more commonly seen in children with an underlying immune deﬁciency.18 Although approximately 50% of children with pyogenic hepatic abscess are less than 6 years old, neonatal hepatic abscesses are rare. However, they can deﬁnitely be lethal in this vulnerable population. In a recent review, only 18 neonatal cases of solitary hepatic abscess were identiﬁed in the English literature from 1900.19 In an earlier review, 24 cases were identiﬁed historically (including cases of multiple abscesses) to which the authors added an additional 13.20 Neonatal liver abscess seems to differ considerably from the disease in older children (Table 63.1). The patent umbilical vein in neonates provides ready access for bacteria to the liver, and umbilical vessel catheterization is a signiﬁcant predisposing factor in hepatic abscess formation.21,22 In hospitalized infants, umbilical vein catheters allow bacteria colonizing the umbilical stump a more direct route to the liver. Less common sources of liver abscesses are inoculation via the portal vein from necrotizing enterocolitis,23 isolated bowel perforations, and other intra-abdominal infections of the newborn. Bacteremia from meningitis or another septic insult can also result in hepatic abscesses via the hepatic artery.24 Multiple pyogenic hepatic abscesses can

Table 63.1 Predisposing factors for neonatal hepatic abscess Prematurity (immunoincompetence) Umbilical vein catheterization (colonizing organisms) Omphalitis Intra-abdominal infection\ (NEC, bowel perforation) Bacteremia (meningitis)

Hepatic abscesses 599

complicate neonatal sepsis. Hepatic abscess has also been reported to be a rare complication of ventriculoperitoneal shunts (six cases have been reported in the literature, primarily in older patients).25 In the last decade, the majority of neonatal cases of hepatic abscess have occurred in premature neonates who are relatively immunoincompetent and have undergone umbilical vessel catheterization (Fig. 63.1).19 The infecting organisms in neonates are more often Gram negative than Gram positive. Kays13 recently reviewed the infectious causes of pyogenic liver abscesses, and in 22 neonates (< 1 month of age) Grampositive aerobes accounted for only 27% of abscesses, whereas Gram-negative aerobes were responsible for 73%. Fungus was the infectious source in 5% (one patient, although an additional case has since been reported19), and anaerobic organisms have not been isolated from any neonatal liver abscess reported in the literature. This is in contrast to older children with hepatic abscess, in which up to 50% of infecting organisms isolated are Gram positive, 25% are Gram negative, 10% are anaerobic, 6% are fungal, and the remainder are of unknown (cryptogenic) etiology. Others have noted polymicrobial infections in up to 50% of hepatic abscesses.26

Figure 63.1 CT scan of a large hepatic abscess in a 5-day-old neonate

sedimentation rate as well as C-reactive protein may be present. In the majority of patients, liver function tests are normal, but direct and indirect hyperbilirubinemia, elevation of the alkaline phosphatase, elevation of serum transaminase, anemia, and hypoalbuminemia have all been reported.18 Therefore, to make the diagnosis in neonates, a high index of suspicion is necessary in conjunction with appropriate imaging techniques.

Radiographic evaluation Plain ﬁlms may suggest the diagnosis of hepatic abscess by the presence of an elevated right hemidiaphragm and right pleural effusion. Sometimes a gas shadow can be visualized in the liver itself, corresponding to the abscess cavity. Improvements in abdominal ultrasound and CT scanning now allow for a more rapid and accurate diagnosis in neonates.27 Ultrasound has the advantage of lower cost, no radiation exposure, relative convenience, and ease of repeating the exam (no sedation is required and the equipment is portable).28,29 A hepatic abscess typically shows low or variable echogenicity by ultrasound, and cystic lesions as small as 1 cm can be identiﬁed separately from liver parenchyma. CT scanning has demonstrated an increased sensitivity compared with ultrasound and it gives a clearer deﬁnition of the abscess.18 The abscess margins variably enhance with the use of i.v. contrast. Figure 63.1 demonstrates the appearance on CT scan of a large hepatic abscess in a 5-day-old full-term baby. This neonate had an umbilical venous catheter in place with progressive hepatomegaly on physical examination. Included in the differential diagnosis of this cystic mass were hepatoblastoma, infantile hemangioendothelioma, mesenchymal hamartoma, and other rare liver tumors. Any neonate with persistent fever and suggestion of upper abdominal tenderness or an enlarged liver should undergo radiographic examination, especially if risk factors are present. If the ultrasound appears normal but clinical suspicion remains high, CT scanning should be performed. Speciﬁc diagnosis requires aspiration of the lesion with Gram stain and culture leading to subsequent identiﬁcation of the infecting organism.

Treatment Presentation and diagnosis The clinical diagnosis of neonatal hepatic abscess remains difﬁcult. The classic ﬁndings of fever, hepatomegaly, and right upper quadrant pain are seldom obvious in the neonate. Signs and symptoms of sepsis may be present, but many infants are simply noted to be irritable with only mild abdominal distention or tenderness. A rapidly enlarging and tender liver is characteristic of a hepatic abscess, but this is not commonly found on clinical examination. Fever, leukocytosis, elevation of the

Systemic antibiotic therapy remains the mainstay of therapy for neonatal hepatic abscess. Initial antibiotic treatment should be started aggressively and include broad coverage. In neonates, empiric treatment should speciﬁcally be directed against Gram-negative bacilli and Staphylococcus aureus. After cultures identify the infecting organism, antibiotics can be narrowed according to the reported sensitivities. Percutaneous aspiration of smaller neonatal hepatic abscesses can be done for diagnostic purposes,30 but macroscopic abscesses require therapeutic drainage of the purulent ﬂuid collection for

600 Hepatic cysts and abscesses

adequate treatment.31 Percutaneous drainage techniques have been demonstrated to be safe and efﬁcacious in children with hepatic abscesses,32 although experience in neonates is limited.19 Furthermore, an open abdominal exploration allows investigation and possible treatment of an intra-abdominal source of the infection. The neonate depicted in Figure 63.1 was treated aggressively with open surgical drainage and i.v. antibiotics (vancomycin to cover coagulase-negative Staphylococcus species cultured from the abscess cavity). This aggressive treatment resulted in nearly complete resolution of the process documented by CT within 6 weeks (Fig. 63.2). Investigators have variably recommended 2–3 weeks of drainage with a total antibiotic course lasting 3–6 weeks.

Figure 63.2 Repeat CT scan 6 weeks following open surgical drainage and i.v. antibiotic treatment demonstrating complete radiographic resolution of the hepatic abscess

AMEBIC LIVER ABSCESS The parasite Entamoeba histolytica is generally considered to be a possible causative organism in older children with hepatic abscess,33,34 but it has rarely been documented to occur in newborns.35 Due to nonspeciﬁc signs and symptoms, the diagnosis again rests on clinical suspicion. Serologic testing via indirect hemagglutination or complement ﬁxation assays can be a useful diagnostic tool. Even though investigators have tried to differentiate the radiographic appearance of amebic vs pyogenic liver abscesses,36 ﬁne-needle aspiration of the abscess cavity is often required. Return of characteristic ‘anchovy paste’ appearing material is suggestive of amebic infection. Rather than drainage as the standard of therapy, amebic liver abscesses can often be treated successfully with a 30-day course of metronidazole and iodoquinal.37,38

REFERENCES 1. Moschowitz E. Non-parasitic cysts (congenital) of the liver with a study of aberrant ducts. Am J Med Sci 1986; 131:674. 2. Saboo RM, Belsare RK, Narang R et al. Giant congenital cyst of the liver. J Pediatr Surg 1974; 9:561–2. 3. Johnston PW. Congenital cysts of the liver in infancy and childhood. Am J Surg 1968; 116:184–91. 4. Donovan MJ, Kozakewich H, Perez-Atayde A. Solitary nonparasitic cysts of the liver. Pediatr Pathol Lab Med 1995; 15:419–28. 5. Avni EF, Rypens F, Donner C et al. Hepatic cysts and hyperdiogenicities: Perinatal assessment and unifying theory on their origins. Pediatr Radiol 1994; 24:569–72. 6. Pul N, Pul M. Congenital solitary non-parasitic cyst of the liver in infancy and childhood. J Pediatr Gastroenterol Nutr 1995; 21:461–2. 7. Merine D, Nussbaum AR, Sanders RC. Solitary nonparasitic hepatic cyst causing abdominal distension and respiratory distress in a newborn. J Pediatr Surg 1990; 25:349–50. 8. Byrne WJ, Fonkalsrud EW. Congenital solitary nonparasitic cyst of the liver: A rare cause of a rapidly enlarging abdominal mass in infancy. J Pediatr Surg 1982; 17:316–17. 9. Benhamou JP, Menu Y. Non-parasitic cystic disease of the liver and intrahepatic biliary tree. In: Blumgart LH, editor. Surgery of the Liver and Biliary Tract. Edinburgh: Churchill Livingstone, 1994:1197–210. 10. Saini S, Mueller PR, Ferrucci JT et al. Percutaneous aspiration of hepatic cysts does not provide deﬁnitive therapy. Am J Roentgenol 1983; 141:559–60. 11. Nelson J, Davidson D, McKittrick JE. Simple surgical treatment of non-parasitic hepatic cysts. Am Surg 1992; 58:755–7. 12. Athey PA, Landerman JA, King DE. Massive congenital solitary non-parasitic cyst of the liver in infancy. J Ultrasound Med 1986; 5:585–7. 13. Kays DW. Pediatric liver cysts and abscesses. Semin Pediatr Surg 1992; 1:107–14. 14. Torres VE. Polycystic liver disease. Contrib Nephrol 1995; 115:44–52. 15. Gang DL, Herrin JT. Infantile polycystic disease of the liver and kidneys. Clin Nephrol 1986; 25:28–36. 16. Roy S, Dillon MJ, Trompeter RS et al. Autosomal recessive polycystic kidney disease: Long-term outcome of neonatal survivors. Pediatr Nephrol 1997; 11:302–6. 17. Davies CH, Stringer DA, Whyte H et al. Congenital hepatic ﬁbrosis with saccular dilation of intrahepatic bile ducts and infantile polycystic kidneys. Pediatr Radiol 1986; 16:302–9. 18. Pineiro-Carrero VM, Andres JM. Morbidity and mortality in children with pyogenic liver abscess. Am J Dis Child 1989; 143:1424–7. 19. Doerr CA, Demmler GJ, Garcia-Prats JA et al. Solitary pyogenic liver abscess in neonates: report of three cases

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20. 21.

22. 23.

24.

25.

26. 27.

28.

and review of the literature. Pediatr Infect Dis J 1994; 13:64–9. Moss TJ, Pysher TJ. Hepatic abscess in neonates. Am J Dis Child 1981; 135:726–8. Williams JW, Rittenbery A, Dillard R et al. Liver abscess in newborn. Complication of umbilical vein catheterization. Am J Dis Child 1973; 125:111–13. Brans YW, Ceballos R, Cassady G. Umbilical catheters and hepatic abscesses. Pediatrics 1974; 53:264–6. Lim CT, Koh MT. Neonatal liver abscess following abdominal surgery for necrotizing enterocolitis. Pediatr Surg Int 1994; 9:30–1. Murphy FM, Baker CJ. Solitary hepatic abscess: a delayed complication of neonatal bacteremia. Pediatr Infect Dis J 1988; 7:414–16. Mechaber AJ, Tuazon CU. Hepatic abscess: Rare complication of ventriculoperitoneal shunts. Clin Infect Dis 1997; 25:1244–5. Brook I, Frazier EH. Microbiology of liver and spleen abscesses. J Med Microbiol 1998; 47:1075–80. Vade A, Sajous C, Anderson B et al. Neonatal hepatic abscess. Comput Med Imaging Graph 1998; 22:357–9. Laurin S, Kaude JV. Diagnosis of liver-spleen abscesses in children–with emphasis on ultrasound for the initial and follow-up examinations. Pediatr Radiol 1984; 14:198–204.

29. Oleszczuk-Raske K, Cremin BJ, Fisher RM et al. Ultrasonic features of pyogenic and amoebic hepatic abscesses. Pediatr Radiol 1989; 19:230–3. 30. Giorgio A, Tarantino L, Mariniello N et al. Pyogenic liver abscesses: 13 years of experience in percutaneous needle aspiration with US guidance. Radiology 1995; 195:122–4. 31. Wong KP. Percutaneous drainage of pyogenic liver abscesses. World J Surg 1990; 14:492–7. 32. Vachon L, Diament MJ, Stanely P. Percutaneous drainage of hepatic abscesses in children. J Pediatr Surg 1986; 21:366–8. 33. Harrison HR, Crowe CP, Fulginiti VA. Amebic liver abscess in children: clinical and epidemiologic features. Pediatrics 1979; 64:923–8. 34. Haffar A, Boland J, Edwards MS. Amebic liver abscess in children. Pediatr Infect Dis J 1982; 1:322–7. 35. Axton JH. Amoebic proctocolitis and liver abscess in a neonate. S Afr Med J 1972; 46:258–9. 36. Barnes P, DeCock KM, Reynolds TN et al. A comparison of amebic and pyogenic abscess of the liver. Medicine 1987; 66:472–83. 37. Maltz G, Knauer CM. Amebic liver abscess: a 15-year experience. Am J Gastroenterol 1991; 86:704–10. 38. Allan RJV, Katz MD, Johnson MB et al. Uncomplicated amebic liver abscess: prospective evaluation of percutaneous therapeutic aspiration. Radiology 1992; 183:827–30.

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7 Anterior abdominal wall defects

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64 Omphalocele and gastroschisis STEVEN W. BRUCH AND JACOB C. LANGER

INTRODUCTION Omphalocele (also known as exomphalos) consists of a central abdominal wall defect that permits herniation of abdominal viscera into the umbilical cord. A membrane that is made out of Wharton’s jelly, from which the umbilical cord emerges (Fig. 64.1), covers the viscera. Pare provided the ﬁrst description of an omphalocele in 1634. Hey reported the successful treatment of an omphalocele by primary repair in 1803, and Ahlfeld described the escharotic treatment using alcohol in 1899. In 1814, Scarpa observed that omphaloceles were often associated with other congenital anomalies. Gastroschisis is a smaller abdominal wall defect to the right of a normally positioned umbilical cord, which permits herniation of intestine (Fig. 64.2), as well as occasionally liver, testis or ovary. There is never an associated sac, and other than nonrotation and intestinal atresia, there are few associated congenital anomalies. Gastroschisis was ﬁrst described by Calder in 1733, and the ﬁrst surgical treatment for gastroschisis was described by Fear in 1878.

Figure 64.1 Omphalocele. The viscera (in this case liver and small bowel) are covered by a sac that is composed of Wharton’s jelly, and the umbilical cord enters the top of the sac

Figure 64.2 Gastroschisis. The defect is to the right of the umbilical cord and the entire intestinal tract is exteriorized. There is no sac. The bowel wall and mesentery are thickened and foreshortened

The surgical repair of abdominal wall defects has evolved over many years, with advances in diagnostic ability, neonatal intensive care, and anesthetic techniques. Although Gross popularized the skin ﬂap closure of large omphaloceles in 1948,1 it was Olshausen who ﬁrst described this technique in 1887.2 In 1966, Izant introduced manual stretching of the abdominal wall to make more room for primary closure.3 Schuster created the ﬁrst mesh silo in 1967 to temporarily house the herniated viscera until primary closure could be accomplished.4 Recently, a spring-loaded silo was developed which permits placement of the silo without the need for fascial sutures.5 Two additional advances in the medical management of infants with abdominal wall defects have had a signiﬁ-

606 Omphalocele and gastroschisis

cant impact over the past 30 years. Raffensperger and Jona were the ﬁrst to use postoperative paralysis and ventilator support in the neonatal intensive care unit to hasten abdominal wall closure, either primarily or after silo placement.6 Filler introduced the use of total parenteral nutrition (TPN) to the neonatal population, which has become a crucial component in the high survival rate of infants with abdominal wall defects.7

EMBRYOLOGY AND ETIOLOGY During the sixth week of embryonic development, the intestines begin to grow rapidly and migrate out of the umbilical ring into the umbilical cord.8 By the tenth week the intestines return to the abdominal cavity, rotating 270° counter-clockwise to attain their normal position. An omphalocele results from failure of the bowel to return to the abdomen, possibly due to delayed closure of the lateral folds with persistence of a large umbilical ring. The defect is centrally located on the abdomen, varies in size, and has a sac covering the abdominal contents that consists of peritoneum, Wharton’s jelly, and amnion. Because the process of intestinal rotation normally occurs after return of the viscera to the abdomen, infants with omphalocele usually have nonrotation or malrotation, and Ladd’s bands may be present across the duodenum. In addition to the intestine, a portion of the liver may also be present in the sac. The liver is often round and globular in appearance, central in location, and has an abnormal ﬁxation to the diaphragm. The hepatic veins appear tortuous and wander close to the skin edge at the superior aspect of the defect. The spleen and ovaries may also be found in the sac. Failure of the cephalic fold to close leads to lower sternal abnormalities and an epigastric omphalocele, which is commonly associated with cardiac defects, pericardial absence, and a diaphragmatic defect together known as pentalogy of Cantrell. Failure of the caudal fold to close leads to a hypogastric omphalocele often associated with bladder or cloacal exstrophy. Gastroschisis results in bowel herniation through a small defect to the right of the normally formed umbilical cord. A vascular accident involving the right omphalomesenteric artery is thought to result in this right-sided defect,9 although a small number of cases may result from rupture of an omphalocele in utero.10 The entire intestinal tract is usually eviscerated, ﬂoating free in the amniotic cavity without an enveloping sac. Ovary, testis and liver are less often involved. The intestines develop a thick inﬂammatory peel, are foreshortened, and have a thickened mesentery – ﬁndings that correlate with functional impairment of motility and nutrient absorption. These changes result from a combination of factors, including contact with the amniotic ﬂuid and constriction at the abdominal wall defect.

The cause of both omphalocele and gastroschisis is unknown. Omphalocele may have a genetic component, as suggested by the high incidence of associated anomalies and chromosomal abnormalities, and also by the high incidence of omphalocele in several knockout models in mice.11 There is some epidemiological evidence linking gastroschisis to a number of vasoactive drugs,12 but these associations require further investigation.

INCIDENCE Omphalocele occurs in one out of 4000 live births, and gastroschisis occurs in one out of 6000–10 000 live births.13 The incidence of gastroschisis around the world has been increasing over the past 30 years, while the incidence of omphalocele has remained relatively constant.14,15 Gastroschisis appears to occur more commonly in young mothers, especially those younger than 20 years of age.16,17

ASSOCIATED ANOMALIES Omphalocele is associated with other anomalies up to 72% of the time.18,19 Of these anomalies, 20% are cardiac, with tetralogy of Fallot and atrial septal defects being the most common.20 Other common anomalies include: • Chromosomal trisomies (trisomy 13, 14, 15, 18, and 21), which occur in 20% of omphaloceles • Beckwith–Wiedemann syndrome (omphalocele, macroglossia, gigantism, and pancreatic islet cell hyperplasia), which occur in 12% of omphaloceles • Pentalogy of Cantrell (epigastric omphalocele, anterior diaphragmatic hernia, sternal defect, pericardial defect, cardiac anomaly – usually ventricular septal defect) • Lower midline syndrome (bladder or cloacal exstrophy, imperforate anus, colonic atresia, sacral vertebral anomalies, and meningomyelocele). Gastroschisis occurs in association with other abnormalities much less frequently. The majority of the associated abnormalities involve the gastrointestinal tract. Intestinal atresia, which is thought to be secondary to a vascular accident or from constriction of the blood supply to the intestine at the defect, occurs in 10–15% of cases. Meckel’s diverticulum and intestinal duplications have also been noted.

FUNCTION OF EXTERIORIZED VISCERA Because of the presence of a sac in most omphaloceles, the exteriorized viscera usually function normally. In

Newborn management 607

infants with gastroschisis, however, the exteriorized intestine becomes thickened and shortened, and suffers from impaired motility and nutrient absorption.21 A number of experimental studies have been done to investigate the etiology of this bowel damage. The results of these studies suggest that: 1 Intestinal damage arises from both amniotic ﬂuid exposure and constriction of the bowel at the abdominal wall defect.22,23 2 The damage occurs late during gestation.24 3 Amniotic ﬂuid exposure causes injury because of meconium, rather than urine, in the ﬂuid.25 4 Amniotic ﬂuid exposure results in changes in collagen composition and the production of mucosal enzymes.26–29 5 Levels of inﬂammatory cytokines in the amniotic ﬂuid of fetuses with gastroschisis are elevated.30 Although there is a signiﬁcant amount of variability in the severity of these abnormalities, intestinal transit and absorption tend to return to normal by 6 months in most infants.

PRENATAL DIAGNOSIS AND MANAGEMENT The unique anatomic characteristics of omphalocele and gastroschisis allow them to be identiﬁed and differentiated using prenatal ultrasound. The diagnosis of omphalocele cannot be made deﬁnitively prior to the tenth gestational week, as the intestines are normally located in the umbilical cord up until that time. Although it is usually possible to sonographically differentiate omphalocele from gastroschisis, prenatal rupture of the omphalocele may make this more difﬁcult. An abdominal wall defect is often suspected on routine screening because of elevation of the maternal serum alphafetoprotein (MSAFP), which is elevated in 90% of mothers carrying babies with omphalocele, and 100% of those with gastroschisis.31 Using a combination of maternal serum screening and ultrasound, the sensitivity and speciﬁcity for prenatal diagnosis of abdominal wall defects should approach 100%.32 Once an abdominal wall defect is identiﬁed, a search for additional anomalies should be carried out. If the problem is clearly gastroschisis, this can be limited to a careful anatomic ultrasound. For fetuses with omphalocele, both structural and chromosomal problems should be sought. Karyotype analysis by amniocentesis or chorionic villous sampling, and anatomic ultrasound, including fetal echocardiography, should be completed. In most series, approximately two-thirds of associated abnormalities are detected prenatally in these fetuses.33 Presently, in utero repair is not recommended for either gastroschisis or omphalocele. Based on the principle that amniotic ﬂuid exposure results in intestinal damage,

several authors have advocated amniotic ﬂuid exchange or amnioinfusion for the fetus with gastroschisis. Animal experiments suggest that bowel damage may be ameliorated with this technique,34 and preliminary clinical experience has been encouraging.35–37 However, further experience with larger groups of patients will be required before this technique is widely accepted. Serial ultrasound examination of herniated bowel in fetuses with gastroschisis should be followed, looking for bowel dilatation and thickening. Late gestational bowel dilatation raises the question of bowel atresia or constriction at the site of the abdominal wall defect, and tends to correlate with a poorer outcome.38 Although the presence of bowel diameter greater than 18 mm has been associated with delay in oral feedings and a higher likelihood of bowel resection,39,40 the signiﬁcance of bowel dilation in fetuses with gastroschisis remains to be deﬁned, and no speciﬁc interventions are currently recommended based on this ﬁnding. The timing, location, and mode of delivery may impact on the outcome of infants with omphalocele and gastroschisis. Most infants with omphalocele should be delivered at term. In contrast, infants with gastroschisis may beneﬁt from early delivery to minimize the damage from exposure of the bowel to amniotic ﬂuid. Many centers choose to deliver at 37 weeks’ gestation after documenting lung maturity, although this remains controversial.41–43 Use of routine cesarian delivery for both omphalocele and gastroschisis also remains controversial. There is general agreement that infants with a very large omphalocele should be delivered in this manner to prevent injury to the exteriorized liver, however infants with smaller defects should probably be delivered by vaginal delivery unless there are obstetric indications for cesarian section.44 Many retrospective studies have been carried out comparing cesarian and vaginal delivery for infants with gastroschisis, with most demonstrating no beneﬁt of cesarian delivery.44–47 In most of the studies in which a beneﬁt was found, the delivery was carried out before term, suggesting that it was the early delivery rather than the cesarian section which conferred the beneﬁt.43,48,49 With very few exceptions, all infants with an abdominal wall defect should be delivered at a perinatal center, where immediate neonatal and surgical expertise are available.41,50

NEWBORN MANAGEMENT The initial treatment of a newborn with omphalocele or gastroschisis consists of ﬂuid resuscitation, nasogastric decompression, avoidance of hypothermia, and local care of the exteriorized viscera. In infants with gastroschisis, the bowel should be inspected to ensure its blood supply

608 Omphalocele and gastroschisis

is not compromised by twisting of the mesentery or constriction at the abdominal wall defect. If the size of the abdominal wall defect in gastroschisis is causing vascular compromise, the defect should be enlarged immediately. The bowel should be wrapped in warm saline-soaked gauze, supported on the anterior abdominal wall, and covered with a waterproof dressing (Fig. 64.3). A bowel bag or cellophane works well for this purpose. In infants with omphalocele, the sac should be inspected for leaks before placing the dressing. Newborns with abdominal wall defects should be placed in a temperature-controlled environment, as they lose a great deal of heat through the exposed bowel. Babies with omphalocele and gastroschisis require up to 2–3 times the amount of ﬂuid a normal term infant would require. Isotonic solutions should be used for resuscitation, and the child should be well hydrated prior to going to the operating room for repair. Once ﬂuid resuscitation has been accomplished, parenteral nutrition, preferably through a central venous catheter, should be initiated. All infants should be carefully examined clinically and radiologically to ensure adequate pulmonary, cardiac, and renal function are maintained. Associated anomalies must be diligently searched for, particularly in those infants with omphalocele.

Figure 64.3 Appropriate dressing of an abdominal wall defect in the delivery room. The viscera are covered with warm salinesoaked gauze, supported on the anterior abdominal wall and covered with a waterproof dressing

SURGICAL MANAGEMENT The goal of surgical management for both omphalocele and gastroschisis is to place the herniated viscera back into the abdomen and to close the fascia. In many cases, this can be done in a single operation. Strategies to help accomplish this include: (1) stretching of the abdominal wall, (2) using normal saline or mucomyst enemas to clear the meconium from the colon, and (3) milking the small bowel contents toward the stomach and aspirating

with a nasogastric tube. For omphalocele, the sac is usually removed after ligating the umbilical arteries and vein. Areas of the sac that are ﬁrmly adhered to a portion of the liver must be left in place to avoid hepatic injury. In some cases, the abdominal wall defect may require enlargement in order to ﬁt the viscera back inside the abdomen. In all cases of abdominal wall defects, the bowel should be inspected to look for associated atresias and for evidence of a rotation abnormality. If an atresia is identiﬁed and the bowel appears to be healthy, the atresia should be repaired with a primary anastomosis. If the bowel is too thickened or inﬂamed, a stoma may be performed or the abdominal wall defect repaired with the plan for repair of the atresia at another laparotomy several weeks later.51,52 Ideally the bowels should be arranged in a position of nonrotation, although in most cases of gastroschisis it is difﬁcult to assess for the presence of malrotation. In infants with omphalocele, the diaphragm should be inspected to ensure there is no defect that would only become apparent after the intestines are placed back into the abdomen. If the viscera do not ﬁt into the abdomen without a signiﬁcant increase in intra-abdominal pressure, a silastic ‘silo’ can be placed and the herniated contents gradually reduced back into the abdomen over the next 1–10 days (Fig. 64.4). The silo should be dressed with povodone–iodine or another antibacterial agent to help decrease the risk of infection. Parenteral antibiotics should be continued until the silo is removed. The contents of the silo should be reduced every 12–24 hours as tolerated by the baby. When the viscera have been successfully returned to the abdomen, the infant is taken to the operating room, the silo is removed, and the fascia is closed along with the overlying skin. The decision to do a primary repair or to place a silo can be difﬁcult. Excessive intra-abdominal pressure may result in abdominal ‘compartment syndrome’, with intestinal ischemia resulting in perforation and ﬁstulization, reduced hepatic and renal blood ﬂow, and reduced circulation to and from the lower extremities. Peak airway pressures have been used for many years as an indicator of excessive intra-abdominal pressure. Experimental and clinical studies have demonstrated that intravesicular or intragastric pressures of < 20 mmHg, in combination with rise in central venous pressure of <4mm Hg correlate with a lower incidence of abdominal compartment syndrome.53–56 These parameters may also be followed during silo reduction, and postoperatively, and if exceeded would suggest that the abdomen should be reopened and a silo placed. Several new concepts have been suggested in the past few years that may improve the outcome for infants with gastroschisis. Immediate repair in the delivery room, as reported by the Detroit group, appears to allow easier abdominal wall closure, earlier extubation, less time to beginning feeding, and a shorter hospital stay. More

Surgical management 609

(a)

(b)

(c)

Figure 64.4 The use of a silo in a child with gastroschisis. (a) The silo is sewn to the abdominal wall, over the bowel. (b) The bowel is slowly reduced once or twice per day. (c) The abdominal wall is ready to be deﬁnitively closed

recently, several groups have advocated routine bedside placement of a spring-loaded silo, which can be introduced into the defect without the need for a general anesthetic. After gradual reduction of the viscera over the next 1–7 days, closure of the fascia is accomplished with only one anesthetic required (Fig. 64.5). This technique has been associated with an improved outcome when compared to the standard approach.5,57 Finally, Bianchi recently reported a technique for closure of gastroschisis at the bedside without the use of anesthesia or a silo.58 Wider adoption of this technique will await further reporting of results.59 Occasionally, an omphalocele is so large that it is unlikely that the abdominal cavity will accept the herniated contents over a reasonable period of time, even with the use of a silo. In other cases, the infant may have severe pulmonary hypoplasia or immaturity, or associated anomalies that preclude an attempt at closure. In these cases, the omphalocele sac may be left intact and allowed to slowly granulate and eventually

(a)

(b)

Figure 64.5 (a) Spring-loaded silo. (b) This device can be placed at the bedside without an anesthetic and permits gradual reduction of the viscera in every case, with only one trip to the operating room

610 Omphalocele and gastroschisis

(a)

Newborns with omphalocele associated with lifethreatening structural or chromosomal anomalies have a poor prognosis, and a frank discussion with the neonatologists and parents should precede any aggressive treatment.

POSTOPERATIVE MANAGEMENT

(b) Figure 64.6 Escharotic management of a large omphalocele. The sac is covered with silver sulfadiazine (a). This results in granulation tissue and ultimately in epithelialization. The resulting ventral hernia (b) can be repaired at any time, when the child’s medical condition improves

epithelialize.60 In the past, this was accomplished by painting with mercurochrome or iodine,61 but mercury or iodine poisoning was reported in some cases and these agents have been largely abandoned. The use of OpSite has also been advocated.62 The authors currently advocate the use of silver sulphadalazine for this purpose, which forms an eschar on the sac. The eschar begins to granulate, then epithelializes, and eventually a pseudo-skin forms from the edges of the wound and covers the entire sac (Fig. 64.6). The resulting ventral hernia is ultimately repaired electively when the child’s other medical problems have improved adequately.

Postoperatively, feedings are started when gastrointestinal function returns; this usually takes much longer for infants with gastroschisis than with omphalocele, and can take weeks to months. If feedings are not proceeding well, the possibility of a missed atresia must be considered, and both upper and lower intestinal contrast studies should be carried out. Prokinetic agents, particularly cisapride, have been shown experimentally and clinically to improve intestinal motility.63,64 Unfortunately, cisapride is no longer available for the neonatal population, and newer agents have not yet been tested in this setting. Necrotizing enterocolitis is relatively common in infants with gastroschisis,65 but the risk may be decreased by prevention of excessive intra-abdominal pressure during reduction of the viscera.5,66 In addition, both omphalocele and gastroschisis are accompanied by an increased incidence of gastro-esophageal reﬂux, especially in the ﬁrst year of life.67Although this can often be managed medically, some children require fundoplication or jejunostomy placement.68 For many infants with an abdominal wall defect, long-term TPN must be used through a central venous catheter, which may be accompanied by complications related to line infections, metabolic disturbances, and liver injury.69

References 611

LONG-TERM OUTCOME The outcome of infants born with gastroschisis depends on the condition of the intestine, and is excellent in over 90% of cases.70–72 A signiﬁcant number of these patients require additional surgery, usually for adhesive intestinal obstruction, and a small group of children suffer from short bowel syndrome or long-term motility disorders which ultimately require small bowel transplantation.73 The outcome for infants with omphalocele is more dependent on the presence and severity of associated malformations. In the absence of severe pulmonary or cardiac anomalies, the majority of these children survive to live normal lives.70,71

REFERENCES 1. Gross RE. A new method for surgical treatment of large omphaloceles. Surgery 1948; 24:277. 2. Olshausen RZ. Zur therapie der nadelschnurhernien. Arch Bynak Berlin 1887; 29:443. 3. Izant RJ, Brown F,Rothmann BF. Current embryology and treatment of gastroschisis and omphalocele. Arch Surg 1966; 93:49. 4. Schuster SR. A new method for the staged repair of large omphaloceles. Surg Gynecol Obstet 1967; 125:837. 5. Minkes RK, Langer JC, Mazziotti MV et al. Routine insertion of a silastic spring-loaded silo for infants with gastroschisis. J Pediatr Surg 2000; 35:843–6. 6. Raffensperger JG, Jona JZ. Gastroschisis. Surg Gynecol Obstet 1974; 138:230. 7. Filler RM, Eraklis AJ, Das JB et al. Total intravenous nutrition. An adjunct to the management of infants with ruptured omphalocele. Am J Surg 1971; 121:454–9. 8. Langer JC. Normal fetal development. In: Oldham KT, Colombani PM, Foglia RP, editors. Surgery of Infants and Children. Philadelphia: Lippincott-Raven Publishers, 1997:41–8. 9. Hoyme HE, Higginbottom MC, Jones KL. The vascular pathogenesis of gastroschisis: intrauterine interruption of the omphalomesenteric artery. J Pediatr 1981; 98:228–31. 10. Glick PL, Harrison MR, Adzick NS et al. The missing link in the pathogenesis of gastroschisis. J Pediatr Surg 1985; 20:406–9. 11. Rauch F, Prud’homme J, Arabian A et al. Heart, brain, and body wall defects in mice lacking calreticulin. Exp Cell Res 2000; 256:105–11. 12. Werler MM, Mitchell AA, Shapiro S. First trimester maternal medication use in relation to gastroschisis. Teratology 1992; 45:361–7. 13. Moore TC, Nur K. An international survey of gastroschisis and omphalocele (490 cases) II. Relative incidence, pregnancy and environmental factors. Pediatr Surg Int 1986; 1:105–9.

14. Rankin J, Dillon E, Wright C. Congenital anterior abdominal wall defects in the north of England, 1986–1996: occurrence and outcome. Prenat Diagn 1999; 19:662–8. 15. Suita S, Okamatsu T, Yamamoto T et al. Changing proﬁle of abdominal wall defects in Japan: results of a national survey. J Pediatr Surg 2000; 35:66–71. 16. Forrester MB, Merz RD. Epidemiology of abdominal wall defects, Hawaii, 1986–1997. Teratology 1999; 60:117–23. 17. Nichols CR, Dickinson JE, Pemberton PJ. Rising incidence of gastroschisis in teenage pregnancies. J Matern Fetal Med 1997; 6:225–9. 18. Moore TC, Nur K. An international survey of gastroschisis and omphalocele (490 cases) I. Nature and distribution of additional malformations. Pediatr Surg Int 1986; 1:46–50. 19. Hughes MD, Nyberg DA, Mack LA et al. Fetal omphalocele: prenatal US detection of concurrent anomalies and other predictors of outcome. Radiology 1989; 173:371–6. 20. Greenwood RD, Rosenthal A, Nadas AS. Cardiovascular malformations associated with omphalocele. J Pediatr 1974; 85:818–21. 21. O’Neill JA, Grosfeld JL. Intestinal malfunction after antenatal exposure of viscera. Am J Surg 1974; 127:129–32. 22. Langer JC, Longaker MT, Crombleholme TM et al. Etiology of bowel damage in gastroschisis. I.: Effects of amniotic ﬂuid exposure and bowel constriction in a fetal lamb model. J Pediatr Surg 1989; 24:992–7. 23. Albert A, Julia MV, Morales L et al. Gastroschisis in the partially extraamniotic fetus: experimental study. J Pediatr Surg 1993; 28:656–9. 24. Langer JC, Bell JG, Castillo RO et al. Etiology of intestinal damage in gastroschisis. II: Timing and reversibility of histologic changes, mucosal function, and contractility. J Pediatr Surg 1990; 25:1122–6. 25. Olguner M, Akgur FM, Api A et al. The effects of intraamniotic human neonatal urine and meconium on the intestines of the chick embryo with gastroschisis. J Pediatr Surg 2000; 35:458–61. 26. Shaw K, Buchmiller TL, Curr M et al. Impairment of nutrient uptake in a rabbit model of gastroschisis. J Pediatr Surg 1994; 29:376–8. 27. Srinathan SK, Langer JC, Blennerhassett MG et al. Etiology of intestinal damage in gastroschisis. III: morphometric analysis of the smooth muscle and submucosa. J Pediatr Surg 1995; 30:379–83. 28. Srinathan SK, Langer JC, Botney M et al. Submucosal collagen in experimental gastroschisis. J Surg Res 1996; 65:25–30. 29. Srinathan SK, Langer JC, Wang J et al. Enterocytic gene expression is altered in experimental gastroschisis. J Surg Res 1997; 68:1–6. 30. Morrison JJ, Klein N, Chitty LS et al. Intra-amniotic inﬂammation in human gastroschisis: possible aetiology of postnatal bowel dysfunction. Br J Obstet Gynaecol 1998; 105:1200–4.

612 Omphalocele and gastroschisis 31. Palomaki GE, Hill LE, Knight GJ et al. Second-trimester maternal serum alpha-fetoprotein levels in pregnancies associated with gastroschisis and omphalocele. Obstet Gynecol 1988; 71:906–9. 32. Lennon CA, Gray DL. Sensitivity and speciﬁcity of ultrasound for the detection of neural tube and ventral wall defects in a high-risk population. Obstet Gynecol 1999; 94:562–6. 33. Holland AJ, Ford WD, Linke RJ et al. Inﬂuence of antenatal ultrasound on the management of fetal exomphalos. Fetal Diagn Ther 1999; 14:223–8. 34. Aktug T, Erdag G, Kargi A et al. Amnio-allantoic ﬂuid exchange for the prevention of intestinal damage in gastroschisis: an experimental study on chick embryos. J Pediatr Surg 1995; 30:384–7. 35. Dommergues M, Ansker Y, Aubry MC et al. Serial transabdominal amnioinfusion in the management of gastroschisis with severe oligohydramnios. J Pediatr Surg 1996; 31:1297–9. 36. Aktug T, Demir N, Akgur FM et al. Pretreatment of gastroschisis with transabdominal amniotic ﬂuid exchange. Obstetr Gynecol 1998; 91:821–3. 37. Sapin E, Mahieu D, Borgnon J et al. Transabdominal amnioinfusion to avoid fetal demise and intestinal damage in fetuses with gastroschisis and severe oligohydramnios. J Pediatr Surg 2000; 35:598–600. 38. Bond SJ, Harrison MR, Filly RA et al. Severity of intestinal damage in gastroschisis: correlation with prenatal sonographic ﬁndings. J Pediatr Surg 1988; 23:520–5. 39. Langer JC, Khanna J, Caco C et al. Prenatal diagnosis of gastroschisis: development of objective sonographic criteria for predicting outcome. Obstet Gynecol 1993; 81:53–6. 40. Pryde PG, Bardicef M, Treadwell MC et al. Gastroschisis: can antenatal ultrasound predict infant outcomes? Obstet Gynecol 1994; 84:505–10. 41. Quirk JGJ, Fortney J, Collins HB et al. Outcomes of newborns with gastroschisis: the effects of mode of delivery, site of delivery, and interval from birth to surgery. Am J Obstet Gynecol 1996; 174:1134–8. 42. Dunn JC, Fonkalsrud EW, Atkinson JB. The inﬂuence of gestational age and mode of delivery on infants with gastroschisis. J Pediatr Surg 1999; 34:1393–5. 43. Sheth NP. Preterm and particularly, pre-labour cesarean section to avoid complications of gastroschisis. Pediatr Surg Int 2000; 16:229. 44. How HY, Harris BJ, Pietrantoni M et al. Is vaginal delivery preferable to elective cesarean delivery in fetuses with a known ventral wall defect? Am J Obstet Gynecol 2000; 182:1527–34. 45. Lewis DF, Towers CV, Garite TJ et al. Fetal gastroschisis and omphalocele: is cesarian section the best mode of delivery? Am J Obstet Gynecol 1990; 163:773–5. 46. Sipes SL, Weiner CP, Sipes DR et al. Gastroschisis and omphalocele: does either antenatal diagnosis or route of delivery make a difference in perinatal outcome? Obstet Gynecol 1990; 76:195–9.

47. Adra AM, Landy HJ, Nahmias J et al. The fetus with gastroschisis: impact of route of delivery and prenatal ultrasonography. Am J Obstet Gynecol 1996; 174:540–6. 48. Moore TC. Elective preterm section for improved primary repair of gastroschisis. Pediatr Surg Int 1988; 4:25–6. 49. Sakala EP, Erhard LN,White JJ. Elective cesarean section improves outcomes of neonates with gastroschisis. Am J Obstetr Gynecol 1993; 169:1050–3. 50. Skupski DW. Prenatal diagnosis of gastrointestinal anomalies with ultrasound. What have we learned? Ann N Y Acad Sci 1998; 847:53–8. 51. Fleet MS, de la Hunt MN. Intestinal atresia with gastroschisis: a selective approach to management. J Pediatr Surg 2000; 35:1323–5. 52. Hoehner JC, Ein SH, Kim PC. Management of gastroschisis with concomitant jejuno-ileal atresia. J Pediatr Surg 1998; 33:885–8. 53. Lacey SR, Bruce J, Brooks SP et al. The relative merits of various methods of indirect measurement of intraabdominal pressure as a guide to closure of abdominal wall defects. J Pediatr Surg 1987; 22:1207–11. 54. Schuck RJ, Sturm B, Deeg KH et al. Intra-abdominal pressure monitoring in newborns with gastroschisis, omphalocele, and diaphragmatic hernia. Pediatr Surg Int 1989; 4:245–8. 55. Lacey SR, Carris LA, Beyer AJ et al. Bladder pressure monitoring signiﬁcantly enhances care of infants with abdominal wall defects: a prospective clinical study. J Pediatr Surg 1993; 28:1370–5. 56. Rizzo A, Davis PC, Hamm CR et al. Intraoperative vesical pressure measurements as a guide in the closure of abdominal wall defects. Am Surg 1996; 62:192–6. 57. Fischer JD, Chun K, Moores DC et al. Gastroschisis: a simple technique for staged silo closure. J Pediatr Surg 1995; 30:1169–71. 58. Bianchi A, Dickson AP. Elective delayed reduction and no anesthesia: ‘minimal intervention management’ for gastroschisis. J Pediatr Surg 1998; 33:1338–40. 59. Dolgin SE, Midulla P, Shlasko E. Unsatisfactory experience with ‘minimal intervention management’ for gastroschisis. J Pediatr Surg 2000; 35:1437–9. 60. Nuchtern JG, Baxter R, Hatch EI. Nonoperative initial management versus silon chimney for treatment of giant omphalocele. J Pediatr Surg 1995; 30:771–6. 61. Burge DM, Glasson MJ. The conservative management of exomphalos major. Aust N Z J Surg 1986; 56:409–11. 62. Ein SH, Shandling B. A new non-operative treatment of large omphaloceles with a polymer membrane. J Pediatr Surg 1978; 13:255–7. 63. Langer JC, Bramlett G. Effect of prokinetic agents on ileal contractility in a rabbit model of gastroschisis. J Pediatr Surg 1997; 32:605–8. 64. Lander A, Redkar R, Nicholls G et al. Cisapride reduces neonatal postoperative ileus: randomised placebo controlled trial. Arch Dis Child 1997; 77:F119–22. 65. Oldham KT, Coran AG, Drongowski RA et al. The development of necrotizing enterocolitis following repair

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of gastroschisis: a surprisingly high incidence. J Pediatr Surg 1988; 23:945–9. Jayanthi S, Seymour P, Puntis JW et al. Necrotizing enterocolitis after gastroschisis repair: a preventable complication? J Pediatr Surg 1998; 33:705–7. Koivusalo A, Rintala R, Lindahl H. Gastroesophageal reﬂux in children with a congenital abdominal wall defect. J Pediatr Surg 1999; 34:1127–9. Langer JC, Mazziotti MV, Winthrop AL. Roux-en-Y jejunostomy button in infants. Pediatr Surg Int 2000; 16:40–2. Wesley JR, Coran AG. Intravenous nutrition for the pediatric patient. Semin Pediatr Surg 1992; 1:212–30.

70. Berseth CL, Malachowski N, Cohn RB et al. Longitudinal growth and late morbidity of survivors of gastroschisis and omphalocele. J Pediatr Gastroent Nutr 1982; 1:375–9. 71. Tunell WP, Pufﬁnbarger NK, Tuggle DW et al. Abdominal wall defects in infants: survival and implications for adult life. Ann Surg 1995; 221:525–30. 72. Davies BW,Stringer MD. The survivors of gastroschisis. Arch Dis Child 1997; 77:158–60. 73. Reyes J, Bueno J, Kocoshis S et al. Current status of intestinal transplantation in children. J Pediatr Surg 1998; 33:243–54.

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65 Omphalomesenteric duct remnants DAVID A. LLOYD

The omphalomesenteric duct normally obliterates by the sixth week of intrauterine life. Incomplete obliteration results in various abnormalities which may be apparent in the newborn infant1 (Fig. 65.1).

PATENT OMPHALOMESENTERIC DUCT The omphalomesenteric duct may persist as an omphalo-ileal ﬁstula (Fig. 65.1b). Morphologically the ﬁstula resembles the ileum, but may contain ectopic gastric, colonic or pancreatic tissue. The infant presents with an umbilical discharge which may be recognizable as small bowel content. An umbilical ‘polyp’ consisting of intestinal mucosa may also be present. The diagnosis is conﬁrmed by passing a catheter through the ﬁstula into the small intestine and aspirating small bowel content, or by injecting radiographic contrast medium into the ﬁstula. When the omphalo-ileal ﬁstula is widely patent, the ileum may prolapse through it, resulting in the ‘steerhorn’ abnormality (Fig. 65.2). This should be reduced and repaired urgently because of the risk of strangulation.

(a)

(b)

(c)

(d)

Figure 65.1 (a) Umbilical polyp and Meckel’s diverticulum. (b) Patent omphalomesenteric duct. (c) Obliterated omphalomesenteric duct with a Meckel’s diverticulum. (d) A cyst in an obliterated omphalomesenteric duct

Figure 65.2 Ileum prolapsed through a patent omphalomesenteric duct (steer-horn abnormality)

Excision of a patent omphalomesenteric duct The oriﬁce of the ﬁstula is mobilized using a circumferential incision, preserving the surrounding umbilical skin (Fig. 65.3a). A separate skin-crease incision is made below the umbilicus. The superior skin ﬂap, which includes the umbilicus, is elevated (Fig. 65.3b) and the ﬁstula is brought out through the sub-umbilical incision (Fig. 65.3c). The abdominal wall fascia is incised transversely on either side of the ﬁstula (Figs 65.3b & 65.3c). The umbilical vessels and the urachus are individually ligated and divided and the peritoneal cavity is entered. The ﬁstula is traced to its termination on the distal ileum. Irving recommends that the position of the cecum should be ascertained in order to exclude a malrotation of the gut;1 if necessary, the incision is extended to the right to improve the exposure. The blood supply to the ﬁstula runs across the ileum (Fig. 65.3d), and should be ligated and divided near its origin on the mesentery. Stay sutures are placed in the ileum on either side of the ﬁstula, which is excised with a margin of ileum using a transverse elliptical incision (Fig. 65.3d). The ileal defect is repaired transversely with a single layer of inverting absorbable sutures (Fig. 65.3e). Interrupted 4–0 absorbable sutures are used to repair the

616 Omphalomesenteric duct remnants

(a)

(b)

(d)

(c)

(e)

Figure 65.3 (a–e) Operation for patent omphalomesenteric duct (see text for details)

linea alba and the sub-umbilical incision is closed with interrupted subcuticular 5–0 sutures. The circular defect in the center of the umbilicus may be left to heal by secondary intention if small, or may be loosely closed with a pursestring suture. When a large ﬁstula is present, it may be necessary to excise the entire umbilicus with a circular incision. A second sub-umbilical incision may not be necessary in this situation. The large circular skin defect is repaired using a subcuticular pursestring suture; the healed wound resembles the umbilicus.

OBLITERATED OMPHALOMESENTERIC DUCT The omphalomesenteric duct may obliterate but persist as ﬁbrous cord attaching the ileum to the umbilicus, often with a diverticulum at the enteral end (Fig. 65.1c). This so-called ‘Meckels band’ may contain one or more cysts (Fig. 65.1d). There is a risk of small bowel volvulus occurring around such a band, usually the ﬁrst manifestation of the abnormality.

UMBILICAL POLYP An umbilical polyp is a remnant of intestinal mucosa at the umbilicus (Fig. 65.1a). The shiny, pink, polypoid tissue produces a persistent discharge which may be blood stained. Often it is diagnosed incorrectly as an umbilical granuloma and initially treated unsuccessfully with topical agents such as silver nitrate, before the true nature of the lesion is recognized. The diagnosis may be conﬁrmed by biopsy and treatment is by excision.

Excision of an umbilical polyp A circumferential incision is made around the polyp, preserving as much of the normal umbilicus as possible (Fig. 65.3a). The skin defect is repaired using an absorbable pursestring suture. Because of the possibility of an underlying connection to the ileum by a remnant of the omphalomesenteric duct, limited exploration of the peritoneal cavity is advisable. A sub-umbilical incision is made as described above (Fig. 65.3a). The

References 617

abdominal wall is opened transversely and the peritoneal cavity entered (Figs 65.3b & 65.3c). If an omphalomesenteric duct remnant is present, it is resected. Closure of the incision is as described for omphalomesenteric duct excision.

MECKEL’S DIVERTICULUM The most common remnant of the omphalomesenteric duct is persistence of the enteral end as a Meckel’s diverticulum (Fig. 65.1a). Complications associated with Meckel’s diverticulum, namely diverticulitis, perforation, bleeding and intussusception, are rare in the newborn period and usually are diagnosed at laparotomy. Ectopic gastric mucosa with secretion of gastric acid leading to ileal ulceration and rectal bleeding may be identiﬁed by radio-isotope scanning of the abdomen.2,3 The rare giant cystic Meckel’s diverticulum may cause small bowel obstruction. In infants with an exomphalos, a Meckel’s diverticulum is often adherent to the sac and is easily damaged by an umbilical cord clamp or during operative removal of the sac. A symptomatic Meckel’s diverticulum should be resected. It is not essential to remove an apparently normal, broad-based diverticulum found incidentally at laparotomy.3

Meckel’s diverticulectomy A right transverse abdominal incision is used. The Meckel’s diverticulum is situated on the antimesenteric border of the distal ileum, and may be bound to the adjacent small bowel mesentery by a covering of peritoneum. These adhesions are divided to mobilize the diverticulum. Occasionally the diverticulum is attached to the umbilicus, from which it must be separated. An inﬂamed Meckel’s diverticulum may be adherent to adjacent tissues. The diverticulum receives its blood supply from mesenteric vessels which cross the ileum;

these are ligated and divided. The mobilized Meckel’s diverticulum is resected using a transverse elliptical incision, as described above for omphalo-ileal ﬁstula (Fig. 65.3d) and repaired transversely (Fig. 65.3e). When diverticulectomy is done for gastrointestinal hemorrhage, the opened ileum is examined to ensure that all ectopic gastric mucosa has been removed. Ileal resection with primary end-to-end anastomosis is an alternative method for managing hemorrhage associated with Meckel’s diverticulum, and ensures removal of all ectopic tissue.1 Ileal resection is also required when the ileum adjacent to the Meckel’s diverticulum is abnormal, as may be the case with Meckel’s diverticulitis. The abdominal incision is closed in layers using 4–0 absorbable sutures, and the skin is approximated with subcuticular 5–0 sutures reinforced with adhesive strips. Postoperative care includes nasogastric tube drainage and intravenous ﬂuids until normal gastrointestinal function is reestablished. Perioperative antibiotics may be given for prophylaxis against wound infection. Recently, the laparoscopic approach has been used to conﬁrm the diagnosis of Meckel’s diverticulum as well as to excise the diverticulum.4

REFERENCES 1. Irving I. Umbilical abnormalities. In: Lister J, Irving IM, editors. Neonatal Surgery, 3rd edition. London: Butterworths, 1990: 396–402. 2. Swaniker F, Soldes O, Hirschl RB. The utility of technetium 99m pertechnetate scintigraphy in the evaluation of patients with Meckel’s diverticulum. J Pediatr Surg 1999; 34(5):760–4. 3. St. Vil D, Brandt ML, Panic S. Meckel’s diverticulum in children: a 20 year review. J Pediatr Surg 1991; 26:1289–92. 4. Teitlebaum DH, Polley TZ, Obeid F. Laparoscopic diagnosis and excision of Meckel’s diverticulum. J Pediatr Surg 1994; 29:495–7.

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66 Bladder exstrophy: considerations and management of the newborn patient FERNANDO A. FERRER AND JOHN P. GEARHART

INTRODUCTION In this chapter, the techniques for managing the newborn with classical bladder exstrophy are discussed based on the author’s experience and data derived from more than 688 patients with bladder exstrophy and cloacal malformations treated at the current authors’ institution. The primary objectives of modern surgical management of classic bladder exstrophy are: 1 a secure abdominal closure; 2 reconstruction of a functional and cosmetically acceptable penis in the male and female external genitalia in the female; and 3 urinary continence with the preservation of renal function and volitional voiding. Currently, these objectives can best be achieved with newborn primary bladder and posterior urethral closure, early epispadias repair, and ﬁnally, bladder neck reconstruction, when the bladder reaches an appropriate volume for an outlet procedure. This chapter will be limited to discussion on the early management and initial primary closure of these infants.

INCIDENCE AND INHERITANCE The incidence of bladder exstrophy has been estimated to be between one in 10 000 and one in 50 000 live births.1 However, data from the International Clearinghouse for Birth Defects monitoring system estimated the incidence to be 3.3 in 100 000 live births.2 Two series have reported a 5 : 1 to 6 : 1 ratio of male-to-female exstrophy births.1,2 The risk of recurrence of bladder exstrophy in a given family is approximately one in 100.2 Shapiro (1984) determined that the risk of bladder exstrophy in the offspring of individuals with bladder exstrophy and

epispadias is one in 70 live births, a 500 fold greater incidence than that in the general population.3 In a multinational review of exstrophy patients (Lancaster) two interesting trends were found: 1 bladder exstrophy tended to occur in infants of younger mothers, and 2 an increased risk at higher parity was seen for bladder exstrophy but not epispadias.2

EMBRYOLOGY Bladder exstrophy, cloacal exstrophy, and epispadias are variants of the exstrophy–epispadias complex. The etiology of this complex has been attributed by Muecke to the failure of the cloacal membrane to be reinforced by ingrowth of mesoderm.4 The cloacal membrane is a bilaminar layer situated at the caudal end of the germinal disc, which occupies the infraumbilical abdominal wall. Mesenchymal ingrowth between the ectodermal and endodermal layers of the cloacal membrane results in formation of the lower abdominal muscles and pelvic bones. After mesenchymal ingrowth occurs, downward growth of the urorectal septum divides the cloaca into a bladder anteriorly and rectum posteriorly. The paired genital tubercles migrate medially and fuse in the midline cephalad to the dorsal membrane before perforation. If the cloacal membrane is subject to premature rupture, its stage of development when membrane rupture occurs determines if bladder exstrophy, cloacal exstrophy, or epispadias will result.5 While multiple explanations have been presented, Marshall and Muecke maintain that the basic defect is an abnormal overdevelopment of the cloacal membrane, preventing medial migration of the mesenchymal tissue and proper lower abdominal wall development. Classic exstrophy accounts for 60% of patients born with this complex.6 Of these patients, 30% are epispadias variants,

620 Bladder exstrophy: considerations and management of the newborn patient

and 10% are cloacal exstrophies or minor variants, such as superior vesical ﬁssure, duplicate exstrophy, and pseudoexstrophy.

ANATOMIC CONSIDERATIONS Exstrophy of the bladder is part of a spectrum of anomalies involving the urinary tract, genital tract, musculoskeletal system, and sometimes the intestinal tract. In classic bladder exstrophy, most anomalies are related to defects of the abdominal wall, bladder, genitalia, pelvic bones, rectum, and anus (Fig. 66.1).

Musculoskeletal defects Patients with classic bladder exstrophy have a characteristic widening of the pubic symphysis caused by malrotation of the innominate bones, in relation to the sagittal plane of the body along both sacroiliac joints. In addition, they display an outward rotation or eversion of the pubic rami at their junction with iliac bones. Recently, new data by Sponseller et al. utilizing computer tomography of the pelvis with three-dimensional (3-D) reconstruction, has further characterized the bony defect associated with both classic bladder exstrophy and cloacal exstrophy.7 Sponseller et al. found that patients with classic bladder exstrophy have a mean external rotation of the posterior aspect of the pelvis of 12° on each side, retroversion of the acetabulum, and a mean 18° of external rotation of the anterior pelvis, along with a 30% shortening of the pubic rami. These rotation deformities of the pelvic skeletal structures contribute to the short, pendular penis seen in bladder exstrophy. Additionally, this rotation also accounts for the increased distance between the hips, waddling gait, and the outward rotation of the lower limbs in these children, which

in itself causes little disability and usually corrects to some degree over time. A recent study using 3-D CT has further increased our understanding of the pelvic anatomy in patients with bladder exstrophy.8 In this paper Stec et al. showed that sacroiliac joints are externally rotated, the pelvis is rotated inferiorly, and the pelvic volume in exstrophy patients is larger than normal controls. These new ﬁndings will hopefully serve to improve our understanding and surgical approach to pelvic osteotomy in these patients.

Abdominal wall defects The triangular defect caused by the premature rupture of the abnormal cloacal membrane is occupied by the exstrophied bladder and posterior urethra. The fascial defect is limited inferiorly by the intrasymphyseal band, which represented the divergent urogenital diaphragm. This band connects the bladder neck and posterior urethra to the pubic ramus on anatomical study. The anterior sheath of the rectus muscles has a fan-like extension behind the urethra and bladder neck that inserts into the intrasymphyseal band. At the upper end of the triangular fascial defect is the umbilicus. In bladder exstrophy, the distance between the umbilicus and the anus is always foreshortened. Although an umbilical hernia is usually present, it is usually of insigniﬁcant size. The umbilical hernia is repaired at the time of the abdominal wall closure. Connelly et al., in review of 181 children with bladder exstrophy, reported inguinal hernias in 81.8% of boys and 10.5% of girls.9

Anorectal defects The perineum is short and broad, with the anus situated directly behind the urogenital diaphragm, displaced anteriorly, and corresponding to the posterior limit of the triangular fascial defect. The divergent levator ani and puborectalis muscles and the distorted anatomy of the external sphincter contribute to varying degrees of anal incontinence and rectal prolapse. Anal continence is usually imperfect at an early age but typically improves. Prolapse virtually always disappears after bladder closure or cystectomy and urinary diversion.

Male genital defects

Figure 66.1 Newborn male infant with classic bladder exstrophy

The male genital defect is severe and the most troublesome aspect of the surgical reconstruction, independent of the decision whether to treat by modern staged closure, combined closure, or by some form of urinary diversion. Formerly it was thought the individual corpus cavernosum were of normal caliber, but appeared to be shorter because of the wide separation of the crural

Prenatal diagnosis and management 621

attachments, the prominent dorsal chordee, and the shortened urethral groove. However, recent data by Silver et al. (1997) has described the genital defect in bladder exstrophy in much greater detail.10 Utilizing magnetic resonance imaging in adult men with bladder exstrophy and comparing this to age and race matched controls, it was found that the anterior corporal length in male patients with bladder exstrophy is almost 50% shorter than that of normal controls. A functional and cosmetically pleasing penis can be achieved when the dorsal chordee is released, the urethral groove lengthened, and the penis somewhat lengthened by mobilizing the crura in the midline. Patients with a very small or dystrophic penis should only be considered for sex reassignment after other opinions are obtained and parents are counseled exhaustively about the implications of this step. Potency is preserved in almost all exstrophy patients. Testis function has not been studied in a large group of postpubertal exstrophy patients, but it is generally believed that fertility is not impaired by testicular dysfunction.

Female genital defects Reconstruction of the female genitalia presents a less complex problem than in the male (Fig. 66.2). The vagina is shorter than normal, hardly greater than 6 cm in depth but of normal caliber. The vaginal oriﬁce is frequently stenotic and displaced anteriorly; the clitoris is biﬁd. The labia, mons pubic, and clitoris are divergent. The uterus enters the vagina superiorly so that the cervix is in the anterior vaginal wall. The fallopian tubes and ovaries are normal. Female patients are typically able to bear children.

Urinary defects At birth, the bladder mucosa may appear to be normal, however, ectopic bowel mucosa or an isolated bowel loop or more commonly, a hamartomatous polyp may be present on the bladder surface. The size, distensibility, and neuromuscular function of the exstrophied bladder, as well as the size of the triangular fascial defect to which the bladder muscles attach, affects the decision to attempt repair. When the bladder is small, ﬁbrosed, inelastic, and covered with polyps, functional repair may be impossible. The more normal bladder may be invaginated or may bulge through a small fascial defect, indicating the potential for satisfactory capacity after successful initial closure. It is not until examination under anesthesia that the true defect can be adequately evaluated as bladders which appear to be small in the nursery may have a substantial amount of bladder sequestered below the fascial defect. The upper urinary tract is usually normal, but anomalous development does occur. Horseshoe kidney, pelvic kidney, hypoplastic kidney, solitary kidney, and dysplasia with megaureter are all encountered in these patients. The ureters have an abnormal course in their termination. The peritoneal pouch of Douglas between the bladder and the rectum is enlarged and unusually deep, forcing the ureter down laterally in its course across the true pelvis. The distal segment of the ureter approaches the bladder from a point inferior and lateral to the oriﬁce, and it enters the bladder with little or no obliquity. Therefore, reﬂux in the closed exstrophy bladder occurs in 100% of cases and subsequent surgery is usually required at the time of bladder neck reconstruction.

PRENATAL DIAGNOSIS AND MANAGEMENT Recent reports have indicated that it is possible to diagnose classic bladder exstrophy prenatally.11,12 The absence of a normal ﬂuid-ﬁlled bladder on repeat examinations suggested the diagnosis, as did a mass of echogenic tissue on the lower abdominal wall.12 In a retrospective review of 25 prenatal ultrasound examinations with the resulting birth of newborn classic bladder exstrophy, several observations were made: 1 2 3 4 5

Figure 66.2 Female infant with classic bladder exstrophy

Absence of bladder ﬁlling A low-set umbilicus Widening of the pubic ramus Diminutive genitalia A lower abdominal mass which increased in size as the pregnancy progressed and as the intraabdominal viscera increased in size.13

Prenatal diagnosis of bladder exstrophy allows for optimal prenatal management including delivery in a

622 Bladder exstrophy: considerations and management of the newborn patient

pediatric center and appropriate prenatal counseling of the parents.

DELIVERY ROOM AND NURSERY CARE At birth, while the bladder mucosa is usually smooth, pink, and intact, it is also sensitive and easily denuded. In the delivery room the umbilical cord should be tied with 2-0 silk sutures close to the abdominal wall so that the umbilical clamp does not traumatize the bladder mucosa and cause excoriation of the bladder surface. The bladder may be covered with a non-adherent ﬁlm of plastic wrap (i.e. Saran Wrap) to prevent the mucosa from sticking to clothing or diapers. In addition, each time the diaper is changed the plastic wrap should be removed, the bladder surface irrigated with sterile saline, and a new square of plastic wrap placed. The parents should be educated by a surgeon with a special interest and experience in managing cases of bladder exstrophy. An exstrophy support team should be available, which includes a pediatric orthopedic surgeon, pediatric anesthesiologists, social workers, nurses with special interests in bladder exstrophy, and a child psychiatrist with experience and expertise in genital anomalies. It is important to note that the need for changing the sex of rearing in classic bladder exstrophy is almost non-existent in the male child. Cardiopulmonary and general physical assessment can be carried out in the ﬁrst few hours of life. Radionuclide scans and ultrasound studies can provide evidence of renal structure, function, and drainage, even in the ﬁrst few hours of life before the patient undergoes closure of the exstrophy defect. A thorough neonatal assessment may have to be deferred until transportation to a major children’s medical center can be arranged. In these days of modern transportation, no child should be more than a few hours away from a neonatal center with full diagnostic and consultative services. During travel the bladder should be protected by a plastic membrane to prevent damage to the delicate newborn bladder mucosa. Occasionally, preoperatively it may become evident that a small ﬁbrotic bladder patch that is stretched between the edges of a small triangular fascial defect without elasticity or contractility cannot be selected for the usual closure procedure. Figure 66.3 shows a bladder that is too small for closure. Examination with the patient under anesthesia may at times be required to assess the bladder adequately, particularly if considerable edema, excoriation, and polyp formation has developed between birth and the time of assessment. Decisions regarding the suitability of bladder closure or the need for waiting should only be made by surgeons with a great deal of experience in the bladder exstrophy condition. A recent review by Dodson et al. at one institution, found

Figure 66.3 Patient with a small ﬁbrotic bladder patch deemed too small for neonatal closure. Note the polypoid nature of the bladder mucosa

on initial judgment that the bladder was too small for closure in 20 patients.14 After a period of time, when the bladder had grown sufﬁciently, closure was undertaken. Long-term follow-up revealed that 50% of these patients remained dry after bladder neck reconstruction and 50% required other adjunctive procedures.

PRIMARY BLADDER CLOSURE Over the past 2 decades, modiﬁcations in the management of functional bladder closure have contributed to a dramatic increase in the success of the procedure. The most signiﬁcant changes in the management of bladder exstrophy have been: 1 Early bladder, posterior urethra, and abdominal wall closure, usually with pelvic osteotomy 2 Early epispadias repair 3 Reconstruction of a competent bladder neck and reimplantation of the ureters 4 (Most importantly) Deﬁning strict criteria for the selection of patients suitable for this approach. The primary objective of functional closure is to convert the patient with bladder exstrophy into one with complete epispadias with incontinence and balanced posterior outlet resistance that preserves renal function, but stimulates bladder growth. Typically epispadias repair is now performed between 6 months and 12 months of age, after testosterone stimulation. Bladder neck repair usually occurs when the child is 4–5 years of

Primary bladder closure 623

age, has an adequate bladder capacity and is ready to participate in a postoperative voiding program. This chapter only addresses initial bladder closure.

Osteotomies

Pelvic osteotomy Pelvic osteotomies performed at the time of closure confers several advantages, including: 1 Easy reapproximation of the symphysis with diminished tension on the abdominal wall closure and eliminates the need for fascial ﬂaps 2 Placement of the urethra deep within the pelvic ring enhancing bladder outlet resistance 3 Bringing the large pelvic ﬂoor muscles near the midline, where they can support the bladder neck and aid in eventual urinary control. After pubic approximation with osteotomy, some patients show the ability to stop and start the urinary stream, experience dry intervals, and in some cases become completely continent.15 In a review article of a large number of patients referred to the current authors’ institution with failed exstrophy, a majority were referred with partial or complete dehiscence of the bladder, or major bladder prolapse, and had not undergone prior osteotomy at the time of initial bladder closure.16 The author’s recommendation is to perform bilateral transverse innominate and vertical iliac osteotomy when bladder closure is performed after 72 hours of age.17 In addition, if the pelvis is not malleable or if the pubic bones are > 4 cm apart at the time of initial examination under anesthesia, osteotomy should be performed, even if closed before 72 hours of age. A well-coordinated surgical and anesthesia team can perform osteotomy and proceed to bladder closure without undue loss of blood or risk of prolonged anesthesia in the child. However, one must realize that osteotomy, posterior urethral and bladder closure, along with abdominal wall closure, is a 5–7-hour procedure in these infants. Combined osteotomy is performed by placing the patient in the supine position, preparing and draping the lower body below the costal margins and placing soft absorbent gauze over the exposed bladder. The pelvis is exposed from the iliac wings inferiorly to the pectineal tubercle and posteriorly to the sacroiliac joints. The periosteum and sciatic notch are carefully elevated and a Gigli saw is used to create a transverse innominate osteotomy, exiting anteriorly at a point halfway between the anterosuperior and anteroinferior spines (Fig. 66.4). This osteotomy is created at a slightly more cranial level than that described for a Salter osteotomy, in order to allow placement of external ﬁxator pins in the distal segments. In addition to the transverse osteotomy, the posterior ilium may be incised from the anterior approach in an

Figure 66.4 Schematic diagram depicting cuts for bilateral transverse innominate and vertical iliac osteotomies

effort to correct the deformity more completely. This is important because anatomical studies have shown that the posterior portion of the pelvis is also externally rotated in patients with exstrophy, and as patients age they lose the elasticity of their sacroiliac ligaments. For this part of the osteotomy, an osteotome is used to create a closing wedge osteotomy vertically and just lateral to the sacroiliac joint. The proximal posterior iliac cortex is kept intact and used as a hinge. This combination of osteotomies easily corrects the abnormalities in both the anterior and posterior aspects of the pelvis. Two ﬁxator pins are placed in the inferior osteotomized segment and two pins are placed in the wing of ileum superiorly. Radiographs are obtained to conﬁrm pin placement, the soft tissues are closed, and the urological procedure is then performed. At the end of the procedure external ﬁxators are then applied between the pins to hold the pelvis in a corrected position. Light longitudinal skin traction is used to keep the legs still. The patient remains in the supine position in traction for approximately 4 weeks to prevent dislodgment of tubes and destabilization of the pelvis. The external ﬁxator is kept on for approximately 6 weeks until adequate callus is seen at the site of the osteotomy. Postoperatively, in newborns who undergo closure without osteotomy in the ﬁrst 48–72 hours of life, the baby is immobilized in modiﬁed Bryant’s traction in a position in which the hips have 90° ﬂexion. When modiﬁed Bryant’s traction is used, the traction is employed for 4 weeks.

Bladder, posterior urethral, and abdominal wall closure The various steps in primary bladder closure are illustrated in Fig. 66.5a–k. A strip of mucosa 2 cm wide, extending from the distal trigone to below the

624 Bladder exstrophy: considerations and management of the newborn patient Development of retropubic space

Bladder Incision completed

Ureteral orifice

Prostatic utricle

Peritoneum Division of bladder attachments

Penis Scrotum

Urachus

(a)

Future line of excision of umbilicus

Obliterated hypogastric aa. reflected

Incision Umbilicus

(f)

Ureteral orifices B1

Hemiclitoris

Incision Vagina

(b)

(c) Anterior rectus sheath

Line of skin incision and closure

Rectus muscle

Mucosal line of closure

Sub-periosteal detachment of crus

Symph. pubis Urogenital diaphragm

(g)

(d)

Umbilical tissue excised

Suspensory ligament divided from body of pubis

Urogenital diaphragm incised

(e)

(h)

Primary bladder closure 625 Ureteral catheters

Position of new umbilicus

Approximating rectus fascia

Symph. pubis approximated by horizontal mattress suture tied anteriorly Catheter removed after closure (i) #

2 nylon

(k)

Second layer closure

(j)

Figure 66.5 (a) Anatomic structures in a male neonate with classic bladder exstrophy. (b) Marking of incisions for closure of female exstrophy patient. (c) Marking of incisions for closure of male exstrophy patient. (d) Incisions for initial closure. (e) Incisions deepened and suspensory ligaments to bladder plate are divided. (f) Dissection proceeds caudally after division of umbilical arteries and veins. (g) Separation of the ﬁbers representing genitourinary diaphragm from the symphysis pubis. (h) Bladder is ready for closure; suprapubic tube is inserted. (i) Ureteral catheters are placed, 3.5–5 Fr. feeding tubes. Bladder is closed in running fashion with absorbable sutures. (j) A second layer closure is performed to buttress initial closure. (k) Closure of fascia is performed after placement of a No. 2 nylon horizontal mattress suture to approximate the pubis

626 Bladder exstrophy: considerations and management of the newborn patient

verumontanum in the male and to the vaginal oriﬁce in the female, is outlined for prostatic and posterior urethral reconstruction in the male and adequate urethral closure in the female. The male urethral groove length is typically adequate and no transverse incision of the urethral plate need be performed for urethral lengthening. The diagrams in Fig. 66.5b–d show marking of the incision with a blue marking pen from just above the umbilicus down around the junction of the bladder and the paraexstrophy skin to the level of the urethral plate. The appropriate plane is entered just above the umbilicus and a plane is established between the rectus fascia and the bladder (Fig. 66.5e,f). The umbilical vessels are doubly ligated and incised and allowed to fall into the pelvis. The peritoneum is taken off the dome of the bladder at this point so that the bladder can be placed deeply into the pelvis at the time of closure. The plane is continued caudally down between the bladder and the rectus fascia until the urogenital diaphragm ﬁbers are encountered bilaterally. The pubis will be encountered at this juncture and a double-pronged skin hook can be inserted in this bone at this time and pulled laterally to accentuate the urogenital diaphragm ﬁbers and help the surgeon radically incise these ﬁbers between the bladder neck, posterior urethra and the pubic bone. Gentle traction on the glans of the penis at this point will show the insertion of the corporal body on the lateral inferior aspect of the pubis. These urogenital diaphragm ﬁbers are taken down sharply with the electrocautery down to the pelvic ﬂoor in their entirety. If this maneuver is not performed adequately, the posterior urethra and bladder will not be placed deeply into the pelvis. Therefore, when the pubic bones are brought together, the posterior vesicourethral unit will be brought anteriorly in an unsatisfactory position for later reconstruction. The corporal bodies are not brought together at this juncture, as later Cantwell-Ransley epispadias will require the urethral plate to be brought beneath the corporal bodies. If the urethral plate is left in continuity, it must be mobilized up to the level of the prostate in order to create as much additional urethral and penile length as possible. Further urethral lengthening can be performed at the time of epispadias repair, around 6 months of age. Apparent penile lengthening is achieved by exposing the corpora cavernosa bilaterally and freeing the corpora from their attachments to the suspensory ligaments on the anterior part of the inferior pubic rami. However, since Silver et al. have shown that there is a 50% shortage of length in the corporal bodies in exstrophy patients vs normal controls, any penile lengthening that is obtained is more correction of chordee and changing the angulation of the penis, rather than true penile lengthening.10 After their incision, the wide band of ﬁbers and muscular tissue representing the urogenital diaphragm is detached subperiostally from the pubis bilaterally (Fig. 66.5g,h). Reluctance to free the bladder neck and urethral wall from the inferior ramus of the pubis moves

the neobladder opening cephalad if any separation of the pubis occurs during healing. The mucosa and muscle of the bladder, and the posterior urethral wall onto the penis are then closed in the midline anteriorly. This oriﬁce should accommodate a 12–14F urethral comfortably. The size of the opening should allow enough resistance to aid in bladder adaptation and to prevent prolapse, but not enough outlet resistance to cause upper tract changes. The posterior urethra and bladder neck are buttressed to the second layer of local tissue if possible (Fig. 66.5i,j). The bladder is drained by a suprapubic non-latex Malecot catheter for a period of 4 weeks. The urethra is not stented in order to avoid necrosis with accumulation of secretions in the neourethra. Ureteral stents provide drainage during the ﬁrst 10–14 days after closure, when swelling due to the pressure of closure of a small bladder may obstruct the ureters and give rise to obstruction and transient hypertension. If there are no problems with the stents during healing, the current authors leaves the stents in for as long as 2–3 weeks. When the bladder and urethra have been closed and the drainage tube placed, pressure over the greater trochanters bilaterally allows the pubic bones to be approximated in the midline. Horizontal No. 2 mattress sutures are placed in the pubis and tied with a knot away from the neourethra (Fig. 66.5I–K). Often times, in a good closure the author is able to use another stitch of No. 2 nylon at the most caudal insertion of the rectus fascia onto the pubic bone. This maneuver will add to the security of the pubic closure. A V-shaped ﬂap of abdominal skin at a point corresponding to the normal position of the umbilicus is tacked down to the abdominal fascia and the drainage tubes exit this oriﬁce. The method described by Hanna is the author’s most commonly performed procedure.18 Before and during the procedure, the patient is given broad-spectrum antibiotics in an attempt to convert a contaminated ﬁeld into a clean surgical wound. Non-reactive sutures of polyglycolic acid (Dexon/Vicryl) and nylon are used to avoid an undesirable stitch reaction or stitch abscesses.

Combined bladder closure and epispadias repair The staged closure of bladder exstrophy has yielded consistently good cosmetic and functional results, and the utilization of osteotomy has improved the potential for successful initial closure and later continence. In an effort to decrease costs, the morbidity associated with multiple operative procedures and possibly to effect continence, there has been recent interest in performing single-stage reconstruction, or combining procedures in appropriately selected patients. This technique was ﬁrst described by Lattimer and Smith for primary closures and by Gearhart and Jeffs in 1991 for failed exstrophy closures.15,19 Grady and Mitchell have recently renewed

References 627

interest in its use in newborn patients,20 results have now been reported in groups of boys undergoing single-stage reconstruction (bladder closure and epispadias repair) in infancy.19.20 In the current author’s opinion, this technique should be limited to boys of older age (older than 6 months) because of recent experimental evidence indicating that newborn bladders differ from bladders in older infants in the level of maturity of muscle and connective tissue components. The senior author believes that these patients should be carefully selected, especially newborns, because of the reasons given earlier. Otherwise, boys presenting after failed initial closure and/or older than 6 months of age, may be candidates for a combination of epispadias repair with bladder closure. Children should be carefully selected based on phallic size, length, and depth of the urethral groove, size of the bladder template, and perivesical and urethral plate scarring in children who have undergone a prior failed closure.

3. 4.

5.

6.

7.

8.

9.

CONCLUSION 10.

A staged approach to treatment in patients with bladder exstrophy is able to provide a satisfactory outcome both cosmetically and functionally in most cases. This approach consists of: 1 Initial bladder closure 2 Repair of epispadias 3 Bladder neck reconstruction. Bladder neck reconstruction is the recommended management based on the current authors’ and institutional experience with over 688 cases of cloacal disorders. Recent reports of a single-stage repair by other authors have proported successful outcomes, however follow-up is limited and numbers of patients in these series is small. In a recent review of over 80 patients, Chan et al. reported a 89% social continence rate within a group of selected patients treated using the aforementioned strategy.21 While recent developments in tissue engineering hold promise to improve outcomes for patients requiring genitourinary reconstruction in the future, staged functional closure remains the ‘gold standard’ for patients with classic bladder exstrophy at the turn of the millennium.

REFERENCES

11.

12. 13. 14.

15. 16.

17.

18.

19. 20.

1. Lattimer JK, Smith MJK. Exstrophy closure: a follow up on 70 cases. J Urol 1966; 95:356. 2. Lancaster PAL. Epidemiology of bladder exstrophy: a communication from the International Clearinghouse for

21.

Birth Defects monitoring systems. Teratology 1987; 36:221. Shapiro E, Lepor H, Jeffs RD. The inheritance of classical bladder exstrophy. J Urol 1984; 132:308. Muecke EC. The role of the cloacal membrane in exstrophy: the ﬁrst successful experimental study. J Urol 1964; 92:659. Ambrose SS, O’Brien DP. Surgical embryology of the exstrophy-epispadias complex. Surg Clin North Am 1974; 54:1379. Marshall VF, Muecke C. Congenital abnormalities of the bladder. In: Handbuch de Urologie. New York: SpringerVerlag, 1968:165. Sponseller PD, Bisson LJ, Gearhart JP et al. The anatomy of the pelvis in the exstrophy complex. J Bone Joint Surg 1995; 77:177. Stec AA, Pannu HK, Tadros YE. Evaluation of the bony pelvis in classic bladder exstrophy: further insights. Urology 2001; 58:1030. Connely JA, Peppas DS, Jeffs RD, Gearhart JP. Prevalence in repair of inguinal hernia in children with bladder exstrophy. J Urol 1995; 154:1900. Silver RI, Yang A, Ben-Chaim J et al. Penile length in adulthood after exstrophy reconstruction. J Urol 1997; 158:999. Gearhart JP, Ben-Chaim J, Jeffs RD et al. Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol 1995; 85:961. Mirk M, Calisti A, Feleni A. Prenatal sonographic diagnosis of bladder exstrophy. J Ultrasound Med 1986; 5:291. Verco PW, Khor BH, Barbary J, Enthoven C. Ectopic vesicae in utero. Australas Radiol 1986; 30:117. Dodson J, Jeffs RD, Gearhart JP. The small exstrophy bladder unsuitable for closure. American Academy of Pediatrics, Washington DC, October 9, 1999. Gearhart JP, Peppas DS, Jeffs RD. Failed exstrophy closure: strategy for management. Br J Urol 1993; 71:217. Sponseller PD, Gearhart JP, Jeffs RD. Anterior innominate osteotomies for failure or late closure bladder exstrophy. J Urol 1991; 146:137. Gearhart JP, Forschner DC, Jeffs RD et al. A combined vertical and horizontal pelvic osteotomy approach for primary and secondary repair of bladder exstrophy. J Urol 1996; 155:689. Hanna MN. Reconstruction of the umbilicus during functional closure of bladder exstrophy. Urology 1986; 27:340. Gearhart JP, Jeffs RD. Management of the failed exstrophy closure. J Urol 1991; 146:610. Grady R, Mitchell ME. Complete repair of exstrophy. J Urol 1999; 162:1415. Chan D, Jeffs RD, Gearhart JP. Determinants of continence after bladder neck reconstruction in the bladder exstrophy population. J Urol (in press).

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67 Cloacal exstrophy JONATHAN I. GRONER AND MORITZ M. ZIEGLER

INTRODUCTION Cloacal exstrophy is an extremely rare malformation that affects between one in 200 000 and one in 400 000 life births.1 It is said to be one of the most complex malformations that a pediatric surgeon can encounter with the expectation of patient survival. In the past 2 decades, the literature on cloacal exstrophy has continued to shift away from improving patient survival, focusing instead on improving the quality of life for these children through appropriate gender assignment, independence from stomal appliances, and improved independence and mobility.

HISTORY Prior to 1960, most surgeons felt that cloacal exstrophy presented insurmountable obstacles to both the patient and surgeon. Infants born with this anomaly were denied treatment and expected to die. Ironically, a child born in 1958 received this ‘standard therapy’ for 18 years of his life and managed quite well, proving that cloacal exstrophy is not necessarily lethal. He later underwent treatment of this anomaly.2 Cloacal exstrophy, also known in the past as vesicointestinal ﬁssure, ileovesical ﬁstula, or extrophia splanchnica, was ﬁrst described by Littre in 1709 and again by Meckel in 1812. The era of operative correction began with Rickham’s 1960 report of a three-stage procedure performed over 8 months.3 Since that time, improvements in operative technique, critical care, and nutritional support have led to earlier correction and increased survival. Although only 17 of 34 patients survived correction during the years 1968–1976, survival of 13 of 15 patients at a single institution was reported in the early 1980s.4 Today, survival from cloacal exstrophy is nearly universal, the mortality being a product of associated renal or cardiac disease. Rather the focus has shifted

to genitourinary and gastrointestinal reconstruction designed to render the patient appliance-free.5

ANATOMY Cloacal exstrophy is the most severe ventral abdominal wall defect (Figs 67.1, 67.2). An omphalocele, which is sometimes very large, is always present. Inferior to the omphalocele sac, a complex midline lesion with multiple mucosal outpouchings is readily apparent. The two lateral mucosal ‘plates’ represent the right and left hemibladders, and a ureteral oriﬁce is present in the lower portion of each. The central mucosal plate is composed of intestinal epithelium and represents the cecum. Up to ﬁve oriﬁces may be present on this surface. The most superior oriﬁce belongs to the terminal ileum, which may be

Figure 67.1 ‘Classic’ cloacal exstrophy. Note the omphalocele, the prolapsed terminal ileum, and the wide separation of the hips due to the laterally displaced pubic bones

630 Cloacal exstrophy Small intestine

Exomphalos

PREOPERATIVE MANAGEMENT Associated anomalies

Proximal bowel orifice

Appendix

Appendix Right hemibladder Distal bowel orifice

Left hemibladder Blind large intestine

Figure 67.2 Anatomy of cloacal exstrophy

prolapsed, leading to the ‘elephant trunk’ deformity. In the middle of the bowel plate are one or two oriﬁces, representing single or duplicated appendices. Finally, the most inferior oriﬁce, which may also be single or double, represents the distal colon, which is almost always shortened with a blind ending.

EMBRYOGENESIS Cloacal exstrophy results from incomplete coverage of the infra-umbilical wall by the secondary mesoderm of the primitive streak, resulting in a ‘rupture’ of the midline structures during the ﬁfth embryonic week. When this development defect occurs after fusion of the genital tubercles (in the seventh week), bladder exstrophy results. If, however, the rupture occurs before the ﬁfth week, the genital tubercles do not fuse; furthermore, the urorectal septum does not descend to separate the future bladder from the future large bowel. The result is a larger midline defect with exposure of both bowel and bladder elements and duplication of the genitalia. The absence of the urorectal septum may cause marked retardation in the development of the colon, resulting in the blind-ending, foreshortened distal gut typically seen in these patients.6 Studies in twins have raised an additional challenge to the classic embryogenesis theory. Several reports have cited cases in which cloacal exstrophy was present in one of the monozygotic twins, when the other twin is normal. This has even occurred in one of a set of conjoined twins, with the other being normal. Two additional reports of the fetal diagnosis of cloacal exstrophy in one of a pair of twins suggests that cloacal membrane rupture as late as 18–24 weeks and 22–26 weeks may account for the broad scope of variations seen in this anomaly.7,8

Anomalies of other organ systems remote from the basic cloacal exstrophy defect are common, occurring in as many as 85% of cases.9 Such abnormalities include the upper urinary tract (42–60%) and hydronephrosis, hydroureter, ureteral atresia, and ureteral duplication; other abnormalities include pelvic kidney, renal agenesis, multicystic kidney, and crossed fused ectopia. Vertebral anomalies occur in 48–75% of cases, while myelodysplasia syndromes are present in 29–46% of cases. Because of the potential for a tethered cord inﬂuencing continence, and its frequent association with imperforate anus, this anomaly must also be excluded. Interestingly, survivors are reported to be of normal intelligence. Associated gastrointestinal anomalies include malrotation, duodenal atresia, Meckel’s diverticulum, and duplications. Associated orthopedic anomalies include club-foot, congenital dislocation of the hips and other potentially severe deformities (26–30%). Omphalocele is almost invariably present in patients with cloacal exstrophy, and abdominal wall features consistent with prune belly syndrome associated with an omphalocele have been reported.10 The majority of children with prune belly syndrome have a form of myelodysplasia as well.11 The bladder exstrophy is constant but variable, the ureteral oriﬁces entering quite laterally. The exposed bowel plate of the ileocecal junction may also vary with openings of duplicated appendices or even a duplicated distal colon, which will be blind-ending with imperforate anus. The ileum may or may not prolapse as an exposed proboscis. The external genitalia are also abnormal. In males the penis and scrotum may be absent, biﬁd, or epispadic, and it will be of variable size and development. The testes are typically undescended, and most commonly are intraabdominal in location (see later). The vas deferens may be normal, absent or duplicated. In females the clitoris is biﬁd or absent and the vagina may be absent, duplicated, or exstrophied. A biﬁd or duplicate uterus is almost uniformly present. Recently, an association between large ovarian cysts and cloacal exstrophy was noted in postpubertal females. All four subjects in the report had severe pelvic pain, and urinary obstruction occurred in three. Ultrasonography was the tool of diagnosis.12

Gender assignment Although there is a male predominance in cloacal exstrophy, the commonly found inadequate corporal structures associated with a biﬁd penis make adequate penile reconstruction difﬁcult. Historically, therefore, most such patients underwent a female gender assignment. Despite their genetic sex, they were reared as a girl,

Preoperative management 631

and an eventual reconstructive operation was designed to develop phenotypic female anatomy complimented by female hormonal replacement. However, in recent years there has been a call to re-examine genotypically congruent sex assignment, even in those newborns with an inadequate phallus, both because of a recognition of a high frequency of sexual dysfunction in genderconverted children and adolescents as well as a realization of the potential for penile reconstruction.13–15 However, males with adequate bilateral or even unilateral phallic structures should receive a male gender assignment. In any case where gender reassignment or conversion is considered, there is a considerable need for parental counseling, endocrinologic input, and input on a longitudinal basis from a trained psychiatrist/psychologist for both the parents and child. In genotypic males with cloacal exstrophy, the testes are typically located intra-abdominally. If a genotypically congruent sex assignment is maintained, then orchidopexy will be needed. Fortunately as a group, the testes, despite their location, retain a near-normal histology.16 In contrast, when gender conversion to the female phenotype is considered, eventual orchiectomy will be required. In genetic females, the biﬁd clitoris and labia are initially left alone. As the child grows, staged operations are used to create an adequate appearance. Failure of midline fusion, a key characteristic of cloacal exstrophy, is frequently manifested in the female reproductive system; duplication of the vagina, uterus, and fallopian tubes are common. Atresia and exstrophy of the vagina are also possible. The latter is difﬁcult to distinguish in the newborn period, due to the large exstrophic bladder above the exposed vaginal tissue. However, diagnosis of this entity is important in planning the staged vaginal reconstruction.

Preoperative evaluation Prenatal ultrasound has become commonplace for the diagnosis of cloacal exstrophy, and speciﬁc criteria have been deﬁned.1 Major diagnostic criteria include nonvisualization of the bladder, a large midline infraumbilical anterior wall defect or cystic abdominal wall structure, omphalocele, or myelomeningocele. Less frequently deﬁned minor criteria include lower extremity defects, renal anomalies, ascites, widened pubic arches, a narrow thorax, hydrocephalus, and a single umbilical artery. This added diagnostic prepartum information allows appropriate education of the parents, planning for the pregnancy, timing and location of the delivery, as well as optimal newborn management, preferably in a center experienced in the care of babies with this anomaly. At birth, the immediate management is directed to stabilization of the baby, protection of the exposed

omphalocele membrane, bladder and bowel, and if present, protection of the myelomeningocele. After a screening physical examination and baseline renal function and electrolyte laboratory studies, an ultrasound of the genitourinary tract along with chest/ abdominal radiographs complete the initial screening for associated anomalies. Cardiac evaluation should be individualized. Normal body temperature is maintained either by covering the exposed mucosa and membranes with warmed sterile saline followed by a plastic wrap, or by enclosing the lower half of the torso in a warm salineﬁlled plastic bag. Careful inspection must be done of the exposed anatomy including the omphalocele, right and left hemibladder, the intestinal plate with the proximal and distal oriﬁce, and appendiceal oriﬁces (often duplicated), and the genital structures (Fig. 67.1). A prenatal or postnatal chromosome study would be useful in determining the genetic sex of the baby. Of equal importance is inspection of the adequacy of the corporal structures in a male, in regard to the potential of reconstructing a penis. At the same time it is important to determine whether or not the gonads are located within the abdomen. At this time it is imperative to assemble the team of pediatric surgeon and urologist, and if other organ system involvement has been identiﬁed, e.g. myelomeningocele, then appropriate additional consultation will be needed. In the circumstance of a genetic male with absent or profoundly underdeveloped corpora with which to reconstruct a penis, it is imperative to add to the evaluative team an endocrinologist as well as a psychiatrist/psychologist versed in gender assignment issues. At that time a team meeting with the family, if not done prenatally, must be arranged, and the magnitude of the problems and their potential solutions discussed. It is then important to prioritize and deﬁne a step-wise management plan that deﬁnes all of the issues including gender assignment. All parties should be in agreement with the plan. The successful therapy of this complex anomaly requires an orderly approach of both sequential and simultaneous steps. The current authors would propose a modiﬁcation of the original ‘phases of management’ recommended by Ricketts et al.17 (Table 67.1) In Phase 1, a myelomeningocele must ﬁrst be covered, and attention to a possible tethered cord can be delayed. The next focus is on coverage of the omphalocele along with takedown of the exposed ileal plate and exstrophied bladder; continuity of the gastrointestinal tract must be reestablished, the entire small and large bowel salvaged, including the appendices, and a colostomy must exit in the lower abdomen. The hemibladders are connected in the posterior midline, and if possible tubularized into a reservoir. The separated pubic rami are approximated in the midline, a maneuver that facilitates both omphalocele closure as well as bladder closure. The gonads and external genitalia are addressed as the ﬁnal step of this initial procedure. The subsequent phases 2–5 of therapy

632 Cloacal exstrophy Table 67.1 Step-wise management plan for cloacal exstrophy Management phase Patient age

Therapeutic procedures

Phase 1

Newborn

Meningocele coverage Closure/coverage of omphalocele Separation of bowel/bladder plates Ileal reconstruction End colostomy Hemibladder approximation/closure Pubic bone approximation Gender assignment/orchidopexy

Phase 2

1–6 months

Feeding access Manage short bowel syndrome

Phase 3

6 months–2 years

Bladder closure if not done Phase 1 Iliac osteotomy First stage genital reconstruction Tethered cord release Midline sagittal anorectoplasty

Phase 4

2–8 years

Bladder augmentation Construction catheterizable urinary reservoir Second stage genital reconstruction

Phase 5

8–18 years

Completion genital reconstruction Exogenous hormone therapy

Adapted from Ricketts RR et al. J Pediatr Surg 1991; 26:444–50

are individualized and planned in a discussion with the family led by the care team. This complex anomaly requires the combined efforts of both pediatric surgeon and pediatric urologist. The team leader must also coordinate a variety of ancillary personnel including a stomal therapist, physical therapist, social worker, and additional family support personnel. Additional participating specialists may include a psychiatrist, psychologist, endocrinologist, neurosurgeon, or orthopedic surgeon. Ideally, such a complex course of reconstruction should be done in a center experienced in the care of children with such anomalies.

OPERATIVE MANAGEMENT

Figure 67.3 Incision for repair of cloacal exstrophy. The bladder plates will be mobilized and the abdominal cavity will be entered in order to repair the omphalocele

Phase I (Table 67.1) In cases with a huge omphalocele, it is practical to consider leaving the intact membrane in place as a barrier for a potential staged closure. However, since in dissecting out the exstrophied bladder and bowel the peritoneal cavity will be entered, the usual approach is to open the abdomen (Fig. 67.3), extending the incision vertically. This will permit eventual primary fascial closure of the omphalocele, aided by approximation of the pubic rami. This same exposure is optimal for staged closure techniques including the application of a

prosthetic silo. Such primary closure can be done most easily in the ﬁrst 48 hours of life, with the beneﬁt of circulating ‘relaxin’ and permanent high-tensile strength suture material placed into either end of the separated pubis. Such bony pelvic closure at the end of the reconstruction will assure that a primary fascial closure will be accomplished in the majority of patients. Newer approaches to abdominal wall coverage and closure include application of the expanded thoraco-epigastric myocutaneous ﬂap.18

Operative management 633

The central bowel plate is then separated from the two lateral hemibladders. Intestinal reconstruction leading to the blind-ending colon segment should emphasize bowel conservation. The exstrophied ileocecal junction should be tubularized to restore continuity of the ileocolonic lumen (Fig. 67.4). Appendices could always be considered as potential catheterizable conduits for achieving urinary dryness and thus should not be sacriﬁced. Similarly, duplicated colon segments, even though blind ending, can be used as interposed properistaltic and antiperistaltic colon conduits to potentially slow intestinal transit time. This is especially beneﬁcial in the usual circumstance of a foreshortened colonic length or in the unusual circumstance of a concomitant functional small bowel foreshortening. An extra colon may also prove to be useful in urinary conduit reconstruction later in the child’s life; for these reasons it should never be sacriﬁced. After mobilizing the blind-ending colon, the tubularized bowel must then be exited as an end colostomy. The placement of this fecal stream stoma will optimally be more laterally located than is usual, especially if a prosthetic pouch is used to close the omphalocele (Fig. 67.5). The free hemibladders are then reapproximated into a single midline posterior bladder wall plate by suture technique, taking care to identify and protect the ureteral oriﬁces (Fig. 67.3). If sufﬁcient bladder surface exists from which to construct an adequate capacity reservoir, then the bladder is also closed anteriorly, forming a urine-collecting chamber (Fig. 67.4). The tubularized bladder is then positioned behind the approximated pubic rami, and the bladder neck drains inferiorly onto the perineum. Practically, most patients will have only the bladder halves approximated posteriorly, which will drain as a cutaneous vesicostomy onto the perineum. Other urinary diversion techniques include end or loop ureterostomies, cutaneous pyelostomies, or even a

Figure 67.4 Tubularization of the distal bowel using the terminal ileum and the foreshortened colon to restore bowel continuity. Approximation of the mobilized hemibladders and midline closure to create a urinary reservoir

Figure 67.5 Lateral placement of the end colostomy to avoid interference with the omphalocele repair. Note the wide separation of the pubic rami

primary ileal conduit. Primary abdominal closure is possible in most patients (Fig. 67.6). For genetically XY babies with a microphallus or a biﬁd phallus, gender conversion should be accomplished at the neonatal procedure by assigning a female phenotype. Corporal tissue should be preserved for eventual construction of a clitoris, and the separated hemiscrota should be preserved for eventual construction of labia. Vaginal reconstruction should be deferred to a later age, and testes can be excised or allowed to remain until reconstruction at puberty. Genital reconstruction of a genetic XX child should be deferred to a later age to permit full evaluation and correction of double systems, potential vaginal atresia, or potential vaginal exstrophy, the latter located caudal to the exstrophied bladder mucosa.

Figure 67.6 Closure of pubic bones at the midline with heavy suture material followed by closure of the abdominal wall. Note the perineal stoma for urinary drainage

634 Cloacal exstrophy

POSTOPERATIVE CARE Postoperatively, the patient should receive ﬂuid and electrolyte management which takes into account a potentially diminished renal reserve. A circumferential wrap should encircle the lower extremities from ankles to mid-abdomen to ‘strap’ together the upper thighs to minimize pelvic tension and possible distraction of the closed pubic rami (Fig. 67.7). Suspension in a modiﬁed Bryant’s traction has also been reported.19 Staged closure of the omphalocele should follow in those cases with an applied prosthetic silo. The fecal stream should be collected by a stomal appliance and the perineum should be isolated either by temporary bladder or ureteral catheters or by permitting free drainage of urine onto the bladder exstrophied plate. At the completion of the repair in the newborn, the associated anomalies should be prioritized and addressed. The myelodysplasia occurring in almost 50% of such patients should be covered and selected use of shunts to treat hydrocephalus should follow. Orthopedic assessment of extremity, pelvis and spinal deformities is necessary, and a long-range treatment plan should be outlined.

LONG-TERM MANAGEMENT The goal for most children with cloacal exstrophy is a stomal-free existence. At a delayed interval, typically Phase 3, pelvic magnetic resonance imaging or computer tomographic imaging, coupled with electrical stimu-

lation of the perineum, can be used to deﬁne the presence of an anorectal pelvic muscle complex. If such muscle is present, a midline sagittal anorectoplasty is feasible in selected patients who also have an adequate small and large bowel length for establishing a continent anorectum. Others have advocated for a primary rectal pull-through procedure done in the newborn period following the anterior approach used for abdominal wall reconstruction.5,19 Urinary ‘dryness’ is frequently accomplished utilizing the principle of a catheterizable stoma into a reservoir. Using either a ‘continent’ nipple valve or the Mitrofanoff principle with an appendix, or a tubularized portion of small bowel, a catheterizable conduit is attached to the reservoir. The reservoir itself could be bowel or bladder augmented with stomach, small or large bowel. These procedures are typically deferred until Phase 3, when the child has grown out of infancy. Genital reconstruction is planned and begun in the neonatal period, when the genotypic sex is identiﬁed and the phenotypic sex of rearing has been decided. All corporal and scrotal/labial tissue needs to be preserved. The corporal tissue, typically biﬁd, becomes critical whether reconstructing a penile shaft or a clitoris. In the phenotypic male, penile reconstruction and orchidopexy will be the two steps of signiﬁcance, and they can be delayed beyond the neonatal period to Phases 3 or 4. In the phenotypic female the clitoris will be at the top of the introitus, which itself is surrounded by labia and a vaginal inlet. An atretic vagina will require construction with a combination of perineal skin ﬂaps and a small or large bowel pull-through. An intact vagina may contain a septum or be duplicated, and this will require septoplasty for construction of an adequate opening. Since most of the uteri will be duplicated, it is most prudent to resect the more rudimentary of the two, attaching the remaining uterus to the vaginal vault. Other than the propensity for cyst formation, the ovaries should be normal.12 Finally, in a gender conversion, the genital reconstruction will make use of previous penile corporal erectile tissue, the hemiscrota, and a skin or bowel-based vaginal reconstruction to recreate the female external genitalia. However, in the neonatal period it may be prudent to do the orchiectomy to limit any putative testosterone imprinting on the nervous system. Hormonal therapy at puberty will develop female secondary sex characteristics.

OUTCOMES

Figure 67.7 Circumferential wrap to prevent distraction of the newly reconstructed pubic symphysis

With the progressively improving survival of cloacal exstrophy, attention has shifted to converting the majority of these children to a stomal appliance-free life. Historically these children were at best committed to both a chronic bowel as well as a chronic urinary stoma,

References 635

and when that was coupled with a degree of genital ambiguity, short bowel syndrome, or spinal dysraphism, the quality of life was best described as unfortunate. What has now been realized is that the majority of such children have a preserved intellect, and also have an anatomy that lends itself to imaginative but real ‘continent’ outcomes. A bowel pull-through procedure is feasible in many patients, and only in the face of no gluteal cleft, poor response of muscle to perineal stimulation, severe sacral deformity, a lipomeningocele, or a ‘rocker-bottom’ should a permanent bowel stoma be considered.5 The remainder of the patients can undergo a pull-through procedure, and if a degree of incontinence exists, a colon washout program or application of the Malone continent antegrade enema will be an adjunct. The most challenging of this group are those children who also have a short small bowel, and in that circumstance various nutritional and pharmacologic manipulations may be in order.20 The reconstructed urinary reservoir is typically of small volume and it is nondynamic. Bladder augmentation has been a process in evolution and includes the use of stomach, large bowel and small bowel, or a potential combination thereof. Ileal urinary conduits can also be used. To enhance bladder continence mechanisms, the bladder neck can be tightened, a bowel nipple valve can be added, Teﬂon® can be injected, and these changes coupled with intermittent catheterization can render the majority of patients dry.4,5,10,13,17,19 At times a Mitrofanoff catheterizable appendix or bowel conduit attached to the bladder has also been proven to be effective. Spontaneous voluntarily controlled perineal voiding is an unrealistic outcome expectation today. The outcomes from genital reconstruction in females are satisfactory, but the ability of a biﬁd uterus and reconstructed vagina to permit fertility is unrealized to date. The greater controversy arises in a genetic male who has a trial at penile reconstruction.14,15 Since the testes, even if located intra-abdominally, appear to be histologically normal, fertility may be preserved.16 If an inadequate phallus is the result of a series of operative procedures, reported emotional disasters are common. More controversial are those genetic males who undergo reassignment to the female phenotype. Acting out male behavior, imprinted genetically or hormonally, has been witnessed, and at adolescence phenotypically ‘assigned’ females have declared their ‘maleness’ and have emotionally struggled with their sexual identity. Whether early removal of the testes in such circumstances will diminish such a testosterone imprinting affect is unknown.21 Though staged management has the inherent difﬁculty of multiple operative procedures, the expectations for an excellent outcome should remain high. The vast majority of these children can be rehabilitated to have a meaning-

ful and functional quality of life, through a careful, individualized, staged reconstruction accomplished by a team experienced in the care of these children.21

REFERENCES 1. Austin PF, Homsy YL, Gearhart JP et al. The prenatal diagnosis of cloacal exstrophy. J Urol 1998; 160:1179–81. 2. Ziegler MD, Duckett JW, Howell CG. Cloacal exstrophy. In: Welch KJ, editor. Pediatric Surgery. 4th edn. Chicago: Year Book, Chicago, 1986; 764–71. 3. Rickham PO. Vesico-intestinal ﬁssure. Arch Dis Childh 1960; 35:97–102. 4. Howell C, Caldamone A, Snyder H et al. Optimal management of cloacal exstrophy. J Pediatr Surg 1983; 18:365–9. 5. Hendren WH. Cloaca, the most severe degree of imperforate anus. Ann Surg 1998; 228:331–46. 6. Gray SW, Skandalakis JE. Embryology for Surgeons. Philadelphia: W.B. Saunders, 1972:519–52. 7. Brach SW, Adzick NS, Goldstein RB, Harrison MR. Challenging the embryogenesis of cloacal exstrophy. J Pediatr Surg 1996; 31:768–70. 8. Langer JC, Brennan B, Lappalainen RE. Cloacal exstrophy: prenatal diagnosis before rupture of the cloacal membrane. J Pediatr Surg 1992; 27:1352–5. 9. Warner BW, Ziegler MM. Exstrophy of the cloaca. In: Ashcraft KW, editor. Pediatric Surgery. 3rd edn. Philadelphia: W.B. Saunders, 2000:493–501. 10. Smith EA, Woodard JR, Broecker BH et al. Current urologic management of cloacal exstrophy: experience with 11 cases. J Pediatr Surg 1997; 32:256–62. 11. McLaughlin KP, Rink RC, Kalsbeck JE et al. Cloacal exstrophy: the neurological implications. J Urol 1995; 154:782–4. 12. Geiger JD, Coran AG. The association of large ovarian cysts with cloacal exstrophy. J Pediatr Surg 1998; 33:719–21. 13. Mathews R, Jeffs RD, Reiner WG et al. Cloacal exstrophyimproving the quality of life: the John’s Hopkins experience. J Urol 1998; 160:2452–6. 14. Sandove RC, Sengezer M, McRoberts JW, Wells MD. One stage total penile reconstruction with a free sensate osteocutaneous ﬁbula ﬂap. Plast Reconstr Surg 1993; 92:1314–23. 15. Perovic S. Phalloplasty in children and adolescents using the extended pedicle island groin ﬂap. J Urol 1995; 154:848–53. 16. Matthews RI, Perlman E, Marsh DW, Gearhart JP. Gonadal morphology in cloacal exstrophy: implications in gender assignment. BJU International 1999; 84:99–100. 17. Ricketts RR, Woodard JR, Zwiren GT et al. Modern treatment of cloacal exstrophy. J Pediatr Surg 1991; 26:444–50.

636 Cloacal exstrophy 18. Schaeffer CS, King LR, Levin LS. Use of the expanded thoracoepigastric myocutaneous ﬂap in the closure of cloacal exstrophy. Plast Reconstr Surg 97:1479–84. 19. Lund DP, Hendren WH. Cloacal exstrophy: experience with 20 cases. J Pediatr Surg 1993; 28:1360–9.

20. Davidoff AM, Hebra A, Balmer D et al. Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy. J Pediatr Surg 1996; 31:771–3. 21. Stolar CJH, Randolph JG, Flanigan LP. Cloacal exstrophy individualized management through a staged surgical approach. J Pediatr Surg 1990; 25:505–7.

68 Prune belly syndrome PREM PURI AND HIDESHI MIYAKITA

INTRODUCTION Prune belly syndrome is characterized by a triad of abnormalities, including an absence or deﬁciency of abdominal wall musculature, cryptorchism and anomalies of the urinary tract. The characteristic deﬁciency of the abdominal wall musculature was ﬁrst described by Frohlich in 1839.1 Parker ﬁrst reported the association of the genitourinary anomalies with the deﬁcient abdominal musculature.2 The term ‘prune belly syndrome’ was coined for this complex by Osler in 1901.3 Eagle and Barrett, in 1950, further deﬁned the triad of absent abdominal wall musculature, undescended testes and urinary tract abnormalities.4 The incidence of prune belly syndrome is estimated to be one in 29 000 to one in 50 000 live births.5–13 Apart from the claim by Adeyokunnu and Familusi of an increased incidence of prune belly syndrome in Nigeria, it does not occur with increased incidence in speciﬁc racial groups or geographic locations.10 This syndrome occurs almost exclusively in boys.13 It is very rare in females;13 only 5% of cases described in the world literature have been reported to occur in females.4–6,14

ETIOLOGY The pathogenesis of prune belly syndrome remains controversial and many theories have been proposed to explain it.3,4 One theory proposes that prenatal obstruction or dysfunction of the urinary tract causes urinary tract dilatation, fetal abdominal distension and subsequent muscle wall hypoplasia and cryptorchism in males.5,6,15–17 An embryological theory proposes that failure of primary mesodermal differentiation leads to defective muscularization of both the abdominal wall and the urinary tract.6,15–17 Although both theories explain some elements of the syndrome, they fail to explain others. Reinberg et al. recently suggested that the two theories should be regarded as complementary mech-

anisms, both operating in any given case.18 They theorized that teratogenic agents produce abnormal development of derivatives of the lateral plate mesoderm and abnormal epithelial–mesenchymal interactions, resulting in abnormal organ development and mechanical or functional obstruction of the urinary tract. Recently Stephens and Gupta proposed a theory of abnormal development of the intermediate mesoderm as a key factor in the pathogenesis of prune belly syndrome.5,19 This theory has two features: the ﬁrst is that the terminal part of the wolfﬁan duct is incorporated into both the prostatic and membranous urethra, and the second is that during incorporation, the ducts including their ureteric buds overexpand. Abnormal ectasia of the terminal wolfﬁan duct occurring between 6 and 10 weeks’ gestation may produce saccular dilatation of the prostatic urethra, prostatic hypoplasia, and the valve-like obstruction in the membranous urethra. The ectasia could explain the attenuated bladder trigone and laterally placed wide ureteric oriﬁces. Involvement of ureteric buds may also produce irregular megaureters. Renal dysplasia can be explained as a result of primary dysplasia of the methanephros or secondary to ureteric ectopia. A single-gene abnormality or chromosomal defect has been suggested as the cause of this syndrome. There is an especially high incidence of prune belly syndrome associated with trisomy 21,20 trisomy 1321,22 and trisomy 18.23,24 The presence of a sex-linked genetically determined recessive gene has been suggested.25 Reports of prune belly syndrome in siblings and cousins, and reports of the syndrome associated with the 45X0 karyotype of Turner syndrome, support this proposal.

PATHOLOGY Abdominal wall The most obvious defect in newborns with the syndrome is the shriveled prune belly-like appearance of the abdominal wall due to a deﬁciency in the abdominal

638 Prune belly syndrome

wall musculature (Fig. 68.1). The affected muscles in decreasing order of frequency are the transversus abdominus, rectus abdominus below the umbilicus, and internal oblique, external oblique and rectus abdominus above the umbilicus.26–28 Biopsy from the abdominal musculature shows that major functioning or recoverable muscle exists in the lateral and upper sector of the abdomen, but that little or no muscle exists in the lower central abdomen.29 Light microscopy shows a thin mass of muscle tissue with an irregular pattern of fatty inﬁltration interdigitated with the muscle. Electron microscopy shows a loss of coherence and internal orientation.30 Z-bands are shattered and disarranged, and glycogen granules are clumped in various areas. The abdominal wall defect may result in chronic constipation and respiratory infection. In addition, this defect increases the risk of postoperative pulmonary complications in patients who undergo general anesthesia. It is also impossible for the patient with a complete manifestation of the triad syndrome to raise himself from the supine position to the sitting position without using the arms or rolling over and pushing up. However, the defect itself does not have prognostic signiﬁcance.

signiﬁcant aberration.6,31–38 Patients who have severe renal dysplasia usually have severe abnormalities of the bladder and urethra at birth and may even have another malformation such as imperforate anus. 39 The degree of renal dysplasia or hydronephrosis does not appear to be related to the degree of abdominal wall deﬁciency.

Ureter The ureters are characteristically markedly elongated, dilated and tortuous. This is the most common urinary tract abnormality, and is present in 81% of patients with prune belly syndrome.32 The lower end of the ureter is more severely affected than the upper one, and there are occasional saccular dilatations of the middle segment. The orifices are usually patent and obstruction is rare. Vesicoureteral reflux is common.32 The ureteric smooth muscle is replaced by fibrous tissue in the affected areas and there is scarcity of muscle bundles on histologic examination.33 Ehlrich and Brown studied the structure by electron microscopy and reported a marked decrease in nerve plexuses with irregularity and degeneration of non-myelinated Schwann fibers.34 These findings are in keeping with the poor peristalsis of the affected ureters.

Bladder

Figure 68.1 A newborn with typical features of prune belly syndrome. Note the shriveled prune-like appearance of the abdominal wall and patent urachus

Urinary tract Abnormalities of the urinary tract are the major factors affecting the prognosis of patients with prune belly syndrome. Patients are at high risk for developing renal failure in infancy and childhood. Within 2 years, 30% of patients with prune belly syndrome die of renal failure or urosepsis.12

Kidney The kidney in prune belly syndrome has many ranges of disorders from total agenesis (rare) or dysplasia, to no

Bladder abnormalities are common in prune belly syndrome. The typical bladder is large, irregular in shape and thick walled. Although the bladder wall is thickened, trabeculation is rare. Histologically, the intrusion of ﬁbrous tissue between sparse muscle layers is similar to the ureters.31 Commonly, there is a patent urachus or urachal cyst in prune belly syndrome. The trigone is surprisingly large, with very widely spaced, usually large and abnormal-appearing ureteric oriﬁces which can be expected to reﬂux.35 The bladder neck is often wide and ill-deﬁned. Pelvic innervation and bladder ganglion cell distribution has been found to be normal.6

Urethra The prostatic urethra is usually wide and elongated at the bladder neck. It tapers to a narrow point at the level of the urogenital diaphragm, even though most patients do not demonstrate true obstruction at this point.36 Often there is a posterior urethral diverticulum formed by a large prostatic utricle. The reduced musculature and prostatic hypoplasia cause a ‘functional obstruction’ to bladder outﬂow.37 The membranous and anterior urethra are sometimes atretic or extremely hypoplastic. There are also reports of abnormalities of the penis, including ventral and dorsal chordee, hypospadias and

Management 639

hypoplastic or absent corpora cavernosa. Other urethral lesions occur with hypospadias, and ventral and dorsal chordee.36 Ejaculation is possible but usually is retrograde due to the open bladder neck. In females, the prune belly syndrome triad consists of lax, aplastic or hypoplastic abdominal musculature, urinary tract anomalies and genital anomalies, most commonly bicornuate uterus and vaginal atresia. Six of the seven female cases reported by Reinberg et al. had vaginal atresia or uterine duplication and frequently coexisted in the same patient.18 Other urogenital anomalies include urogenital sinus and ambiguous genitalia.

Testes Bilateral cryptorchidism is an essential characteristic of prune belly syndrome. The testes may be located anywhere from just inferior to the lower pole of the kidney to near the ureterovesical junction.31,38 Maldescent of the testes is believed to be related to absence of the abdominal muscles and the gubernaculum. In fetuses with prune belly syndrome, testicular histology revealed reduced spermatogonia and Leydig cell hyperplasia.40,41 Testicular biopsy samples of infant testes in prune belly syndrome demonstrate atypical germ cells with large nuclei and prominent nucleoli and intense alkaline phosphatase staining localized to the cytoplasmic membrane.41 The similarity of histological appearance of these testes to those in intratubular germ cell neoplasia suggests that long-term follow-up of these patients for the development of invasive germ cell tumors is important. A few cases of malignancy in the testes of patients with prune belly syndrome have been reported.42–44

ASSOCIATED ANOMALIES There is a high incidence of associated anomalies in patients with prune belly syndrome. Non-urological associated anomalies in patients with prune belly syndrome occur in 65%–73% of patients.6,45–50 Malrotation of the gut with a single mesentery and the occasional sequelae of volvulus and obstruction is the most common gastrointestinal anomaly. The other gastrointestinal anomalies are gastroschisis and omphalocele, imperforate anus, Hirschsprung’s disease and duodenal atresia.39,48,49 Cardiovascular anomalies such as atrial and ventricular septal defects and tetralogy of Fallot have been reported in about 10% of cases.50 Pulmonary anomalies are common, the most severe of which is hypoplasia of the lungs associated with in utero oligohydramnios. Skeletal anomalies have frequently been reported in patients with prune belly syndrome.39 The most common abnormalities are talipes deformities, congenital dis-

locations of the hip and compression deformities of the limbs.

MANAGEMENT Surveillance programs and improved accuracy of prenatal ultrasound have allowed early diagnosis of major genitourinary malformations.51 Unfortunately fetal detection of prune belly syndrome has not led to an improved outcome.52,53 There are a few sporadic reports in the literature regarding successful placing of vesicoamniotic shunts in order to achieve urinary bladder decompression and corrected amniotic ﬂuids levels.54,55 Several conditions must be met for vesicoamniotic shunt therapy to have a good chance of success: the karyotype must be normal, other malformations must be excluded and renal function must be determined by serial analysis of fetal urine prior to procedure. Generally, the shunt must be inserted as early as possible. A newborn with a lax abdominal wall and absent testes in the scrotum should be considered to have prune belly syndrome and should undergo careful palpation of the abdomen to evaluate for megaureters, megacystitis and renal size. Routine neonatal chest X-ray to search for pulmonary hypoplasia or pneumothorax is advocated. An ultrasound scan will almost always be the ﬁrst imaging study and will demonstrate the dilatation and redundancy of the urinary tract.5,6,38 This examination should be followed by either radionuclide renal imaging or an excretory urogram (i.v. pyelogram). It is better initially simply to assume that reﬂux is probably present. Laboratory investigation should include serum electrolytes, urea nitrogen and creatinine determinations, along with urinalysis and urine cultures. It is better to avoid a catheterization procedure in order to lessen the possibility of introducing urinary infection. Based on the severity of renal disease, patients can be classiﬁed into three groups.6,52 The ﬁrst group is characterized by the occurrence of severe urinary tract impairment, which almost always includes urethral obstruction, oligohydramnios and features of Potter syndrome. These patients die, as neonates, of respiratory failure due to pulmonary hypoplasia. Renal failure contributes but does not play a major role in the deaths. The New York State review of survival of patients with prune belly syndrome demonstrated a persistently high infant mortality rate with nearly half of the deaths occurring within 24 hours of life, and two-thirds occurring before 1 week of age.7 In the second group of patients, mild impairment of renal function may progress to renal failure. Patients in the third group have the least severe form of the syndrome. Although radiological investigations may show an abnormal urinary tract, there is usually neither obstruction nor impaired function. Patients in this group do not require surgery other than orchidopexy.

640 Prune belly syndrome

Infants who have mild or incomplete external features are candidates for long-term surveillance and a nonoperative approach.38 Recently, Noh et al. summarized clinical parameters which predict renal failure in children with prune belly syndrome.53 A total of 35 children with prune belly syndrome were analyzed. The authors concluded that bilateral abnormal kidneys on ultrasound or renal scan, a nadir serum creatinine of greater than 0.7 mg/dL, and clinical pyelonephritis are signiﬁcant prognostic factors for the development of renal failure in these children. When a neonate has recurring bacteriuria, rising serum creatinine levels or increasing dilatation of the upper urinary tract, vesicostomy may be indicated. This expenditious procedure will usually provide effective bladder drainage and allow a major reconstructive procedure to be postponed until it can be performed under optimal circumstances. Cutaneous vesicostomy is an effective procedure for temporary diversion in patients with severe hydronephrosis, hydroureterosis and a poorly emptying bladder.56 Details of the operative technique of vesicostomy are described in Chapter 91. The urinary tracts in patients with prune belly syndrome are characterized by stasis; stasis predisposes to bacteriuria, which leads to deteriorating renal function as well as to troublesome symptoms. Some surgeons advocate pyelostomy in the neonatal period to achieve drainage. Cutaneous ureterostomies are offered only if the ureters are enormously dilated near the kidney and the pelvis are quite small.56 Patients with prune belly syndrome have a variability of degrees of renal and urinary tract involvement, so therapeutic options must be contemplated on an individual case-by-case basis, whether medical or surgical. After infancy, patients with prune belly syndrome may require deﬁnitive surgery, such as ureteral tailoring, reimplantation of ureters and reduction cystoplasty. Because of the risk of testicular malignancy in these patients, it is generally accepted that orchidopexy should be performed. The two-stage Fowler-Stephens technique usually is necessary, since the vessels are too short for a one-stage procedure.57 Laparoscopic orchidopexy has also been performed in patients with prune belly syndrome.6 Abdominal wall plication may be required for cosmetic improvement when the patient is around 1 year of age. Randolph et al. and Monfort et al. have reported suitable techniques of abdominoplasty.29,58 Monfort’s approach to management of prune belly syndrome entails comprehensive early reconstruction in two stages.58 The ﬁrst stage, which is undertaken in the ﬁrst month of life, consists of distal ureterectomy with tapering, reimplantation of the ureter and reduction cystoplasty at the bladder dome. The second stage, which is undertaken 6 months later, consists of abdominal wall plasty with orchidopexy. Monfort’s operation preserves the umbilicus and strengthens, ﬂattens and thickens the abdominal wall.58–60

REFERENCES 1. Frohlich F. Der Mangel der Muskon, Insbesondere der Seitenbauchmuskeln. Dissertation. Wurzburg; C.A. Zurn, 1839. 2. Parker RW. Case of an infant in whom some of the abdominal muscles were absent. Trans Clin Soc Lond Wurzburg 1895; 28:201. 3. Osler W. Congenital absence of the abdominal musculature, with distended and hypertrophied urinary bladder. Bull Johns Hopkins Hosp 1901; 12:331. 4. Jennings RW. Prune belly syndrome. Semin Pediatr Surg 2000; 9(3):115–20. 5. Wheatley JM, Stephens FD, Hutson JM. Prune-belly syndrome: ongoing controversies regarding pathogenesis and management. Semin Pediatr Surg 1996; 5(2):95–106. 6. Smith EA, Woodard JR. Prune-belly syndrome. In: Gearhart JP, Rink RC, Mouriguand PDE, editors. Pediatric. Philadelphia: W.B. Saunders, 2001:577–92. 7. Druschel CM. A descriptive study of prune-belly in New York state, 1983 to 1989. Arch Pediatr Adolesc Med 1995; 149:70–6. 8. Eagle JF, Barrett GS. Congenital deﬁciency of abdominal musculature with associated genitourinary abnormalities. A syndrome: report of nine cases. Pediatrics 1950; 6:726. 9. Baird PA, MacDonald EC. An epidemiologic study of congenital malformations in the anterior abdominal wall in more than half a million consecutive live births. Am J Hum Genet 1981; 33:470. 10. Adeyokunnu AA, Familusi JB. Prune-belly syndrome in two siblings and a ﬁrst cousin. Am J Dis Child 1982; 136:23–5. 11. Garlinger P, Ott J. Prune belly syndrome. Possible genetic implications. Birth Defects, 1974; 10:173–80. 12. Greskovich FJ III, Nyberg LM Jr. The prune belly syndrome: a review of its etiology, defects, treatment and prognosis. J Urol 1988; 140:707–12. 13. Shaw RA, Smyth J, Pringle K. The prune belly syndrome in a female. Pediatr Surg Int 1990; 5:202–7. 14. Gonzalez R, Reinberg Y, Burk B et al. Early bladder outlet obstruction in fetal lambs induces renal dysplasia and the prune belly syndrome. J Pediatr Surg 1990; 25:342–5. 15. Popek EJ, Tyson RW, Miller GJ et al. Prostate development in prune belly syndrome (PBS) and posterior urethral valves (PUV): etiology of PBS – lower urinary tract obstruction or primary mesenchymal defect? Pediatr Pathol 1991; 11:1–29. 16. Pagon RA, Smith DW, Shepard TH. Urethral obstruction malformation complex: a cause of abdominal muscle deﬁciency and the ‘prune belly’. J Pediatr 1979; 94:900–6. 17. Straub E, Spranger J. Etiology and pathogenesis of prune belly syndrome. Kidney Int 1981; 20:695–9. 18. Reinberg Y, Shapiro E, Manivel C et al. Prune belly syndrome in females: a triad of abdominal musculature deﬁciency and anomalies of the urinary and genital system. J Pediatr 1991; 118:395–8.

References 641 19. Stephens FD, Gupta D. Pathogenesis of the prune-belly syndrome. J Urol 1994; 152:2328–31. 20. Amacker EA, Grass FS, Hickey DE et al. An association of prune belly anomaly with trisomy 21. Am J Med Genet 1986; 23:919–23. 21. Beckmann H, Rehder H, Rauskolb R. Prune belly sequence McKeown, associated with trisomy 13. Am J Med Genet 1984; 19:603–4. 22. McKeown CM, Donnai D. Prune belly in trisomy 13. Prenat Diagn 1986; 6:379–81. 23. Frydmann H, Magenis RE, Mohands TK et al. Chromosome abnormalities in infants with prune belly anomaly: associated with trisomy 18. Am J Med Genet 1983; 15:145–8. 24. Hoagland MH, Frank KA, Hutchins GM. Prune belly syndrome with prostatic hypoplasia, bladder wall rupture, and massive ascites in a foetus with trisomy 18. Arch Pathol Lab Med 1988; 112:1126–8. 25. Williams DI, Burkholder GV. The prune belly syndrome. J Urol 1967; 98:244–51. 26. Housden LG. Congenital deﬁciency of the abdominal muscles. Arch Dis Childh 1934; 9:219. 27. Lattimer JK. Congenital deﬁciency of the abdominal musculature and associated genito-urinary anomalies. A report of 22 cases. J Urol 1958; 79:343. 28. Silverman FN, Huang N. Congenital absence of the abdominal muscles, associated with malformation of the genitourinary and alimentary tracts. Arch Dis Childh 1950; 80:91. 29. Randolph J, Cavett C, Eng G. Abdominal wall reconstruction in the prune belly syndrome. J Pediatr Surg 1981; 16:960. 30. Mininberg DT, Montoya F, Okada K. Subcellular muscle studies in prune belly syndrome. J Urol 1973 ; 109:524. 31. Wigger JH, Blance WA. The prune belly syndrome. Path Ann 1977; (Part I)12:17. 32. Nunn IN, Stephens FD. The triad syndrome: a composite anomaly of the abdominal wall, urinary system and testes. J Urol 1961; 86:782. 33. Palmer JM, Tessluk H. Ureteral pathology in the prune belly syndrome. J Urol 1974; 111:701. 34. Ehrlich RM, Brown WJ. Ultrastructural anatomic obstructions of the ureter in the prune belly syndrome. Birth Defects 1977; 13:101. 35. Woodard JR, Zucker I. Current management of the dilated urinary tract in prune belly syndrome. Urol Clin N Am 1990; 17:407–18. 36. Kroovand RL, Al-Ansary RM, Perlmutter AD. Urethral and genital malformations in prune belly syndrome. J Urol 1982; 127:94. 37. Moermann P, Fryns JP, Godderis P et al. Pathogenesis of the prune belly syndrome: a functional urethral obstruction caused by prostatic hypoplasia. Pediatrics 1984; 73:470. 38. Woodhouse CRJ, Ransly PG, Williams DJ. Prune belly syndrome report of 47 cases. Arch Dis Childh 1982; 57:856.

39. Walker J, Prokurat AI, Irving IM. Prune belly syndrome associated with exomphalos and anorectal agenesis. J Pediatr 1987; 22:215–17. 40. Orvis BR, Bottles K, Kogan BA. Testicular histology in fetuses with the prune belly syndrome and posterior urethral valves. J Urol 1988; 139:335. 41. Massad CA, Cohen MB, Kogan BA et al. Morphology and histochemistry of infant testes in the prune belly syndrome. J Urol 1991; 146:1598–1600. 42. Woodhouse CJR, Ranley PG. Teratoma of the testis in the prune belly syndrome. Br J Urol 1983; 55:580. 43. Sayze R, Stephen R, Chonko AM. Prune belly syndrome and retro-peritoneal germ cell tumour. Am J Med 1986; 81:895. 44. Parra RO, Cummings JM, Palmar DC. Testicular seminoma in a longterm survivor of the prune belly syndrome. Eur Urol 1991; 19:79–80. 45. Burbige KA, Amodio J, Berdon WE et al. Prune belly syndrome: 35 years of experience. J Urol 1987; 137:86–90. 46. Ashcraft KW. Prune belly syndrome. In: Pediatric Urology. Philadelphia: W.B. Saunders, 1990:257–67. 47. Brinker MR, Palutsis RS, Sarwark JF. The orthopedic manifestations of prune belly syndrome (Eagle-Barrett) syndrome. J Bone Joint Surg 1995; 77:251–7. 48. Cawthern TH, Bottene CA, Grant D. Prune belly syndrome associated with Hirschsprung’s disease. Am J Dis Child 1979; 133:65. 49. Willert J, Cohen H, Yu YT. Association of prune belly syndrome with gastroschisis. Am J Dis Child 1978; 132:526. 50. Adebonojo FO. Dysplasia of the abdominal musculature with multiple congenital anomalies: prune belly syndrome. J Nat Med Ass 1973; 65:327. 51. Cromie WJ, Lee K, Houde K, Holmes L. Implications of prenatal ultrasound screening in the incidence of major genitourinary malformations. J Urol 2001; 165(5):1677–80. 52. Reinberg Y, Manivel JC, Pettinato, Gonzalez R. Development of renal failure in children with the prune belly syndrome. J Urol 1991; 145:1017–19. 53. Noh PH, Cooper CS, Winkler AC et al. Prognostic factors for long-term renal function in boys with the prune-belly syndrome. 1999; 162(4):1399–1401. 54. Leeners B, Sauer I, Schefels J et al. Prune-belly syndrome: therapeutic options including in utero placement of a vesicoamniotic shunt. J Clin Ultrasound 2000; 28(9):500–7. 55. Perez-Brayﬁeld MR, Gatti J, Berkman S et al. In utero intervention in a patient with prune-belly syndrome and severe urethral hypoplasia. Urology 2001; 1178. 56. Duckett JW. Prune belly syndrome. In: Welsh KJ, Randolph JG, Ravitch MM et al. editors. Pediatric Surgery. Vol. 2. Chicago: Year Book Medical, 1986: 1193–1203. 57. Woodard JR. The prune belly syndrome. Urol Clin N Am 1978; 5:75.

642 Prune belly syndrome 58. Monfort G, Guys JM, Bocciardi A et al. A novel technique for reconstruction of the abdominal wall in the prune belly syndrome. J Urol 1991; 146:639–40. 59. Parrot TS, Woodard JR. The Monfort operation for

abdominal wall reconstruction in the prune belly syndrome. J Urol 1992; 148:688–90. 60. Bukowski TP, Smith CA. Monfort abdominoplasty with neoumbilical modiﬁcation. Urology 2000; 164(5):1711–13.

69 Conjoined twins HARRY APPLEBAUM

INTRODUCTION

PREOPERATIVE EVALUATION

The birth of conjoined twins remains an unusual and noteworthy event to physicians and laymen alike. They are reported to occur in approximately one in every 50 000 deliveries, with females predominating over males by a ratio of 2:1.1 While most believe that conjoined twins result when incomplete ﬁssion of the zygote’s primitive streak occurs during the second week of gestation, there is also evidence that they may result from the union of two separate embryonic disks.2 The most prominent site of connection between the twins classiﬁes them. These areas include skull (craniopagus), thorax (thoracopagus), upper abdomen (xiphopagus), lower abdomen (omphalopagus), pelvis (ischiopagus), or sacrum (pygopagus). They may also be described as symmetrical and asymmetrical forms, depending upon the degree of development of the respective twins.

Ethics

PRENATAL EVALUATION The routine use of obstetrical ultrasound usually allows the prenatal diagnosis of conjoined twins to be made with certainty. Computed tomography (CT) scanning and magnetic resonance imaging (MRI) can be used as a secondary diagnostic tools to evaluate the extent of shared organs. This information has permitted perinatologists and pediatric surgeons to adequately counsel expectant parents as to probable long-term functional outcomes.3 It enables obstetricians to prepare for controlled delivery of these babies by cesarian section, while allowing the marshalling of adequate personnel and resources to resuscitate both twins simultaneously.

Numerous legal and ethical issues surround the birth of conjoined twins. These must be dealt with prior to acute or elective surgical separation. The survival of the twins must be balanced with their expected quality of life and the wishes of the parents. Decisions can only be made after full and complete diagnostic evaluation and consultation with physicians familiar with the problems of separating conjoined twins. In addition, care must be taken to ensure the legal propriety of any steps taken that may endanger the life of one twin at the expense of the other. These decisions should be made in an atmosphere of calm and quiet, and away from the pressure of the media or curious onlookers. In general, it is of course ideal to save both lives. If only one twin can survive, however, then it is preferable to attempt to salvage one infant than to inevitably lose both.4 In some situations, particularly in many cases of craniopagus twinning, successful separation is impossible with currently available technology, and surgery should not be offered.5

Emergent operation An emergent or urgent separation of conjoined twins is indicated when: (1) one twin is stillborn, (2) one twin has a life-threatening anomaly that cannot be corrected, (3) there is damage to the connecting bridge during the delivery, and (4) there is great disparity in size between the twins such that one is a parasite of the other.6 An emergent operation to correct a congenital anomaly can be performed without separation of the twins if the corrective procedure can be done easily and does not endanger their survival. This is often preferable to a

644 Conjoined twins

interdependency and relative function, the feasibility of operative separation and survival, and the best way to optimize future function (Table 69.2). The evaluation of conjoined twins with a shared central nervous system is difﬁcult: physicians with neurosurgical training must be available in order to determine the possibility of separating these twins. MRI, CT and cerebral angiography may all be helpful in determining the proper treatment plan in these children. This topic is beyond the scope of this chapter and interested readers are referred to other excellent reviews.7 Conjoined twins with a shared heart and great vessels will require detailed non-invasive studies such as electrocardiography, radionuclide scans, CT angiography, MRI and echocardiography. In addition, many of these patients will require invasive angiographic studies to fully delineate intracardiac anatomy, direction of ﬂow, intracardiac pressure, and anomalies of the great vessels. Pulmonary function is usually adequately evaluated by physical examination, chest radiograph and arterial blood gas studies. Further studies will be determined by the degree of respiratory compromise present. CT and MRI will help determine the extent to which the chest wall and diaphragm are joined, and whether tissue expansion, muscle ﬂaps, or prosthetic patch material will be necessary in order to achieve soft-tissue closure after separation. The evaluation of the liver and pancreaticobiliary tree can be carried out by a variety of imaging studies. Anatomical details can be obtained from ultrasonography, CT and MRI.8 Information regarding relative function, blood, and bile ﬂow can be obtained from MRI

complete separation at an early age. The conjoined twins should ideally be operated on after a full diagnostic evaluation and after the twins have had an opportunity to grow and develop. It is generally recognized that allowing a period of several months for physiological maturation and growth to occur results in less operative risk from cardiopulmonary instability and hemorrhage and the availability of larger areas of tissue that can be mobilized for closure of separation-created defects.

Classiﬁcation Conjoined twins are classiﬁed by their most prominent site of connection. These sites and their relative frequencies are listed in Table 69.1. Combinations may be used to describe all possibilities for joining, such as omphalo-ischiopagus to describe an abdominal and pelvic connection (Table 69.1).

Diagnostic studies The diagnostic evaluation of conjoined twins will depend on the location of the connecting tissue bridge and the degree to which organs are shared. Table 69.2 lists recommended reoperative diagnostic modalities for each type of conjoined twin. The evaluation of conjoined twins should be carried out in a logical manner, with a determination as to which organ systems are shared being the primary goal. These shared systems should then be examined in detail in order to determine the degree of

Table 69.1 Relative frequency and prominent site of connection in conjoined twins Site

Name

Incidence (%)

Skull

Craniopagus

Thorax

Thoracopagus

40

Heart, great vessels, liver, biliary tract, upper gastrointestinal tract

Upper abdomen Lower abdomen

Xiphopagus Omphalopagus

34

Liver, biliary tract, upper and lower gastrointestinal tract, genitourinary tract

Pelvis

Ischiopagus

6

Liver, biliary tract, upper and lower gastrointestinal tract, genitourinary tract

Sacrum

Pygopagus

18

2

Possible shared organs Nervous system

Lower gastrointestinal tract, genitourinary tract, nervous system

Table 69.2 Preoperative diagnostic modalities for conjoined twins Name Craniopagus Thoracopagus Xiphopagus Omphalopagus Ischiopagus Pygopagus

Plain X X X X X X

CXR

ECG

Echo

Cardiac cath

UGI

X X X

X X

X X

X X

X X X X X

BE

IVP

US X X X

X X

X X

CT

MRI

Angio

X X X X X X

X X X X X X

X

X X

CXR = Chest X-ray; ECG = Electrocardiograph; Echo = Echocardiogram; Cardiac cath = Cardiac catheterization; UGI = Upper gastrointestinal series; BE = Barium enema; IVP = Intravenous pyelogram; US = Ultrasound; CT = Computerized tomography; MRI = Magnetic resonance imaging; Angio = Angiogram

Operative management 645

and radionuclide liver and biliary scans. In addition, abnormalities in hepatic venous outﬂow and inferior vena caval drainage can be determined by angiography. Ultrasonography, CT, MRI and conventional cystography and pyelography may evaluate the genitourinary tract. These studies will determine the number of kidneys and their location, the presence of a urogenital sinus or cloaca, the status of the urinary bladders, and whether reﬂux or hydronephrosis is present. Cystoscopy may be helpful in determining the number and condition of the bladder and ureters. In females, determining the presence or absence of a vagina, uterus and cervix is important in order to plan a successful separation with as much functional tissue as possible. In males, the status of the penis, urethra, testicles and scrotum must be known in order to plan separation and to determine whether a gender change must be contemplated.9 In cases of shared limb or bone structures, conventional radiographs, CT and MRI scanning are all useful in determining the best treatment. Arteriography may be necessary in order to determine the origin of the vascular supply of a limb and to which twin it should be given. The blood supply to different areas of soft tissue may need to be studied in order to determine whether operative defects can be primarily covered or whether adjunctive measures may be taken. i.v. ﬂuorescein and use of a Wood’s lamp or light transmission probe with photometric analysis can be utilized for this purpose.10 It is important to plan skin incisions and determine closure techniques prior to operation. Pediatric orthopaedic consultation is often useful.

Timing The timing of separation should be decided on a caseby-case basis. Simple separations in conjoined twins without major life-threatening operative risks should be differentiated from complex separations where operation may result in danger to either twin. These less risky procedures may ideally be carried out between the ages of 3 and 6 months. This timing allows for the growth and maturation of the infants, while at the same time permitting expeditious separation at an early age before signiﬁcant socialization and determination of body image occur. In addition, this plan safely minimizes the time the parents are required to care for the nonseparate twins and permits separation before they grow large enough to become unwieldy as a joined pair. Complex separations should be delayed long enough to allow maturation and development of a larger physiological reserve. This plan also maximizes the amount of soft tissue available for eventual reconstruction through natural growth and the stretching that occurs as the twins push against each other. It hopefully helps avoid the need for tissue expanders or prosthetic tissue patches with their attendant risk of infection. If placement of

tissue expansion devices appears to be needed for softtissue closure, they may be placed during this time so as to achieve maximal effect. If life-threatening deterioration in one or both of the twins occurs, then urgent or emergent separation may need to be performed. Another theoretical timing consideration that must be considered is the availability of a donor organ when one twin may be a candidate for organ transplantation in order to ensure its best possible chance of survival.

OPERATIVE PLANNING The operative separation of conjoined twins should be a careful, well-planned and rehearsed procedure. A multidisciplinary group is needed in order to fully consider the preoperative, operative and postoperative management. This team should consist of surgeons, anesthesiologists, circulating and operating room nurses, and pediatric specialists. Laboratory, blood bank and respiratory therapy personnel should also be alerted and aware that a conjoined twin separation is being contemplated. The objective of these discussions is to minimize crowding and confusion. Decisions must not only be made about surgical techniques and incisions, but also about placement of operating tables, ventilators, anesthetics, ﬂuid management, cardiovascular monitoring and warming equipment. Estimates of blood volume and mixing should be made in order to determine the degree to which circulation is shared. Rehearsal is mandatory in order to teach personnel how to coordinate their actions and to ﬁne-tune equipment placement. Standard infant resuscitation mannequins of the approximate size of the infants are ideal for this exercise. Color coding of equipment, personnel monitoring lines and leads, and vascular lines, is helpful in order to avoid confusion during the procedure. Draping techniques must be carefully planned to avoid confusion and maintain sterility as one patient becomes two. The size and availability of operating space in each hospital will dictate the need for one or two operating rooms. In general the use of two rooms is recommended in order to reduce confusion and allow each team to concentrate in an optimal manner. Rehearsal is also necessary in order to determine the best position of the twins on the operating table so as to avoid gravitational or compressive effects on intravascular volume and respiratory function.

OPERATIVE MANAGEMENT Operative management of conjoined twins depends a great deal upon the different organ systems involved and the degree to which the different organs are shared. Each must be approached so as to maximize the chance for full function and overall survival of the twins.

646 Conjoined twins

Central nervous system fusion This topic is beyond the scope of this chapter. See the excellent review by Winston et al. for further information.7

Cardiovascular fusion The separation of conjoined hearts is difﬁcult and carries an extremely high morbidity and mortality rate.1 The usual anomaly is one of junction at the ventricle, resulting in a six-chambered heart with insufﬁcient cardiac tissue for long-term maintenance of both twins. Limited success has been reported for separation of one pair of twins joined at the atria. In most cases, one infant is given the entire cardiac complex in order to have some chance of survival. Extensive intraoperative reconstruction is frequently necessary. One technique that may have promise in the future is cardiac excision, intraoperative ex vivo reconstruction, and subsequent autotransplantation. Another alternative that may hold some promise of salvaging both twins is that of cardiac transplantation of one infant and reconstruction of the heart of the other. The closure of these patients after separation is also quite formidable, as they essentially become two patients with ectopia cordis. Consideration must be given to use of muscle or soft-tissue ﬂaps, bone grafts and prosthetic material. In addition, use of perioperative soft-tissue expanders to allow maximal soft-tissue coverage should be considered (see later).

Figure 69.1 MRI of omphalopagus twins demonstrating a relatively avascular plane between the shared livers

Hepatobiliary, pancreatic and upper intestinal fusion With thorough preoperative and intraoperative evaluation, twins joined at the liver, biliary tree, pancreas or duodenum can often be successfully separated.8 In cases where there is a small tissue bridge containing only liver, a relatively avascular cleavage plane can often be found (Figs 69.1 & 69.2). Delaying separation when there is a large tissue bridge containing vital organs will reduce the risk of the procedure. In older infants, the liver has increased substance and a stronger capsule and thus will hold sutures better than in the newborn, thereby reducing the risk of hemorrhage. At operation, an effort should be made to leave each twin with an intact biliary drainage system. In cases of a shared ductal system a portoenterostomy may have to be performed in one twin to allow each to have adequate drainage. Primary or future hepatic transplantation may need to be considered as part of the management plan in these situations.

Intestinal fusion and omphalocele Omphalopagus conjoined twins frequently have an associated omphalocele. If the sac is unruptured, the

Figure 69.2 Intraoperative view of avascular plane shown in Figure 69.1. This was easily divided using electrocautery, with minimal blood loss

ideal treatment is non-operative, in an attempt to allow the sac to epithelialize. If the sac ruptures, initial closure of the defect is usually preferable to a rushed formal separation. Some conjoined twins may have an atretic segment of intestine which causes a neonatal bowel obstruction. If present, these can be excised and primary anastamosis performed. Conjoined segments of intestine may be separated or left intact until formal separation.10 If necessary an entrostomy or colostomy may be performed as a temporizing measure, although this approach is ideally avoided because of the increased risk of ﬂap contamination at the time of separation. It should be emphasized that there is no need to perform complete separation of the twins at the initial operation when repairing an omphalocele or atresia, unless a lifethreatening complication ensues.6 Early separation may be carried out in uncomplicated cases where there is

References 647

clearly a minimal visceral attachment and the infants are relatively healthy.

Lower gastrointestinal fusion and genitourinary tract fusion Complex lower gastrointestinal and genitourinary fusions are common in ischiopagus and pygopagus conjoined twins. Thorough preoperative evaluation is the key to planning separation. At operative separation of the twins, an attempt to preserve the bowel and bladder sphincter mechanisms should be made, utilizing a muscle stimulator to identify important muscle groups. If it appears that only enough tissue is present for continence in one infant, an effort should be made to give at least one infant a chance to have a functioning sphincter mechanism. O’Neill et al.10 have suggested initial correction of as much as possible of the neorectal and genitourinary anomalies. Others have suggested that it may be wiser to perform a diverting colostomy and allow growth and maturation to occur before attempting a deﬁnitive continence procedure.9 Placement of an ileostomy, colostomy, suprapubic catheter or vesicostomy may all be necessary. Nearly all patients will need later staged modiﬁcations of their initial procedures to optimize results.

Bone fusion The vascular supply to each limb may need to be identiﬁed in order to permit salvage of a limb with the appropriate twin. If there is gross deformity of a limb or if it appears to be nonfunctional, it may be advantageous to sacriﬁce the bony structures while preserving the soft tissue as a pedicle ﬂap for abdominal closure or softtissue coverage. In addition, if there are not four separate limbs, a decision must be made as to distribution of the tissue. The majority of these patients will require multiply staged orthopedic procedures and long-term rehabilitation in order to obtain optimal function.

The techniques of tissue expansion have increased the surgeon’s ability to close large soft-tissue defects; they have been used extensively in plastic surgery to close defects of the scalp, chest wall, abdomen and extremities. In order to utilize them effectively, several general principles should be considered. In most cases, multiple tissue expanders placed throughout the ﬁeld to be expanded are more effective than a single large expander. In addition, placement in a subcutaneous pocket seems to carry lower morbidity than a deep intraperitoneal pocket, although expanders may be placed under muscles such as the latissimus dorsi to produce an enlarged musculocutaneous ﬂap. In certain situations this may be of beneﬁt, since an expanded subcutaneous skin ﬂap and a muscle ﬂap that can be skin grafted can be obtained from the same area. Expanders placed with distal ports are less likely to be inadvertently punctured or become infected. At the time of placement, and later in the ofﬁce, injecting the expander with ﬂuid colored with methylene blue makes it easier to identify the port at sequential inﬂations prior to separation. In order to ensure maximal tissue expansion, the expander is injected frequently with small volumes over a period of several months. This method allows the expander to be signiﬁcantly overinﬂated to obtain the greatest possible coverage. After the desired expansion has been obtained, a waiting period of several months is necessary in order to maintain the stretch. At the time of separation, signiﬁcant shrinkage of the expanded ﬂaps may be encountered between the times of incision and wound closure. If possible, the expanders should be left in place (inﬂated) until it is time to close the wound. If this is not feasible, acute re-expansion may assist in providing enough tissue to effect wound closure. Finally, at closure the smooth-walled capsule surrounding the expander may be used as an additional layer of wound closure for added strength. If the available local ﬂaps are carefully inventoried and tissue expanders are strategically placed and inﬂated prior to operative separation, the resulting soft-tissue defects should be closed with a minimum of difﬁculty, and with a low risk of wound sepsis and subsequent procedures.

Soft-tissue coverage POSTOPERATIVE CARE A major difﬁculty in the division of conjoined twins is obtaining coverage of the points of separation. Simple intraoperative stretching of the abdominal wall or other available soft tissue may sufﬁce when relatively small defects remain, as is often the situation following division of omphalopagus liver bridges. A transverse or T-shaped closure of the abdominal musculature in these patients often solves the problem of a broad costal margin at the superior aspect of the defect. Silo closure may also be considered in this situation. When closing larger defects, various local rotation ﬂaps can be utilized. They are, however, frequently insufﬁcient to completely close the defect.

Separated conjoined twins will require monitoring and care appropriate to the degree of injury suffered during operation. In nearly all cases, this will require admission to an intensive care unit for close nursing care.

REFERENCES 1. Votteler TP. Conjoined twins. In: O’Neill JA, editor. Pediatric Surgery. 5th edn. Chicago: Mosby-Year Book, 1998: 771–9.

648 Conjoined twins 2. Spencer R. Theoretical and analytical embryology of conjoined twins: Part I: Embryogenesis. Clin Anat 2000; 13:36–53. 3. Barth RA, Filly RA, Goldberg JD et al. Conjoined twins: prenatal diagnosis and assessment of associated malformations. Radiology 1990; 178:201–7. 4. Annas GJ. Siamese twins: Killing one to save the other. Hastings Center Report, 1987:27–9. 5. Raffensperger J. A philosophical approach to conjoined twins. Pediatr Surg Int 1997; 12:249–55. 6. Walton JM, Gillis DA, Giacomantono JM et al. Emergency separation of conjoined twins. J Pediatr Surg 1991; 26:1337–40.

7. Winston ER, Rockoff MA, Mulliken JB et al. Surgical division of craniopagi. Neurosurgery 1987; 21:782–7. 8. Richardson RJ, Applebaum H, Taber P et al. Use of magnetic resonance imaging in planning the separation of omphalopagus conjoined twins. J Pediatr Surg 1989; 24:683–5. 9. Hsu HS, Duckett JW, Templeton JM et al. Experience with urogenital reconstruction in ischiopagus conjoined twins. J Urol 1995; 154:563–7. 10. O’Neill JA Jr, Holcomg GW III, Schnaufer L et al. Surgical experience with thirteen conjoined twins. Ann Surg 1988; 208:299–312.

8 Tumors

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70 Epidemiology and genetic associations of neonatal tumors SAM W. MOORE AND JACK PLASCHKES

maximal growth and development to take into consideration.6–9

INTRODUCTION Although 50% of childhood cancer occurs under the age of 5 years1 and clear evidence of inheritability exists in many childhood carcinomas, malignant tumors occur uncommonly at birth or during the neonatal period.2 By way of contrast, benign tumors and masses are not uncommon and certain apparently benign neonatal masses may undergo malignant change if untreated. Many of these tumors respond to therapy and have a good prognosis but the mortality rate is estimated to be 6.26 per million live births.3,4 Because of their relative rarity, there is also a paucity of objective information on the optimal treatment and long-term outcome of neonatal tumors.5 In addition, there is the generally unfavorable impact of radical therapeutic measures given during the period of

INCIDENCE OF NEONATAL TUMORS Neonatal tumors comprise 2% of childhood malignancies but from an epidemiological point of view, there is little clarity as to the real prevalence, sites of origin and pathological nature of neonatal tumors and reported series vary from unit to unit (Table 70.1) varying from 17–121 per million live births (Table 70.2).5,6,10,11,14,15,19 The reported incidence in the UK and USA respectively is approximately one in every 12 500–27 500 live births.2 The Manchester Children’s Registry estimated the incidence to be 121.29 per 106 child-years when all children under 1 year of age including those with leukemias and

Table 70.1 Published series of ‘neonatal’ tumors since 1980 Date

Author

Country

Time span

No. of cases

1978 1982 1985 1986 1987 1987 1988 1989 1989 1990 1992 1994 1992 1994 1995 1996

Barson10 Gale et al.11 Isaacs12 Pinter and Hock13 Las Heras14 Campbell et al.6 Davis et al.15 Crom et al.5 Plaschkes et al.23a Mur17 Werb et al.18 Borch et al.19 Teinturier et al.20 Parkes et al.21 Moore et al.22 Plaschkes et al.23

UK USA (Philadelphia) USA (Los Angeles) Hungary USA (Los Angeles) Canada (Toronto) Scotland (Glasgow) USA (Memphis) Switzerland (Bern) Argentina Australia (Melbourne) Denmark (Copenhagen) France (Paris) UK (Birmingham) South Africa SIOP

N/I N/I 1958–82 1975–87 1964–78 1922–82 1955–86 1962–88 1973–87 1967–90 1939–89 1943–85 1975–86 1960–89 1957–91 1987–91

270 ? 22 ? 110 4.4 141 (+infants) 11.8 42 3 102 1.7 51 1.6 34 2.1 39 2.6 51 2.2 46 0.9 76 1.8 75 7.5 149 (+21 leukemic) 5 60 1.8 192 38.5

SIOP = International Society of Paediatric Oncology

Per year Source Pathology review Hospital series Pathology review Hospital series Hospital registry Hospital series Hospital series Hospital series Hospital series Hospital series Autopsies National cancer registry Hospital series Population-based registry Hospital series International tumor registry

652 Epidemiology and genetic associations of neonatal tumors Table 70.2 Incidence of neonatal tumors – published series Country

Author

Incidence

Source

UK UK UK USA Switzerland Hungary Denmark

Barson10 Oxford Children’s Cancer Group40a Manchester Children’s Tumour Registry41 Bader and Miller42 Plaschkes and Dubler19 Pinter and Hock13 Borsch et al.19

70 per million live births 17 per million live births 121.29 per 106 child-years 36.4 per 106 child-years 93 per million live births 100.5 per million live births 23 per million live births

National Survey by Pathologists (GB)* Cancer Registry Tumour Registry, population based† Third National Cancer Survey (USA) Hospital activity analysis Hospital activity analysis‡ Danish Cancer Registry (ICD)

* Benign–malignant † <1 year (including neonates) includes leukemia and lymphoma ‡ <3 months

lymphomas are counted.10 Overall the highest incidence has been reported in Japanese children and the lowest in black children in the USA.1

Pediatric Oncology from 12 different centers presented with metastatic disease.10 Some may be incidental ﬁndings and some larger masses may be diagnosed with antenatal ultrasonography.

AGE AND SEX PATHOLOGY The majority of tumors are diagnosed when the infant is between 1 and 4 weeks of age. Fewer malignant tumors are diagnosed at birth, although benign or potentially malignant tumors are frequently encountered at birth. The male-to-female ratio is equal in the majority with the exceptions of retinoblastoma (male preponderance) and teratoma (female preponderance).

PRENATAL DIAGNOSIS With the advent of routine prenatal ultrasonographic screening and the considerable recent advances in technology, many neonatal tumors are now diagnosed antenatally. This is particularly true of patients with mixed germ cell tumors of the sacrococcygeal region and patients with renal tumors. One of the difﬁculties in assessing the true incidence of neonatal tumors is the non-reporting of tumors occurring in stillborn babies and babies dying in the neonatal period. The advent of neuroblastoma screening programs has brought more to light but does not appear to affect the prognosis. The biological characteristics of neuroblastomas detected by screening in Japan have been shown to be mostly favorable.24 Few of these tumors have N-myc ampliﬁcation although 10–20% have unfavorable histological features.

CLINICAL PRESENTATION Although many present with benign masses, 34% of 192 patients reported by the International Society of

A particular problem exists in classifying neonatal tumors in that histological features of malignancy do not always correlate with clinical behavior. As a result there are at least four clinical groupings of neonatal tumors:23 1 Tumors that are clearly malignant by all the usual criteria but: • Behave more like those occurring in older children • Behave better than expected • Behave worse than expected • Demonstrate unpredictable or uncertain behaviour. 2 Tumors that show local invasiveness but have no metastatic potential 3 Benign tumors that are either: • Life threatening because of size and location • Have a known tendency towards malignant transformation. 4 Extreme rarities, e.g. malignant carcinomas which are similar to adult-type tumors.

TUMOR TYPES The distribution of the various histological types of tumors appears to be relatively constant when compared to other published series (Table 70.3). In a study of 192 cases collected from 12 different countries by the International Society of Pediatric Oncology 1987–1991, 33 different types of tumors were reported to occur within the neonatal period.23 Teratoma was the most frequently encountered type in our own17 as well as other large series21,23 and is followed by neuroblastoma, leukemia and soft tissue tumors. Certain tumors (e.g.

Etiology and carcinogenesis 653 Table 70.3 International Society for Paediatric Oncology (SIOP) tumor registry 1987–1991 Diagnosis Neuroblastoma Teratoma Rhabdomyosarcoma Retinoblastoma Mesoblastic nephroma Hepatoblastoma Undifferentiated sarcoma Histiocytosis Fibromatosis Hemangiopericytoma Renal (unclassiﬁed) Yolk sac tumor Brain tumor Choriocarcinoma Fibrosarcoma Liver tumors Prospective neuroectodermal tumor (PNET) Angioﬁbroma Arterioventricular malformations Embryonal tumors Ependymoblastoma Glioma grades III–IV Infantile myoﬁbromatosis Juvenile xanthogranuloma Leiomyosarcoma Melanoma Neuroﬁbroma Oligodendroglioma Rhabdoid tumor Testicular carcinoma Wilms’ tumor Total

No. cases 85 24 13 10 8 6 5 4 3 3 3 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 192

retinoblastomas and brain tumors) vary in incidence depending on hospital referral patterns. Renal and liver tumors occurred less frequently in the neonatal period.10 Other types of tumors tend to be largely rarities. True carcinoma as seen in adults remains extremely rare in childhood, making up only 1–2% of patients.16

ETIOLOGY AND CARCINOGENESIS The etiology of cancer in children is multifactorial and includes both genetic and environmental factors.

true of neonatal tumors where most cancer cells are monoclonal, have a high incidence of chromosomal changes and some speciﬁc genetic mutations as well as a clear inherited predisposition to malignancy. Modern genetic surveillance techniques offer potential opportunities for prevention, in contrast to most malignancies encountered in older patients. The ﬁrst genetic abnormality associated with malignancy was the Philadelphia or Ph1 chromosome,25 which was found on the affected cells of patients with chronic myeloid leukemia (CML). This ﬁnding implicated genetic mechanisms in the etiology of cancer and opened new areas for diagnosis and prognosis. Neonatal tumors provide a unique opportunity to study familial and genetic associations because minimal interactions between genetic and environmental factors have occurred that soon after birth. Once a disease gene has been cloned there needs to be a characterization of the associated genetic mutations. Testing for known areas of mutation can then be achieved by directly probing the affected patients’ DNA. Available assays include single-stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE) and heteroduplex analysis. In DNA fragments of less than 200 bp, the SSCP is 85% sensitive for detection of a germline mutation but does not localize mutations within a fragment or reveal the details of the sequence alteration. Over the past decade, many further genetic associations have been identiﬁed in tumors due to the application of recombinant DNA technology. Most mutations associated with malignancy in the neonate are inherited from the parents or occur spontaneously as the result of a de novo mutational event. Because of this, the majority of cancers arising from these defects could possibly be preventable. This is in contrast to those tumors found largely in adults, where the gene–environmental interactions (e.g. smoking) form the basis of the development of cancer. There are essentially three groups of genetic abnormalities involved in the epidemiology of neonatal tumors: 1 Genes resulting in a high risk of malignancy (e.g. in retinoblastoma) 2 Genetically determined syndromes where an increased risk of malignancy exists 3 Genes which confer a higher risk by conferring an increased susceptibility to environmental factors. The incidence will be inﬂuenced by the incidence of these abnormalities in the population/family at risk.

Genetic factors in neonatal tumors

GENES RESULTING IN A HIGH RISK OF MALIGNANCY

Malignant tumors are accepted as being a largely genetically based disorder at cellular level and have been implicated in both non-hereditary and hereditary forms of malignancy in children and adults. This is particularly

The best example of this group is the RB1 gene, which confers a risk of retinoblastoma. Other examples include Li-Fraumeni syndrome, where there is an association of rhabdomyosarcoma, soft

654 Epidemiology and genetic associations of neonatal tumors

tissue tumors, breast carcinoma adrenocortical carcinoma, brain tumors and leukemia. As many of the genetic mutations associated with malignancy in children appear to occur spontaneously, a double ‘hit’26 is a likely mechanism.

TWO-HIT THEORY Knudson,26 in an attempt to understand the pathogenesis of neonatal retinoblastomas, extrapolated statistical data and proposed that retinoblastoma resulted from a combination of a prezygotic (germinal) mutation as well as postzygotic (somatic) event. This suggestion resulted in the so-called ‘two-hit’ theory, i.e. that retinoblastoma can be initiated by two events. Later on this was conﬁrmed by Comings27 who suggested that both of these events could apply to mutations of the RB1 gene. It is now widely accepted that inherited or de novo chromosomal mutations or deletions may be may result in a susceptibility to cancer. The ‘two-hit’ hypothesis holds that two genetic events are involved in the development of malignancy. The initial mutation would either be inherited or result from a spontaneous genetic event. The rate-limiting step depends on the effect of the initial mutation on the activity of tumor suppressor genes, which results in abnormal cell growth giving rise to tumor formation. This provides the basis for understanding the pathogenesis of a number of tumors occurring in the neonatal period and has since been validated for retinoblastoma but also holds true for other tumor types (e.g. Wilms’ tumor). The clearest examples of genetic involvement are associations with retinoblastoma, Wilms’ tumor, neuroblastoma and other tumors.

Genetically determined high-risk syndromes The identiﬁcation of a genetic association of a speciﬁc tumor may be hampered due to the fact that the precise genetic mechanisms may not be recognized by the current genetic testing methods. Etiological factors involved in the pathogenesis of certain tumors (e.g. Wilms’ tumor) appear to be more complicated than those of others (e.g. retinoblastoma). Increases in familial occurrence or an increased risk in monozygomatic twins may be present and an association between a speciﬁc malignancy and a set of alleles at a speciﬁc locus thus identiﬁed. This may not be exclusive to the particular tumor under study and may be associated with the pathogenesis of other types of tumors. Examples of this are the associations between leukemia, lymphomas, central nervous system (CNS) neoplasms and soft tissue tumors as well as the RB1 and WT1 genes amongst others. The evaluation of clinical associations and syndromes linked to speciﬁc tumor types is therefore of considerable importance.

Mendelian single gene-related syndromes Syndromes arising from defects in chromosomal breakage syndromes or disorders of sexual differentiation may lead to malignancy. A number of examples of Mendelian single-gene malignancy-related syndromes are described and are listed in Box 70.1. These may be autosomal dominant, recessive or X-linked. In addition, certain disorders of sexual differentiation may also be associated with cancer in the pediatric age group. Autosomal dominant syndromes include familial colonic polyposis, neuroﬁbromatosis, and the nevoid basal cell carcinoma syndrome (Gorlin syndrome) as well as the blue rubber bleb and Sotos syndromes. Skeletal abnormalities such as multiple exostoses, polyostotic ﬁbrous dysplasia and Mafuccis syndrome are also associated with a higher incidence of tumor formation. These tumors do not normally present in the neonatal period and are added for completeness, but are extremely interesting from a genetic point of view (i.e. in tracing the affected individuals in family groups). Autosomal recessive syndromes associated with tumors include xeroderma pigmentosum, Fanconi anemia, Bloom syndrome and ataxia telangiectasia syndromes. Bloom syndrome includes a sensitivity to ultraviolet light, growth retardation and immunodeﬁciency which is associated with a higher rate of associated malignancy occurring at an earlier age,28 e.g. leukemias and gastrointestinal malignancies. Fanconi’s

Box 70.1 Inherited syndromes and childhood malignancy Chromosome breakage syndromes Bloom syndrome Fanconi’s anemia Ataxia telangiectasia Xeroderma pigmentosa Neurochristopathies Neuroﬁbromatosis Tuberous sclerosis Turcot’s syndrome Multiple mucosal neuroma syndrome Basal cell naevus syndrome Metabolic disorders Tyrosinemia (hereditary) Alpha-1 antitrypsin deﬁciency Glycogenolysis (type 1) Immune deﬁciency disorders Sex-linked lymphoproliferative syndrome Wiskott-Aldritch syndrome Severe combined immunodeﬁciency Bruton’s agammaglobulinemia

Etiology and carcinogenesis 655

anemia is also linked to leukemia and liver tumors. Tumors associated with an autosomal recessive familial inheritance as well as those associated with immunodeﬁcient X-linked recessive syndromes occur outside of the neonatal period, suggesting some degree of an initiating environmental inﬂuence. The Ebstein-Barr virus has been suggested as a possible pathogenetic factor29 in the X-linked lymphoproliferative syndrome. Of particular interest are the fragile chromosomal syndromes, where fragile sites associated with breakage and repair of chromosomal defects are transmitted through families. A high percentage of the inheritable and constitutive fragile sites have been mapped to genetic sites associated with human cancer.30 These chromosomal rearrangements have been associated with malignancy in at least six out of the 16 inheritable fragile chromosome sites and has also been identiﬁed in other non-inherited fragile chromosome sites.30 As a result of the chromosome fragility in these cases, deletions and chromosomal fragments may occur. Should the fragile sites break close to a proto-oncogene location, the activation of the oncogene may result in the malignant transformation of the cells. In several disorders in sexual differentiation, the incidence of gonadal tumors has been increased.

Familial associations with cancer Although loss of a chromosome segment of a speciﬁc chromosome pair (heterozygosity) may be involved in the pathogenesis of certain tumors,31,32 a speciﬁc chromosome from one of the parents appears to be given preference in particular situations.31 Examples of this are the loss of a maternally derived gene on chromosome 11 in sporadic Wilms’ tumor32 and the successive loss of function of both alleles of RB (retinoblastoma susceptibility gene) in the development of retinoblastoma as well as certain sarcomas such as osteosarcoma.31 Genetic processes other than chromosome anomalies may also be involved in the familial transmission of a tendency to develop certain tumors. Large cohort studies of offspring of parents with cancer have failed to show an overall increased risk for tumors.33 There is also little evidence to suggest that cancer treatment confers an additional risk. In a separate study of 36 survivors of 82 neonatal tumors, the current authors found no familial increase in the incidence of malignancy, although chromosomal abnormalities were identiﬁed in three patients.34 One patient had a chromosome 21 abnormality, one had trisomy 13 and in the other a distinctive familial translocation pattern was located on the 9th chromosome in a girl with a neuroblastoma. The lack of increase in incidence agrees with the ﬁndings of previous studies,5,35,36 where no inherited effects of childhood tumors or tumor therapy were identiﬁed in survivors of childhood neoplasms.

Other syndromes associated with an increased genetic risk of cancer Although a family history may be observed in the group of neurocristopathies associated with neural crest abnormalities, the tumors tend to appear at a later age. Examples of this are phaeochromocytoma, von Recklinghausen’s disease, Sturge–Weber syndrome, tuberous sclerosis and von Hippel–Landau disease as well as the MEN II tumor syndrome. Other congenital syndromes which confer an increased risk of malignancy include the WAGR and Denys–Drash syndromes in Wilms’ tumors, the Beckwith-Wiedemann and Down syndromes, and neuroﬁbromatosis (NF1 gene). There is an increased risk of leukemia and other tumors in patients with Down syndrome.37 Leukemoid reactions may be more difﬁcult to distinguish in the neonatal period.38 Abnormalities of the neuroﬁbromatosis 1 gene (NF1) have been identiﬁed in patients with von Recklinghausen’s disease and a number of different mutations on the tumor suppressor gene have been described in chromosome 17q. An additional NF2 suppressor gene has been identiﬁed on chromosome 22q, leading to tumors such as acoustic schwannomas and other neural tumors. There is a certain amount of overlap in phenotypic expression in syndromes such as the BeckwithWiedemann, Denys–Drash, Simpson-Golabi-Behmel, and Perlman as well as other overgrowth syndromes. Nephroblastomatosis may be a feature of a number of these syndromes and long-term survey is required as these could put patients at risk for embryonic tumors. There are additional associations between Wilms’ tumor, aniridia, urogenital malformations and mental retardation (WAGR) and the Denys–Drash syndromes.39 This latter syndrome includes features of intersex disorders, nephropathy and Wilms’ tumor. Although initially described only in males with pseudohermaphroditism,39,40 this syndrome has been extended to include female children with ambiguous genitalia, nephropathy and Wilms’ tumor.41 An observed constant association with genetic mutations located at chromosome 11p13 (WT1 or Wilms’ tumor gene) and the Denys–Drash syndrome indicates a possible molecular marker for this syndrome. The exact site of the point mutation which was identiﬁed in the majority of cases was located on the WT1 exon 9, which affects the amino acid residue 394 arginine.42 There is also an association between other tumors such as hepatoblastomata or adrenocortical carcinoma and Wilms’ tumor, which may coexist in 6–10% of patients. Genetic factors which are involved in an increased risk of tumors include tyrosinosis, the MEN II and III syndromes, congenital adrenal hyperplasia, the basal cell nevus and Li-Fraumeni syndromes.43 Genetic mutations predisposing to malignant disease include the Wilms’ tumor 1 gene. In this instance, an 11p13 chromosomal

656 Epidemiology and genetic associations of neonatal tumors

defect is often typical. A further example is the neuroﬁbromatosis type 1 gene, which is common in certain tumors. Gene ampliﬁcations have been reported in certain tumors. Ampliﬁed N-myc and N-ras oncogenes have been observed in neuroblastomas. This N-myc ampliﬁcation has been shown to be associated with the more severe form of the malignancy.

Increased susceptibility to environmental factors Events during pregnancy could be of key signiﬁcance in the development of neonatal tumors. The distinction between environmental and genetic factors is being eroded and it is clear that both may inﬂuence the development of a neonatal tumor in the offspring. These events during pregnancy include ionizing radiation, drugs taken during pregnancy, infections and tumors in the mother, environmental exposure and congenital malformations (birth defects). Associated congenital anomalies have been reported to occur in as much as 15% of neonatal tumors.

Radiation-induced tumorigenesis Ionizing radiation has been clearly implicated in the etiology of a number of tumors in children. This may involve prenatal as well as postnatal exposure. There is a dose-related increase in tumor incidence or a tendency for tumors to occur at a younger age following prenatal or neonatal radiation exposure.44 This is also true of internally deposited radionucleotides administered in the prenatal or neonatal periods.45 It is clear from experimental evidence that deletions, point mutations, translocations and other genetic abnormalities occur as a result of ionizing radiation. As a result a state genomic instability may occur, which may in turn result in malignant transformation. There does appear to be an increased susceptibility to ionizing radiation in the LiFraumeni syndrome mouse model (p53-deﬁcient mice), which suggests some environmental inﬂuence in the development of tumors.46

Effect of drugs in pregnancy Drugs may act as carcinogens or co-carcinogens in association with other agents or a particular genetic background. There is also clear evidence that tumors may arise in the children of mothers taking medication. One of the best examples of this is the fetal hydantoin syndrome.47 There is some evidence of tumors arising from estrogens taken during pregnancy, and sacrococcygeal tumors have also been associated with maternal intake of acetazolamide.48 This may be a greater problem than was initially thought. Satge et al.49 showed a history

of medications being taken in 39 out of 89 (44%) neonatal tumor patients. Out of the 39 tumors, nine were malignant, of which the main types were neuroblastomas and teratomas. Three groups of drugs were identiﬁed: IARC group 1 diethylstilboesterol and oral contraceptives, IARC group 2 possibly carcinogenic to humans and IARC group 3, where no association has been proven. To date the association of vitamin K with carcinogenesis remains unproven.50

Environmental exposure Results of epidemiological studies are inconsistent as far as environmental exposure is concerned but only weak associations with risk factors such as smoking have been identiﬁed.51 Other environmental factors such as exposure to electromagnetic radiation have proved to be difﬁcult to determine from an epidemiological point of view.

SPECIFIC CLINICAL ASSOCIATIONS OF NEONATAL TUMORS Retinoblastoma The work of Knudson in 197126 was based on an analysis of the age of presentation of hereditary as opposed to non-hereditary cases. His hypothesis that these tumors resulted from two separate genetic events was extended to suggest that these events could be mutations of the same RB1 gene. It has subsequently been shown that 90% of individuals with the RB1 gene will develop a retinal tumor. A small number of these patients (5%) have additional associated genetic disturbances (e.g. deletions or translocations at 13q14). In patients with familial associations, it appears that chromosome 13, which is retained in the tumor cells, comes from the affected parent. The cloning of the RB1 gene52 indicated an association with other tumors such as osteosarcoma and breast carcinoma as well as retinoblastoma. The retinoblastoma protein (pRB) is part of the control of genes involved in the cell cycle, interacting with a number of transcriptional factors by modulating their activity. As such, inactivation of the RB1 gene can also be involved in the development of other malignancies and patients with RB1 mutations carry a risk of developing other tumors such as osteogenic sarcomas, ﬁbrosarcomas and melanomas in early adult life. Although the deletion of the RB1 gene is speciﬁc to particular tumors, unstable RB1 mRNA may be detected in many tissues.53 A further mechanism therefore appears to control the rate of transcription of RB1 mRNA. There is some indication that this may be via inhibition of cyclin-D-dependent kinases via lesions of p16(INK4a).

Speciﬁc clinical associations of neonatal tumors 657

Wilms’ tumor Wilms’ tumor is the most common pediatric renal tumor with a peak age of incidence of 3–4 years. Although rare in the neonatal period, patients with synchronous bilateral Wilms’ tumor, familial cases and those with abnormalities are noted to be signiﬁcantly younger. Predisposing associations with aniridia, congenital abnormalities of the genitourinary tract, and hemihypertrophy may be associated with nephroblastomatosis, which may lead to an early Wilms’ tumor (Box 70.2). The familial associations have been shown to be part of an autosomal dominant trait, and are of the order of 1% with a somewhat slight female preponderance, particularly in multicentric and bilateral tumors. Genetic deletions in children suffering from the uncommon association between aniridia, urogenital malformations and mental retardation (WAGR syndrome) were initially shown to involve a constitutional chromosomal deletion in the short arm of one copy of chromosome 11p13. This has been identiﬁed the WT1 gene, which appears to act as a tumor-suppressor gene;54 a deletion resulting in development of a Wilms’ tumor.42 The gene encodes a zincﬁnger transcription factor, which binds GC-rich sequences and acts as either an activator or repressor of transcription for a number of growth factors (including IGF-2); this may be a possible explanation of its mechanism of action.55

Box 70.2 Syndromes associated with Wilms’ tumor 1. 2. 3. 4. 5. 6.

Aniridia (0.75–1%) Hemihypertrophy (3.3%) Beckwith–Wiedemann syndrome (3.7%) Musculoskeletal abnormalities (2.9%) Genitourinary abnormalities (5.2%) Other syndromes associated with Wilms’ tumors

Denys–Drash syndrome Nephroblastoma Male pseudohemaphroditism Glomerulonephritis Nephrotic syndrome Renal failure WAGR syndrome (11p13 deletion) Nephroblastoma Anorectal malformation Genitourinary anomalies Mental retardation Beckwith–Wiedemann syndrome Klippel Trelaunay syndrome Other associated tumors Hepatoblastoma (6–10% of Wilms’ tumors) Adrenocortical carcinoma

The Knudson model for Wilms’ tumor has been validated through molecular identiﬁcation of the WT1 gene.56,57 Neonatal Wilms’ tumors, although rare, are known to be associated with nephroblastomatosis in the kidneys. Although this may represent the stage 1 of the Knutsen two-hit theory, it would appear that the genetic factors involved in Wilms’ tumor are much more complex than those involved in other tumors such as retinoblastoma. In addition to the WT1 gene at 11p13, there is evidence of a second WT gene at 11p15 (WT2 gene). A high reported frequency of LOH at 1p35–p36 (DIS247) suggests that this may be involved in the pathogenesis of Wilms’ tumor.58 In addition, a LOH for 16q is a structural alteration identiﬁed in 20–30% of Wilms’ tumors. The p53 alteration also appears to be required for the progression to the anaplastic subtype. Further associations with p53 analogs (p73 and p63/KET) suggest that association with the p53 family may be important to cell growth and differentiation.59 Haploinsufﬁciency in the PAX6 gene is also strongly associated with aniridia.60 Familial Wilms’ tumors do not, however, map to the 11th chromosome61 as FWT1 is on 17q12-q21 and FWT2 on 19q13. Other susceptibility genes still remain to be found. The WT1 gene is also associated with syndromes such as the Denys–Drash syndromes and nephroblastomatosis, and is also associated with approximately 10% of non-familial Wilms’ tumors. In addition, mutations of the Wilms’ tumor gene tend to involve the paternal allele,62 suggesting that other mechanisms such as genetic imprinting also apply to Wilms’ tumors. The inactivation of maternal alleles at chromosome 11p15 are not an uncommon ﬁnding in Wilms’ tumor and suggest that maternally expressed genes at this region play an important role in Wilms’ tumor pathogenesis. Further genetic abnormalities may be present but be of a more subtle nature and not as easily identiﬁed by current testing methods.

Neuroblastoma Neuroblastoma is frequently diagnosed in the neonate, is often advanced at diagnosis and commonly metastasizes widely to bone marrow, liver, lymph nodes, bone cortex and lung. Despite this, it is unique in its clinical behavior in the neonatal period in that although many tumors metastasize widely and aggressively, others differentiate spontaneously, maturate to a benign form and may eventually disappear. Studies have shown a favorable outcome in the majority of mass-screened patients24 and suggest a better biological component in these patients. The majority of neuroblastomas are stage IVS at diagnosis in the neonatal period, which although widely spread, means that these patients have a relatively good prognosis. As a result, a number of molecular genetic features of neuroblastoma cells are important

658 Epidemiology and genetic associations of neonatal tumors

prognostic factors and are currently of value in directing treatment. Genetic studies have demonstrated chromosomal abnormalities in up to 80% of cases of neuroblastoma. The most important of these are MYCN ampliﬁcations, deletions of chromosome 1p and aneuploidy. In most cases, the defect is found to be on chromosomes 1 and 17, the most consistent being a deletion on the short arm of chromosome 1 (1p36.1–1p36.3).63 Additional chromosomal abnormalities have been identiﬁed at 4p, 6q, 9q, 10q, 11q, 12q, 13q, 14q, 16q, 22p and 22q.64 Ampliﬁcation of the N-myc oncogene (usually found on chromosome 2), has been associated with a more advanced form of the malignancy and is a poor prognostic sign.65 Recent reports of the downregulation of activin-A by MYCN offers an explanation for this as deprived neuroblastoma cells experience a decrease in growth-inhibitory signal transduction leading to excessive cell growth.66 It is interesting to note that p53 gene mutations are absent in neuroblastomas67 although they are present in other tumors of childhood.

TERATOMA Germ cell tumors account for approximately 3% of pediatric malignancies worldwide and occur in gonadal (male and female) and extragonadal sites. Epidemiology should include abortions and stillbirths as the related mortality rate is high. The majority of teratomas are located in the sacrococcygeal region and gonads in childhood. Sacrococcygeal tumors are mostly benign at birth and the majority do not develop to malignancy if adequate surgical removal is carried out before the infants is 3 months of age. After this time the risk of malignancy increases if residual tumor is present and older children may require chemotherapy along with delayed surgical excision. Teratomas are thought to arise from the primordial germ cells as the result of an early event. A genetic tendency towards spontaneous gonadal teratomas is seen in a speciﬁc strain of experimental mice (strain 129).68 An association with autosomal dominant familial recurrence has been reported and there also appears to be a Mendelian dominant genetic predisposition to the development of a presacral mass in association with anorectal, sacral and urogenital abnormalities.69 Patients with an imperforate anus and a hemisacrum have a high incidence of presacral masses which are teratomas and may occasionally be malignant.69 Recent evidence points to an association with the long arm of chromosome 7 and Currarino’s triad.70 Mediastinal teratomas have been shown to develop in the second trimester.71 Their sensitivity to chemotherapy and the existance of reliable tumor markers are important prognostic factors.

SOFT TISSUE TUMOR Spicer72 reported 33 different soft tissue tumors occcurring in the ﬁrst month of life, which he divided into ﬁve clinical groups depending on prognosis and outcome. The relatively good outcome of tumors despite aggressive characteristics is a feature of presentation at this age. Rhabdomyosarcomas (RMSs) are associated with a number of syndromes: Beckwith–Wiedemann, LiFraumeni and WAGR syndromes as well as neuroﬁbromatosis (type 1). Loss of heterogenicity of the short arm of chromosome 11 (11p15 locus 12) is seen in embryonal RMS tumors and leads to an overexpression of the insulin growth factor II (IGF-II) gene. A speciﬁc and unique chromosomal translocation between chromosomes 2 and 13 [t(2;13) (q35;q14)], has been described in a subset of alveolar RMS73,74 and may act as a marker for patients with a poorer prognosis. This translocation occurs close to the junction of the PAX3 gene, which maps to the breakpoint region on chromosome 2 (related to neuromuscular development) and the ALV gene. The breakpoint is described as being in the 3’ region and a consistant rearrangement of the 5’ portion of the PAX3 gene on chromosome 2q35 has been identiﬁed, which may act as a new transcription factor for these tumors.75 This PAX/FKHR fusion gene is found in as many as 60% of alveolar RMS cases but a further 10% of patients may carry the EWS/ETS fusion gene (occasionally along with the PAX/FKHR gene in histological types that carry a particularly poor prognosis). It is therefore largely accepted that cytogenic analysis should be an integral part of diagnostic examination of patients with RMS and that a PCR analysis may aid the early diagnosis of alveolar RMS. A further breakpoint on chromosome 1p has been identiﬁed as an additional candidate area for RMS.76 Loss of 1p36 corresponds to the locus for PAX7, a paired homeobox characteristically altered in alveolar RMS tumors. In a recent study,77 gains of chromosomes 2, 7, 8, 11, 12, 13q21, and 20 were most frequent as was losses of 1p35–36.3, 6, 9q22, 14q21–32 and 17. The 1p region is interesting as it is also associated with neuroblastomas. The site at 9q22 corresponds to that of the putative suppressor gene (PTCH) associated with the mouse model of the Gorlin syndrome.77 The Beckwith–Wiedemann syndrome is also associated with an increased risk of soft tissue sarcomas (approximately 7.5%), especially if hemihypertrophy is present. Detection of abnormal myogenic transcription factors (MyoD, myogenin and Myf5), detection of the PAX/FHKR chimeric transcription factors (see later for details) or detection of other fusion genes such as EWS/WT1 in desmoplastic small round cell tumors, EWS/|ATF-1 in clear cell sarcomas, SSX/SYT in synovial cell sarcomas or the TLS/CHOP in liposarcomas. Other areas of recent interest in rhabdomyosarcomas are the association between mutations in the p53 tumor

Antenatally diagnosed tumors 659

suppressor gene associated with adverse outcome, the inverse relationship between the increase in functional IGF-II alleles and the suppression of the H19 gene on human 11p15.5. It appears that IGF-II gene is overexpressed and appears to have a signiﬁcant role in stimulating the growth of RMS tumors.78 It is as yet unclear if p53 mutations are of pathogenetic importance or as a result of progression events but p53 has been shown to be an infrequent mutation in childhood ﬁbrous tumors.79 RMS cell lines express the speciﬁc gene of muscle differentiation myoD, which characteristically marks these tumors.80 An overexpression of myoD in RMS is thought to inhibit the development of muscle cells. Some primitive RMSs express myogenic transcription factors but lack other normal muscle cytogenetic markers. The roles of extracellular matrix components, angiogenesis inhibition as well as the roles of the potent inhibitor of neoangiogenesis TNP470 and the DRAL (downregulated in rhabdomyosarcoma LIM protein) in regulating normal myoblast development, all require further evaluation. Similar to other tumors, diploid (33%) and tetraploid (25%) tumors denote an unfavorable prognosis in comparison to hyperdiploid tumors (73%) regardless of histologic type.74 The observed preferential retention of parental alleles in certain embryonal tumors such as Wilms’ tumor and RMS suggests a possible role for genomic imprinting in these tumors.

HEPATOBLASTOMA Congenital abnormalities are associated with hepatoblastoma in up to one-third of cases but a familial occurrence is extremely rare. Although relatively little is known about the molecular basis of hepatoblastomas in infancy, it has been postulated that a the mechanism of tumorigenesis is similar to that of Beckwith–Wiedemann syndrome-associated tumors such as Wilms’ tumor, RMSs and hepatoblastomas, which suggests a common genetic pathway involving chromosome 11. Chromosomal imbalances appeared to be signiﬁcantly more common in patients with LOH at the 11p site.81 Multiple deletion or point mutations have been described in hepatoblastomas but gains on chromosomes 1q and 2 are typical with 2q24 being viewed as the critical chromosomal band. In addition, gains on 8q and 20 have been shown to have a signiﬁcantly higher association with a poor outcome.81 There is considerable support for associations with trisomies 2 , 8 and 20 in the development of HB.82 A high incidence of associated mutations of the APC gene on the 5th chromosome has also been observed. As this gene is normally associated with familial polyposis, patients with this genetic abnormality stand an increased risk of

developing hepatoblastoma. This connection exists because the APC gene affects the degradation of betacatenin by phosphorylation sites on exon 3. Mutations of these phosphorylation sites leads to accumulation of the beta-catenin protein in the nucleus as well as activation of a number of tumor-related mutations.83 This data suggests that activation of beta-catenin signaling is an obligatory step in hepatoblastoma pathogenesis.

OTHER TUMORS Other genetic aberrations associated with tumors such as the loss of heterozygosity on chromosome 5q in identifying the gene for familial polyposis of the colon, defects in tumor-suppressive genes on 17q (p53) and 18q (DCC) in carcinoma of the colon and translocation of the end of the long arm of chromosome 8 with chromosome 14, or an alteration in C-myc regulation or p5384 in Burkitt’s lymphoma are interesting associations with pediatric tumors but are not particularly associated with the neonatal period.

ANTENATALLY DIAGNOSED TUMORS Clinical appproach to antenatally diagnosed tumors The reasons for highlighting neonatal tumors are manifold but include the following: 1 Increased diagnosis of neonatal tumors due to routine ultrasonography during pregnancy brings to light tumors whose natural history and optimal management is unclear 2 Increased knowledge and understanding of pathophysiology and biological behavior of tumors may reduce unnecessary harmful forms of therapy 3 Molecular genetics in these tumors identiﬁes risk factors and provides models for understanding carcinogenesis in other tumors 4 Environmental and teratogenic factors may be identiﬁed. All evidence points toward the fact that the natural history of neonatal tumors is different (mostly better) than that of comparable tumors in older children. The basis of this behavior is largely unknown and hard epidemiological and etiological data in this group is lacking. It is important that the identiﬁcation of the genetic associations of these tumors continues and the cancerproducing genes to identify the genetic alleles associated with malignancy are investigated further. In addition, it is important that families with a genetic susceptibility to malignant tumors be investigated in order to identify speciﬁc genetic locuses which may or may not be related

660 Epidemiology and genetic associations of neonatal tumors

to a speciﬁc allele. Because of the rarity of these tumors, it is clear that international collaborative studies and research projects are necessary to achieve this goal.

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References 661 39. Denys P, Malvaux P, Van den Berghe H, Tanghe W, Proesmans W. Association d’un syndr’me anatomopathologique de pseudohemaphroditism masculin, d’une tumeur de Wilms d’une nephropathie parenchymateuse et d’un mosa‹cism XX/XY. Arch Fr Pediatr 1967; 24:729–39. 40. Drash A, Sherman F, Hartmann W, Blizzard RM. A syndrome of pseudohemaphroditism, Wilms tumour, hypertension and degenerative renal disease. J Pediatr 1970; 76:585–93. 40a. Broadbent VA. Malignant disease in the neonate. In: Robertson N ed. Textbook of Neonatology, Edinburgh: Churchill Livingstone, 689–695. 41. Thorner P, McGraw M, Weitzman S, Balfe W, Klein M, Baumal R. Wilms tumour and glomerular disease. Occurrence with features of membranoproliferative glomerulonephritis and secondary focal, segmental glomerulosclerosis. Pathol Lab Med 1984; 108:141–6. 42. Coppes MJ, Campbell CE, Williams BRG. The role of WT1 in Wilms tumorigenesis. FASEB J 1993; 7:886–95. 43. al-Sheyyab M, Muir KR, Cameron AH, Raafat F, Pincott JR, Parkes SE, Mann JR. Malignant epithelial tumours in children: incidence and etiology. Med Pediatr Oncol 1993; 21(6):421–8. 44. Doll R, Wakeford R. Risks of childhood cancer from fetal irradiation. Br J Radiol 1997; 70:130–9. 45. Sikov MR. Tumour development following internal radionucleotides during the perinatal period. IARC Sci Publ 1989; 96:403–19. 46. Kemp CJ, Wheldon T, Balmain A. p53 deﬁcient mice are extremely susceptable to radiation-induced tumorigenesis. Nature Genet 1994; 8:66–9. 47. Sherman S, Roisen N. Fetal hydantoin syndrome and neuroblastoma. Lancet 1976; ii:517. 48. Worsham GF, Beckmann EM, Mitchell EH. Sacrococcygeal teratoma in a neonate associated with maternal use of acetazolamide. JAMA 1978; 240:251–2. 49. Satge D, Sasco A, Little J. Antenatal therapeutic drug exposure and fetal/neonatal tumours: review of 89 cases. Pediatr Perinat Epidemiol 1998 12:84–117. 50. Passmore SJ, Draper G, Brownbill P, Kroll M. Ecological studies between hospital policies on neonatal Vitamin K administration and subsequent occurrence of childhood cancer. Br Med J 1998; 316(7126):184–9. 51. Schuz J, Kaatch P, Kaletsch U, Meinert R, Michaelis J. Association of childhood cancer with factors related to pregnancy and birth. Int J Epidemiol 1999; 28(4):631–9. 52. Friend SH, Bernards R, Rogelj S et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteogenic sarcoma. Nature 1986; 323:643–6. 53. Goddard AD, Balakier H, Canton M et al. Infrequent genomic arrangement and normal expression of the putative RB1 gene in retinoblastoma tumours. Mol Cell Biol 1988; 8:2082–8. 54. Orkin S, Goldman D, Sallan S. Development of homozygosity for chromosome 11p markers in Wilms tumour. Nature (Lond) 1984; 309:172–4.

55. Madden S, Cook D, Morris J, Gashler A, Sukhtame V, Rauscher F. 111. Transcriptional repression mediated by the WT1 Wilms tumour gene product. Science (Washington DC) 1991; 253:1330–3. 56. Call K, Glaser T, Ito C et al. Isolation and characterization of a zinc ﬁnger polypeptide gene at the human chromosome 11 Wilms tumour locus. Cell 1990; 60:509–20. 57. Knudson A, Strong L. Mutation and cancer: a model for Wilms tumour of the kidney. J Natl Cancer Inst 1972; 48:313–24. 58. Steinberg R, Freud E, Zer M et al. High frequency of LOH for 1p35-p36 (D1S247) in Wilms tumour. Cancer Genet Cytogenet 2000; 117(2):136–9. 59. Scharnhorst V, Kekker P, van der Eb AJ, Jochemsen AG. Physical interaction between Wilms tumour 1 and p73 proteins modulates their functions. J Biol Chem 2000; 275(14):10202–11. 60. Chao LY, Huff V, Strong LC, Saunders GF. Mutation in the PAX6 gene in twenty patients with aniridia. Hum Mutat 2000; 15(4):332–9. 61. Strong LC, Compton DA, Chao L et al. Lack of linkage of familial Wilms tumour to chromosome band 11p13. Nature 1988; 336:337–8. 62. Wilkins RJ. Genomic imprinting and carcinogenesis. Lancet 1988; i:329–30. 63. Cowell J, Rupniak H. Chromosome analysis of human neuroblastoma line TR14 showing double minutes and an abberration involving chromosome 1. Cancer Genet Cytogenet 1983; 9:273–80. 64. Woods WG, Lemieux B, Tuchman M. Neuroblastoma represents distinct clinical-biologic entities: a review and perspective from the Quebec Neuroblastoma screening project. Pediatrics 1992; 89:114–18. 65. Brodeur GM, Seeger RC, Schwab M et al. Ampliﬁcation of n-myc in untreated human neuroblastomas correlates with advanced disease state. Science 1984; 224:1121–4. 66. Breit S, Rossler J, Fotsis T, Schweigerer L. N-myc downregulates Activin-A. Biochem Biophys Res 2000; 247(2):405–9. 67. Vogan K, Bernstein M, Leclerc J et al. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res 1993; 53:5269–73. 68. Ilmensee K, Stevens LC. Teratomas and chimeras. Sci Am 1979; 240:87–98. 69. Ashcraft K, Holder TM. Hereditary presacral teratoma. J Pediatr Surg 1974; 9:691–7. 70. Lynch SA, Bond P, Copp AJ et al. A gene for autosomal dominant sacral agenesis maps to the holoprosencephaly region at 7q36. Nature Genet 1995; 11:93–5. 71. Froberg MK, Brown RE, Maylock J, Poling E. In utero development of a mediastinal teratoma: a second trimester event. Prenat Diag 1994; 14(9):884–7. 72. Spicer RD. Neonatal soft tissue tumours. Br J Cancer 1992; (Suppl 18)S80–83. 73. Douglass E, Valentine M, Etubanas E et al. Speciﬁc

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71 Hemangiomas and vascular malformations PREM PURI AND LASZLO NEMETH

INTRODUCTION Hemangiomas were ﬁrst described by McKenzie in 1864.1 Presently, the term ‘hemangioma’ is used to describe a variety of vascular lesions with different etiologies and natural histories. They are the most prevalent congenital lesions in infants and children.2–13 The incidence of hemangiomas has been estimated to be 0.54 per 1000 live births.3 Of all newborns, Up to 75% have a vascular mark present at birth.7,8,14,15 Most of these lesions disappear without treatment. Girls are affected two to three times more often than boys.4–6,16 Functional complications reportedly occur in 20% of all hemangiomas and lifethreatening complications develop in 3–5% of children with hemangioma.3

PATHOLOGY Sweetser in 1921 was the ﬁrst to differentiate the capillary hemangiomas of infancy as a distinct entity from the cavernous lesions.17 Traditionally, hemangiomas have been classiﬁed as capillary, cavernous or mixed, depending on the size of the vessels involved.18 Histologically capillary hemangiomas are composed of small, thinwalled vessels of capillary size that are lined by a single layer of ﬂattened or plump endothelial cells usually surrounded by a discontinuous layer of pericytes, and reticular ﬁbers. These pericytes produce transforming growth factor β (TGF-β), which controls the growth rate of endothelial cells.3 Recently it has been shown that not only (TGF-β), but also vascular endothelial growth factor and basic ﬁbroblast growth factor are expressed in pericytes.19 These growth factors express throughout the hemangioma lifecycle and play an important role in proliferative and early involuting phases. Furthermore type IV collagen and the beta chain of laminin and perlecan were detected in the basement membranes in all phases. Collagen types I, III, and IV were present in basal membranes throughout the phases and with increasing

density in the stromal areas with involution, although type I collagen was less prominent during the proliferative phase. In cavernous hemangiomas, tangles of thinwalled cavernous vessels and spaces are seen, which are separated by a scanty connective tissue stoma. Mixed hemangiomas show histologic features of both types. The pathogenesis and natural history of hemangiomas are poorly understood but are comparable to the developing blood supply of an embryonic limb bud. Instead of the usual orderly development of arteries, veins and capillaries, an arteriovenous ﬁstula persists in the hemangioma.20 Thus a typical capillary angioma represents a localized arteriovenous ﬁstula. Controversy exists as to whether hemangiomas are hamartomas or true neoplasms;21 the majority opinion is in favor of considering them as hamartomas.1,4,5,22,23 Even this concept has been challenged by Mulleken,24,25 who is of the opinion that ‘hamartoma’ is too general a term which could be applied to any lesion that histologically shows proliferation of cells normally present in a tissue. By deﬁning the cellular features of cutaneous vascular lesions in relation to their history and clinical outcome, he has suggested that childhood vascular lesions should be classiﬁed as hemangiomas or vascular malformations. The underlying pathology of hemangiomas and vascular malformations is similar: both represent mesodermal rests of vasoformative tissue from which the vascular tree develops.16 Hemangiomas contain a signiﬁcantly higher number of calcitonin gene-related peptide (CGRP), substance P, and Met-enkephalin-positive ﬁbers. The most signiﬁcant rise in number is that of CGRP-positive ﬁbers. This neuropeptide is a known mitogen, which could be responsible for the growth of the hemangiomatous blood vessels. Substance P is a nociceptive neurotransmitter and its presence can explain the pain which often accompanies even tiny intramuscular hemangiomas.26

Hemangiomas Hemangiomas are lesions that grow rapidly during the ﬁrst few months of life and then begin to involute.

664 Hemangiomas and vascular malformations

During the growth period there is increased endothelial cell activity demonstrable by hyperplasia and incorporation of [3H] thymidine into the cells. There is also an increase in the number of mast cells during this period. In this involution phase ﬁbrosis and fat deposition is seen with an absence of [3H] thymidine-labelled endothelial cells.18,25

Box 71.1 Classiﬁcation of vascular lesions in infants and children (From Mulliken & Glowacki)25 Hemangiomas Proliferating phase Involuting phase

Vascular malformations Capillary Venous Arterial Lymphatic Fistulas

Vascular malformations These grow pari pasu with the child, fail to regress, show no evidence of endothelial mitotic activity and are not hypercellular. They are lined by ﬂat, mature, endothelium, demonstrate no [3H] thymidine incorporation and have normal ultrastructural characteristics. Any combination of capillary, arterial, venous and lymphatic elements may exist in these lesions.18,20,26,27 Port wine stains, traditionally classiﬁed as hemangiomas should be included under vascular malformations. They have been shown to be derived from a progressive ectasia of the superﬁcial vascular plexus and there is a marked decrease in the sympathetic autonomous nerves associated with these vessels. This leads to failure in regulation of blood ﬂow and this is the basis of progressive vascular ectasia in port wine stains.22 Another interesting ﬁnding in strawberry hemangiomas is an abnormally high population of cytosol-speciﬁc estrogen binding receptors.28 Both hemangiomas and vascular malformations are benign lesions. Malignant transformation is exceedingly rare, but hemangiosarcoma is reported to occur after irradiation of a hemangioma.

CLINICAL FEATURES AND CLASSIFICATION The clinical features produced by a hemangioma will depend on the type of lesion, its site of occurrence and the development of complications. The traditional classiﬁcation into capillary, cavernous and mixed hemangiomas is obsolete; it has no predictive value in the natural history of the lesion. Edgerton, in 1976, proposed a logical classiﬁcation based upon their appearance, anatomical features and physiology.3,23,29 Although this has been superseded by the classiﬁcation based on endothelial characteristics by Mulliken, from a clinical point of view Edgerton’s classiﬁcation is more useful (Box 71.1 & Table 71.1).25,29 A recent revision of Mulliken and Glowacki’s classiﬁcation has broadened the category of vascular tumors of infancy to include hemangiopericytoma, pyogenic granuloma, tufted angioma, and kaposiform hemangioendothelioma.30

Type 1 – Neonatal staining These marks are present at birth, appearing as light pink staining patterns on the midline base of the neck and

Table 71.1 Classiﬁcation of hemangioma (From Edgerton)15,29 Type

Characteristic

1

Neonatal staining

2

Intradermal capillary hemangioma A. Salmon patch B. Port wine stain C. Spider angioma

3

Juvenile capillary hemangioma A. Strawberry mark B. Strawberry capillary hemangioma C. Capillary cavernous hemangioma

4

Arteriovenous ﬁstulas A. Arterial hemangioma B. Hemangiomatous goganism

5

Cirsoid angioma (Race mose aneurysm)

near the glabella. They almost always disappear within a few months of birth, therefore, no therapy is necessary.

Type 2 – Intradermal capillary hemangiomas These are usually present at birth and are located in the deep dermal layers; their patterns correspond to the skin distribution of sensory nerves in the area: • Salmon patch: a variety of intradermal capillary hemangioma. Lesions vary from light pink to rust in color and blanche on pressure. They are most frequently found on the nape of the neck, eyelids, glabella and mid-forehead. They remain constant over a period of many years. • Port wine stain (Fig. 71.1): deeper in color than the salmon patch, these usually involve a larger surface area. The port wine stain does not regress spontaneously; treatment options are laser therapy or surgical excision with skin grafting. • Spider angiomata: These lesions are small and multiple. They consist of a small central dermal arteriole with a network of capillaries radiating out in a stellate fashion. They appear at 3 or 4 years of age and take several years to regress. Deﬁnite therapy consists of applications of ﬁne-needle diathermy cautery to the central arteriole.

Hemangiomas in special sites 665

Figure 71.1 Port wine stain involving right side of forehead and face in an infant

Type 3 – Juvenile capillary hemangiomas This is the only type of hemangioma in which spontaneous resolution occurs: • Strawberry marks: pale halos of skin surrounding radiatory telangiectasias. Since spontaneous resolution is the rule, only observation and reassurance is enough. • Strawberry capillary hemangiomas (Fig. 71.2): the most common type. They are present at birth or appear as tiny red spots in the ﬁrst few days of life. The lesions are bright red or purple in color with well-deﬁned margins, are lobulated, and blanche with pressure. Spontaneous regression occurs in most cases. • Capillary cavernous hemangiomas (Fig. 71.3): These are poorly deﬁned hemangiomas which involve

Figure 71.3 Hemangioma with capillary and cavernous components

cutaneous vessels and occasionally, larger venous sinusoids. They are easily reduced by digital pressure. Spontaneous regression usually takes place but is never complete. Other therapeutic options are dealt with in the section on treatment.

Type 4 – Arteriovenous ﬁstulas These are found almost exclusively in adults, and have a predilection for the lips and perioral skin.

Type 5 – Cirsoid angioma This is primarily a venous hemangioma and is uncommon. Surgical excision is the preferred treatment.

HEMANGIOMAS IN SPECIAL SITES Head and neck Hemangiomas have a predilection towards the head and neck region – 38–60% occur in this region4,6,9 – though this is only one-seventh of the total body surface area.

PAROTID HEMANGIOMAS Hemangiomas are the most common tumor in the parotid region. They account for 50% of all parotid tumors in infants compared with that of only 2% in adults.31 Compression therapy has been advocated as an alternative to conservative management.32

ORBITAL HEMANGIOMAS (Fig. 71.4)

Figure 71.2 Typical strawberry capillary hemangioma

Orbital hemangiomas occur in approximately one in 200 live births.10 Upper lid hemangiomas can cause occlusion or refractive amblyopia.33 The incidence of amblyopia

666 Hemangiomas and vascular malformations

diagnosis of intracranial hemangiomas followed by complete surgical resection postnatally may yield excellent results in these patients.40

Thoracic hemangiomas Intrathoracic hemangiomas are rare and when present, the symptoms are unusual. One case presented with pulmonary hypertension,41 others as pulmonary pseudocyst,42 or respiratory distress and hyperinﬂation of one lung.43

Hepatic hemangiomas

Figure 71.4 Hemangioma of the face involving the right eyelid, parotid region and lower lip and chin

and anisometropia were 43% and 68%, respectively.34,35 Intralesional steroid injections have been successfully used in such cases33 but eyelid necrosis33 and depigmentation can complicate such therapy.

Patients with hemangiomas of the liver usually present with hepatomegaly and congestive cardiac failure.44 The greatest risk is in the ﬁrst 6 months of life, when treated medically alone, congestive cardiac failure in such situations has a mortality of around 70%. Early identiﬁcation of these lesions is important. Scintigraphy using 99m Tc-labelled red cells offers an accurate method of identiﬁcation of these lesions.45 Multinodular hemangiomatosis of the liver is a clinical syndrome, the features of which are hepatomegaly, congestive cardiac failure and cutaneous hemangioma. This lesion may cause thrombocytopenia and consumptive coagulopathy.7,46

LARYNGEAL HEMANGIOMAS The most common visceral hemangiomas are laryngeal hemangiomas.20 Of all the clinical manifestations of hemangiomas, airway obstruction secondary to a subglottic hemangioma is the most life-threatening symptom. The true incidence of subglottic hemangiomas is not known. Hollinger described 846 cases of congenital laryngeal anomalies, of which 13 were subglottic hemangiomas.36 Symptoms are usually present at birth, however 85–90% of affected children develop symptoms within the ﬁrst 3 months of life. Of infants with subglottic hemangiomas, 50% will have associated cutaneous hemangiomas.37 Conﬁrmation of diagnosis usually needs a laryngoscopy and bronchoscopy and most symptomatic cases will need a tracheostomy. Intralesional steroid injection has been used successfully.38

Gastrointestinal hemangiomas These rare lesions may present as part of the blue rubber bleb nevus syndrome47 or with massive intestinal bleeding from isolated colonic hemangioma.48,49

Umbilical and placental hemangiomas These lesions are extremely rare. Umbilical hemangiomas may be diagnosed by antenatal ultrasonography.44,50,51 If undetected this lesion can present with severe bleeding at birth.52 Fetal anemia from fetomaternal transfusion caused by placental hemangioma is a very unusual presentation.53

COMPLICATIONS OF HEMANGIOMAS INTRACRANIAL HEMANGIOMAS Cutaneous hemangiomas may have associated intracranial angiomatous malformation and arteriovenous malformations of the great vein of Galen.15 In the newborn, such cases present with congestive cardiac failure, whereas in older children the presenting symptoms may include headache, hydrocephalus, focal neurologic signs or subarachnoid hemorrhage.7 An unusual case of Von-Hippel Lindau disease characterized by almost total replacement of the spinal cord and medulla by capillary hemangioblastoma has been reported.39 Early prenatal

The minor complications of hemangiomas are ulceration, infection and bleeding of cutaneous hemangiomas (Fig. 71.5). Perineal hemangiomas are more prone to develop these complications; treatment by conservative measures alone is difﬁcult and is associated with a high morbidity rate. Laser therapy has been used successfully in such cases.54 The life-threatening complications of hemangiomas are the development of congestive cardiac failure and Kasabach-Merritt syndrome.

Investigation 667

Benign neonatal hemangiomatosis In benign neonatal hemangiomatosis (BNH), there are multiple skin hemangiomas without visceral involvement. They usually follow a benign course,17 but in some cases the skin lesions do not regress and new ones appear.59

Diffuse neonatal hemangiomatosis

Figure 71.5 Hemangioma over the right scapula with central ulceration, infection and bleeding

Congestive cardiac failure is a complication of hepatic hemangiomas2,45 and giant cutaneous hemangiomas7,55,56 occur as a result of arteriovenous shunting leading to a high output state. The mortality in congestive cardiac failure from medical treatment alone is high,2 therefore other therapeutic measures designed to aggressively treat the hemangioma should be instituted at the earliest opportunity.

Kasabach-Merritt syndrome This syndrome, ﬁrst described by Kasabach and Merritt in 1940,57 features platelet trapping by hemangiomas causing thrombocytopenia and consumptive coagulopathy. The sequestration of platelets in the hemangiomas in such cases has been conﬁrmed by investigations demonstrating increased uptake of chromium51 tagged platelets within the hemangioma. It is now clear that most patients with the Kasabach-Merritt phenomenon do not have typical hemangiomas but instead have kaposiform hemangioendotheliomas or tufted angiomas.7 The exact trigger mechanism which initiates platelet trapping is not fully understood.24 Two-thirds of these cases present in the ﬁrst 3 months of life during active growth of the lesion; only 12% of cases occur after 1 year of age.58 The mortality rate is high, at about 40%. Initial treatment consists of heparin, aspirin, fresh blood, platelet transfusion and steroids. If the infant becomes stable on this regime, surgical excision should be attempted. If surgery is not feasible, long-term treatment with steroids, compression therapy or embolization of the feeder vessels should be attempted.55

HEMANGIOMA-ASSOCIATED SYNDROMES There are a number of syndromes involving various combinations of cutaneous and visceral hemangiomas.

Diffuse neonatal hemangiomatosis (DNH) is a rare entity in which cutaneous and visceral hemangiomas coexist.17,60 The outlook may be improved by early diagnosis, therefore, any infant presenting with multiple skin hemangiomas should be investigated for visceral involvement.61 Magnetic resonance imaging can be very useful in such cases.62 Unusual presentation of DNH with infantile spasms has been reported;63 high-dose corticosteroids can be effective treatment in DNH.59 Recently interferon alpha-2a (INF-α2a) has been successfully used in the treatment of DNH.64

Sturge-Weber syndrome This syndrome consists of port wine-type malformations distributed along the ophthalmic division of the trigeminal nerve and hemangiomas of the meninges and choroid plexus, on one side of the body. This can lead to cortical damage, convulsions, mental defects, hemiparesis and hemianosmia affecting the contralateral side of the body.

Blue rubber bleb nevus syndrome This is an autosomal dominant syndrome featuring multiple cutaneous hemangiomas with similar lesions in the gastrointestinal tract.23,47

Von Hippel-Lindau syndrome Angiomatous changes in the retina and cerebellum in association with hemangiomas, cysts or tumors of other organs are the features of this syndrome.65

INVESTIGATION Most hemangiomas are diagnosed clinically and do not warrant additional investigations. When visceral hemangiomas are suspected, computerized axial tomography,66 magnetic resonance imaging,62 and lung scintigraphy41 are useful in making a diagnosis. But ultrasonography is the ﬁrst line of investigation in the search for visceral hemangiomas; with the increasing use of

668 Hemangiomas and vascular malformations

these investigative tools in the antenatal period, more and more hemangiomas are diagnosed antenatally.51,52,57,67 Hepatic hemangiomas have been accurately diagnosed using scintigraphy with Tc99-labelled red cells;45 this is helpful to evaluate vascularization and plan therapy. It may be used selectively for detection and follow-up of maxillofascial hemangioma.68 Indium platelet scintigraphy has been successfully used to demonstrate platelet trapping in Kasabach-Merritt syndrome.69 Complications in hemangiomas such as Kasabach-Merritt syndrome and congestive cardiac failure will need additional appropriate investigation to be performed.

MANAGEMENT In deciding treatment of hemangiomas and vascular malformations, four factors need to be considered: (1) natural history of the lesion, (2) site, (3) likelihood of developing function-threatening or life-threatening complications, and (4) therapeutic options available.

NATURAL HISTORY The tendency of hemangiomas to spontaneously regress was ﬁrst emphasized by Lister in 1938.71 Hemangiomas present at birth show a proliferative phase in the ﬁrst 6–9 months, followed by a stable period of 6–12 months. Slow spontaneous involution takes place in some cases, starting at the center and completing in 1–7 years.2,27 Involution takes place in all cases; this is perfect in 50% of cases, but residual skin changes are left behind in 25% of cases. The remaining 25% undergo an alarming course, invade skin and modify bone growth due to their mass effect. They also regress, however various skin changes and functional impairment remains depending on the site of the lesion. The importance of site and complication in the management has already been dealt with in this chapter.

TREATMENT OPTIONS Conservative Spontaneous involution in the vast majority of cases forms the basis of this expectant approach. Parents should be reassured and the natural history of such lesions should be explained to them. In the 20% of cases that develop, function-threatening complications and 3–5% of cases that go on to develop life-threatening complications, this approach should be abandoned.

MEDICAL TREATMENT Corticosteroids When treatment is needed for hemangiomas, oral corticosteroids should be considered as the ﬁrst option. The recommended dosage is prednisolone 2–3 mg/kg/day.27 The mechanism of action of these drugs is not fully understood. In adrenalectomized rats, corticosteroids increase vascular sensitivity to circulating vasoconstrictors;23 they may also have an effect on precapillary sphincters causing constriction.27 Recent experiments have shown that there are estradiol receptors in hemangioma tissues. Steroids may occupy these sites and block the uptake of estradiol, which may have a supporting function in hemangiomas.27 Growing strawberry hemangiomas may be more responsive to treatment than stable hemangiomas. Therapy should be continued for 6–8 weeks; response rates ranging from 45% to 90% have been quoted.2,27 It may be necessary to repeat the course several times in the event of rebound growth. When used in infants with alarming hemangiomas of infancy, 30% of cases had excellent results, 30% were total failures and 40% had equivocal results.14 All the usual precautions to using steroid therapy should be adhered to and side effects are usually reversible with cessation of treatment. Early immunologic damage however has been reported.72

Antiﬁbrinolytic agents These agents are not commonly used in treating hemangiomas. Regression in cavernous hemangiomas is thought to be related to local clot formation and subsequent ﬁbrosis. Ongoing ﬁbrinolysis may inhibit this natural resolution and therefore, administration of an antiﬁbrinolytic agent should prevent ﬁbrinolysis and promote resolution. There have been several reports of improvement in hemangiomas with the use of antiﬁbrinolytic therapy.27,69 Ideally these agents should be used only in the presence of elevated ﬁbrinogen degradation products in blood. The agents available for clinical use are epsilon amino caproic acid and tranexamic acid.

Interferon alpha Although still used only in few centers, INF-α has been shown to inhibit growth of massive hemangiomas.2,73 This may be related to its effect on endogenous cortisol secretion. Based on diurnal cortisol activity, INF-α is given at 3 million u/m2/day intravenously in the evenings during a 4–9-week period. Both INF-α2a and INF-α2b have been successfully used to produce regression of lifethreatening corticosteroid-resistant hemangiomas of infancy.7, 73,74 The interval between the administration of

Laser treatment 669

INF-α and the response to the treatment ranges from a few weeks to several months. Common side effects include irritability, neutropenia, and abnormalities of liver enzymes. A particularly worrisome side effect, spastic diplegia, has been reported in as much as 20% of patients.7

New drugs New steroids which are angio inhibiting have been developed and their results in clinical trials are expected in the near future.7,75

Intralesional steroid therapy Long-acting steroids dexamethasure and triamcinolone have been effective as topical injections in hemangioma.17 A short general anesthesia is needed because multiple punctures are painful. The response rate is good in 50% of cases. It has been used in periorbital hemangiomas with success, but eyelid depigmentation,29 necrosis and subcutaneous fat atrophy76 have been reported when used on the upper eye lid.

can be signiﬁcant morbidity associated with resection of large lesions, depending on the location and amount of intraoperative hemorrhage. Surgical options include: (1) arterial ligation or (2) resection.

Arterial ligation Circumferential ligation of afferent and efferent vessels as sole therapy for large lesions has been reported. In one series there was an 86% cure rate when arterial ligation was combined with steroid therapy in complex hemangiomas.2 The disadvantages of arterial ligation are regrowth of hemangiomas due to development of collaterals and the inability to use the vessels for embolization if necessary.27

Resection The difﬁculty with resection of hemangiomas depends on the site and size of the lesions. The use of hypothermia and cardiopulmonary bypass for large sacral hemangiomas,78 low tracheal hemangiomas,79 and hepatic hemangiomas80 has been described.

Therapeutic embolization LASER TREATMENT Superselective angiography and embolization have been used as a deﬁnitive or preoperative adjunct in the treatment of cutaneous and deep hemangiomas in adults. Their use in children has lagged, because of the increased technical challenge created by the small vessels and by contrast and ﬂuid limitations. Success in infants with this form of treatment is increasingly reported, however, especially in inaccessible lesions, and in function and lifethreatening situations.25,77 Various agents used for embolization include autologous blood clots or muscle, methyl acrylate, steel balls and silicone spheres. Their mechanism of action apparently involves thrombi formation around the embolic material with propagation into the distal branches of the vessels.4 Hemangiomas respond dramatically with arrest of the proliferative phase and shrinking of the mass. The complications when used in hemangiomas of the head and neck include back ﬂow of particles into the internal carotid artery, leading to cerebrovascular accidents and into branches of external carotid artery, leading to tissue damage and skin necrosis.27 Death following attempted embolization of arteriovenous malformations of the vein of Galen has been reported.27

SURGERY Surgery is reserved for the few cutaneous lesions that fail to resolve or large lesions that threaten function. There

The increased effectiveness of the laser for the treatment of vascular lesions is due to its ability to selectively destroy cutaneous blood vessels. The degree of selectivity depends on the various laser parameters that are inherent in each type of laser.

CO2 laser The CO2 laser produces intense light in the invisible infrared spectrum and is absorbed by water, which makes up 75–90% of most biological tissue. This water vaporizes at the focal length of the beam. The advantages of a CO2 laser are that it cuts like a knife and seals small vessels and destroys small nerve endings. Scarring is similar to that of conventional surgery but causes less pain and edema. The CO2 laser was reported to be successful in the treatment of port wine stains which failed to respond to argon or continuous wave dye laser therapy.81

Argon laser Successful use of the argon laser in the treatment of port wine stains and capillary lesions has been a signiﬁcant development but the response in children younger than 10–12 years is poor, with markedly decreased fading and an increased incidence of scarring.16 Argon light has a

670 Hemangiomas and vascular malformations

wave length of 4880–5145 A. The hemoglobin pigment is highly absorptive in this range; argon light is transformed into heat within the erythrocyte to produce vessel thrombosis. Skin appendages are spared and healing takes place much as with a superﬁcial burn.4 In many centers a ‘test spot’ is performed to assess the response of an individual port wine stain to argon laser therapy. Laser power, which causes whitening of the spot represents the smallest effective laser power. This is used for remainder of the lesion.82 Apart from its use in port wine stains, the argon laser is used effectively in ulcerated anogenital hemangiomas in infants.54

type of therapy to be effective hemangiomas have to be accessible, circumferential pressure is desirable, the pressure should be applied preferably 24 hours a day, the pressure should be exerted over the whole hemangioma and compliance from the parents is essential.92 It has been speculated that prolonged compression of vessels might cause narrowing of their lumen, which may provoke stasis of blood ﬂow and eventual thrombosis. Their successful use in parotid hemangiomas has been reported.93 The advantage of this method of treatment is that it is safe, simple and inexpensive.

Radiotherapy Nd:YAG laser The Nd:YAG laser has low tissue absorption, permitting a deep penetration and coagulation effect. The volume of radiant energy distribution is 100–1000 times greater than for a CO2 laser of equal spot size. Because of the large treatment volume, one cannot judge the amount of destruction accurately. There is a greater chance of transmural injury to the underlying structures. YAG laser in combination with interluminal injection of steroids has been used successfully in periorbital hemangiomas in infants.83 In a comparative study between the results of treatment with argon and Nd:YAG lasers, the argon laser gave good results when used on small, ﬂat lesions. The Nd:YAG laser is superior in reducing large, bulky lesions. On the basis that results of treatment are better in small lesions and because lesions are smaller when infants are only a few weeks old, a plea is made for earlier treatment of hemangiomas in infants.84

Pulsed dye laser There are increasing reports of successful treatment of hemangiomas with ﬂashlamp-pumped dye laser.85-87 Because of the limited depth of penetration (approximately 1 mm), this laser works better for thin, superﬁcial hemangiomas than for those that are destined to be both superﬁcial and deep. This method of treatment has been successfully used for the treatment of periorbital port wine stains88 and for cutaneous hemangiomas.89 The results are better in younger children and superﬁcial lesions.90,91 This is a safe and effective method of treatment with a low incidence of scarring and pigmentary alterations.

OTHER MEASURES External compression In 1961, Wallerstern reported successful management of a cavernous hemangioma by pressure bandage. For this

Radiotherapy is no longer advocated in the treatment of hemangiomas because of the risk of development of malignancy in the long term. In a follow-up study of a cohort of 14 647 individuals younger than 18 months old who were irradiated for skin hemangioma between the years 1920 and 1959, among them there were 56 cases of breast cancer, 14 of thyroid cancer, 16 brain tumors and eight tumors of bone and soft tissues. A statistically signiﬁcant positive dose–response relationship was found in thyroid cancer and in tumors of bone and soft tissues. For breast cancer and brain tumors, no signiﬁcant dose–response relationship could be found.94 Cryotherapy, which is popular in some countries in Europe and South America, has been reported to have favorable results with superﬁcial hemangiomas but concern about potential scarring has limited its use in North America.7,95

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angioma in an infant. J Comput Assist Tomogr 1991; 15:163–5. Paltiel HJ, Burrows PE, Kozakewich HP et al. Soft-tissue vascular anomalies: utility of the US for diagnosis. Radiology 2000; 214:747–54. Fiore F, Califano L, Cortese A, Zupi A. Haemangioma of the maxillofacial area. Usefulness of 99Tcm-labelled red cell scintigraphy. Nucl Med Commun 1993; 14:378–83. Shulkin BL, Argenta LC, Cho KJ. Kasabuck-Merritt syndrome: Treatment with Epsilon-Amino caproic acid and assessment by Indium III platelet scintigraphy. J Paediatr 1990; 117:746–9. Akyuz C, Yaris N, Kutluk MT et al. Management of cutaneous hemangiomas: a retrospective analysis of 1109 cases and comparison of conventional dose prednisolone with high-dose methiprednisolone therapy. Pediatr Hematol Oncol 2001; 18(1):47–55. Lister WA. Natural history of strawberry naevi. Lancet 1938; 1:1429–34. Gunn T, Reece ER, Metrukos K et al. Depressed T cells following neonatal steroid treatment. Pediatrics 1981; 67:61–7. White CW, Walfe SJ, Koras DN. Treatment of childhood angiomas disease with recombinant interferon alfa 24. J Pediatr 1991; 118:59–66. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening haemangiomas of infancy. N Engl J Med 1992; 326:1456–63. Ingben D, Fujitu T, Kishimoto S et al. Synthetic analogues of fumagillin that inhibit angiogenesis and supress tumour growth. Nature 1990; 348:555–7. Townsend LM, Buckley EG. Linear subcutaneous fat atrophy after a single contorcosteroid injection for ocular adenexal hemangioma. Am J Opthalmol 1990; 109:102–3. Sato Y, Freg EE, Kisker CT et al. Embolization therapy in the management of infantile hemangioma with Kasaback Merritt Syndrome. Paediatr Radiol 1987; 17:503–4. Milligan NS, Edwards JC, Monro JL et al. Excision of giant haemangioma in the newborn using hypothermia and cardio pulmonary bypass. Anesthesia 1988; 40:875–8. Franks R, Rothera M. Cardio pulmonary bypass for resection of low tracheal hemangioma. Arch Dis Child 1990 65:630–32. Renne RD, Ashcraft KW, Hodder TM et al. Hepatic hemangioma: resection using hypothermic circulatory arrest in the newborn. J Pediatr Surg 1988 23:924–6. Lannigan SW, Cotterie JA. The treatment of port wine stain with carbondioxide laser. Br J Dermatol 1990; 123:229–35. Carruth JAS, Shakesperare P. Towards ideal treatment for the port wine stain with the argon laser: better prediction and an ‘optimal’ technique. Lasers Surg Med 1986; 6:2–4. Apfelberg DB, Maser MR, White DN et al. Beneﬁts of contact and non contact YAG laser for periorbital hemangiomas. Ann Plast Surg 1990; 24:397–408.

References 673 84. Achaeur BM, Victoria M, Vander Kam RN. Capillary hemangioma (strawberry mark) of infancy: comparison of Argon and ND:YAG laser treatment. Plast Reconstr Surg 1989; 84:60–70. 85. Garden JM, Polla LL, Tan OT. The treatment of port wine stains by the pulsed dye laser. Arch Dermatol 1988; 124:889–96. 86. Reyes BA, Geronemus R. Treatment of port wine stain during childhood with the ﬂash lamp – pumped pulsed dye laser. J Am Acad Dermatol 1990; 23:1142–8. 87. Achauer BM, Vander Kam VM, Miller SR. Clinical experience with the pulsed-dye laser in the treatment of capillary malformations (port wine stain): a preliminary report. Ann Plast Surg 1990 25:344–52. 88. Holy A, Geronemus RG. Treatment of periorbital port wine stains with the ﬂashlamp-pumped dye laser. Arch Ophthalmol 1992; 110:793–7. 89. Garden JM, Bakus AD, Paller AS. Treatment of cutaneous haemangiomas with ﬂashlamp-pumped dye laser. Prospective analysis. J Pediatr 1992; 120:555–60.

90. Strauss RP, Resnicke SD. Pulse dye laser therapy for port wine stains in children: psychosocial and ethical issues. J Pediatr 1993; 122:505–10. 91. Goldman MP, Fitzpatrick RE, Ruiz-Esparza J. Treatment of port wine stains (capillary malformation) with the ﬂashlamp-pumped pulsed dye laser. J Pediatr 1993; 122:71–7. 92. Stingel S. Giant hemangioma: treatment with intermittent pneumatic compression. J Pediatr Surg 1987; 1:7–10. 93. Totsuka Y, Fukuda H, Tomita K. Compression therapy for parotid haemangioma in infants: a report of three cases. J Craniomaxillofac Surg 1988; 16:366–70. 94. Furst CJ, Lundell M, Holm LE. Tumours after radiotherapy for skin hemangioma in childhood. A case control study. Acta Oncologica 1990; 29:557–62. 95. Cremer HJ, Djawari D. Frühtherapie der kutanen Hämangiome mit der Kontaktkryochirugie. Chir Prax 1995; 49:295–312.

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72 Congenital nevi BRUCE S. BAUER AND JULIA CORCORAN

INTRODUCTION

Congenital melanocytic nevi

Congenital cutaneous lesions are common presenting problems in the practice of pediatric surgery. The pigmented lesions can be subdivided easily into those of vascular origin vs those of melanocytic and dermal origin. Commonly these latter lesions are termed ‘moles’ or ‘nevi.’ Although the bulk of these lesions are small and benign, some cover large portions of the body or can be in conspicuous locations presenting challenging reconstructive problems. Furthermore, their potential for malignant degeneration causes anxiety for the parent, primary care physician and surgeon alike. The goal of this chapter is to classify the more common cutaneous lesions, review the pathophysiology and natural history, summarize the risk of malignant degeneration and provide a rational approach to treatment. Indications for complex reconstructive procedures and novel techniques will also be discussed.

These lesions are composed of nevus cells of melanocytic origin, which vary in the amount of pigment they carry. At birth, these lesions can be quite faint and seem to appear over the ﬁrst year of life as they become more pigmented. Their color can range from a pale tan to a deep bluish black. On physical examination, they have increased skin markings compared to the surrounding normal skin and may have coarse, terminal hairs. Examination of congenital melanocytic nevi (CMN) with the skin under tension and loupe magniﬁcation or with a dermatoscope reveals small pigment granules in the periphery of the lesion, which are speciﬁc to small congenital nevi.2 On occasion, peripheral satellite lesions may be present. Over time, the surface of these lesions can change and become more verrucous or irregular and the pigmentation may become darker. Erosion and breakdown can occur as well. These changes are not uncommon at or near puberty and do not indicate necessarily a malignant change in the nevus. Embryologically, these lesions are ectopic rests of nevus cells. Melanoblasts, the precursors to melanocytes, migrate from the neural crest to the skin, mucus membranes, eyes, mesentary, chromafﬁn system and meninges, where they differentiate into dendritic melanocytes. When a disturbance in this migration and differentiation occurs, the result is an ectopic population of nevus cells. Nevus cells are melanocytes that differ from ordinary melanocytes histologically by being arranged in nests or clusters, having a rounded rather than dendritic shape and tending to keep their pigment in their cytoplasm rather than transferring it to surrounding keratinocytes.3 Histologically, efforts have been made to identify characteristics speciﬁc to congenital melanocytic nevi in contrast to those acquired later in life. A reliable microscopic differentiation between the two could help determine the true rate of melanoma in association with these lesions. Nevus cells when found within the eccrine ducts or glands, follicular epithelium, and blood vessels

CONGENITAL NEVI Congenital nevi are those cutaneous lesions apparent at birth or that become apparent prior to 1 year of age. The word ‘nevus’ is a generic term best deﬁned as a hamartoma that is an overgrowth of mature cells normally present in the affected part, but with disorganization and often with one element predominating.1 This broad deﬁnition applies to a variety of cutaneous lesions that can be congenital or acquired. The majority of congenital lesions are melanocytic in nature, including common congenital melanocytic nevi, Nevi of Ota, Nevi of Ito, nevi spilus, café au lait spots and Mongolian spots. Other non-melanotic lesions such as sebaceous nevi (of Jadassohn), neural nevi and epidermal nevi can be present at birth. Several other nevi have a propensity to appear in childhood and should be discussed here including intradermal nevi, blue nevi and Spitz nevi.

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are speciﬁc for congenital melanocytic nevus but not all CMN will demonstrate these ﬁndings.4 In large congenital melanocytic nevi, nevus cells have been found in underlying subcutaneous tissue, fascia and musculature. Clinically, congenital melanocytic nevi are classiﬁed as small, intermediate or giant based on their size, but this classiﬁcation actually carries signiﬁcance with respect to potential development of malignancy and the surgical technique and timing of their removal. Small nevi are those < 1.5 cm in diameter and present in approximately one in 100 children at birth.5 Large or giant nevi are > 20 cm in diameter and occur in approximately one in 20 000 births. Intermediate lesions lie between 1.5 cm and 20 cm and have a quoted incidence of six per 1000.6 These concrete divisions are deceiving, however, being based on body surface area in adulthood. Using body surface area changes between infancy and adulthood, others have suggested that a 9 cm lesion on the head and neck of an infant or 6 cm on the body will become giant nevi. Other deﬁnitions include lesions > 2% of total body surface area.7

SMALL CONGENITAL MELANOCYTIC NEVI Most congenital pigmented nevi can be categorized as small and are excised easily in a single procedure. The lifetime risk for melanoma in these patients has been quoted to occur in 4.9 out of 100 people when the patient provides the history that the lesion is congenital and in 0.8–2.6 out of 100 people when determined by histologic criteria of ﬁndings consistent with CMN in melanoma specimens.8 Practically speaking, however, the risk of melanoma before puberty is nil, being quoted as one in 200 000 individuals. For this reason many pediatricians, pediatric dermatologists and pediatric surgeons defer the removal of these lesions to an age when excision can be performed under local anesthesia in the ofﬁce, eliminating the risks associated with general anesthesia. Clearly, some lesions lie in cosmetically sensitive areas and for the psychological beneﬁt of the child should be removed earlier, even if general anesthesia is required. From a practical point of view, these procedures are best done either before the child starts toddling or just prior to school entrance. The stage in between these two ages is fraught with falls, scrapes, fear and lack of patient cooperation. The experience is better for the patient, parent and surgeon alike by avoiding elective nevus removal in the toddler. There is little beneﬁt to delaying surgery in those lesions, which because of their location, will likely require general anesthesia at any age.

LARGE CONGENITAL MELANOCYTIC NEVI The appearance of these dark, often hairy lesions over a large portion of a newborn infant’s face, trunk or

extremity is often devastating for parents who have been anxiously awaiting the birth of their child. Early consultation with a pediatric surgeon or pediatric dermatologist can help educate the family and decrease the stress of the situation by providing concise information about the nature of the nevus, its natural history and the options for its management. If presented in a compassionate manner, even the news of a multiplestage reconstruction over many years can be well accepted by the families. In 20 years of practice as an active pediatric plastic surgeon, the senior current author has developed treatment plans for the management of these lesions with the idea that esthetic and functional outcome are as important as removal of the nevus itself (see Figs 72.1–4). The immediate concern for the family and pediatrician is the potential for these patients to develop malignant melanoma. The literature estimates the risk of developing melanoma to range between 2–31%. The populations and numbers in these various studies explain the wide variance. In a retrospective study, Quaba and Wallace examined patients with CMN covering > 2% of the body surface area and found the melanoma risk to be 8.5% during the ﬁrst 15 years of life.9 Approximately 50% of malignancies that develop in large CMN do so in the ﬁrst 3 years, 60% by childhood and 70% by puberty. These numbers encourage the early removal of large lesions. A second concern with large CMN located over the cranium and spine, especially in an axial orientation, is the potential for neurocutaneous melanosis. Symptomatic neurocutaneous melanosis has been reported in the literature since the mid-19th century, characterized by mental retardation, hydrocephalus and/or seizures in the presence of large CMN. Post-mortem examinations found leptomeningeal melanosis and benign or malignant melanotic tumors of the central nervous system.10 Currently, asymptomatic patients can also be identiﬁed speciﬁcally by T1 shortening in magnetic resonance imaging. Foster et al. reported that 23% (10 of 43) of at risk patients had neurocutaneous melanoma found on MRI imaging.11 Only one patient developed neurologic sequelae of hypotonia, developmental delay and seizures during the 5-year follow-up period. The ﬁnding of asymptomatic neurocutaneous melanosis does not imply the development of neurologic symptoms, but portends a risk for later development of benign or malignant melanotic tumors. These ﬁndings may have implications for how aggressive the surgeon might be in debulking vs removing the entire cutaneous lesion, but further study is required to weigh the implications of these ﬁndings on to the chosen treatment protocol. As previously mentioned, nevus cells in the large lesions can be found in the underlying musculature, fascia and subcutaneous adipose. Knowing the depth of these cells and presence of leptomeningeal rest leads the reﬂective surgeon to conclude that surgical treatment is better

Large congenital melanocytic nevi 677

Figure 72.1, 2 This infant female was born with a giant pigmented nevus of the perineum and buttocks

Figure 72.3, 4 Using several different techniques, including ﬂaps and expansion, near total excision has been accomplished without loss of urinary or fecal continence and with a reasonably normal appearance

viewed as debulking of these lesions, rather than complete removal. Patches of darker color and raised areas often exist within these large CMN. The areas can represent neural nevus, which is a form of intradermal nevus with melanocytes that appear to be histologically like Schwann cells and with nerve organelles such as

Meissner’s and Pacinian corpuscles. The patches also can represent areas of local proliferation but do not necessarily behave in an aggressive manner. Histologic ﬁndings of low mitotic rate, lack of necrosis, evidence of maturation in the cell population and lack of high-grade nuclear atypia are clues to a benign course. Sometimes, the best description of these areas, however, is

678 Congenital nevi

melanocytic tumor of uncertain potential. Unusual areas such as these should be addressed earlier in the course of reconstruction.

Other congenital nevi BLUE NEVI Blue nevi are smooth, almost blue-black lesions, which can be present at birth but are more likely to appear during childhood and puberty. Frequently they are found on the extremities or the head. Females are affected more often than males. Two variants exist; common and cellular. The common blue nevus is relatively small, < 1 cm, sharply demarcated and dome-shaped. In this benign lesion, the melanocytes are dendritic in nature, within the dermis and possibly into the subcutaneous tissue, but the epidermis is normal. The cellular blue nevus tends to be larger, 1–3 cm, has less regular borders and is found frequently in the lumbosacrum. Melanocytes can be spindle-shaped and found in aggregates admixed with dendritic melanocytes. The lesions tend to be wider at the surface than at the base. There are reported cases of malignant degeneration within cellular blue nevi. For this reason, removal of blue nevi is recommended.

MONGOLIAN SPOTS Mongolian spots commonly appear as blue-gray macular discoloration resembling a bruise over the lumbosacral area of newborn infants, especially in darker skinned individuals. On occasion they can appear in atypical locations such as the upper thorax or extremities. Usually these benign lesions regress spontaneously by the age of 3–4 years, but can persist in unusual cases. Histologically, widely scattered dendritic melanocytes lie in the lower two-thirds of the dermis.13 No speciﬁc therapy is necessary, however laser treatments can obliterate persistent lesions.

NEVUS OF OTA/NEVUS OF ITO The Nevus of Ota and Nevus of Ito are macular, bluegray ﬁeld defects in the area of the ﬁrst and second branches of the trigeminal nerve or in the scapular, deltoid and supraclavicular area, respectively. The mucosae of the nose and mouth and the sclera, retina and conjunctiva can also be involved in the Nevus of Ota. These lesions are ﬁeld defects of dermal melanocytosis, like Mongolian spots. Unlike Mongolian spots, these lesions do not spontaneously regress and can become hyperpigmented during puberty. Usually these lesions are present at birth, but may become apparent around puberty, only rarely appearing during childhood; they are more common in females and more frequent in darker skinned individuals, being reported most frequently in Indian and Asian populations. In 10% of cases, the Nevus of Ota is bilateral, and these cases are

associated with extensive Mongolian spots. Histologically, the dermis contains elongated, dendritic melanocytes scattered among the collagen bundles, mostly located in the upper third of the reticular dermis; they can have raised areas within them that are indistinguishable from a blue nevus beneath the microscope. These lesions are considered to be benign, however reports of malignant changes exist in a few cases, with the tumors having the histologic appearance of a malignant or cellular blue nevus.13 Historically, cryosurgery and or non-selective destruction with CO2 laser was used with mixed esthetic results. Current laser technology allows the surgeon to take advantage of selective photothermolysis to direct the laser energy to destroy the melanocytes without bothering the overlying layers with excellent cosmetic results. Good results have been obtained with the Q-switched ruby laser, the Q-switched Alexandrite laser and the Q-switched Nd: YAG laser. Multiple treatments are required with each of these modalities.12

CAFÉ AU LAIT MACULES Café au lait macules are sharply demarcated areas of light tan to brown pigmentation which present in normal individuals or can be associated, when multiple, with syndromes such as neuroﬁbromatosis. Histologically, there is increased pigment in macromelanosomes within keratinocytes in the basal layer. These lesions are benign. If they are in cosmetically sensitive areas, laser ablation can be considered. Recurrence after laser therapy is commonly reported, but successful ablation has also been reported.13

NEVUS SPILUS Nevus spilus, also called speckled lentiginous nevus, also has light tan to brown macules with areas of speckling within it. The presence of the ‘speckles’ or freckles within it separate it clinically from the café au lait macule. Histologically, there is both increased pigment within the keratinocytes of the basal layer and an increased number of melanocytes as well. The speckles can be areas of freckling, congenital melanocytic nevi or blue nevi. Any suspicious areas within the lesion can be excised for biopsy as a nevocellular portion of the lesion may still carry a malignant potential. If the entire defect is in a cosmetically sensitive area, it can be removed surgically.

SEBACEOUS NEVI The sebaceous nevus was described by Jadassohn at the turn of the century. It presents as a waxy, hairless, yelloworange plaque, usually on the scalp, head or neck. It is a hamartoma of sebaceous glands (Fig. 72.5). The lesions tend to become more verrucous, itchy and excoriated. Sebaceous nevus syndrome is the combination of large sebaceous nevi of the scalp and face associated with developmental delay, seizures, ophthalmalogic and bony

Large congenital melanocytic nevi 679

tissue is limited, a decision must be made as to whether or not surgery is even warranted. To this end, several treatment options have been entertained including dermabrasion, curettage, laser and, at the other end of the spectrum, extensive excision and grafting with cultured skin or skin substitutes. Some brief comments are warranted before addressing our standard surgical options and approaches.

DERMABRASION, CURETTAGE, AND LASER TREATMENT

Figure 72.5 This sebaceous nevus is classic in appearance and location. Clinically these lesions are signiﬁcant for a 15–20% chance of development of basal cell carcinoma in the teenage years

abnormalities. Removal is recommended for these lesions because of a well-documented 15–20% risk of malignant degeneration, generally basal cell carcinoma.

SPITZ NEVI Although not usually congenital, Spitz nevi occur frequently in young children. They are pink, raised, ﬁrm lesions that often are confused with pyogenic granulomas because of the appearance and history of rapid growth at onset. On occasion, they can be pigmented as well. The original name for these lesions was ‘benign juvenile melanoma’ and under the microscope the rather bizarre histology can be confusing, if the patient’s age and history are not supplied to the pathologist. These lesions are not malignant, but do grow rapidly and tend to recur aggressively if not completely excised. A generous border of normal tissue (i.e. 3–4 mm) should be excised along with the lesion to decrease the chances of recurrence.

Each of these options has been entertained as a means of reducing the overall ‘nevus cell load’ and diminishing the visual impact of the nevus. Both dermabrasion and curettage found origin in the recognition that in infancy the greater mass of nevus cells is in a more superﬁcial location within the upper reticular dermis and epidermis. While the former works at abrading away the surface cells, the latter separates the superﬁcial cells at what is said to be a natural cleavage plane between the superﬁcial and deep dermis. Both techniques require treatment early in the neonatal period, at less than 15 days of age, in order to be effective. Cases have been reported with good early cosmesis with both approaches; however, post-treatment biopsy studies with both techniques, and in the current authors’ experience, demonstrate residual nevus cells throughout the original ﬁeld of the previous nevus, even if the surface coloration is lighter. Long-term studies by Magalon et al.14 have demonstrated a gradual darkening of the pigmentation throughout the areas treated (Figs 72.6–7).The growth of terminal hair and other skin adnexa within the area is also unaffected, as the follicles are located in the underlying subcutaneous plane. This late appearance of pigmentation and adnexa, even if perhaps lighter than it would have been, may present as great a stigma for the affected individual as the initial nevus. Follow-up exami-

Philosophy of surgical management While opinions still vary regarding the potential risk of malignant change, and opinions are still actively voiced regarding the potential for unsightly scarring following surgery, it is imperative that a treatment philosophy be developed that will assure both optimal esthetic and functional outcomes. Where the burden of nevus involvement is massive and the available normal donor

Figure 72.6 The paler area within this nevus was curetted immediately after birth. Seeing this early result, the entire area was curetted. Note: follow up photograph on next page

680 Congenital nevi

hyperpigmentation and hypopigmentation can occur as well. Exposure of the skin to ultraviolet radiation in the perioperative period can lead to signiﬁcant burning and secondary scarring. Because congenital melanocytic nevi have nevus cells in all layers of the epidermis, dermis and subcutaneous tissue, it is unrealistic to think that any laser would be capable of eliminating the nevus without damaging, i.e. burning and scarring, the tissue. Furthermore, because the lesion is vaporized there is no surgical specimen for histologic conﬁrmation of the benign or malignant nature of the lesion. While it may prove to be of use for reducing pigmentation in sensitive facial areas (e.g. on the eyelids) it would be expected to be of limited beneﬁt and likely to require repeated treatment over time. Whether or not the radiant energy required for laser treatment has a negative impact on the nevus cells within the remaining lesion has yet to be determined, and may not be apparent for many years into the future.

Figure 72.7 Now as a toddler, the patient has a typical result for curettage. Because the lesion is not excised in toto, pigmented elements resurface within the scariﬁed tissue making both clinical observation and histologic evaluation difﬁcult

nations can be more difﬁcult, as scarring during healing can occur, changing the physical appearance of the lesion. The presence of scar and the passage of time may complicate further later complete excision and reconstruction of the lesion, or certainly, have a signiﬁcantly greater psychological impact on the affected child than excision in infancy or early childhood. What remains to be determined is whether the reduced nevus cell load has a beneﬁt in reducing the overall risk of malignant change; that is an issue for which there may never be a clear answer. The same issues arise in consideration of the laser as a means of treating nevi. Many patients request information about the use of the laser to manage these lesions, hoping for removal without scarring. Selective photothermolysis is appropriate in macular dermal melanocytosis such as Nevus of Ota and Nevus of Ito, non-regressing Mongolian spots, nevus spilus, and café au lait macules in cosmetically sensitive locations.15 These particular lesions have minimal thickness, are not located in the epidermis and are unlikely to be malignant, which makes them ideally suited for management with lasers. Treatment hinges on the surgeon picking a laser of correct wavelength and pulse-width to allow selective destruction of the melanocytes without damaging the overlying epidermis and underlying adnexal structures. Serial treatments are required. Inappropriate selection of the wavelength or dosimetry can lead to secondary scarring with laser treatments. Temporary

OVERVIEW OF CURRENT SURGICAL TREATMENT OF LARGE AND GIANT PIGMENTED NEVI As previously mentioned, the challenge in surgical treatment of large and giant nevi is to select a treatment program that will allow complete excision and reconstruction at an early age, minimize scarring, and minimize the need for later treatment. Surgical planning must satisfy these requirements in order to provide an optimal functional and esthetic outcome. In 1988, the senior author16 presented a coordinated approach to early excision of these lesions in 78 patients. That report outlined a spectrum of treatment options, from skin graft to tissue expansion and assessed the effectiveness of excision and reconstruction with each technique in each body region. The current work has been directed at presenting a revised and updated surgical approach to treatment based on both further follow-up of the original group of patients and experience with an additional 152 patients, thus bringing the total to 230, from 1979 to mid-2000. It is beyond the scope of this chapter to speciﬁcally look at the treatment of multiply matched nevi in each body region and from this understand the nuances of each of the changes in treatment that have come about in the second decade of treatment. However the highlights of these modiﬁcations will be covered and reviewed here, with the presentation directed at supporting these current changes.

Scalp Giant CPN of the scalp were reconstructed in stages, with placement of one or more tissue expanders in a

Overview of current surgical treatment of large and giant pigmented nevi 681

subgaleal plane beneath the normal scalp skin. Following adequate expansion (generally from 10–12 weeks), the expanders were removed, the lesion excised and the defect closed using both advancement and transposition ﬂaps (Figs 72.8–10). One infant underwent four serial expansions, yet most required only one or two expansions. Better ﬂap design resulted in a better hair pattern and less of a need for serial expansion. There were no infants with permanent skull deformities associated with tissue expansion, although temporary cranial molding may be noted (spontaneous correction generally within 3–4 months).

Figure 72.10 Several months postoperatively the ﬂap color and shape is good. With scar massage, the incision lines will fade within 2–3 years

Face

Figure 72.8 Subgaleal skin expanders were placed in this infant for planned excision of the large temporoparietal congenital pigmented nevus. Expander placement has been planned to provide both hair bearing and glaborous skin to facilitate an esthetic reconstruction

Large and giant nevi of the cheek, forehead, nose, and neck were treated with tissue expansion whenever possible, with the addition of expanded full-thickness skin grafts for the periorbital and nasal area when required, or on occasion with a prefabricated and expanded ﬂap carried on a superﬁcial temporal artery pedicle. The planning of expansion and reconstruction for nevi of the forehead must be directed at minimizing any possibility of distortion of the eyebrow or normal distance from brow to hairline. Nevi extending into the temporal area must be treated by expansion of both scalp and forehead, and ﬂaps designed to establish both normal position and hair direction for the temporal region. The increasing use of transpositional ﬂaps and serial expansion when necessary allow better reconstruction of facial esthetic units.

Trunk

Figure 72.9 The appearance at the end of the expander removal and ﬂap rotation

Some of the most signiﬁcant strides have been made in better understanding and applying tissue expansion to the treatment of giant nevi of the trunk. Better expanded ﬂap design and, when regional expansion is not possible, using expanded distant ﬂaps with microvascular transfer has resulted in both improved functional and esthetic outcomes where previously large grafted areas diminished the outcome in both these areas (Figs 72.11–14).

682 Congenital nevi

Figure 72.13 Immediate postoperative result Figure 72.11 This giant congenital pigmented nevus over the midline should be worked up for potential meningeal and cerebral melanosis. With careful planning and expansion, even a lesion this large can be excised in toto with immediate reconstruction

Figure 72.14 Several months later, the skin texture and color are good. The linear scar is starting to soften and will improve with time and scar massage Figure 72.12 Expanders in place after 3 months of serial expansion

The most common location of giant nevi was found to be over the posterior trunk, often extending anteriorly in a dermatome distribution. Anterior trunk lesions were usually treated with an abdominoplasty technique either with or without expansion depending on the overall size of the lesion. Lesions involving the posterior trunk were reconstructed using tissue expansion with subsequent transposition or advancement closure. The great emphasis on increased use of ﬂap transposition has allowed excision and reconstruction of bathing trunk nevi and large thorax lesions previously felt to be treatable only with split-thickness skin grafting. A small series

of patients have now undergone either excision and reconstruction of shoulder, upper back, and posterior neck nevi with either the complete reconstruction or a large portion of it accomplished using microvascular transfer of a free expanded TRAM ﬂap. It is with the increased application of tissue expansion and diminished reliance on skin grafting that late contour deformities on the trunk, frequently seen at junction points between grafted and ungrafted areas have been signiﬁcantly reduced. These modiﬁed techniques have resulted in esthetic beneﬁts far beyond what could be accomplished with alternative treatments, both past and present.

Overview of current surgical treatment of large and giant pigmented nevi 683

Extremities Congenital large and giant nevi of the extremities still present a considerable challenge due to the limitations of expansion techniques in many of these areas, and the relatively poor esthetic outcome experienced with some grafting techniques. The current authors’ prior approach utilized both split-thickness and expanded full-thickness skin grafts for most lesions, but the longterm soft-tissue contour defect as well as pigment abnormalities in the grafted skin have led to the use of alternative approaches when possible. In upper extremity lesions, use of transposition ﬂaps from the upper back and shoulder, have effectively eliminated contour defects to the proximal upper extremity (Figs 72.15–17). An expanded free TRAM ﬂap has offered a possible avenue for larger lesions, and pedicle ﬂaps from the ﬂank (both expanded and non-expanded) have offered ways of improving long-term contour (e.g. complete

uniform single ﬂap coverage following excision of a circumferential nevus from elbow to wrist with an expanded pedicle ﬂap from the abdomen and ﬂank. Figs 72.18–20). Similar approaches will be applied to increasingly larger lesions on the lower extremity as the current authors’ experience progresses.

Figure 72.17 Minimal deformity is found at the donor site

Figure 72.15 Expanders need not be placed adjacent to the lesion itself. Pedicle ﬂaps from the ﬂank are often used for extremity reconstruction. Use of the expander allows direct closure of the donor site, obviating the need for a skin graft, and allows a nice reconstruction of the extremity

Figure 72.16 Long-term result

Figure 72.18 Coverage of mobile areas such as the shoulder are always challenging. As no local ﬂaps are available, free tissue transfer (free TRAM ﬂap) is the workhorse of reconstruction

684 Congenital nevi

those who would otherwise recommend leaving the lesion alone for fear of a poor esthetic result, and for the longterm beneﬁt of the patient, by not only minimizing the stigmata associated with the giant nevus, but minimizing the need for major reconstruction in later life.

REFERENCES

Figure 72.19 The abdomen has an expander placed not under the planned ﬂap but adjacent to it to allow for primary closure after harvesting a maximally sized TRAM ﬂap

Figure 72.20 A nice contour and result are noted at both the shoulder and abdominal donor site

SUMMARY The treatment of congenital large and giant nevi presents a continuing challenge to all individuals involved with these patients. The ability to present an organized discussion of current views on risk of malignant change to parents, patients (when old enough), referring physicians, and other allied health care workers is critical. The current authors have adopted a treatment approach that takes into consideration the varied opinions regarding malignant risk, emphasizes the beneﬁts of early excision on lowering that risk, and most importantly, provides a means of dealing with these often devastating lesions in a manner that optimizes the esthetic outcome. This latter key issue is one that must be fulﬁlled both to satisfy the concerns of

1. Dorland’s Pocket Medical Dictionary. 25th edn. Philadelphia: W.B. Saunders Company, 1995 p 571. 2. Alper JC, Holmes LB, Mihm MC. Birthmarks with serious medical signiﬁcance: Nevocellular nevi, sebaceous nevi and multiple café au lait spots. J Pediatr 1979; 95:696–700. 3. Elder D, Elenitsas R. Benign pigmented lesions and malignant melanoma. In: Elder D, editor. Lever’s Histopathology of the Skin. 8th edn. Philadelphia: Lippincott-Raven Publishers, 1997 pp 625–684. 4. Rhodes AR, Silverman RA, Harrist TJ, Melski JW. A histologic comparison of congenital and acquired nevomelanocytic nevi. Arch Dermatol 1986; 121:1266–73. 5. Alper JC, Holmes LB. The incidence and signiﬁcance of birthmarks in a cohort of 4.641 newborns. Pediatr Dermatol 1983; 1:58–68. 6. Illig L, Weidner F, Hundeiker ME. Congenital nevi less than or equal to 10 cm as precursors to melanoma: 52 cases, a review and a new conception. Arch Dermatol 1985; 121:1274–81. 7. Quaba AA, Wallace AF. The incidence of malignant melanoma (0–15 years of age) arising in ‘large’ congenital nevocellular nevi. Plast Reconstr Surg 1986; 78:174–9. 8. Rhodes AR, Melski JW. Small cutaneous nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 1982; 100:219–24. 9. Quaba AA, Wallace AF. The incidence of malignant melanoma (0–15 years of age) arising in ‘large’ congenital nevocellular nevi. Plast Reconstr Surg 1986; 78:174–9. 10. Kadonaga JN, Frieden IJ. Neurocutaneous melanosis: Deﬁnition and review of the literature. J Am Acad Dermatol 1991; 24:747–55. 11. Foster RD, Williams ML, Barkovich AJ et al. Giant congenital melanocytic nevi: The signiﬁcance of neurocutaneous melanosis in neurologically asymptomatic children. Plast Reconstr Surg 2001; 107:933–41. 12. Grande Carpo B, Grevelink JM, Virnelli Grevelink S. Laser treatment of pigmented lesions in children. Semin Cutan Med Surg 1999; 18:233–43. 13. Alster TS. Complete elimination of large café au lait birthmarks by the 510-nm pulsed dye laser. Plast Reconstr Surg 1995; 96:1660–4. 14. Magalon G, Casanova D, Bardot J, Andrac-Meyer L. Early curettage of giant congenital naevi in children. Br J Dermatol 1998; 138:341–5.

References 685 15. Grande Carpo B, Grevelink JM, Virnelli Grevelink S. Laser treatment of pigmented lesions in children. Semin Cutan Med Surg 1999; 18:233–43.

16. Bauer BS, Vicari FA. An approach to excision of congenital giant pigmented nevi in infancy and early childhood. Plast Reconstr Surg 1988; 82:1012–21.

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73 Lymphatic malformations (cystic hygroma) JACOB C. LANGER AND VITO FORTE

INTRODUCTION Lymphatic malformations were previously referred to as ‘cystic hygromas’ or ‘lymphangiomas’, and consist of a group of developmental anomalies of the lymphatic system. Although usually present in the newborn period, they may appear during the ﬁrst or second decade of life, or rarely in adulthood.1,2 Lymphatic malformations range from small, clinically insigniﬁcant masses to huge debilitating or disﬁguring lesions which penetrate widely into surrounding structures. Although they are usually found in the neck and shoulder regions, they may also occur in the mediastinum, retroperitoneum, groin, and other areas. This chapter will provide an overview of the diagnosis and management of these often difﬁcult lesions with emphasis on those involving the head and neck region.

PATHOLOGY Lymphatic malformations consist of cystic cavities ﬁlled with clear or straw-colored ﬂuid, which grow slowly, often surrounding and inﬁltrating adjacent structures. Three histologic patterns are recognized – capillary, cavernous and cystic – which can coexist in the same lesion. The cysts are lined by endothelium and the ﬂuid is often identical with lymph. The reason for growth in cystic hygromas has been debated. Some authors suggest that cystic hygromas are actually neoplasms with the potential for new tissue formation,3 while others feel that an increase in size is a result of thrombosis and organization within the tumor.4

EMBRYOLOGY AND ETIOLOGY According to Sabin, the lymphatic system arises from the formation of the ﬁve primitive ‘lymph sacs’: paired jugular sacs lateral to the jugular vein, a retroperitoneal

sac at the root of the small bowel mesentery, and paired sacs posterior to the sciatic veins.5 These sacs produce buds which arborize centrifugally to form the peripheral lymphatic system. Later work by Kampmeier6 suggested that the lymphatic cavities actually form from slits in the reticulum of the large venous plexuses in the neck. Cyst formation would result from failure of the lymphatic spaces to join with the venous system.7 Lymphatic malformations may therefore be caused by sequestration of a sac or part of a sac,8 failure of fusion with the venous system,9 or secondary obstruction of lymphatic drainage.10 The recently recognized association of lymphatic malformations with cardiovascular and venous malformations has led to a number of further theories involving abnormalities of the extracellular matrix and neural crest migration during early embryonic development.11,12 Recent clinical work examining the pathology of these tumors,8 as well as observations on prenatally diagnosed cases,13 have called some of these theories into question, and suggest that there may be a number of different mechanisms which may result in a lymphatic malformation.

PRENATAL DIAGNOSIS Lymphatic malformations are often diagnosed sonographically before birth.14 The differential diagnosis of a cystic lesion in the fetus is extensive,15 but in experienced hands the correct diagnosis can be made in most cases.16 Although most lymphatic malformations presenting to the pediatric surgeon have an excellent prognosis, prenatal sonography has revealed a high ‘hidden mortality’ rate among fetuses with this condition.17–20 The majority of fetuses with a lymphatic malformation develop hydrops fetalis or diffuse lymphangiomatosis prior to fetal demise (Fig. 73.1). There is often either an associated chromosomal abnormality (usually Turner syndrome,9 although many others have been reported21), or a familial syndrome associated with other structural anomalies, such as multiple pterygium syndrome22 or

688 Lymphatic malformations (cystic hygroma)

Figure 73.1 Prenatal ultrasound of a fetus with Turner syndrome and a large posterior cervical cystic hygroma. Note the diffuse subcutaneous edema (E), which is indicative of hydrops fetalis. H = fetal head; C = cystic hygroma

Robert syndrome.23 Although most of these fetuses die in utero, spontaneous regression has occasionally been seen in fetuses with Turner or Noonan syndromes.13,24,25 Lymphatic malformations presenting in the fetus have a different natural history and prognosis from those presenting postnatally.13,26 The natural history of cervical lesions detected prenatally varies according to the gestational age at which nuchal thickening appears, and the presence of associated hydrops or abnormal karyotyping. The cases diagnosed in ﬁrst trimester without any other abnormality usually have a good prognosis with spontaneous resolution in the majority.27–29 However, those with hydrops and abnormal karyotyping have a poorer outlook. The prognosis of patients detected in the second trimester is usually poor,30 but those in whom a lymphatic malformation is diagnosed in late gestation form a different group. These cases are comparatively rare,31–33 and likely to represent an etiologic mechanism occurring during the latter half of pregnancy. The prognosis in this group is much more favorable, and the prenatal diagnosis should be followed by delivery and aggressive surgical management at a perinatal center. Occasionally a fetus may be identiﬁed with a large anterior cervical lymphatic malformation which causes airway obstruction. These pose a challenge at the time of delivery and are best managed using the ex utero intrapartum (EXIT) procedure to gain access to the airway prior to dividing the umbilical cord34 (Fig. 73.2). In severe cases, a tracheostomy can be carried out or the child can be placed on extracorporeal membrane oxygenation as part of the EXIT procedure.

CLINICAL PRESENTATION AND IMAGING The majority of lymphatic malformations occur in the head and neck (Table 73.1), axilla or retroperitoneum;

(a)

(b) Figure 73.2 (a) Prenatal sonogram showing a large pretracheal lymphatic malformation. H = fetal head; T = lymphatic malformation. (b) The EXIT procedure, in which intubation is accomplished prior to delivery while the patient is still on placental support

Table 73.1 LMs of the head and neck at the Hospital for Sick Children (1988–2000).65(updated) Sites of involvement (130 patients) Site

No. cases

Neck* Posterior Anterior Submandibular Face and oropharynx† Tongue Floor of mouth Cheek Parotid Larynx Mediastinum and chest wall * Neck only – 69, entire neck (all three sites) – 17. † Face and oropharynx only – 19.

97 40 38 37 46 14 14 17 14 5 14

Clinical presentation and imaging 689

involvement of the mediastinum, groin, extremities, or face are less common.35,36 Approximately 80% are diagnosed before the patient is 5 years old, and over half present in the newborn period. Typically, these lesions present as a soft, ﬂuctuant swelling in the lateral or anterior neck, which may or may not increase in size with age and often are asymptomatic (Fig. 73.3). Occasionally, huge malformations involving the ﬂoor of the mouth or the larynx will present at birth in a newborn with airway obstruction (Fig. 73.4). Rapid increases in size or sudden pain may be due to hemorrhage into the tumor, or to infection. Abdominal malformations usually present as an asymptomatic abdominal mass (Fig. 73.5), or occasionally with chylous ascites. Lymphatic malformations of the extremities may be small and localized, or may involve the entire extremity in an inﬁltrative and debilitating fashion (Fig. 73.6).

(a)

Investigations Sonography is useful for deﬁning the cystic nature of the lesion,37,38 and Doppler studies can determine whether there is ﬂow within it.39 Computed tomography (CT) is extremely useful for assessing relationships to adjacent structures, especially within the mediastinum and retroperitoneum.40,41 Coronal CT imaging may provide better visualization of neck and mediastinal masses in the newborn.42 Magnetic resonance imaging (MRI) is an excellent technique for determining anatomic location in complicated cases, and is usually superior to CT in illustrating the relationship of the lesion to vital neuro-

(b) Figure 73.4 Newborn with large cystic hygroma and airway obstruction. (a) Preoperatively. (b) Postoperatively

Figure 73.3 Five-month-old child with moderately sized lymphatic malformation, which was relatively asymptomatic

vascular structures such as the carotid artery and brachial plexus.43–45 The new generation of ultra-fast MRI scanners has permitted this technique to be used more frequently in small infants, and even in affected fetuses.46 Boxen described the use of lymphoscintigraphy to deﬁne the lymphatic supply of a large lymphatic malformation,47 and this technique may be useful for planning a surgical approach or for identifying the source of a persistent lymphatic leak in the abdomen or pleural space. Often a combination of techniques must be used to completely deﬁne the anatomic relationships of a large or complicated lesion (Fig. 73.7).

690 Lymphatic malformations (cystic hygroma)

(a) Figure 73.5 MRI image of a retroperitoneal cystic hygroma presenting as an asymptomatic abdominal mass in a newborn (arrow)

Differential diagnosis The diagnosis of lymphatic malformation is usually straightforward and can be easily differentiated from lymphadenopathy, teratomas and other solid tumors based on the clinical examination and imaging studies. Hemangiomas may be present in the same location, but do not transilluminate and tend to collapse upon compression. Lipomas may also be confused with superﬁcial lymphatic malformations, but will not have a cystic appearance on ultrasound examination.

(b)

NON-OPERATIVE MANAGEMENT Most authors advise early surgical excision of lymphatic malformations, to avoid the complications of infection, hemorrhage, and continued growth with further inﬁltration of surrounding tissues.8 Spontaneous regression of these lesions after birth is thought to be rare.48 In the past, the high mortality rate associated with resection stimulated the development of nonsurgical techniques using irradiation,49 incision and drainage, or injection of sclerosing agents50 or boiling water.8 Although safe surgical excision is now possible in most cases, some reports in the past decade have advocated injection sclerotherapy for cases which are located in regions where resection would be too hazardous, for cases which have been incompletely resected, and for recurrent tumors. The agents which have been used with the most success are OK-432, a bacterial product from Streptococcus pyogenes,51,52 anti-neoplastic agents such as bleomycin53 or cyclophosphamide,54 and ﬁbrin sealant.55 Multiple injections under general anesthetic may be required before a successful outcome is achieved. The current authors’ own experience would suggest that the lesions that are reportedly responsive to agents such as

(c) Figure 73.6 Large cystic hygroma involving the right upper extremity and right side of the chest wall. (a) Note the gross deformity and edema, as well as the inﬁltrative nature of the lesion as seen on the MRI scan (b, c)

OK-432, namely moderate- to large-sized cystic malformations, are those that can be safely excised with a single operative intervention. These ‘easier’ lesions also form the critical mass of cases required for gaining the surgical experience necessary for the successful surgical

Surgical management 691

(a)

(c)

(b)

(d)

Figure 73.7 Combination of imaging techniques in a newborn with a large cervico-axillary-mediastinal cystic hygroma. (a, b) The CT scan demonstrates the lesion well, and may be easier to perform in a newborn infant than MRI. (c) MRI may be better at showing the relationship of the lesion to vascular structures, the heart, and the brachial plexus, and can provide excellent coronal images, particularly in a larger child. (d) Ultrasound was used to demonstrate the massively dilated superior vena cava and internal jugular vein

management of the more complex lymphatic malformations.

SURGICAL MANAGEMENT Most lymphatic malformations are easily resected without undue mortality or morbidity, as long as the following principles are adhered to:

1 Adequate exposure must be obtained. 2 Meticulous dissection must be used in order to preserve vital structures, including the nerves, vessels, trachea, and esophagus. The current authors have had success with the exclusive use of a microbipolar dissection technique.56 This technique is of particular advantage when dissection is carried out close to important neurovascular structures. 3 Since this is a benign disease, it is not justiﬁable to

692 Lymphatic malformations (cystic hygroma)

sacriﬁce a vital structure in order to completely excise the lesion. 4 Whenever possible, the lymphatic supply to the lesion should be ligated to prevent postoperative accumulation of lymph. In the head and neck region, the lymphatic supply to a lymphatic malformation is usually not visible, but it is possible that the microbipolar dissection technique may ‘weld’ these channels shut. Lymphatic malformations of the neck can usually be approached through a transverse cervical incision under general intratracheal anesthesia. Perioperative antibiotics should be employed. After division of the platysma muscle, the mass is carefully dissected from all surrounding structures (Fig. 73.8). The large cystic malformations are usually well-encapsulated, and every attempt should be made not to rupture the cysts. The ﬂuid within the cyst aids the surgeon in deﬁning the cyst wall, and therefore in ﬁnding the correct plane in which to dissect. Particular care must be taken to avoid injury to the carotid artery and its branches, or to the internal jugular vein. Preservation of other large venous channels if possible may also be beneﬁcial in promoting regional drainage. A number of nerves are often closely associated with the lesion, including the facial nerve, spinal

accessory nerve, vagus nerve, and brachial plexus. Although pathological studies have shown that microscopic tumor is often left behind,3 recurrence is rare when all gross tumor is removed. Once the malformation has been removed, and, if possible, the lymphatic supply to the malformation ligated, a closedsuction drain should be left in the tumor bed to prevent early accumulation of ﬂuid. Dietary restriction of longchain triglycerides in the postoperative period may be of some beneﬁt in reducing the amount of chylous lymph production. A small number of cervical lesions extend into the axilla or mediastinum. For axillary extension, the child should be elevated 15–20º on the involved side, with the arm draped free, and both cervical and axillary crease incisions should be used.8 The cervical component is approached ﬁrst, separating the lesion away from the brachial plexus until the cysts are seen to pass below the clavicle. The axillary portion is then dissected free. The most difﬁcult aspect of the operation is removing the lesion from the brachial plexus behind the clavicle, where it is often densely adherent. Only careful, meticulous dissection will permit complete removal of the malformation without injury to the nerves. Extension into the mediastinum also presents a difﬁcult technical challenge. The best approach is one-

Figure 73.8 Exposure of a cervical cystic hygroma. Note location of vital neurovascular structures, which must not be damaged during the dissection

Complications 693

stage resection through an ‘inverted hockey-stick’ incision, as described by Grosfeld et al.,57 where a transverse neck incision is extended inferiorly into a midline sternotomy. Modiﬁcations of the Grosfeld approach, by either leaving a bridge of skin between the horizontal cervical and midline sternotomy incisions or by performing a partial upper sternotomy through the cervical incision, may provide a cosmetically superior result without signiﬁcantly compromising exposure. These approaches provide adequate exposure to safely dissect the lesion away from the jugular, carotid and subclavian vessels, and the aortic arch, esophagus, and pericardium, with preservation of the phrenic, vagus, and recurrent laryngeal nerves. The rare lymphatic malformation which is conﬁned to the mediastinum can be approached either through a lateral thoracotomy or a midline sternotomy.58 Perhaps the most difﬁcult lesions to approach surgically are the massive lesions which involve the tongue, ﬂoor of the mouth, and larynx. These lesions are usually present at birth, and may result in early airway obstruction, either by sheer mass effect or as a result of hemorrhage into the tumor. In many cases, a tracheostomy is necessary as a lifesaving procedure, followed by multiple extensive operative procedures.59 For prenatally diagnosed cases, access to the airway can be achieved at the time of cesarian section before clamping the umbilical cord.60 The same surgical principles are employed as outlined earlier, but the strategy for each patient must be individualized. Recurrence rates in these patients are higher, but do not seem to correlate with the removal of all macroscopic tumor.61 Historically, repeated or staged surgical approaches seemed to offer the best hope for palliation. Currently, if at all possible and feasible, the current authors’ ﬁrst choice is an aggressive, single-staged resection to avoid the need for tracheotomy or gastric tube feeding. The option of a more aggressive surgical approach has been made possible by advancements in anesthetic techniques, improved specialized neonatal and pediatric postoperative care units, and the use of the microbipolar dissection technique. The use of laser technology for controlling airway obstruction from laryngeal or tracheal involvement has also been highly successful in this group of patients.61,62 Lymphatic malformations involving the tongue pose a very difﬁcult problem. As a general principle, direct surgical treatment of the tongue should be avoided if possible. Intermittent swelling of the tongue can be effectively controlled with systemic steroids. Capillary lymphatic malformations involving the mucosal surface of the tongue (also known as simplex) can cause blistering, bleeding and pain, and are best handled with laser resurfacing techniques. Persistent, symptomatic macroglossia involving the intrinsic muscles of the tongue may require reduction glossoplasty. Lymphatic malformations involving the ﬂoor of the mouth and tongue may also lead to bony malformations of the growing mandible, which may require subsequent surgical correction.63

Lymphatic malformations in the abdomen usually originate in the retroperitoneum or the intestinal mesentery. Resection using meticulous technique is usually possible, although often some of the lesion must be left behind. Remaining cysts should be unroofed, since complications such as postoperative ascites are rarely seen. Image-guided laser coagulation has also been reported for unresectable lesions.64 Occasionally a lymphatic malformation will present with scrotal swelling, and may be misdiagnosed and operated upon as a hydrocele. Once the diagnosis has become clear, these lesions should undergo complete resection if possible. Lymphatic malformations of the extremities range from small, easily resected cysts to large, inﬁltrating lesions. The large malformations are often accompanied by poor lymphatic drainage, which predisposes the limb to edema, infection, and inhibition of function. Complete excision of these lesions may be impossible, and amputation may ultimately be necessary.

COMPLICATIONS In the modern era, the mortality rate associated with surgical resection of a lymphatic malformation should approach zero. Early intervention before infectious complications or airway obstruction, and strict adherence to the principles described earlier, permit safe removal with little morbidity in the majority of cases. The complications of surgery include seroma, infection, and neurological sequelae such as Horner syndrome, facial nerve palsy, or spinal accessory nerve injury. Although these problems are usually transient, surgical intervention may occasionally be required.65 Table 73.2 outlines the perioperative complications seen in 130 consecutive surgical cases at the current authors’ center (updated from the institutional review carried out in 1996).65 Table 73.2 Perioperative complications (120 cases)65(updated) Complication

No.

Infection Bleeding* Cranial neuropathy Marginal mandibular branch VII† Cranial nerve XI Cranial nerve XII Horner syndrome Seroma Salivary ﬁstula Wound dehiscence Tongue edema

6 5 12 10 1 1 1 4 1 3 3

*Requiring blood transfusion. † Paresis resolved completely – 7.

694 Lymphatic malformations (cystic hygroma)

Recurrence can occur after surgical excision, especially if the ﬁrst resection has been incomplete. These recurrences may represent ﬂuid re-ﬁlling cysts which had been decompressed, or may be due to ﬁlling of more distal cysts in which drainage had been interrupted by the surgical procedure. Ultrasonography, CT, and MRI may all be useful for demonstrating these recurrent lesions.66 Options for management include further resection or injection sclerotherapy, depending on the anatomical location and the likelihood of injury to neurovascular structures.

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15. Rempen A, Feige A. Differential diagnosis of sonographically detected tumours in the fetal cervical region. Eur J Obstet Gynecol Reprod Biol 1985; 20:89–105. 16. Rahmani MR, Fong KW, Connor TP. The varied sonographic appearance of cystic hygromas in utero. J Ultrasound Med 1986; 5:165–8. 17. Byrne J, Blanc WA, Warburton D, Wigger J. The signiﬁcance of cystic hygroma in fetuses. Hum Pathol 1984; 15:61–7. 18. Marchese C, Savin E, Dragone E et al. Cystic hygroma: prenatal diagnosis and genetic counselling. Prenat Diagn 1985; 5:221–7. 19. Garden AS, Benzie RJ, Miskin M, Gardner HA. Fetal cystic hygroma colli: antenatal diagnosis, signiﬁcance, and management. Am J Obstet Gynecol 1986; 154:221–5. 20. Pijpers L, Reuss A, Stewart PA, Wladimiroff JW, Sachs ES. Fetal cystic hygroma: prenatal diagnosis and management. Obstet Gynecol 1988; 72:223–4. 21. Cowchock ES, Wapner RJ, Kurtz A, Chatzkel S, Barnhart JS, Lesnick DC. Not all cystic hygromas occur in the UllrichTurner syndrome. Am J Med Genet 1982; 12:327–31. 22. Hertzberg BS, Kliewer MA, Paulyson-Nunez K. Lethal multiple pterygium syndrome: antenatal ultrasonographic diagnosis. J Ultrasound Med 2000; 19:657–60. 23. Graham JM, Stephens TD, Shepard TH. Nuchal cystic hygroma in a fetus with presumed Robert’s syndrome. Am J Med Genet 1983; 15:163–7. 24. Chodirker BN, Harman CR, Greenberg CR. Spontaneous resolution of a cystic hygroma in a fetus with Turner syndrome. Prenat Diagn 1988; 8:291–6. 25. Macken MB, Grantmyre EB, Vincer MJ. Regression of nuchal cystic hygroma in utero. J Ultrasound Med 1989; 8:101–3. 26. Tannirandorn Y, Nicolini Y, Nicolaidis PC, Fisk NM, Arulkumaran S, Rodeck CH. Fetal cystic hygromata: insights gained from fetal blood sampling. Prenat Diagn 1990; 10:189–93. 27. Nadel A, Bromley B, Benacerraf BR. Nuchal thickening or cystic hygromas in ﬁrst or early second trimester fetuses prognosis and outcome. Obstet Gynecol 1993; 82:43–8. 28. Johnson MP, Johnson A, Holzgreve W et al. First trimester simple hygroma: Cause and outcome. Am J Obstet Gynecol 1993; 168:156–61. 29. Shulman LP, Emerson DS, Grevengood C, Felker RE, Phillips OP, Elias S. Clinical course and outcome of fetuses with isolated cystic nuchal lesions and normal karyotypes detected in the ﬁrst trimester. Am J Obstet Gynecol 1994; 171:1278–81. 30. Thomas RL. Prenatal diagnosis of giant cystic hygromas: prognosis, counselling and management: case presentation and review of the recent literature. Prenat Diagn 1992; 12:919–23. 31. Lyngbye T, Haugaard L, Klebe JG. Antenatal sonographic diagnoses of giant cystic hygroma of the neck. Acta Obstet Gynecol Scand 1986; 65:873–5.

References 695 32. Benacerraf BR, Frigoletto FD. Prenatal sonographic diagnosis of isolated congenital cystic hygroma, unassociated with lymphedema or other morphologic abnormality. J Ultrasound Med 1987; 6:63–6. 33. Goldstein I, Jakobi P, Shoshany G, Filmer S, Itskoviz I, Maor B. Late-onset isolated cystic hygroma: the obstetrical signiﬁcance, management, and outcome. Prenat Diagn 1994; 14:757–61. 34. Liechty KW, Crombleholme TM, Flake AW, Morgan MA, Kurth CD, Hubbard AM, Adzick NS. Intrapartum airway management for giant fetal neck masses: the EXIT (ex utero intrapartum treatment) procedure. Am J Obstet Gynecol 1997; 177:870–4. 35. Ninh TN, Ninh TX. Cystic hygroma in children: a report of 126 cases. J Pediatr Surg 1974; 9:191–5. 36. Bhattacharyya NC, Yadav K, Mitra SK, Pathak IC. Lymphangiomas in children. Aust NZ J Surg 1974; 9:191–5. 37. Sheth S, Nussbaum AR, Hutchins GM, Sanders RC. Cystic hygromas in children: Sonographic-pathologic correlation. Radiology 1987; 162:821–4. 38. Orrison WW, Sty JR. Ultrasound in the diagnosis of lymphangioma. Wis Med J 1989; 80:30–2. 39. Dates CP, Wilson AW, Ward-Booth RP, Williams ED. Combined use of Doppler and conventional ultrasound for the diagnosis of vascular and other lesions in the head and neck. Int J Oral Maxillofac Surg 1990; 19:235–9. 40. Mahboubi S, Potsic WP. Computed tomography of cervical cystic hygroma in the neck. Int J Pediatr Otorhinolaryngol 1989; 18:47–51. 41. Davidson AJ, Hartman DS. Lymphangioma of the retroperitoneum: CT and sonographic characteristics. Radiology 1990; 175:507–10. 42. Friedman L, Halls SB. Coronal computed tomography. Can Assoc Radiol J 1990; 41:287–90. 43. Cutillo DP, Swayne LC, Cucco J, Dougan H. CT and MR imaging in cystic abdominal lymphangiomatosis. J Comput Assist Tomogr 1989; 13:534–6. 44. Siegel MJ, Glazer HS, St. Amour TE, Rosenthal DD. Lymphangiomas in children: MR imaging. Radiology 1989; 170:467–70. 45. Fung K, Poenaru D, Soboleski DA, Kamal IM. Impact of magnetic resonance imaging on the surgical management of cystic hygromas. J Pediatr Surg 1998; 33(6):839–41. 46. Quinn TM, Hubbard AM, Adzick NS. Prenatal magnetic resonance imaging enhances fetal diagnosis. J Pediatr Surg 1998; 33:553–8. 47. Boxen I, Zhang ZM, Filler RM. Lymphoscintigraphy for cystic hygroma. J Nucl Med 1990; 31:516–18. 48. Saigo M, Munro IR, Mancer K. Lymphangioma – a long term follow up study. Plast Reconstr Surg 1975; 56:642. 49. Figi FA. Radium in the treatment of multilocular lymph cysts in the neck in children. AJR 1929; 21:473–80.

50. Harrower G. Treatment of cystic hygroma of the neck by sodium morrhuate. Br Med J 1933; 2:148–55. 51. Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK-432: a new sclerosing therapy for cystic hygroma in children. Br J Surg 1987; 74:690–1. 52. Ogita S, Tsuto T, Nakamura K, Deguchi E, Iwai N. OK-432 therapy in 64 patients with lymphangioma. J Pediatr Surg 1994; 29:784–5. 53. Okada A, Kubota A, Fukuzawa M, Imura K, Kainata S. Injection of bleomycin as a primary therapy of cystic lymphangioma. J Pediatr Surg 1992; 27:440–3. 54. Dickerhoff R, Bode VU. Cyclophosphamide in nonresectable cystic hygroma. Lancet 1990; 335:1474–5. 55. Castanon M, Margarit J, Carrasco R, Vancells M, Albert A, Morales L. Long-term follow-up of nineteen cystic lymphangiomas treated with ﬁbrin sealant. J Pediatr Surg 1999; 34:1276–9. 56. Pizzuto MP, Brodsky L, Duffy L, Gendler J, Nauenberg E. A comparison of microbipolar cautery dissection to hot knife and cold knife cautery tonsillectomy. Int J Pediatr Otorhinolaryngol 2000; 52:239–46. 57. Grosfeld JL, Weber TR, Vane DW. One-stage resection for massive cervicomediastinal hygroma. Surgery 1982; 92:693–9. 58. Moore TC, Cobo JC. Massive symptomatic cystic hygroma conﬁned to the thorax in early childhood. J Thorac Cardiovasc Surg 1984; 89:459–68. 59. Seashore JH, Gardiner LJ, Arlyan S. Management of giant cystic hygromas in infants. Am J Surg 1985; 149:459–65. 60. Langer JC, Tabb T, Thompson P, Paes BA, Caco C. Management of prenatally diagnosed tracheal obstruction: access to the airway in utero prior to delivery. Fetal Diagn Ther 1992; 7:12–16. 61. Cohen SR, Thompson JW. Lymphangiomas of the larynx in infants and children: a survey of pediatric lymphangioma. Ann Otol Rhinol Laryngol 1986; (Suppl)127:1–20. 62. Apfelberg DB, Maser MR, Lash H, White DN. Sapphire tip technology for YAG laser excisions in plastic surgery. Plast Reconstr Surg 1989; 84:273–9. 63. Osborne TE, Levin LS, Tilghman DM, Haller JA. Surgical correction of mandibulofacial deformities secondary to large cervical cystic hygromas. J Oral Maxillofac Surg 1987; 45:1015–21. 64. Cholewa D, Waldschmidt J, Stroedter L. Transcutaneous and laparoscopic laser treatment in extensive retroperitoneal lymphangiomas in childhood. Langenbecks Arch Chir Suppl Kongressbd 1998; 115:399–404. 65. Raveh E, de Jong AL, Taylor GP, Forte V. Prognostic factors in the treatment of lymphatic malformations. Arch Otolaryngol Head Neck Surg 1997; 123:1061–5. 66. Hancock BJ, St. Vil Y, Luks FI et al. Complications of lymphangiomas in children. J Pediatr Surg 1992; 27:220–4.

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74 Cervical teratomas MICHAEL W. L. GAUDERER

INTRODUCTION Cervical teratomas, although rare, are an important cause of neck masses in newborns and children. Because these lesions are often quite large, they can lead to precipitous airway obstruction necessitating prompt recognition and surgical intervention. Antenatal diagnosis and new techniques of intrapartum management have recently contributed to an improved outlook for the survival of newborns at greatest risk of airway compromise.

PATHOLOGY Teratomas are neoplastic lesions composed of tissues foreign to the anatomical site of origin, including all three germ layers. It is believed that most cervical teratomas arise from the embryonic thyroid anlage, although frequently clear association with the gland cannot be demonstrated.1–3 Roediger et al. presented a comprehensive discussion of the histogenesis of this lesion in 1974.4 Although a wide variety of tissues from all three germinal layers have been found in cervical teratomas, there is a 68% incidence of neural tissue, which in many cases predominates in the solid portion of the tumor.1 Thyroid tissue is present in 30% of specimens. The majority of cervical teratomas in the pediatric age group are benign (Fig. 74.1a–c); however, malignancy with and without distant metastases has been reported.1,5–7 Conversely, the incidence of malignancy in adults with cervical teratomas is reported to be as high as 70%.8 Although cervical teratomas are generally located anteriorly to the major neck structures (Fig. 74.2), signiﬁcant distortions of normal anatomy are frequently encountered (Fig. 74.3).1,7,9 Teratomas are usually single lesions, however they may occur in more than one site in the head and neck.10 The presence of a teratoma arising in one fetus of a

twin pregnancy has been described.11 Associated anomalies are rare.1

INCIDENCE AND CLINICAL MANIFESTATIONS In four large series of teratomas in infancy and childhood, the incidence of cervical location ranged from 2.3–9.3%.12–15 Cervical teratomas are reported to occur in all races and there is a slight female preponderance.1,16 There is a high incidence of prematurity, polyhydramnios and birth dystocia. Polyhydramnios is probably secondary to inability of the fetus to swallow amniotic ﬂuid.3 Stillbirth is usually associated with giant cervical lesions and due to a combination of compression of vital structures and congestive heart failure.17 The most common clinical presentation, in addition to the mass, is respiratory difﬁculty.2,16,17, 18 Respiratory symptoms may vary from total apnea to mild dyspnea or coughing with feedings. The dyspnea may also be positional. Although airway compression may not be noted at birth, it may progress rapidly over several hours to a lifethreatening obstruction. These cervical teratomas clearly represent a spectrum. Some children are referred beyond the neonatal period19 while in others it only becomes manifest in adulthood.1,8 A classiﬁcation of cervical teratomas,1 taking into consideration the age and clinical presentation (Table 74.1), clearly shows that almost half of the patients are newborns with respiratory distress (group II). Operative and non-operative management is accompanied by a 43% mortality in this sub-group.1 The mortality rates in groups I and III will probably remain unchanged. However, establishment of an adequate airway followed by prompt excision of the tumor should lead to improved survival in group II, the most common presentation. Therefore, once such a lesion is diagnosed after birth, prompt excision is mandatory. If diagnosed antenatally, recently developed intrapartum airway establishment techniques may be applied effectively;20–23 this may change the prognosis of select patients in group II (Table 74.1).

698 Cervical teratomas

(a)

(b)

(c) Figure 74.1 (a) One-day-old, full-term female newborn born with right cervical teratoma that extended into the oral ﬂoor, displacing the tongue to the left (arrow). The lesion was ﬁrm, partially cystic and limited to the right anterior cervical triangle. She had mild respiratory distress, worsening when placed in the supine position. On the second day of life, the 6.5 × 5.5 × 4.5 cm mass was excised through a transverse cervical incision, combined with intraoral dissection. The thyroid gland was not involved. Analysis of the specimen revealed a benign cystic teratoma containing neuroglia, choroids plexus, smooth muscle, respiratory and squamous epithelium, and pancreas. Transient difﬁculty with oral feedings occurred in the immediate postoperative period. (b) Same child at 3 months of age. Notice the well-healed scar following the natural skin crease and the normal position of the tongue. (c) Same child at 6 years. The scar is no longer discernible. Tongue motion and dentition are normal

DIAGNOSIS Cervical teratomas can accurately be diagnosed antenatally1,18,24 using ultrasonography, the most useful postnatal imaging study. Plain radiographs demonstrate calciﬁcation within the lesion in 16% of pediatric cases.1 Tracheal deviation is common. Other imaging modalities

such as radioisotope scans, computed axial tomography (Fig. 74.3) and magnetic resonance imaging (MRI) are helpful in more complex cases, but should be used with great caution because sedation for longer exposure times may be needed. MRI can be helpful in planning the operation, as it demonstrates planes of dissection and position of vital cervical structures that have been

Management 699 Table 74.1 Classiﬁcation of cervical teratomas by age and clinical presentation based on the review of 217 cases Group I. Stillborn and moribund live newborn II. Newborn with respiratory distress III. Newborn without respiratory distress IV. Children age 1 month to 18 years V. Adult

No. cases

% total cases

Malignant (%)

Mortality (%)

27 99 37 31 23

12.4 45.6 17.1 14.3 10.6

2 (7.4) 2 (2) 0 0 16 (69.6)

100.0 43.4* 2.7 3.2 43.5†

*Includes operative and non-operative treatment. † Incomplete follow-up for six malignant cases.

Figure 74.2 Very large cervical teratoma in a premature child

displaced by tumor growth.5 It is also useful in the prenatal evaluation in preparation for operating on placental support.25 Thyroid function tests and serum calcium levels are typically found to be normal. Alphafetoprotein levels can be elevated and should return to normal after excision.

Differential diagnosis Differential diagnoses should include cystic hygroma, lymphangioma, branchial cleft abnormalities, congenital goiter, thyroglossal duct cyst, dermoid cyst, neuroblastoma and duplications.

MANAGEMENT The most difﬁcult aspect of the management of orocervical teratomas is the establishment and maintenance of an adequate airway.1,7,18 Orotracheal or nasotracheal intubation requires skill and patience in these infants due to tracheal deviation and/or compression. A useful adjunct is nasotracheal intubation with the aid of ﬂexible ﬁberoptic scope. The endotracheal tube is slipped over the scope and the endoscope is then inserted. Once the tip of the ﬂexible scope reaches the carina, the endotracheal tube is advanced and positioned. The distance between the carina and the end of the tube can then easily be

Figure 74.3 CT scan of the neck of a 5-month-old female patient. The lesion was initially thought to be a hemangiolymphangioma. Fortunately, this child had minimal or no airway compression, in spite of the location of the mass. The removed specimen was a benign teratoma containing neuroglia, choroids plexus, respiratory epithelium, pancreas, muscle and cartilage

determined by direct visualization. Tracheostomy, as an emergency procedure, has obvious limitations, although it may be necessary in extreme situations.18,22 Whenever possible, a tracheostomy should be avoided because it increases operative as well as postoperative morbidity.1 If the teratoma is composed of one or more large cysts, emergency aspiration may be employed to reduce tumor size and alleviate pressure on the airway. An exciting advance in the management of fetuses with a high probability of upper-airway compromise at or immediately after birth, is the development of the ex utero intrapartum treatment (EXIT).20–23 This technique permits the establishment of a secure airway while the child is on placental support. The procedure requires a multidisciplinary approach of team members from the

700 Cervical teratomas

(a)

Endotracheal tube (tapes not shown)

Teratoma

Deviated trachea

Incision

Marks to facilitate closure apposition

Figure 74.5 Complete excision of a large cervical teratoma. Notice the smooth surface of the removed specimen and the retraction of the redundant skin ﬂaps by the guy sutures

(b) Figure 74.4 (a), (b). Operative approach to the case in Figure 74.3 (a). The intubated child’s neck is elevated over a roll. Wide draping with adhesive plastic sheets allows for excellent exposure and helps prevent temperature loss. The incision is drawn with a marking pen to one of the skin creases, if possible. To facilitate proper apposition of the redundant skin following resection, multiple small cross-stitches are drawn with the pen. Following the skin incision, the marks are replaced by guy sutures that are helpful for traction on the ﬂaps as well as the ﬁnal approximation. It must be remembered during the dissection that the trachea may not be in the center. Other vital structures may also be markedly displaced

involved specialties: obstetrics, anesthesia, pediatric surgery and neonatology.20–23 The incision for cervical and orocervical teratomas should be carefully planned to allow access not only to the neck, but also to the upper mediastinum or oral cavity, if needed. As opposed to lymphangiomas, teratomas can usually be dissected without great difﬁculty (Fig. 74.4a,b). The lesion is often attached to one of the lobes of the thyroid. When the dissection reaches this

Figure 74.6 Histological section of a cervical teratoma demonstrating an array of various tissues

level, every attempt should be made to preserve the thyroid and parathyroids. Dissection around the trachea and the esophagus must be carried out with great care to avoid injury to the recurrent laryngeal nerves (Fig. 74.5). Tracheal as well as esophageal deviation should be constantly kept in mind. In the small neck of the newborn, deep dissection can lead to injury to the phrenic nerves.

References 701

Once the tumor is removed, a soft, ﬁne silicone rubber drain is placed and attached to a closed drainage system. The musculo-aponeurotic layers are approximated with ﬁne synthetic absorbable sutures and the skin is closed with subcuticular stitches. Postoperatively, vocal cord and diaphragmatic function should be assessed and recorded. Calcium levels are measured in the immediate postoperative period and thyroid function tests are obtained after a few weeks. If the alphafetoprotein levels were initially elevated, follow-up determinations should be sought.

CONCLUSION The overall prognosis for cervical teratomas is good, particularly in the newborn, with little or no respiratory distress (Table 74.1).1,7,14,19 If the lesion is diagnosed in utero, appropriate preparations can be made to assure prompt establishment of a good airway immediately at or following birth. Carefully planned excision is then possible. This should increase the survival in the newborn with signiﬁcant respiratory compromise.

REFERENCES 1. Jordan RB, Gauderer MWL. Cervical teratomas: an analysis. Literature review and proposed classiﬁcation. J Pediatr Surg 1988; 23:583–91. 2. Saphir O. Teratoma of the neck. Am J Pathol 1929; 5:313–22. 3. Silberman R, Mendelson IR. Teratoma of the neck. Report of two cases and review of the literature. Arch Dis Childh 1960; 35:159–70. 4. Roediger WE, Spitz L, Schmaman A. Histogenesis of benign cervical teratomas. Teratology 1974; 10:111–18. 5. Touraj T, Applebaum H, Frost DB. Congenital metastatic teratoma: diagnostic and management considerations. J Pediatr Surg 1989; 24:21–3. 6. Baumann FR, Nerlich A. Metastasizing cervical teratoma of the fetus. Pediatr Pathol 1993; 13:21–7. 7. Azizkhan RG, Haase GM, Applebaum H et al. Diagnosis, management, and outcome of cervicofacial teratomas in neonates: a Children’s Cancer Study. J Pediatr Surg 1995; 30:312–16. 8. Als C, Laeng H, Cerny T et al. Primary cervical malignant teratoma with a rib metastasis in an adult: ﬁve-year survival after surgery and chemotherapy. A case report with a review of the literature. Ann Oncol 1998; 9:1015–22.

9. Hester TO, Camnitz PS, Albernaz MS et al. Superﬁcial carotid artery secondary to cervical teratoma. Ear Nose Throat J 1991; 70:524–6. 10. Dudgeon DL, Isaacs H Jr, Hays DM. Multiple teratomas of the head and neck. J Pediatr 1974; 85:139–40. 11. Hitchcock A, Sears RT, O’Neill T. Immature cervical teratoma arising in one fetus of a twin pregnancy. Case report and review of the literature. Acta Obstet Gynecol Scand 1987; 66:377–9. 12. Bale PM, Painter DM, Cohen D. Teratomas in childhood. Pathology 1975; 1:209–18. 13. Berry CL, Keeling J, Hilton C. Teratomas in infancy and childhood: a review of 91 cases. J Pathol 1969; 98:241–52. 14. Grosfeld JL, Ballantine TV, Lowe D et al. Benign and malignant teratomas in children: analysis of 85 patients. Surgery 1976; 80:297–305. 15. Tapper D, Lack EE. Teratomas in infancy and childhood. A 54 year experience at the Children’s Hospital Medical Center. Ann Surg 1983; 198:398–410. 16. Elmasalme F, Giacomantonio M, Clarke KD et al. Congenital cervical teratoma in neonates. Case report and review. Eur J Pediatr Surg 2000; 10:252–7. 17. Grisoni ER, Gauderer MWL, Wolfson RN et al. Antenatal diagnosis of sacrococcygeal teratomas: prognostic features. Pediatr Surg Int 1988; 3:173–5. 18. Zerella JT, Finberg FJ. Obstruction of the neonatal airway from teratomas. Surg Gynecol Obstet 1990; 170:126–31. 19. Nmadu PT. Cervical teratoma in later infancy: report of 13 cases. Ann Trop Paediatr 1993; 13:95–8. 20. Mychalishka GB, Bealer JF, Graf JL et al. Operating on placental support: the ex utero intrapartum treatment (EXIT) procedure. J Pediatr Surg 1997; 32:227–31. 21. Liechy KW, Crombleholme TM, Flake AW et al. Intrapartum airway management for giant fetal neck masses: the EXIT (ex utero intra-partum treatment) procedure. Am J Obstet Gynecol 1997; 177:870–4. 22. Smith GM, Boyd GL, Vincent RD et al. The EXIT procedure facilitates delivery of an infant with a pretracheal teratoma. Anesthesiology 1998; 89:1573–75. 23. Murphy DJ, Kyle PM, Cairns P et al. Ex-utero intra-partum treatment for cervical teratoma. Br J Obstet Gynecol 2001; 108:429–30. 24. Patel RB, Gibson JY, D’Cruz CA et al. Sonographic diagnosis of cervical teratoma in utero. Am J Roentgenol, 1982; 139:1220–22. 25. Hubbard AM, Crombleholme TM, Adzik NS. Prenatal MRI evaluation of giant neck masses in preparation for the fetal EXIT procedure. Am J Perinatol 1998; 15:253–7.

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75 Sacrococcygeal teratoma KEVIN C. PRINGLE

INTRODUCTION A sacrococcygeal teratoma is a neoplasm arising from the caudal end of the spine, usually protruding from the inferior end of the infant’s spinal column and displacing the anus forwards. These tumors are much more common in girls, with the female-to-male ratio being at least 3:1.1–9 The incidence is approximately one in 40 000 live births.10,11 Most authorities agree that sacrococcygeal teratoma is the result of continued multiplication of totipotent cells from Hensen’s node which fail to involute at the end of embryonic life.7,12,13 Pantoja and Rodriguez-Ibanez reviewed the conﬂicting theories as to the origin of these tumors.14 However, most authorities reject the concept that these are suppressed twins or parasitic fetuses, and the theory that these tumors arise from migrating germ cells travelling from yolk sac to gonad also appears to be unlikely. A familial distribution of sacrococcygeal teratoma has occasionally been reported.15–17

PATHOLOGY Willis deﬁned the term teratoma as follows: ‘A teratoma is a true tumor or neoplasm composed of multiple tissues of kinds foreign to the part in which it arises’.13 The sacrococcygeal teratoma was second on Willis’ list of sites where teratomata are found, but in almost all pediatric surgical series, the sacrococcygeal site is the most common site listed.1–4,18 By deﬁnition, then, sacrococcygeal teratomata are composed of several types of tissue, usually derived from two or three germ layers. Robbins19 deﬁnes a teratoma as ‘a tumor composed of cells representing more than one germ layer’. In fact, however, in any tumor consisting of an epithelial component and a supporting stroma, at least two germ layers are represented. Most carcinomata, therefore, would meet Robbins’s deﬁnition of a teratoma. Within any one tumor, the cells can vary from totally benign (even forming well-formed teeth, hair or other

organs) to cells that appear frankly malignant. However, many sacrococcygeal teratomata contain malignantlooking cells (usually described as ‘immature’), but if they are completely excised they do not recur. For this reason, the diagnosis of malignant sacrococcygeal teratoma can only be made if there are distant metastases.18 The risk of malignancy depends on two factors: the site and the extent of the tumor and the age at diagnosis. Tumors diagnosed after 2 months of age have a high risk of being malignant. An exception to this statement is the relatively rare presacral ‘dermoid’ tumors, which often present in adolescence or adult life with constipation or urinary obstruction, but if excised completely appear to be totally benign. Altman et al. classiﬁed sacrococcygeal teratomata into four groups when they reported the results of the American Academy of Pediatric Surgical Section Survey.18 (Fig. 75.1) type I tumors are almost exclusively exterior with a minimal pelvic component. They are rarely malignant (0% in the AAP survey). Type II tumors have a signiﬁcant pelvic component. In the AAP survey, 6% of type II tumors were malignant. Type III tumors have an intrapelvic and intra-abdominal component greater than the external component. The intra-abdominal component can usually be palpated on abdominal examination. In the AAP survey, 20% of type III tumors were malignant. The type IV tumors are exclusively presacral; they had an 8% incidence of malignancy in the AAP survey.

PRESENTATION The most common presentation has been as a large sacral mass that is immediately obvious at birth.1–5,12,18 The malignant tumors tend to present as a swelling of the buttock at 5–6 months of age. However, a more frequent presentation in recent times has been antenatal diagnosis by ultrasonography during antenatal ultrasound scans.20–29 Series reporting the antenatal diagnosis of sacrococcygeal teratomata have revealed that the

704 Sacrococcygeal teratoma

majority of those fetuses diagnosed as having a sacrococcygeal teratoma are likely to die before delivery.20,22,30–32 Most of the fetuses reported to have died following antenatal diagnosis had tumors with a mass as great as or greater than the rest of the fetus. It is, therefore, entirely possible that these fetuses die of heart failure as the fetal heart is unable to pump sufﬁcient blood to nourish both the tumor and the rest of the fetus. Certainly, in most of the antenatal series reported, fetal hydrops (nonimmune hydrops) is very common, and is associated with an increased risk of fetal demise.20,23,25,27–32 In 1990, Ikeda et al. reported characteristics of 20 cases of prenatally diagnosed sacrococcygeal teratomas.27 Six infants delivered at a gestational age of from 25–32 weeks died prenatally; 14 cases delivered after 32 weeks’ gestation survived. Other recent articles, including three from the group in Chapel Hill (all reporting the same nine antenatally diagnosed sacrococcygeal teratomata33–35) also report a high mortality rate if fetal hydrops is noted or if the diagnosis is made early in gestation.27–29,31,32 Recent improvements in magnetic resonance imaging (MRI) technology have enabled this modality to be used in the fetus without the need for fetal sedation or paralysis.36–38 As more experience is gained with these techniques, it may well become possible to deﬁne the anatomy of the tumor much more accurately, and it may even be possible to accurately determine the blood supply to the tumor in utero. The improved diagnosis and the almost uniform mortality rate associated with fetal hydrops have provided a considerable impetus for some groups to consider fetal surgery for selected cases of antenatally diagnosed sacrococcygeal teratomata. The groups in San Francisco and at Children’s Hospital of Philadelphia have had the greatest experience with this approach,39–43 although other groups have also attempted fetal surgery44 or percutaneous shunting or drainage to allow vaginal delivery45,46 for these tumors. The results, so far, have been mixed.39–46 A detailed discussion of this aspect of the management of sacrococcygeal teratomata is beyond the scope of this chapter, but it would be fair to say that the role of fetal intervention in the presence of this tumor has not yet been deﬁned. One further presentation (not often reported) is when the tumor becomes impacted during delivery and either causes the death of the fetus by obstructing delivery, or the tumor ruptures during delivery and the infant bleeds to death shortly after birth.28,47–49

CLINICAL FEATURES

Figure 75.1 Sacrococcygeal tumors as classiﬁed by Altman et al18

Most cases presenting as neonates to pediatric surgeons will have a large skin-covered mass protruding from the coccygeal region, pushing the anus and vagina anteriorly (Fig. 75.2). There may be large veins visible on the surface and these usually drain into the surrounding

Postnatal diagnosis 705

Figure 75.2 Premature infant with a large sacrococcygeal tumor that weighed almost as much as the rest of the infant. Note the displacement of the anus (arrow) and the vulva

structures. Large tumors may have ruptured (in which case they will bleed profusely) or may have an ulcerated area on the surface. Neonates with a tumor approaching the size of the rest of their body may be delivered prematurely and will often have some features of nonimmune hydrops.21,23–29,31,32 Infants presenting with malignant tumors usually present with a rapidly growing buttock mass.50,51 In such cases, distant metastases are usually present at diagnosis. With the increasing use of antenatal ultrasound in many countries in recent times, this should become an extremely rare presentation. The management of these tumors is beyond the scope of this chapter. Recent advances in multimodal therapy of these tumors has resulted in survival rates as high as 80%.52 Children and adolescents with a benign presacral tumor usually present with constipation or urinary retention.15,17,53–55 A retrorectal mass is easily recognizable on rectal examination. Again, management of these tumors is beyond the scope of this chapter. In all cases, the tumor is ﬁrmly attached to and may be said to arise from the anterior surface of the coccyx. It may displace the coccyx posteriorly, but almost without exception, the sacrum is normal. The current author has seen one infant who was delivered at 30 weeks’ gestation with a large sacrococcygeal teratoma associated with agenesis of the coccyx and the last two sacral vertebrae.24 Very rarely, however, the tumor can extend superiorly. In one reported case, the tumor extended within the spinal canal as high as T4.56 In most cases, the majority of the blood supply to the tumor is derived from the middle sacral artery5,57 and during removal, once this vessel is controlled, blood loss is usually minimal. This is not always the case and a preliminary abdominal procedure to control the middle sacral artery in very large tumors, as suggested by some authors recently,58–60 can occasionally yield very

disappointing results, with only a very small vessel being identiﬁed.61 In addition, on two occasions in the current author’s personal series, the bulk of the venous drainage from the tumor returned through the sacral hiatus and back to the azygous system via a large network of very friable epidural veins. This resulted in a frighteningly large loss of blood when the sacrum was divided. In both cases, the initial blood loss was controlled with pressure and the middle sacral artery was rapidly controlled, allowing the deﬁnitive control of the bleeding from the divided sacral canal with gelfoam on one occasion and bone wax on the other. With the improvement of the resolution of modern ultrasound machines and the introduction of color ﬂow mapping using Doppler ultrasound, it may be possible to determine whether the venous return is via the sacral hiatus. The limited experience from the current author’s center suggests that this is possible. However, it should be stated that in the very few patients in which preoperative color ﬂow mapping has been used, no sacral ﬂow has been noted either on ultrasound or at operation. Clearly, more experience is needed before this technique can be recommended as a routine part of the preoperative work-up. Some authors have advocated laparoscopic procedures to divide the middle sacral artery;60 this may be technically difﬁcult if there is a large intra-abdominal component of the tumor.

POSTNATAL DIAGNOSIS The major differential diagnosis that should be considered is an anterior meningocele. This can usually be ruled out by physical examination, including rectal examination. In sacrococcygeal teratoma, the rectal examination will invariably reveal a solid presacral component. If an anterior meningocele is present, this will be cystic, and an anterior sacral defect will often be palpable. Dillard et al. point out the need to observe the anterior fontanelle during the rectal examination.4 In anterior meningocele, pressure on the sacral mass will result in a bulging fontanelle. The diagnosis can be conﬁrmed by radiography of the lumbosacral region, which will show a characteristic defect in the sacrum in a patient with a meningomyelocele. Another recently described addition to the list of differential diagnoses is a sacrococcygeal chordoma.62 Lemire et al. have produced a list of 20 different lesions that can possibly enter into the differential diagnosis.63 Most of these are extremely rare, but will usually be distinguishable from sacrococcygeal teratoma on careful physical examination. An abdominal ultrasound is useful to determine the size and consistency of any pelvic or abdominal component. It may be necessary to pass a catheter into the bladder and ﬁll the bladder with water to allow it to be used as a sonic window.

706 Sacrococcygeal teratoma

With the rapid improvements in magnetic resonance imaging (MRI) technology, it is now possible to utilize MRI in neonates with minimal sedation, although in most cases a general anesthetic is still required for a detailed examination. Software packages allowing the use of MRI to delineate vascular anatomy are now available.64–66 If oil is instilled into the rectum during the MRI examination while T1-weighted images are gathered, then the oil can be used as a contrast medium during the scan.67,68 MRI should clearly distinguish between sacrococcygeal teratoma and anterior meningocele, and may be able to detect the occasional extension of the tumor through the sacral hiatus into the spinal canal.56

PREOPERATIVE MANAGEMENT If the lesion is intact and the infant is stable, then there is no need for immediate resection. However, a case can be made for resecting these lesions within the ﬁrst 24 hours after birth, since the gut is not usually colonized in the ﬁrst 24 hours after birth. Early resection, therefore, will reduce the risk of infection if the ﬁeld is contaminated by stool during the resection. Perioperative antibiotics are advisable. They should be given immediately before surgery commences and be continued for 24–48 hours postoperatively. If the infant has been fed, or is several days old, then a case can be made for a formal bowel preparation prior to the operation. Blood should be cross-matched, and adequate intravenous access is vital. An arterial line may also be useful during the operation. It is worthwhile to obtain blood for alphafetoprotein levels before surgery as a baseline, in order to conﬁrm postoperatively that alphafetoprotein levels continue to fall at a normal rate. 25,69-71 It should be noted that in very rare cases, the alphafetoprotein level might not be elevated.72 If the tumor has ruptured, then a pressure bandage may stem the blood loss for a brief time. However, there is some concern that this may ‘squeeze’ immature cells into the venous drainage from the tumor. These cells will most likely lodge in the lungs. However, failure to slow the rate of blood loss in these infants may ensure that metastatic disease is not a problem for that infant. Obviously, emergency surgery is indicated in these circumstances. There is often a reluctance to attempt the surgical removal of a tumor that might be as large as the rest of the baby. There can be an understandable desire to let the baby grow before attempting the removal of the tumor, which will most likely be benign. This temptation should be resisted, however, as the risk of malignancy increases with age, suggesting that many of the tumors that were benign at birth become malignant after about 2 months.3,5,7,8,12,15 If a surgeon in a

peripheral hospital encounters one of these lesions, then transfer to a pediatric surgical unit is advisable, if this is possible.

OPERATION The patient is anesthetized, intubated and positioned prone with a roll under the hips. The roll is positioned so that the infant’s weight is taken on the anterior superior iliac spines. It is vital that the abdomen be left hanging free to ensure that respiration is not inhibited by the baby’s weight. For this reason, the baby’s shoulders should be supported either by a smaller roll lying transversely across the apex of the chest at the level of the medial ends of the clavicles, or by two rolls running parallel to the spine, each supporting the glenohumeral joints. The former option is illustrated in Fig. 75.3. A catheter should be placed in the bladder to measure urine output throughout the procedure. Many authorities state that the anus should be ‘prepped’ out of the ﬁeld.12,73 This author ﬁnds that approach both inconvenient and impractical, as access to the anus is often required during the procedure. The cautery pad can usually be placed across the shoulders. A clear plastic drape may conserve body heat and assist in prevention of hypothermia. The addition of a perforated blanket through which is pumped warmed, ﬁltered air also helps to maintain body temperature. A chevron incision is made in the skin over the dorsum of the mass (Fig. 75.4a,b) and it continued down to fascial layers. It is preferable not to dissect beyond the level of the deep fascia at this stage of the dissection. There are often several large veins in the subcutaneous tissue on either side of the midline; these should be divided between ties. The incision should be placed so as to preserve as much normal skin as possible. Excess skin can always be trimmed later if necessary. The apex of the chevron should be over the lower sacrum. In

Figure 75.3 Infant with a sacrococcygeal teratoma positioned for surgical resection of the tumor. Note the large transverse roll under the pelvis and the smaller roll under the upper chest

Operation 707 Incision

(a)

Middle sacral vessels

(a)

Middle sacral vessels

(b) Figure 75.4 (a) Lateral view of the incision over the tumor. All normal skin that can possibly be preserved is retained, to be trimmed later if necessary. (b) Skin incision in the infant shown in Figure 75.2. Her head is to the right

the midline, the dissection should continue directly down to the sacrococcygeal junction, or even down to the fourth or ﬁfth sacral vertebra. The edges of the sacrum are deﬁned, and a clamp is passed across the sacrum at this level, keeping the tips of the forceps against the ventral surface of the bone (or cartilage) to ensure that the forceps pass between the sacrum and the underlying middle sacral vessels, which are usually substantial vessels, supplying the bulk of the blood supply to the tumor. Once this maneuver is complete, the sacrum (which is usually completely, or at least largely, cartilaginous) can be divided with a scalpel and the tumor displaced slightly inferiorly to expose the middle sacral vessels (Fig. 75.5a,b). As mentioned earlier, this can very rarely result in catastrophic blood loss from the epidural veins, if the bulk of the venous return is passing back to the baby via the sacral hiatus. It may be necessary to divide some of the attachments of the thinned-out remnants of the levators to the edges of the lower end of the sacrum and coccyx to enable the distal portion of the sacrum and coccyx to be displaced caudally. The middle sacral vessels are then ligated in

(b)

Figure 75.5 (a) Sacrum divided with the middle sacral vessels slung on ties. (b) The divided ﬁfth sacral vertebral body, showing the tumor arising from the ventral surface of the coccyx

continuity and divided. This early division of the middle sacral vessels is essentially the same as the procedure advocated by Smith et al. 57 This maneuver opens a plane of dissection that is outside the tumor capsule, but deep to the thinned-out remnants of the levators and gluteus maximus. The levators may be so thin as to be almost invisible (Fig. 75.6), but they will contract on stimulation, either with a muscle stimulator or the electrocautery. The dissection should continue laterally in this plane either side of the midline until the muscles are lost in the fascia of the tumor. At this point, they can be divided along a line parallel to the skin incision. This will allow the tumor to be further displaced in a caudal direction. Attention is then directed to the pelvic extension of the tumor. Using blunt dissection with peanut swabs in the plane anterior to the middle sacral vessels, it is usually possible to displace the pelvic component of the tumor anteriorly until its upper extent is reached. This is normally an essentially avascular plane anterior to the

708 Sacrococcygeal teratoma

Figure 75.6 The sacrum has been divided and the forceps demonstrate the thinned-out levators (the head is to the right)

sacrum, although some vessels feeding into the tumor from the internal iliac vessels may be encountered laterally. These can usually be controlled with cautery. In most cases, the tumor can be dissected out from the pelvis and rolled inferiorly over the patient’s legs (Fig. 75.7). This maneuver exposes the upper end of the rectum, which can be identiﬁed by a Vaseline gauze pack (placed immediately before the operation is commenced) or by passing a ﬁnger in through the anus. The tumor can be dissected off the rectum with a combination of sharp and blunt dissection, and rolled inferiorly until the plane of dissection moves away from the rectum and the anal canal. At all times during this dissection, it is best to try to maintain the plane of dissection on the capsule of the tumor and to preserve all normal structures no matter how distorted and thinned-out they are. As the tumor is rolled inferiorly, it eventually becomes apparent that the plane of dissection has reached the subcutaneous tissue

Levators

along the inferior surface of the tumor, posterior to the anus. Once the dissection has reached this point, the dissection can be terminated as long as the inferior skin ﬂap that has been developed is of sufﬁcient length to allow easy closure of the wound (Fig. 75.8). The inferior skin ﬂap can then be divided from the tumor and the tumor delivered from the ﬁeld. A careful check of the tumor bed is carried out to ensure that meticulous hemostatis has been achieved. If the peritoneum has been opened during the pelvic dissection, then it is closed if possible. Attention is then directed to reconstruction of the pelvic ﬂoor and closure of the wound. The remnants of the levator sling are identiﬁed and the central portion is sutured to the perichondrium of the anterior surface of the sacrum using 5-0 Maxon® (Cynamid Tyco Healthcare Group, Norwalk, Connecticut 06856 USA) (a monoﬁlament absorbable suture) (Fig. 75.9a,b). This same suture is used for all subsequent muscle and fascial reconstruction. These initial fascial sutures, rather than the skin closure, should determine the siting of the anus. This aspect of the reconstruction, therefore, should be carried out with care to ensure both a functional and cosmetically pleasing result. If a drain is to be placed, then it is placed at this stage, in the presacral space, led out through the gap in the levators and tunnelled out through the subcutaneous tissue of the buttock. A closed- suction drain is preferred. If there are remnants of the levators recognizable lateral to the midline, these are repaired with interrupted 5-0 Maxon sutures. The medial edges of gluteus maximus are then closed in the midline over the sacrum and the lower part of the levator sling (Fig. 75.10). The skin ﬂaps are then trimmed to length. If possible, the

Rectum

Coccyx

Figure 75.7 Completion of the pelvic dissection with the tumor rolled inferiorly, exposing the rectum

Figure 75.8 Completion of the pelvic dissection. The tumor has been dissected off the rectum (arrow) and the dissection has reached the stage where the division of the inferior skin ﬂap can be contemplated. (Same patient as Fig. 75.2; the head is to the right.)

Operation 709

Levators

(a)

subcutaneous tissues are closed with a running 5-0 polyglycolic acid suture and the skin is closed with a running 5-0 polyglycolic acid subcuticular suture. A Steristrip and collodion dressing is then applied. If it is not possible to close the subcutaneous tissue, then a subcuticular suture may not be adequate for skin closure. In this case, 5-0 nylon skin sutures are placed (Fig. 75.11a,b). The rectum is packed with Vaseline ribbon gauze at the completion of the procedure in an attempt to obliterate dead space. It is useful to suture a 2-0 silk suture to the end of this pack to aid its retrieval, should the pack become displaced higher up the rectum in the immediate postoperative period. Preliminary abdominal exploration is indicated in three circumstances: 1 If there is a large abdominal component73,74 2 If the tumor has been ruptured and is actively bleeding61 3 In the rare case when a premature baby is delivered in a hyperdynamic state and preliminary devascularisation is needed to stabilize the patient before proceeding to deﬁnitive resection.29

(b) Figure 75.9 (a) Levators sutured to the perichondrium of the sacrum. These sutures set the anal position. (b) The levators have been sutured to the sacral perichondrium, resulting in the setting of the deﬁnitive anal position. (Arrow indicates the anus: same patient as in Fig. 75.2; the head is to the right.)

(a)

Glutei

(b)

Figure 75.10 Closure of the glutei, posterior to the sacrum. This closure is continued inferior to the divided sacrum

Figure 75.11 (a) Diagrammatic representation of the completed skin closure. (b) End result in the same patient illustrated in Figure 75.2

710 Sacrococcygeal teratoma

In these cases, the abdomen is opened via a transverse infra-umbilical incision placed just below the upper limit of any intra-abdominal mass or just below the umbilicus if there is no abdominal component. In either case, the aim is to ﬁnd and ligate and then divide the middle sacral vessels if at all possible. If this is not possible, then either an arterial occlusive sling61 or a small vascular clamp is placed across the aorta below the origin of the inferior mesenteric artery. The abdomen is closed temporarily with a running 3-0 nylon mass closure and dressed with a clear plastic adhesive dressing. The patient is repositioned and the tumor is then resected from behind as outlined previously. When the pelvic portion of the dissection is completed, the patient is repositioned in the supine position and the clamp or aortic occlusive sling is removed before the abdomen is closed in layers with 4-0 Maxon sutures to the fascia and 5-0 Dexon subcuticular sutures to the skin. More recently, some authors59 have advocated an abdominoperineal approach in all cases with routine devascularization of the tumor through an abdominal approach, followed by resection of the tumor (under the same anesthetic) with the patient in the supine position. Some surgeons in Melbourne (B. Bowkett, personal communication) also advocate resection of the tumor in the supine position, with the initial incision being in the midline, extending from the sacrum down to the tumor. These authors cite the ability to devascularize the tumor from the abdominal approach and the ease with which external cardiac massage can be applied as the main advantages of this approach. The current author retains signiﬁcant reservations about this approach. There is a need to control the blood supply to the tumor from above in a minority of cases and it is felt that if there is a signiﬁcant venous drainage through the epidural veins, then blood loss from this source would be extremely difﬁcult to control with the patient in the supine position.

months to return to normal. The infant should then be followed at monthly intervals for 3 months and then at 3-monthly intervals for 1 year. At each visit, a rectal examination will detect any local recurrence and an alphafetoprotein level will detect any distant spread. The alphafetoprotein level is often very high (of the order of ’100 000 IU or more25,69) and even in normal babies it may be over 100 000 IU.69–71 These high levels usually take over a year to fall to normal adult levels. As long as the alphafetoprotein level continues to fall steadily, recurrence is thought to be unlikely. However, it is important to not rely solely on the alphafetoprotein levels, as in one patient in the current author’s series, a very large pelvic recurrence (sufﬁciently large to produce urinary obstruction) occurred in the presence of a continuously falling alphafetoprotein level. None of the other patients who developed recurrent tumors (including the patient who developed metastases in the inguinal lymph nodes) showed a rise in the alphafetoprotein levels. Follow-up should continue for at least 5 years, and preferably through puberty, if at all possible. It is important to obtain renal ultrasounds on an annual basis for the ﬁrst few years, and vital to obtain one on an urgent basis if there are any new urinary symptoms. One patient in the current author’s series had a normal renal ultrasound close to her second birthday in April. In September of that year, she presented for routine follow-up with a history of having had three urinary tract infections in the last 2 months. A renal ultrasound obtained shortly after that visit revealed severe hydronephrosis bilaterally, and her serum creatinine level was signiﬁcantly elevated, having been normal only a few months before. Urodynamic studies revealed that she had a hostile, high-pressure neurogenic bladder. The hydronephrosis resolved considerably with the introduction of clean intermittent catheterization, although this has placed a considerable strain on the family.

POSTOPERATIVE MANAGEMENT

PROGNOSIS

The infant is nursed in a prone position for several days postoperatively. The urinary catheter can be removed as soon as the baby’s condition is stable and the infant can be extubated as soon as its respiratory condition allows. The infant can usually be fed as soon as it is extubated. The Vaseline pack is usually removed in the ﬁrst postoperative day by pulling on the 2-0 silk suture left attached to the distal end. Any drain can usually be removed within the ﬁrst few days of the procedure. Alphafetoprotein levels should be determined immediately postoperatively and on discharge. In spite of the fact that alphafetoprotein is stated to have a half-life of only 3 days, the levels usually take several

In the absence of distant metastases at presentation, and if the excision is complete, then the life expectancy should be normal, although the appearance of the buttocks usually leaves something to be desired (Fig. 75.11b). Continence, surprisingly, is usually normal, although the cautionary tale mentioned earlier should be noted. There are very few papers in the literature that focus on long-term outcome. One recent paper49 reported the results in a series of 23 patients followed for up to 22 years. Four patients with malignant tumors had recurrence-free intervals ranging from 9–14 years. They had two patients with nocturnal enuresis, one of which

References 711

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magnetic resonance imaging of fetal sacrococcygeal teratoma. Acta Obstet Gynecol Scand 1997; 76:917–22. Okamura M, Kurauchi O, Itakura A et al. Fetal sacrococcygeal teratoma visualized by ultra-fast T2 weighted magnetic resonance imaging. Int J Gynaecol Obstet 1999; 65:191–3. Lwakatare F, Yamashita Y, Tang Y et al. Ultrafast fetal MR images of sacrococcygeal teratoma: a case report. Computerized Med Imaging & Graphics 2000; 24:49–52. Bullard KM, Harrison MR. Before the horse is out of the barn: fetal surgery for hydrops. Semin Perinatol 1995; 19:462–73. Graf JL, Housely HT, Alabanese CT et al. A surprising histological evolution of preterm sacrococcygeal teratoma. J Pediatr Surg 1998; 33:177–9. Paek BW, Jennings RW, Harrison MR et al. Radiofrequency ablation of human fetal sacrococcygeal teratoma. Am J Obstet Gynecol 2001; 184:503–7. Kitano Y, Flake AW, Crombleholme TM et al. Open fetal surgery for life-threatening fetal malformations. Semin Perinatol 1999; 23:448–61. Graf JL, Alabanese CT, Jennings RW et al. Successful fetal sacrococcygeal teratoma resection in a hydropic fetus. J Peditar Surg 2000; 35:1489–91. Hecher K, Hackeloer BJ. Intrauterine endoscopic laser surgery for fetal sacrococcygeal teratoma. Lancet 1996; 347:470. Garcia AM, Morgan WMIII, Bruner JP. In utero decompression of a cystic grade IV sacrococcygeal teratoma. Fetal Diagn Ther 1998; 13:305–8. Kay S, Khalife S, Laberge JM et al. Prenatal percutaneous needle drainage of cystic sacrococcygeal teratomas. J Pediatr Surg 1999; 34:1148–51. Sarlo K. Total rupture of giant sacrococcygeal teratoma. Kinderchirurgie 1984; 39:405–6. Hoehn T, Krause MF, Wilhelm C et al. Fatal rupture of a sacrococcygeal teratoma during delivery. J Perinatol 1999; 19:596–8. Schmidt B, Haberlik A, Uray E et al. Sacrococcygeal teratoma: clinical course and prognosis with a special view to long-term functional results. Pediatr Surg Int 1999; 15:573–9. Chretien PB, Milam JD, Foote FW et al. Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region: clinical and pathologic aspects of 21 cases. Cancer 1970; 26:522–35. Ein SH, Mancer K, Adeyemi SD. Malignant sacrococcygeal teratoma endodermal sinus, yolk sac tumor – in infants and children: a 32-year review. J Pediatr Surg 1985; 20:473–7. Gobel U, Schneider DT, Calaminus G et al. Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 2001; 19:1943–50. Ghazali S. Presacral teratomas in children. J Pediatr Surg 1973; 8:915–18.

54. Gwinn JL, Dockerty MB, Kennedy RLJ. Pre- sacral teratomas in infancy and childhood. Pediatrics 1955; 16:239–49. 55. Swinton NW, Lehman G. Presacral tumors. S Clin N Am 1958; 38:849–57. 56. Ribeiro PR, Guys JM, Lena G. Sacrococcygeal teratoma with an intradural and extramedullary extension in a neonate: case report. Neurosurgery 1999; 44:398–400. 57. Smith B, Passaro E, Clatworthy HW. The vascular anatomy of sacrococcygeal teratomas: its signiﬁcance in surgical management. Pediatr Surg 1961; 49:534–9. 58. Angel CA, Murillo C, Mayhew J. Experience with vascular control before excision of giant, highly vascular sacrococcygeal teratomas in neonates. J Pediatr Surg 1998; 33:1840–2. 59. Kamata S, Imura K, Kubota A et al. Operative management for sacrococcygeal teratoma (SCT) diagnosed in utero. J Pediatr Surg 2001; 36:545–8. 60. Bax NM, van der Zee DC. Laparoscopic clipping of the median sacral artery in huge sacrococcygeal teratomas. Surg Endosc 1998; 12:882–3. 61. Lindahl H. Giant sacrococcygeal teratoma: a method of simple intraoperative control of hemorrhage. J Pediatr Surg 1988; 23:1068–9. 62. Cable DG, Moir C. Paediatric sacrococcygeal chordomas: a rare tumour to be differentiated from sacrococcygeal teratoma. J Pediatr Surg 1997; 32:759–61. 63. Lemire RJ, Graham CB, Beckwith JB. Skin-covered sacrococcygeal masses in infants and children. J Pediatr 1971; 79:948–54. 64. Davis WL, Warnock SH, Harnsberger HR et al. Intracranial MRA: single volume vs multiple thin slab 3D time-of-ﬂight acquisition. J Comp Assist Tomogr 1993; 17:15–21. 65. Marchal G, Michiels J, Bosmans H et al. Contrastenhanced MRA of the brain. J Comp Assist Tomogr 1992; 16:25–29. 66. Ehricke H-H, Schad LR, Gadermann G et al. Use of MR angiography for stereotactic planning. J Comp Assist Tomogr 1992; 16:35–40. 67. Pringle KC, Sato Y, Soper RT. Magnetic resonance imaging as an adjunct to planning an anorectal pull through. J Pediatr Surg 1987; 22:571–4. 68. Sato Y, Pringle KC, Bergman RA et al. Congenital anorectal anomalies: MR imaging. Radiology 1988; 168:157–162. 69. Johnston PW. The diagnostic value of alpha-fetoprotein in an infant with sacrococcygeal teratoma. J Pediatr Surg 1988; 23:862–3. 70. Tsuchida Y, Endo Y, Saito S et al. Evaluation of alpha-fetoprotein in early infancy. J Pediatr Surg 1978; 13:155–62. 71. Tsuchida Y, Hasegawa H. The diagnostic value of alphafetoprotein in infants and children with teratomas: a questionnaire survey in Japan. J Pediatr Surg 1983; 18:152–5. 72. Hung TH, Hsieh CC, Hsieh TT. Sacrococcygeal teratoma associated with a normal alpha-fetoprotein concentration. Int J Obstet Gynecol 1997; 58:321–2. 73. Coran AG, Behrendt DM, Weintraub WH et al. Surgery of the Neonate. Boston: Little, Brown, 1978.

References 713 74. Hendren WH, Henderson BM. The surgical management of sacrococcygeal teratomas with intrapelvic extension. Ann Surg 1970; 171:77–84.

75. Marina N, Fontanesi J, Kun L et al. Treatment of childhood germ cell tumours. Review of the St Jude Experience from 1979 to 1988. Cancer 1992; 70:2568–75.

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76 Nasal tumors ALFRED LAMESCH AND PETER LAMESCH

INTRODUCTION There are various types of congenital tumors and they may be classiﬁed in accordance with their embryonic origin (Box 76.1).

EMBRYOLOGY At an early stage of development there is a protrusion of the forebrain and dura through the foramen cecum into the prenasal space, which is limited by frontal and nasal bones on the anterior aspect and a cartilaginous capsule posteriorly. During further development the dural process is sealed and the foramen obliterated. Any failure of this obliterating procedure leaves a canal, a pathway favoring extension of the glial tissue, hence the development of encephaloceles or gliomas. An encephalocele is a herniation of brain tissue into the prenasal space; a glioma is derived from an encephalocele sequestered from the brain.

Box 76.1 Classiﬁcation of nasal tumors by embryonic origin Ectodermal group Dermoid cyst Dermoid sinus Neurogenic group Meningocele Encephalocele Glioma Neuroﬁbroma Mesodermal group Hemangioma Vascular malformation Mixed origin Teratoma

The frontal and nasal bones are formed by intramembranous ossiﬁcation. At this stage of development, there is a gap between those bones, the fonticulus nasofrontalis, ﬁlled by a membrane; the dura and the skin are in contact without interposition of bony tissue. Part of the ectoderm may fail to separate from the dura and so remain in the depth of the prenasal space. This displaced ectopic ectodermal tissue is the origin of a dermoid cyst. If a connection with the skin exists, a dermoid sinus will result. All these tumors are located in the midline (nasofrontal) or asymmetric unilateral (naso-ethmoidal) position. They are present at birth. They often produce hypertelorism, telecanthus and nasal deformity.

CONGENITAL TUMORS OF NEUROGENIC ORIGIN Nasal glioma Gliomas of the nose are rare;1 their incidence is one in 250 000 births with a male-to-female ratio of 3:1.2,3 Nasal gliomas account for approximately 20% of all congenital nasal masses;4 53% of the tumors are extranasal, 34% intranasal, while 13% are both extra- and intranasal.1 A comprehensive description and review of 176 cases reported in the literature was published by Lamesch et al.1 A nasal glioma is a ﬁrm, gray-pink to purple, rounded or dome-shaped polypoid, non-compressible and nonpulsatile mass of glial tissue of congenital origin that may appear in an extranasal or intranasal location at or near the root of the nose (Fig. 76.1). They show no impulse when the patient cries. The covering skin may look like a hemangioma. Gliomas are unilateral or in the midline, but are usually located at the side of the nasal bridge. The root of the nose is often enlarged; there may be an orbital hypertelorism. The diameter of the tumor varies from 1–3 cm. Their growth rate is usually the same as that of tissues in the region, according to the infant’s growth.

716 Nasal tumors

nasal tumors from basofrontal encephaloceles to avoid inadvertent exposure of the brain during the surgical removal of mass lesions. For congenital tumors of neurogenic origin, it is important to make the diagnosis of a possible connection to an intracranial lesion in the anterior cranial fossa. Computed tomography (CT) scanning is useful to visualize bony defects, but is not reliable for soft-tissue contrast. Magnetic resonance imaging (MRI) is superior for imaging brain tissue; it should therefore be used preferentially for deﬁnition of the tumor mass, to disclose intracranial extension.

TREATMENT

Figure 76.1 Nasal glioma in a newborn

The intranasal type is located high in the nasal fossa. The septum may be displaced and the nasal passage may be obstructed. Increased lacrimation may result from compression of the lacrimal duct. These tumors may present as early neonatal respiratory distress.5 In intra–extranasal gliomas, there is a communication between the two components of the tumor, usually through a defect in the nasal bone or at the lateral margin of the nasal bone. Nasal gliomas are benign tumors; malignant degeneration has not been described. Recurrences, due to incomplete excision, are rare (11%). In 13% of the cases, there is a connection with the intracranial nervous system by a pedicle of glial or ﬁbrous tissue, passing through the cribriform plate. Levine et al. reported a case in which a nasal glioma was masqueraded as a capillary hemangioma with a subsequent inadequate treatment, which documents the eventual need of a histologic examination.6

Though benign and relatively slow-growing, these tumors can cause disturbances of growth and subsequent deformity by encroachment upon the bony framework of the nose. Furthermore, they are unsightly and some of them, located at the root of the nose such as encephaloceles and gliomas may interfere with vision. Hence, early surgical treatment is advisable. Complete surgical excision of nasal gliomas – with repair of any hypertelorism – is the treatment of choice. The most conservative cosmetic surgical technique should be chosen if intracranial connection is ruled out.

TECHNIQUE An elliptical incision is made around the base of the tumor and the mass is removed in toto. In order to avoid recurrences, it is important to excise or coagulate the small deep stalk, which may pass upwards for a short distance under the nasal bone. This tract is exposed by splaying open the nasal bones through a midline nasal incision. In the case of a high situated intranasal glioma, an extracranial extranasal approach may be necessary to provide wide access to the nasal cavity. Lateral rhinotomy is most often used. Burkhardt and Tobson described an endoscopic approach in a case with intranasal glioma.7 In cases with an intracranial lesion, craniotomy is mandatory.

HISTOLOGY

COMPLICATIONS

A glioma consists of glial and ﬁbrous tissue with an overlying ﬂattened epidermis. Astrocytes are the predominant cell type. It does not contain a cerebrospinal ﬂuid (CSF)-ﬁlled space communicating with the ventricular system of the brain or the subarachnoid space.

Incomplete excision This can be avoided by preoperative imaging and careful dissection in order to expose a stalk or a possible intracranial connection. Complete excision prevents recurrence.

DIAGNOSIS – IMAGING Preoperative imaging is essential for planning the appropriate surgical approach by delineating the exact site and extension of the tumor. It is important to distinguish

Dural defect As normally there is no permeable communication with the subdural space, an accidental dural defect is theoretical. Should it occur, it must be promptly closed to prevent a CSF ﬁstula. If such a defect is large, an epicranium graft may be needed for safe tight closure.

Congenital tumors of neurogenic origin 717

Hematoma This can be avoided by careful hemostasis with bipolar coagulation: Skin defect In some cases the skin defect is closed directly. Large defects can be covered by free skin grafting, by glabellar skin ﬂaps or by tissue expansion: 1 Free skin graft. This is an ideal method for covering skin defects, when there is a suitable recipient ground. Reconstruction is obtained without additional scars. The technique is easy and the cosmetic result is excellent. The graft takes in almost all cases. The best skin graft is a retro-auricular fullthickness skin graft.

(a)

(c)

Figure 76.2 (a–c) Classic glabellar ﬂap

2 Flaps. The skin in the glabellar donor area provides a good color and texture match for the resurfacing of the upper nasal defect. The glabellar ﬂap can be transferred in three ways: as a classic glabellar ﬂap, as a midline transposition ﬂap and as an island ﬂap: • Classic glabellar ﬂap. The time-honored reconstructive technique in the upper nasal area. The drawback is that eyebrow hair may be moved down into the medial canthal area by rotation of the skin (Fig. 76.2a–c). • The most versatile ﬂap is the midline transposition ﬂap or ﬁnger ﬂap, which is a good method for reconstructing the glabellar region. The ﬁnger ﬂap is reliable and suitable. The ﬁnger has a simple design and allows transfer of the thin

(b)

718 Nasal tumors

non-hair-bearing skin. The harvesting area is closed directly. If the ﬂap has any skin excess, it will be exhibited by a standing cone in the inferior rotation area. This excess can be trimmed without any problem of blood supply. The result of this method is usually excellent (Fig. 76.3a–c). • The glabellar island ﬂap is an interesting procedure, but it takes longer. Magniﬁcation is recommended. The main advantage of this technique is the lack of skin distortion, i.e. a standing cone. The harvesting defect is closed directly with excision of triangles of skin superiorly and inferiorly. There is no deformation of local morphology. The initial swelling due to the subcutaneous pedicle will subside with time (Fig. 76.4a–d).

(a)

(c)

Figure 76.3 (a–c) Finger ﬂap – midline transposition ﬂap

3 A new method could be used: tissue expansion as described by Radovan.8 This is a two-stage procedure.

Meningocele and encephalocele The encephalocele is a protrusion of brain inside a dural sac through a skull defect. The tumor contains an ependyma-lined space ﬁlled with CSF which communicates with the ventricular system. Encephaloceles are located at the root of the nose, midline (nasofrontal) or asymmetric lateral (naso-ethmoidal).9 The bridge of the nose is broadened and often hypertelorism and nasal deformity are produced. Depending on the contents, meningoceles and encephaloceles are taut or soft,

(b)

Congenital tumors of neurogenic origin 719

(a)

(b)

(c)

(d)

Figure 76.4 (a–d) Glabellar island ﬂap

compressible and pulsatile tumors, enlarging when the patient cries.

PREOPERATIVE EXAMINATION The defect at the base of the skull is demonstrated by radiological examination. Intracranial lesions are best disclosed by MRI or CT scanning.

COMPLICATIONS The main postoperative complication is leakage of CSF because of a large dural defect. This must be tightly closed to prevent a ﬁstula. If the defect is too large for direct closure, an epicranial or a fascia lata graft may be used.

TREATMENT

Congenital dermoid cysts and dermoid sinus

The treatment of choice is excision of the tumor with the herniated brain and tight closure of the dural defect. Usually there are no problems for closure of the wound, the covering skin being normal.

Congenital dermoid cysts are the most frequently found congenital nasal tumors. They are usually located along the midline of the nose. The dermoid sinus appears externally as a dimple with protruding hair. The dimple

720 Nasal tumors

usually leads to a sinus tract which extends along the nasal septum, underneath the nasal bones, toward the base of the anterior cranial fossa; it may enter the skull (dumb-bell cyst).

HISTOLOGY Dermoid cysts and sinuses are lined by squamous epithelium with various dermal appendages such as glands and hair follicles.

COMPLICATIONS Repeated infections may form multiple sinus tracts, making complete excision difﬁcult. The mass of the cyst may erode nasal bones and associated sinuses.

TREATMENT The treatment of choice is operative removal, preferably before infections occur.

TECHNIQUE A midline nasal incision and excision of the mass is the best technique. The tract passing into the nasal septum must be exposed by opening the nasal bones. All epithelial elements must be removed. The stalk is carefully dissected cephalad; if it enters the skull, a craniotomy is mandatory in order to remove the intracranial part of the lesion.

REFERENCES 1. Lamesch P, Froment N, Lamesch AJ. Nasal glioma. Report of a case and review of the literature. Pediatr Surg Int 1988; 3:176–80. 2. Lehner M, Rickham PP. Tumours of the head and neck. In: Rickman PP, editor. Neonatal Surgery. 2nd edn. London: Butterworths, 1978:91–2. 3. Whitaker SR, Sprinkle PM, Chou SM. Nasal glioma. Arch Otolaryngol 1981; 107:550–4. 4. Hughes GB, Sharpino G, Hunt W. Management of the congenital midline nasal mass. Head Neck Surg 1980; 2:222–3. 5. Puppala B, Mangurten HH, McFadden J et al. Nasal glioma. Presenting as neonatal respiratory distress. Deﬁnition of the tumor mass by MRI. Clin Pediatr 1990; 29:49–52. 6. Levine M, Kellis A, Lash R. Nasal glioma masquerading as a capillary hemangioma. Ophthalmic Plast Reconstr Surg 1993; 9:132–4. 7. Burkhardt W, Tobon D. Endoscopic approach to nasal glioma. Otolaryngol Head Neck Surg 1999; 120:747–8. 8. Radovan C. Tissue expansion in soft-tissue reconstruction. Plast Reconstruct Surg 1984; 74:482–92. 9. Turgut M, Ozcan OE, Benli K et al. Congenital nasal encephalocele: a review of 35 cases. J Craniomaxillofac Surg 1995; 23:1–5.

77 Neuroblastoma RAYMOND J. FITZGERALD

INTRODUCTION Malignant neoplasia presenting in the neonatal period is rare.1–6 Neuroblastoma is the most common malignant tumor found in neonates and infants younger than 1 year old. Approximately 50% of cases of neuroblastoma occur during the ﬁrst 2 years of life.7 It is a neoplasm of the sympathetic nervous system made up of primitive cells derived from the neural crest. Neuroblastoma may originate in any of those sites where sympathetic ganglia are found and very rarely even in the central nervous system, but most commonly it arises in the abdomen and particularly from the adrenal glands.3,8 Hays and Smith, in a review of 60 cases of neuroblastoma in infants under 1 year of age, found that the primary site was the abdomen and pelvis in 60% of cases, chest in 33% and neck in 5% of cases.9 Neuroblastoma occurs more frequently in boys (2:1) and the reported incidence is one in 7000–10 000 children.10 This tumor has been detected with increased frequency in patients with neuroﬁbromatosis, Beckwith–Wiedemann syndrome, Hirschsprung’s disease, nesidioblastosis, fetal hydantoin syndrome, fetal alcohol syndrome and others.10 Most embryomas, of which neuroblastoma is an example, are present at birth.11 One major question is whether the prognosis would improve if it were possible to detect these tumors prenatally instead of sometime later. Neuroblastoma in situ in the adrenal gland has been found 40 times more commonly than the disease presents clinically, suggesting that most tumors regress spontaneously.12 Furthermore, there is a signiﬁcant spontaneous regression rate (or conversion to a ganglioneuroma) in clinically detectable neuroblastomas early in life. Neuroblastomas have been identiﬁed prenatally by ultrasonography13 and in infancy by mass screening for urinary metabolites.14 It is difﬁcult to predict which cases detected by screening will regress and which will progress to invasive disease. It seems that the more aggressive tumors are not being picked up at screening and there are several possible reasons for this, including

the timing of the screening process.15 Screening is not yet of proven value but this may change if an alteration of timing is more effective in ﬁnding aggressive disease earlier.16,17 Familial cases of neuroblastomas were reviewed in 1972 by Knudson and Strong18 and, more recently, neural crest tumors by Robertson et al.19 The risk of neuroblastoma in siblings or offspring of patients with neuroblastoma appears to be less than 6%. It seems likely that a hereditary component to the disease is most likely to be present in a relatively select group of patients – perhaps those with multiple primaries and those presenting early, but clinical ﬁndings do not identify hereditary cases. Furthermore, efforts to isolate a familial neuroblastoma predisposition gene have, to date, been unsuccessful.20

CLINICAL FEATURES It seems likely that immune mechanisms protect the mother from transplacental spread of neuroblastoma, but maternal symptoms of sweating, headache and tingling of the hands from the transplacental passage of catecholamines have been described.21 A large, tumorfree placenta has been described, associated with fetal neuroblastoma.22 Neuroblastoma invasion of the placenta has been reported and the cases resembled erythroblastosis fetalis.23–25 The symptoms and signs are related largely to the site of origin of the disease or its metastases. Most neonates will present with abdominal distension and the most common initial sign of neuroblastoma is a palpable abdominal mass. The mass felt is often the grossly enlarged liver from metastatic disease, but may be the primary tumor which is ﬁxed, nodular and may extend across the midline. Sometimes the newborn may present with subcutaneous metastases which are often multiple. The blue tinge to these nodules has led to the use of the term ‘blueberry mufﬁn baby’.26 Respiratory distress, either from diaphragmatic compression by a grossly enlarged liver or from tracheal

722 Neuroblastoma

compression in cervical tumors, is a feature in some cases. In the older child, and less commonly in the neonate, the clinical ﬁndings include those resulting from bony metastases (such as orbital ecchymosis) or spinal cord compression by ‘dumbbell’ tumors. Horner syndrome may be noted when the tumor involves the cervical or upper thoracic sympathetic trunk. Central nervous system manifestation (cerebellar ataxia with opsomyoclonus and nystagmus) has not been described in the neonate. Spinal cord compression can result in hemiplegia by tumor extension through the intervertebral foramina. Pelvic neuroblastoma must be differentiated from other pelvic tumors such as rhabdomyosarcoma or presacral teratoma. Hemorrhage into the tumor has been described in the neonate requiring transfusion.27 Indeed, a bleeding diathesis, with thrombocytopenia, may result from massive bone marrow involvement or clotting factor deﬁciency from massive hepatic involvement. General manifestations such as ‘malignant malaise’, failure to thrive, anemia or malnutrition may be present in advanced disease. Severe diarrhea, due to secretion of vasoactive intestinal peptides (VIPs) by the tumor, is rarely a presenting feature in infants. Hypertension is present in some cases and may be related to excessive catecholamines or secondary effects on the kidney.

STAGING Accurate staging of neuroblastomas is important from a therapeutic and prognostic point of view and also to compare results of treatment accurately. The classiﬁcation described by Evans et al.28 has been widely used, although there are others including Tumor Node Metastrases (TNM)29 and St Judes.30 An internationally agreed staging sytem31–33 has been introduced and is outlined in Table 77.1. This international neuroblastoma staging system (INSS) combines components of initial distribution of disease as well as surgical rectability. Uniform evaluation of response to therapy is also part of the INSS. More recently the system has been modiﬁed and the foundation has been laid for the development of International Neuroblastoma Risk Groups.34 The modiﬁcations include an alteration at the ‘midline’ so that tumors must inﬁltrate to or go beyond the opposite side of the vertebral column. Furthermore, more than 10% of bone marrow involvement in stage 4S would be considered to be a characteristic of stage 4.

INVESTIGATION Plain radiographs of the tumor may appear to show a soft-tissue shadow and may have ﬁnely stippled calci-

Table 77.1 International staging system for neuroblastoma* Stage

Features

1

Localized tumor conﬁned to the area of origin; complete gross excision, with or without microscopic residual disease; identiﬁable ipsilateral or contralateral lymph nodes negative microscopically

2A

Unilateral tumor with incomplete gross excision; identiﬁable ipsilateral and contralateral lymph nodes negative microscopically

2B

Unilateral tumor with complete or incomplete gross excision; with positive ipsilateral regional lymph nodes; identiﬁable contralateral lymph nodes negative microscopically

3

Tumor inﬁltrating across the midline with or without original lymph node involvement; or unilateral tumor with contralateral regional lymph node involvement

4

Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver and/or other organs (except as deﬁned in stage 4S)

4S

Localized primary tumor as deﬁned for stages 1 or 2 with dissemination limited to liver, skin and/or bone marrow

*This staging system, by dividing stage 2 into A and B, takes cognisance of the worse prognosis when lymph nodes are involved (in particular, contralaterally involved nodes) and highlights the need for lymph node biopsy.

ﬁcation, although this is less common in neonates. A chest X-ray will show a thoracic primary or metastases, although less sensitively than would a computed tomography (CT) scan. Cervical and chest neuroblastomas are dealt with elsewhere in this book. In the more common adrenal primary, excretory urography may show renal displacement but this type of imaging has no place currently in the management of neuroblastoma. Widening of the adjacent intervertebral foramina is sometimes seen in paraspinal tumors, indicating extradural extension. The detection of bony metastases by skeletal X-ray survey has largely been superseded by isotope scanning (Fig. 77.1). Nevertheless a conventional skeletal survey is recommended if skeletal scintigraphy is negative, provided that treatment would be altered should it prove to be positive. Radiolabelled metaiodobenzylguanidine (MIBG) scanning has proved important as a discriminant of malignant undifferentiated tumors in infants.35 Primary and recurrent neuroblastoma tumors and metastases can be demonstrated using this technique. Using the radioactive-labelled monoclonal antibody UJ13A, Goldman et al. showed that immunological localization of neuroblastoma is useful in identifying residual disease.36

Investigation 723

Figure 77.2 Large left abdominal neuroblastoma lying in front of left kidney with central area of necrosis (CT scan)

Figure 77.1 Isotope bone scan showing increased uptake in the vault

Ultrasonographic scanning is an important diagnostic tool used to differentiate abdominal masses in the neonate and the baby’s lack of adipose tissue is a help in ultrasound diagnosis. The usual sonographic appearance of an abdominal neuroblastoma is that of a variable echogenic mass depending on the degree of hemorrhage, necrosis and calciﬁcation, compressing or displacing the kidney appropriately (usually ‘down and out’ in the case of the adrenal). CT studies may be carried out alone or with water-soluble contrast myelography if intraspinal extension of the tumor is suspected and in all with intrathoracic or cervical primaries. This imaging method deﬁnes anatomical details and may show extension into adjacent organs and lymph node involvement (Fig. 77.2). However, ultrasonography has been very satisfactory in aiding preoperative planning of surgery. There is great advantage in the surgeon attending the ultrasonographic imaging, and together with the ultrasonographer deﬁning detailed anatomy. In particular, it has proved useful in delineating the tumor relationship to important vessels including the aorta with its coeliac, superior mesenteric and renal branches as well as the inferior vena cava. Magnetic resonance imaging (MRI), has advantages in evaluating childhood neoplasia.37,38–39 In providing excellent differentiation of soft-tissue planes, it does so without the use of ionizing radiation or contrast injection. It also has the ability to evaluate bone marrow metastases and to document if extradural tumor extension has occurred. It may prove useful in the longer term follow-up of patients. However, sedation or anesthesia for these patients may be problematical in

view of the long scanning times involved. It is not indicated in the initial evaluation of children with presumptive abdominal neuroblastoma, but is valuable in selected cases including the assessment of dumb-bell tumors (Fig. 77.3). As a member of the amine precursor uptake and decarboxylation (APUD) group of tumors, which derive from neural crest cells, the greater majority of neuroblastomas secrete a number of metabolites such as catecholamines, dihydroxyphenylalanine (DOPA), dopamine, metanephrine, homovanillic acid (HVA), 3methoxy-4-hydroxymandelic acid (HMMA), known more commonly as vanillylmandelic acid (VMA), and others which may be determined in urine or serum. A positive result will depend on how exhaustively these metabolites are sought.40 As 24-hour collections of urine can prove problematical in children, accurate assessment can be achieved by random sampling and comparing the metabolite excretion to that of creatinine. These tests have proved valuable in the diagnosis and follow-up of patients with neuroblastomas and they may also indicate cell maturity, for example, a VMA/HVA ratio of > 1.5 indicates a better prognosis.

Figure 77.3 Dumb-bell-shaped tumor extending through spinal foramen with minimal compression of the cord (MRI scan)

724 Neuroblastoma

Increased serum levels of neuron-speciﬁc enolase (NSE) and ferritin may indicate advanced aggressive disease, as may the absence of E-rosette inhibitory factor.41–43 NSE levels must be evaluated on the basis of age-related reference values and Berthold et al. found that initial values were not prognostically predictive in stage 4S disease.44 Other less speciﬁc markers have been detected in patients with neuroblastomas, including carcinoembryonic antigen (CEA) lactic dehydrogenase isoenzymes 2 and 3, vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). Tsuchida has reviewed the place of markers in childhood solid tumors.45 Multiple-site bone marrow aspiration and biopsy are necessary staging procedures.46 In bone marrow, the neuroblast is a small, round cell in which the cytoplasm is scanty, nucleus hyperchromatic and the nuclear chromatin coarse. The histology on tumor excision will usually be diagnostic, but imprint cytology and/or special stains including immunocytochemistry using monoclonal antibodies may be needed. Rosette formation may be observed and may be a sign of early tumor differentiation. Most tumors contain eosinophilic neuroﬁbrillary tissue surrounding cells and an increase in this suggests some differentiation. Further maturation to ganglion cells may be seen mixed with neuroblasts or complete replacement with ganglion cells. Electron microscopy may be helpful in undifferentiated tumors and occasionally tissue culture has been helpful in tumor diagnosis.47 Drug sensitivity tests using tissue culture are not in general use currently. Histological features may be of some value in predicting prognosis, but have not been as accurate as has been found in other embryomas such as nephroblastoma.48,49 It will often be possible, in nonresectable disease, to make a diagnosis on clinical features, imaging and biochemistry taken with bone marrow aspirates; however, biopsies by needle or excision of a centimeter cube of tumor specimen, are increasingly seen as necessary to establish the biological features of the disease. Cytogenetic studies on neuroblastoma tissue have shown chromosomal abnormalities, the most common of which is deletion of the short arm of chromosome 1 (1p) and unbalanced gain of the long arm of chromosome 17 (17q).50,51 Deletions of 11q and 3p have also been described.52 The DNA content of tumor cells may have prognostic signiﬁcance; diploid tumors having a worse outlook.53,54 The oncogene N-myc is ampliﬁed (increased numbers of gene copies) or overexpressed (increased mRNA or N-myc protein) in many tumors at an advanced stage, while patients with stages 1, 2 or 4S disease uncommonly show ampliﬁcation of N-myc or overexpression.53–56 Furthermore, the expression of class I major histocompatibility complex may reﬂect a more benign tumor behavior.10 Currently the role of the TRK family of neurotrophin receptors in the growth of neuroblastomas is being extensively studied; these receptors may act as prognostic markers.

TREATMENT OF NEONATAL AND INFANT NEUROBLASTOMA The management of neuroblastoma in this age group should be colored by the recognition that patients will have a considerably better prognosis than those presenting later than 1 year of age. Chemotherapy and radiotherapy in neonates is fraught with difﬁculties, both in the short and long term, and should be avoided unless vitally necessary. Just when these modalities of management are indicated is not always certain, but it is clear that surgery plays a signiﬁcant role. Surgery may be useful in the resection of the primary neoplasm where indicated ab initio, in the resection of the primary post-treatment and in the diagnosis by biopsy which may on occasion be done laparoscopically, or in the insertion of central venous access lines for chemotherapy for total parenteral nutrition (TPN), blood sampling and in bone marrow transplantation. On occasion second look surgery may be justiﬁed for diagnostic or resection purposes.

STAGE 4S NEUROBLASTOMA (INSS) Evans et al. recognized a special stage 4 (4S) category because it had become clear that when the primary tumor is localized (stages 1 or 2) and the metastatic disease is conﬁned to liver, skin or bone marrow, or any combination of these without bony involvement, the prognosis was good without anti-tumor treatment.57 Subsequently it was shown that most patients were in the ﬁrst months of life, that the majority survived with minimal treatment and that a large percentage showed evidence of spontaneous regression. In a prospective study, Evans et al. conﬁrmed the good prognosis in this group of children, with a projected 2-year survival rate of 87%.57 Nine of the 31 patients reported in this study had continued growth or spread after initial treatment and four died. Of the nine patients, six were neonates at diagnosis and the very young seemed vulnerable to the mechanical complications caused by a greatly enlarged liver. More recently, in 80 patients with stage 4S disease, ﬁve of six deaths occurred in infants younger than 2 months at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation.58 Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may beneﬁt from earlier or more intensive treatment. Indeed Hsu et al. developed a semiquantitative scoring system based on the severity of signs and symptoms59 (Table 77.2). They found neonates were more likely than infants to develop more severe symptoms and were more likely to die when a score of two or more developed. Early intervention was therefore recommended (1) for 4S

Stage IV (INSS) 725 Table 72.2 Functional compromise due to levels of hepatomegaly59 Feature

STAGE 1 (INSS)

Severity

Score

Mild Severe

1 2

Respiratory compromise Tachypnea over 60 b.p.m. with need for O2 supplementation Need for C pap or mechanical ventilation

Mild/ moderate Severe

1 2

Venous return Leg edema Leg edema with scrotal and/or sacral edema

Mild Severe

GI Emesis of > 10% of intake Repeated emesis requiring i.v. ﬂuids

Renal Oliguria with output < 2 ml/kg/hour Mild Oliguria with signs of renal failure Severe with rising blood urea nitrogen (BUN) and creatinine Hepatic Thrombocytopenia /DIC platelet count < 50 000 cH

Severe

1 2

1 2

2

neonates who developed a score of 1, and (2) for older infants with a score > 2. Under these circumstances, low-dose radiotherapy localized to part of the liver (avoiding the spine, kidneys and ovaries [in girls]) and/or chemotherapy adjusted for age, with agents such as vincristine, cyclophosphamide, etoposide, or carboplatin is indicated. A delayed response is not unusual and the insertion of a large Silastic patch60 has been effective in relieving compression. However, this leaves the already compromised patient more open to infection and spontaneous liver regression may take weeks to occur. This form of treatment is not always successful.59,61 It is unlikely that resection of the primary tumor during the ‘ﬂorid’ stage of the disease is of therapeutic value. It may however be advisable, although this is controversial, to remove the primary tumor when the remote tumor has regressed because it is known that it may subsequently become active again.57 In most instances this will require an adrenalectomy, although occasionally in 4S disease the primary is elsewhere and indeed, in some, no primary is identiﬁed. Bourhis et al. showed, in a small series of neuroblastoma stage 4S patients, that N-myc ampliﬁcation and/or diploidy had a fatal outcome and these biological parameters may identify patients for whom a more aggressive therapy is required.62 In general it would seem that aggressive therapy is indicated where biological features show adverse disease and furthermore resection of the primary neoplasm should be performed in high-risk stage 4S cases with poor prognostic biological markers when feasible.

In tumours of this stage, complete surgical excision is proved histologically and biopsy of nodes is negative. No further treatment is given, but careful follow-up is indicated.

STAGE 2A (INSS) Following incomplete excision but negative node biopsies, further therapy may not be indicated in children under 1 year of age.57,63 Others have used postoperative radiation in this circumstance64,65 and Rosen et al. have used combination chemotherapy.64

STAGE 2B (INSS) Even with stage 2B disease an expectant policy may be justiﬁed in the neonate. However, it may soon become easier to detect patients requiring further treatment using assessment of copies of the N-myc oncogene and other prognostic indicators.

STAGE 3 (INSS) Tumors at stage 3 will rarely be resectable and overaggressive debulking, which might result in life-threatening hemorrhage or nephrectomy, is not justiﬁable. Chemotherapy, however, is likely to result in a more localized, less vascular and resectable tumor, although the surgery may be difﬁcult.

STAGE 4 (INSS) In general, these patients are treated with chemotherapy to achieve clinical remission of metastatic disease with shrinkage of the primary tumor when surgery should then be attempted. The surgery for this post-chemotherapy tumor is often difﬁcult and is outlined later in this chapter. There would appear to be little place for radiotherapy in stages 3 and 4 disease in the neonate.

Chemotherapy Vincristine and cyclophosphamide remain the two most commonly used chemotherapeutic agents for neuroblastoma in the neonate. A good tumor response to sequentially scheduled vincristine, cyclophosphamide, cis-platinum and VM26 (OPEC) has been observed in

726 Neuroblastoma

children over 1 year of age. Modiﬁcations of this multiagent scheme may prove possible with suitable reductions in dose. Other drugs of use may be carboplatin, vinblastine, bleomycin, decarbazine and adriamycin. Various chemotherapeutic trials are under way both in Europe and in the USA, and allogenic and autologous bone marrow transplantation after highdose chemotherapy (melphalan) and total body radiotherapy is also being attempted in older children. While there appears to have been a signiﬁcant extension of survival time using these heroic methods, the outlook for those with stages 3 and 4 disease remains particularly poor in the child older than 1 year.66 There seems little doubt that attention to nutrition, and this may involve TPN, is of value in advanced neuroblastoma.10 The place of radiolabelled monoclonal antibodies and metaiodobenzylguanidine (MIBG) or immunotherapy in the treatment of this tumor has yet to be established.

OPERATIONS FOR NEUROBLASTOMA Preoperative treatment All patients, prior to surgery, should have a full blood count to include hemoglobin, white cell count and platelet count. A coagulation screen is advisable, as are liver function tests if the liver is involved. Operations on neuroblastoma are often hazardous and hemorrhage is a frequent problem, hence a reliable venous infusion site or two is necessary. If the tumor is in the pelvis or abdomen, then the infusion is better placed either in an arm or neck vein. Blood pressure monitoring using an arterial line in an unhindered site is important, not only to monitor the effects of anesthetics but also blood loss and the effects of catecholamine release during surgery. Electrocardiography and pulse monitoring are also essential. A central venous pressure line and a Swan–Ganz pulmonary artery catheter have been helpful during difﬁcult surgery. Urinary output is monitored using a urinary catheter where indicated. Sufﬁcient fresh blood should be crossmatched and a careful monitoring of blood loss during the procedure is imperative. The consequences of previous chemotherapy and radiation should be taken into account, for example the patient may be more prone to infection or to poor healing. Intraspinal extension with or without spinal cord compression should be excluded when the primary tumor is paraspinal at any site. Laminectomy or laminotomy with excision of the intraspinal extension will usually be indicated before the operation for removal of the main tumor. Cervical and thoracic aspects will be dealt with elsewhere in text.

Abdomen The child lies in the supine position with a rolled towel under the lower chest and upper abdomen. If the imaging indicates a likely stage 1 or 2 tumor, then a transverse incision, mostly on the affected side, is usually sufﬁcient and heals well. The muscles are divided with diathermy, including both recti muscles. At laparotomy, the extent of tumor and spread are assessed.

Left adrenal gland (Fig. 77.4) The lienorenal ligament is divided, allowing mobilization of the spleen and pancreas medially. The lateral peritoneal attachment of the splenic ﬂexure and superior part of the descending colon is also divided, allowing mobilization of the colon medially and inferiorly. The ipsilateral renal vessels are identiﬁed. The tumor is dissected away from these vessels and the adrenal vein divided between ligatures, where it joins the renal vein. The same process is carried out with the renal artery pari passu, and there may be more than one branch going to the tumor. Titanium clips may be useful in this dissection. Dissection medially between the aorta and the tumor will identify at least one middle adrenal artery supplying the mass and should be divided similarly. During this part of the dissection, care needs to be taken to preserve the vital superior mesenteric artery and the coeliac trunk. A smaller branch from the inferior phrenic artery will be encountered as the dissection proceeds. Further veins will be encountered during the dissection and should be divided seriatim as the tumor is dissected from the diaphragm. Figure 77.5 shows a resected specimen.

Right adrenal gland (Fig. 77.6) This operation is likely to be technically more difﬁcult than on the left adrenal gland. The same basic procedures are followed as for the left, and the lateral attachment of the superior ascending colon and hepatic ﬂexure are divided and the colon retracted medially and inferiorly. The division of the peritoneum is extended up to the right of the duodenum, which is then mobilized after the fashion of Kocher. This allows access to the upper kidney, part of the adrenal and the inferior vena cava (IVC). Retraction on the liver anteriorly and superiorly will allow division of the right triangular ligament along with parts of the coronary ligament, to allow the liver to be retracted sufﬁciently to give access to the whole of the front of the adrenal gland with its tumor. Care is taken not to damage the IVC, which is intimately applied to the liver. The perinephric fascia (Gerota) is divided over the kidney and the renal vessels dissected medially, dividing any branches going to the adrenal between ligatures.

Operations for neuroblastoma 727

(a)

Figure 77.5 Resected specimen Celiac artery Spleen

IVC, and should be divided between ligatures. Vessels entering superiorly are likely to be branches of the right inferior phrenic artery and should be divided as the adrenal is dissected off the diaphragm.

Lymph nodes

Pancreas

Superior mesenteric artery

(b) Inferior vena cava

Aorta

Any obviously involved lymph nodes may be taken with the adrenal during the dissection. Lymph node sampling is recommended for staging purposes, taking into account that the main lymph drainage from the adrenal is to the renal hilar nodes, the para-aortic and on the left side through the adjacent esophageal hiatus to posterior mediastinal nodes. Clinically normal glands sometimes contain tumor.

Gross upper abdominal tumors (c)

Figure 77.4 Operation for left adrenal tumor. (a) Incision as indicated. (b) The lienorenal ligament has been divided allowing mobilization of the spleen and pancreas to the right. The renal vessels are visible and dissected out – branches to the tumor are divided. Next the tumor is dissected from the aorta dividing any vessels. Superiorly also branches from the inferior phrenic vessels are divided between ligatures or using titanium clips. (c) Tumor removed, the vascular supply having been divided

Usually the main venous drainage from the right adrenal is directly into the IVC and great care is taken during the dissection of the tumor from the IVC, to which it is closely applied. Blunt and sharp dissection is required to dissect out the vein, which is ligated. It is sometimes preferable to apply a vascular clamp to the side of the vena cava and use a ﬁne vascular (e.g. Prolene) running suture to achieve hemostasis. The right middle adrenal artery will enter the adrenal, having passed behind the

Patients with gross upper abdominal tumors (Fig. 77.7) will mostly be classiﬁed as having stage 4 tumors and the diagnosis made by bone marrow biopsy, biochemistry and imaging techniques. Biopsy of the tumor will facilitate studies of tumor biology, including ploidy and Nmyc oncogene status as well as detailed histology. Some stage 3 tumors will be operable at the outset but most patients will have had chemotherapy. After several weeks the tumor often shrinks to ‘manageable’ proportions and the bone marrow is likely to be free of tumor. The tumor is also more ‘compact’ and the vascularity reduced; this allows for more aggressive surgery when macroscopic abdominal clearance is possible. The tumor considered here is one where the aorta with its celiac trunk, superior mesenteric artery and other vessels such as the ipsilateral renal ones are surrounded by tumor. Detailed imaging just prior to surgery is indicated. The author has found Doppler ultrasonography to be very helpful in this regard. When nephrectomy seems likely, the current function of the other kidney must be assessed (by 99mTc diethylene triamine pentaacetic acid (DTPA) and/or 99mTC dimercaptosuccinic acid (DMSA) scan).

728 Neuroblastoma

(a) (a) Inferior vena cava Celiac artery

(b) Superior mesenteric Renal vein artery Renal artery

Figure 77.7 Gross tumor – primary left adrenal. (a) Incision: inverted chevron. (b) The spleen and pancreas have been mobilized off the tumor and placed medially and superiorly, and the duodenum and head of pancreas have been mobilized medially. The large tumor is visible surrounding the superior mesenteric artery and renal vessels and encroaching on the celiac. To preserve the important branches of the aorta, a dissection is required to divide the tumor painstakingly by blunt and sharp dissection, working from ‘tumor-free positions’ (c)

Figure 77.6 Right adrenal tumor. (a) Incision as indicated. (b) The duodenum and head of pancreas with important structures in the lesser omentum mobilized to the left. The renal vessels are dissected out and branches to the tumor are divided. Medially the tumor is juxtaposed to the IVC and sharp dissection may be needed to separate it. At least one vein will need to be divided here and it may need a vascular suture (as opposed to ligating). (c) The tumor has been removed

OPERATION A bilateral subcostal incision extending well out laterally gives excellent exposure (inverted chevron). A careful assessment is made of the tumor and in this instance the left adrenal gland was the primary tumor

with massive extension of tumor surrounding the renal vessels, the aorta and its main branches, and the IVC. The colon, duodenum and head of the pancreas, spleen and body of the pancreas are mobilized, as described earlier. Depending on the degree of renal involvement, it may or may not prove possible to dissect the tumor from the kidney and its vessels. The tumor is divided and split very carefully in an attempt to unwrap it from the renal vessels. In this instance it will be assumed that this has proved to be possible and that nephrectomy is not necessary. The tumor is mobilized from the renal bed toward the midline. This will necessitate dividing the tumor very carefully down to the renal vessels and

References 729

freeing it as far as the aorta. The ultrasound dissector has proved to be useful at times in this dissection. Tumor branches from the renal vessels are divided. The aorta is dissected next inferiorly, where it is tumor-free, toward the tumor and the tumor is split right over the aorta. This is a painstaking and time-consuming dissection. The inferior mesenteric artery may be divided with impunity, if necessary fairly close to the aorta, provided that the superior mesenteric artery is preserved. The superior mesenteric artery is carefully dissected out from the tumor and protected in a sling. Further dissection behind the pancreas will encounter the coeliac trunk with its three main branches (hepatic, left gastric and splenic) and these are all carefully preserved. It is possible therefore by dividing the tumor into two parts to proceed with resection. Tumor vessels are divided to the IVC and from the aorta. As the tumor is dissected from the diaphragm, further vessels will need to be divided. The main body of tumor left of the aorta is now resected. The remaining tumor to the right of the aorta is dissected toward the right side, taking any involved glands with it. Dissection from the IVC may prove to be difficult, and sharp dissection may be required. Pelvic position With the patient lying in the supine position and a urinary catheter in situ, a Pfannenstiel-type incision is made. After careful assessment, the bladder is retracted anteriorly and the ureters protected. The tumor will be lying in front of the sacrum and may extend laterally for some distance. It may push the rectum to one side or extend behind it. The peritoneum around it is incised and a trial of dissection is carried out to see if resection is possible. It is stressed that no major structure should be divided and, in particular, the sacral and coccygeal nerve plexuses should be preserved. Improved access to the pelvis may be achieved by splitting the symphysis pubis or the pubic bone a little to one side of it and distracting the pelvis.67

COMPLICATIONS OF SURGERY The risk of surgery in experienced hands is acceptably low. However, the risks of anesthesia, hemorrhage and infection on a compromised infant have to be considered. Particular risks of hemorrhage are with a vascular primary tumor or an extensive tumor in stage 4 following chemotherapy. Renal infarction following dissection for renal vessels has been described. As with any major abdominal surgery, prolonged ileus, bowel obstruction and intussusception are possible. Chylous ascites can be a problem but this usually responds to conservative management.

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78 Soft-tissue sarcoma DAVID A. LLOYD

Although soft-tissue sarcomas are rare in the newborn period, this possibility must be borne in mind when a nodule or mass is encountered in an infant.1–4 The usual presentation is with a mass, or with a complication such as bleeding or obstruction of a hollow organ or an oriﬁce. A thorough assessment for evidence of local or distant spread is made by physical examination and appropriate imaging studies, notably ultrasound scanning computed tomography (CT) and magnetic resonance imaging (MRI). Bone marrow aspiration and trephine may also be indicated. The diagnosis is conﬁrmed by tissue biopsy. There are no tumor markers for soft-tissue sarcoma.

PRINCIPLES OF MANAGEMENT The treatment of soft-tissue sarcomas in the newborn infant involves surgery and chemotherapy, and requires interdisciplinary consultation. Radiotherapy is avoided except as a last resort, because of the effects on tissue growth. In the newborn infant, drug doses are modiﬁed to avoid complications, notably myelosuppression and infection. The response to chemotherapy varies between the different types of tumor. For most tumors a successful outcome depends on achieving a complete excision, but a mutilating, radical excision should be avoided in the newborn infant, as primary chemotherapy may be effective in reducing the bulk of the mass, enabling a less radical excision to be done later.5–7 Tumor staging is used to plan adjuvant therapy, and depends on adequate and accurate information being provided by the surgeon. This should include a description of the site and extent of the tumor, whether or not complete resection was achieved, the amount and location of residual tumor, the condition of local and regional lymph nodes, and the presence and location of metastases. For patients who do not have a primary resection, pretreatment staging is used.

STAGING For malignant mesenchymal tumors (MMT), the TNM system is used for pretreatment and postoperative staging of the tumor. Therapy is based on staging and the histologic characteristics, resectability and site of the tumor (Box 78.1). Box 78.1 SIOP classiﬁcation for clinical TNM staging in childhood MMT.* Pre-treatment staging I T1 Tumor localized to organ or tissue of origin N0 No evidence of regional lymph node involvement M0 No evidence of metastasis II

T2

Tumor involving one or more contiguous organ or tissues, or with adjacent malignant effusion

N0 M0 III

Any T N1 Evidence of regional lymph node involvement M0

IV

Any T Any N M1 Evidence of distant metastases

Postsurgical staging pT1 Tumor limited to organ or tissue of origin; complete excision and histologically conﬁrmed tumor-free margins pT2 Tumor invasion beyond organ or tissue of origin; complete excision and histologically conﬁrmed tumor-free margins pT3 Tumor incompletely resected pT3a Evidence of microscopic residual tumor pT3b Evidence of macroscopic residual tumor or ‘only initial biopsy for diagnosis’ * It is anticipated that from 2004 the Children’s Oncology Group (USA) staging system will be used.

734 Soft-tissue sarcoma

SURGICAL METHODS These guidelines are based on protocol MMT-98 of the Sociéte Internationale D’Oncologie Pédiatrique, Zurich, Switzerland.

Biopsy The biopsy should be performed by or in consultation with the surgeon responsible for the ultimate management of the patient. An inappropriately sited biopsy incision may make a subsequent complete resection impossible and compromise the outcome. Methods of biopsy, other than excision, include direct or endoscopic biopsy for superﬁcial tumors, such as vaginal or bladder botryoid tumors, needle biopsy for prostatic and other accessible tumors, or incisional biopsy. The most direct approach to the tumor should be used, placing the needle puncture site or incision so that, where possible, it can be included in the skin incision at subsequent deﬁnitive resection (Fig. 78.1). Incisional biopsy is restricted to obtaining sufﬁcient tissue for diagnostic purposes; tissue planes should not be dissected unnecessarily and tumor spillage must be kept to a minimum. The tissue layers are then accurately repaired. An excisional biopsy is preferred if the lesion is small and can be removed with an adequate margin of normal tissue. Tissue should always be submitted fresh, if possible. The pathologist should be alerted prior to the operation so that resected tissues can be collected and immediately processed. If ﬁxative has to be used, it should be formalin based.

disease, primary total excision is the treatment of choice, provided that this can be done with an adequate tissue margin and without causing undue morbidity and disﬁgurement. An inadequate excision with microscopic residual leaves no gross tissue to allow assessment for chemosensitivity, therefore biopsy followed by chemotherapy is the preferred option when there is doubt about the likelihood of achieving a complete resection. The skin incision must allow adequate exposure of the tumor and adjacent structures. When there has been a previous biopsy, the incision must encompass the biopsy site (Fig. 78.1), which is excised en bloc with the tumor. The objective is to remove the entire tumor with a 2 cm margin of grossly normal tissue. Structures inﬁltrated by the tumor should be excised en bloc unless this will result in unacceptable morbidity. Care must be taken to avoid breaching the capsule. Where applicable, consideration should be given to using the cutting electocautery or laser knife. Following removal of the tumor, biopsies are taken from the tumor bed to conﬁrm complete excision. Where the margin is dubious, further tissue should be excised. The boundaries of the tumor bed, including the sites of biopsy, are marked with titanium clips. Stainless steel clips should be avoided as these cause ‘starburst’ distortion on computed tomography (CT).

Lymph node sampling Local and regional lymph nodes should be sampled for histological examination even, if they appear to be normal; this is necessary for accurate staging and grouping. Radical lymph node dissection usually is not indicated.

Primary excision

Delayed excision

When the tumor is localized and there is no metastatic evidence of lymph node involvement or metastatic

When primary resection cannot be done without unacceptable functional or cosmetic morbidity, the tumor is managed by biopsy followed by chemotherapy. Depending on the response, a less extensive delayed excision may be possible.

Amputation For extremity lesions which are not resectable, or when complete tumor excision would severely compromise limb function, amputation may be indicated, but this should not be carried out as a primary procedure.

Re-excision of tumor bed Figure 78.1 The incision (solid line) for incisional biopsy of a soft-tissue sarcoma is placed so that it will be encompassed by the incision (broken lines) for deﬁnitive excision. Both incisions are in the same axis of the limb

When a tumor has been excised without an adequate margin of normal tissue, re-operation to excise the tumor bed should be considered, particularly for sarcomas which are not chemosensitive;9 this also applies when

Speciﬁc tumors 735

there is microscopic evidence of tumor at the margins of excision. Successful re-excision may convert the lesion to a more favorable stage. Re-exploration for biopsy alone is not recommended since a negative biopsy is not a reliable prognostic indicator.

SPECIFIC TUMORS Rhabdomyosarcoma This is the commonest soft-tissue sarcoma occurring in infants. The prognosis depends on the resectability of the primary lesion, the presence or absence of metastases (surgical–pathological stage), the site of the primary tumor and the histologic characteristics of the lesion.10 Sites where the prognosis is favorable are the vagina, bladder, prostate, para-testicular, orbit and head (except parameningeal). The most common histologic type in these areas is the embryonal tumor. Age under 1 year is not a favorable prognostic factor for rhabdomyosarcoma. Chemotherapy is required for all tumors, even when excision appears to be complete. Chemotherapy alone may produce a satisfactory response but the relapse rate is high, and excision or radiotherapy is required in addition. The drugs usually used are vincristine and actinomycin-D with cyclophosphamide or ifosphamide.

GENITO-URINARY RHABDOMYOSARCOMA Infants have a higher rate of vaginal and bladder–prostate primary lesions than older children.11 Approximately 80% are the embryonal type. These tumors may present with an abdominal mass, urinary retention, vaginal discharge (which may be blood stained), or protrusion of the tumor from the introitus (sarcoma botryoides) (Fig. 78.2). In the latter situation, direct biopsy is simple. Bladder and vaginal tumors can be biopsied endoscopic-

Figure 78.2 Rhabdomyosarcoma (sarcoma botryoides) in an infant with Robert’s syndrome. At birth, the lesion was a small frond-like polyp at the introitus

ally. For prostatic lesions, needle biopsy may be done using a transperineal or transrectal approach. Primary excision may be possible for superﬁcial localized lesions. Resection of the pelvic organs should be avoided in the newborn infant, the preferred treatment being chemotherapy followed by delayed excision of residual tumor.8 This eventually may necessitate cystectomy, hysterectomy or vaginectomy. Partial cystectomy with bladder preservation may be possible for tumors arising in the urachus or bladder vault.

PARATESTICULAR RHABDOMYOSARCOMA A rare tumor in neonates,12 presentation is with a hard painless mass in the scrotum or groin. The tumor is explored through an inguinal incision (Fig. 78.3). The spermatic cord is identiﬁed and occluded using a noncrushing clamp while the testis is mobilized and examined. If a tumor is conﬁrmed, radical orchidectomy is performed, ligating and dividing the spermatic cord at the internal inguinal ring proximal to the clamp (Fig. 78.4). Biopsy of the mass is not recommended, but if deemed essential, should be done after occluding the spermatic cord as described, taking care to avoid tumor spillage into the operative ﬁeld. If a scrotal incision has been used for the initial exploration of a malignant paratesticular tumor, hemiscrotectomy and high excision of the spermatic cord are recommended (Fig. 78.5). Formal retroperitoneal lymph node dissection is not recommended following radical orchidectomy. For staging, the less extensive procedure of retroperitoneal node biopsy or sampling is indicated when the CT scan demonstrates lymph node enlargement or if the orchidectomy specimen shows spermatic cord inﬁltration by tumor.

TRUNK AND EXTREMITY RHABDOMYOSARCOMA Tumors at these sites are predominantly of the unfavorable alveolar histologic pattern and have the highest

Figure 78.3 Inguinal incision for exploration of the testis when a tumor is suspected. The medial end of the incision overlies the pubic tubercle

736 Soft-tissue sarcoma

using a synthetic patch.14 Reoperation is beneﬁcial when the margins of excision are inadequate. Local lymph nodes should be removed for microscopic examination if they are easily accessible. Rarely, a tumor may present with regional node involvement and an undetectable latent primary tumor; treatment is with chemotherapy.

HEAD AND NECK RHABDOMYOSARCOMA

Figure 78.4 Exploration of the testis for testicular or paratesticular tumor. The spermatic cord is occluded with a non-crushing clamp while the testis is mobilized and examined. If a tumor is present, radical orchidectomy is performed by ligating and dividing the cord proximal to the clamp

A rhabdomyosarcoma occurring on the head or neck usually is not amenable to primary excision and is treated by biopsy followed by chemotherapy. Radical excision may be necessary to extirpate residual or recurrent tumors; radiotherapy also should be considered. Orbital rhabdomyosarcoma responds well to chemotherapy and radiotherapy, but enucleation may be necessary if the tumor recurs. Parameningeal tumors have a high risk of extension into the central nervous system, and evaluation must include cerebrospinal ﬂuid examination and CT scan or MRI of the head and neck. Intrathecal chemotherapy may be indicated.

Fibrosarcoma

Figure 78.5 The incision for hemiscrotectomy (arrow) is a ‘tennis racquet’ incision based over the inguinal region and encircling the hemiscrotum. The original incision is included in the specimen

relapse and lowest survival rates. These tumors present either as an asymptomatic mass or they may mimic an acute abscess or hematoma and may be inappropriately incised and drained. Complete excision with a margin of normal tissue has the best outcome, and may be done primarily if the tumor is small, or after chemotherapy has reduced the size and vascularity of the tumor.13 Compartmentectomy, removing from origin to insertion the whole muscle mass containing the tumor, has not been shown to confer any additional beneﬁt over wide excision. Inﬁltrating lesions of the chest or abdominal wall may require full-thickness excision of the body wall, including pleura or peritoneum, with reconstruction

Congenital ﬁbrosarcoma and infantile ﬁbrosarcoma usually have a favorable outcome, unlike ﬁbrosarcoma in adolescents and adults.15,16 Congenital ﬁbrosarcoma occurs most commonly on the extremities, but may arise at any site. There may be local inﬁltration, and recurrence rates up to 43% have been reported after local excision. Metastases are rare under 5 years of age; this is particularly true for congenital generalized ﬁbrosarcomatosis, in which spontaneous resolution has been recorded. Age at presentation is the main prognostic factor. Microscopically, the tumor resembles ﬁbrosarcoma in adults and there are no features which will identify those likely to disseminate. The distinction from aggressive ﬁbromatosis is not clear. The overall survival rate for infants is 85%–90%. Solitary lesions which are increasing in size or have shown no signs of spontaneous regression should be treated by excision or primary chemotherapy. Because the risk of dissemination is low, it is not essential to include a wide margin of normal tissue, particularly when this would lead to major structures being sacriﬁced or when the cosmetic outcome would be unsatisfactory. Recurrences can be treated by local excision without compromising the prognosis. Congenital ﬁbrosarcoma may respond to chemotherapy using vincristine, actinomycin-D and cyclophosphamide. This will allow a less extensive delayed resection of the lesion, and may even lead to complete remission without excision. Therefore, when primary excision is not appropriate, tissue biopsy should be followed by a trial of chemotherapy.17 Delayed excision is undertaken when maximum tumor response has been achieved. Wide

References 737

excision or amputation may be required for tumors which do not regress. 3.

Synovial sarcoma These highly malignant tumors are characterized by early dissemination and a high frequency of local recurrence. Initial local excision or biopsy to establish the diagnosis is followed by wide local excision either before or after chemotherapy. Enlarged regional nodes are biopsied. All patients subsequently receive postoperative chemotherapy. Because of the high recurrence rate, amputation or radiotherapy should be considered when excision is incomplete.

4. 5.

6. 7.

Neuroﬁbrosarcoma and liposarcoma These tumors have a high incidence of local recurrence, and do not respond well to radiotherapy. Responses to multi-agent chemotherapy have been reported but tumor control depends on complete excision or amputation.

CONCLUSIONS Soft-tissue sarcomas, of which rhabdomyosarcomas are the most common, differ in their natural history and in their response to chemotherapy and radiotherapy. In the neonate, surgery plays a greater role than in any other age group. The optimal treatment of a localized softtissue mass is wide excision with a clear margin, if this can be achieved without compromising function, growth or appearance. The exception is congenital ﬁbrosarcoma, which may not require excision. If malignancy is conﬁrmed on microscopic examination and the margins are not adequate, re-excision may be beneﬁcial. For most tumors, resection is followed by chemotherapy. When primary local excision is not appropriate, the mass is biopsied. If malignancy is conﬁrmed, chemotherapy is begun and delayed excision is performed after maximum remission has been achieved. Amputation is an option for extremity lesions when primary excision is incomplete. Radiotherapy should be avoided in the newborn infant except as a last resort.

8.

9.

10.

11.

12.

13.

14.

15.

REFERENCES 1. Campbell AN, Chan HSL, O’Brien A et al. Malignant tumours in the neonate. Arch Dis Childh 1987; 62:19–23. 2. Dillen PW, Whalen TV, Azizkhan RG et al. Neonatal soft

16. 17.

tissue sarcomas: the inﬂuence of pathology on treatment and survival. J Pediatr Surg 1995; 30:1038–41. Xue H, Horwitz JR, Smith MB et al. Malignant solid tumours in neonates: a 40 year review. J Pediatr Surg 1995; 30:543–5. Halperin EC. Neonatal neoplasms. Int J Radiat Oncol Biol Phys 2000; 47(1):171–8. Koscielnak E, Harms D, Schmidt D et al. Soft tissue sarcomas in infants younger than 1 year of age: a report of the German Soft Tissue Sarcoma Study Group (CWS-81). Med Pediatr Oncol 1989; 17:105–10. Plowman PN, Pinkerton CR. Pediatric Oncology. London: Chapman and Hall, 1992. Salloum E, Flamant F, Caillaud JM et al. Diagnostic and therapeutic problems of soft tissue tumours other than rhabdomyosarcoma in infants under 1 year of age: a clinicopathological study of 34 cases treated at the Institut Gustave-Roussy. Med Pediatr Oncol 1990; 18:37–43. Martelli H, Oberlin O, Rey A et al. Conservative treatment for girls with nonmetastic rhabdomyosarcoma of the genital tract: A report from the Study Committee of the International Society of Pediatric Oncology. J Clin Oncol 1999; 17(7):2117–22. Cecchetto G, Carli M, Sotti G et al. Importance of local treatment in pediatric soft tissue sarcomas with microscopic residual after primary surgery: results of the Italian Cooperative Study RMS-88. Med Pediatr Oncol 2000; 34(2):97–101. Ragab AH, Heyn R, Tefft M et al. Infants young than 1 year of age with rhabdomyosarcoma. Cancer 1986; 58:2606–10. Salloum E, Flamant F, Rey A et al. Rhabdomyosarcoma in infants under 1 year of age: experience of the Institut Gustave-Roussy. Med Pediatr Oncol 1989; 17:424–8. Cakmak O, Karaman A, Cavusoglu YH, Oksal A. Paratesticular rhabdomyosarcoma in a neonate. J Pediatr Surg 2000; 35(4):605–6. Neville HL, Andrassy RJ, Lobe TE et al. Preoperative staging, prognostic factors, and outcome for extremity rhabdomyosarcoma: a preliminary report from the Intergroup Rhabdomyosarcoma Study IV (1991–1997). J Pediatr Surg 2000; 35(2):317–21. Dang NC, Siegel SE, Phillips JD. Malignant chest wall tumours in children and young adults. J Pediatr Surg 1999; 34(12):1773–8. Briselli MF, Soule EH, Gilchrist GS. Congenital ﬁbromatosis: report of 18 cases of solitary and 4 cases of multiple tumours. May Clin Proc 1980; 55:554–652. Brock P, Renard M, Smet M et al. Infantile ﬁbrosarcoma. Med Pediatr Oncol 1991; 19:210. Ninane J, Grosseys S, Panteon E et al. Congenital ﬁbrosarcoma: pre-operative chemotherapy and conservative surgery. Cancer 1986; 58:1400–6.

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79 Hepatic tumors YOSHIAKI TSUCHIDA AND NORIO SUZUKI

INTRODUCTION Tumors of the liver are uncommon in infants and children; in newborns they account for 2.0–5.9% of all solid benign and malignant tumors.1–3 Common hepatic tumors in the ﬁrst 3 months of life are hemangiomas and hemangioendotheliomas, but hepatoblastomas and hepatic mesenchymal hamartomas are also encountered. However, other liver tumors are extremely rare. Very low birth weight4 and trisomy 185 are occasionally associated with the occurrence of hepatoblastoma. The association of familial adenomatous polyposis (FAP) with hepatoblastoma has also been noted6 and the gene for FAP has been localized to chromosome 5q.7 Familial occurrence of hepatoblastoma has also been reported occasionally8,9 and it is important to note that both siblings with hepatoblastoma reported by Aoyama et al. developed familial adenomatous polyposis of the colon afterwards.9 Abnormalities on the short arm of chromosome 11 have been shown in both Beckwith– Wiedemann syndrome and hepatoblastoma, and loss of heterozygosity (LOH) has frequently been observed.10 Parada et al. recently noted the importance of trisomies 2, 8, and 20 and rearrangement of 1q in the development of hepatoblastoma.11 Vascular hepatic tumors are the commonest hepatic tumors in neonates and infants. These may occur as single cavernous hemangiomas or as hemangioendotheliomas, either involving the whole liver segment as multiple circumscribed lesions or conﬁned to one or two hepatic lobes. They are frequently associated with cutaneous strawberry hemangiomas. Hepatomegaly is not a major factor, but in advanced cases, thrombocytopenia due to platelet trapping and/or congestive heart failure due to arteriovenous shunting are seen.12,13 Serum alphafetoprotein (AFP) levels in infants or newborns with vascular hepatic tumors are usually elevated, as in patients with hepatoblastomas. However, it must be taken into account that AFP from a hepatoblastoma and that from surrounding normal liver tissue, as in cases of benign hepatic tumors, are different in their carbo-

hydrate moiety, which can be clearly differentiated with the lens culinaris hemagglutinin (LCH) binding test.14 Most infants with hepatoblastomas show upper abdominal distension. A ﬁrm hepatic mass may be palpated by chance during routine examination of the abdomen in infants with other clinical complaints. The general condition is usually good, but some newborn cases are accompanied by increasing respiratory distress.1 In general, the younger the patient, the higher the incidence of the fetal-type (well-differentiated) hepatoblastoma and single mass lesion. Histologically, hepatoblastomas consist of the fetal-type hepatoblastoma, embryonal-type hepatoblastoma, immature-type hepatoblastoma, and macrotrabecular hepatoblastoma (Box 79.1).15,16 Hemihypertrophy is one of the commonly associated anomalies, and thrombocytosis and virilizing symptoms may be seen. Among malignant liver tumors other than hepatoblastoma, there are adult-type hepatocellular carcinoma, Box 79.1 Common benign and malignant hepatic tumors in infancy and childhood Benign hepatic tumors Hemangioma Hemangioendothelioma Mesenchymal hamartoma Focal nodular hyperplasia Malignant hepatic tumors Hepatoblastoma Fetal type Embryonal type Immature type Macrotrabecular type Hepatocellular carcinoma Fibrolamellar hepatocellular carcinoma Angiosarcoma Malignant mesenchymal sarcoma Primary yolk sac tumor Pseudotumors Inﬂammatory pseudotumor

740 Hepatic tumors

ﬁbrolamellar hepatocellular carcinoma, malignant mesenchymal sarcoma, angiosarcoma, and primary yolk sac tumor (Box 79.1).15–17 Hepatocellular carcinoma of the adult type accounts for 12.5–20% of primary malignant hepatic tumors18 but usually occurs in children older than 5 years of age. This type of hepatic carcinoma is more frequently seen in countries such as Taiwan, where vertical transmission of the hepatitis B antigen is prevalent.19 Mesenchymal hamartoma of the liver is not a malignant tumor, but it grows rapidly, especially in early infancy, and may cause respiratory distress.20 This tumor can be diagnosed prenatally.21 Focal nodular hypertrophy and inﬂammatory pseudotumor22 are benign hepatic lesions, seen more often in relatively older children (> 2 years of age).

DIAGNOSTIC EVALUATION It is vitally important to establish a correct diagnosis before commencing treatment. Diagnostic evaluation should be based on both imaging and study of serum tumor markers. Ultrasound tomography, computed tomography (CT), and magnetic resonance imaging (MRI) are useful in diagnosis, particularly in demonstrating whether the tumor is a single mass or consists of multiple lesions. If it shows multiple, round, wellcircumscribed homogeneous masses of similar size, the diagnosis of multiple hemangioendothelioma is most plausible.23 Hepatoblastoma with intrahepatic metastases should be suspected if one relatively large mass and multiple smaller lesions are found. Generally, MRI is more useful than CT in the diagnosis of hepatoblastoma. If MRI and/or CT show a single mass (Figs 79.1 & 79.2), other examinations such as serum AFP with subfractionation14 and angiographic techniques are employed to arrive at a correct preoperative diagnosis.

Figure 79.1 MRI of the liver of a 55-month-old girl with hepatoblastoma. Her birth weight was 717 g. A round, solitary tumor was located in the left lobe, and was of the fetal (welldifferentiated) type histologically

Figure 79.2 CT scan of the liver of a 6-month-old infant with hepatoblastoma. A round, solitary tumor was located interlobarly in the anterior segment of the right lobe and the median segment of the left lobe. The tumor was removed by left trisegmentectomy and was of the fetal (well-differentiated) type histologically

Scintigraphic evaluation with 99mTc-labelled red blood cells may offer an accurate method of identifying hemangiomas of the liver, and allows differentiation from primary hepatic neoplasms.24 Hepatic arteriography or abdominal aortography is used for diagnosis and mainly for preoperative preparation.13 Findings differ for hemangiomas and hepatoblastomas, but it is difﬁcult in some cases to obtain a deﬁnitive preoperative diagnosis with these methods. It has been reported that the AFP level is elevated not only in hepatoblastoma but also in other hepatic tumors, such as mesenchymal hamartomas and hemangiomas of the liver.25 However, the serum AFP levels in patients with these tumors are near the upper limit of the physiologically normal ranges for this protein (Fig. 79.3),26 whereas serum AFP is elevated to exceedingly high levels beyond the upper limit in 96.6% of infants and children with hepatoblastoma.27 A patient with infantile hepatitis occasionally has a serum AFP level as high as 540 000 ng/ml; in this case, imaging is useful. In addition, a test of binding of AFP with LCH clearly distinguishes between hepatoblastomas and benign hepatic diseases. AFP from benign hepatic diseases does not react with LCH, while large amounts of AFP from hepatoblastomas bind to LCH (Fig. 79.4).28 The younger the age of infants with hepatoblastomas, the greater the proportion of LCH-reactive AFP fraction.28 Unfortunately, this test is at present routinely available only at a limited number of laboratories.

Indications for surgery, preoperative chemotherapy, and arteriography 741

INDICATIONS FOR SURGERY, PREOPERATIVE CHEMOTHERAPY, AND ARTERIOGRAPHY

AFP (mg/ml) 1 000 000

100 000

10 000

1000

100

10

1

30

60

90

120

150

180

210

240

270

300

Age in days

Figure 79.3 Graph shows normal value of AFP in early infancy. Each point represents serum AFP of an otherwise healthy infant with inguinal hernia, and the nomogram is designed so that 95% of serum AFP values in normal infants are included between the uppermost and lowermost curves (From Tsuchida et al.,23 by permission of Elsevier Science)

Figure 79.4 Top of the ﬁgure shows the results of LCH-binding test of AFP from patients with hepatoblastoma. There are two peaks of LCH reactive and non-reactive subfractions of AFP. The bottom of the ﬁgure shows those of AFP from normal newborns and from patients with benign hepatic conditions such as biliary atresia and neonatal hepatitis. Only one peak of LCH non-reactive AFP was shown (From Tsuchida et al.,28 by permission of Elsevier Science)

Hepatic cavernous hemangioma and hemangioendothelioma may regress spontaneously, but such regression is rare in the case of large lesions. Therapeutic modalities include anticongestive therapy, high-dose corticosteroids, irradiation, embolization, hepatic artery ligation, and partial hepatic resection.29 Resection of the tumor by lobectomy is the treatment of choice whenever feasible, but when the whole liver is involved, ligation of the common hepatic artery is indicated. In hepatoblastoma, complete excision of the tumor has been the treatment of choice and the major path to long-term survival. According to published reports on hepatoblastoma and hepatocellular carcinomas in infants and children, approximately 40% are ‘unresectable’ at the time of diagnosis.18 Despite the higher incidence of solitary tumors in the ﬁrst 3 months of life, advanced unresectable hepatoblastoma has also been reported.30 Complete excision should be preceded in such patients by preoperative chemotherapy. Doxorubicin and cisplatin are the agents of choice, and should be administered systemically.31 Good complete response rates have been reported to occur following aggressive preoperative systemic chemotherapy.32 The preoperative systemic chemotherapeutic regimens of the Paediatric Oncology Group, the Children’s Cancer Group, the German Cooperative Paediatric Liver Tumor Study, and the International Society of Paediatric Oncology Group (SIOPEL study) are all effective, and make up nearly 80% of all hepatoblastoma resectable preoperatively.33–36 Summaries of these regimens are shown in Table 79.1. Doxorubicin and cisplatin can also be given via the intra-hepatic arterial route. One infant with bilateral lobe metastases in the current authors’ series was also treated successfully by hepatic arterial catheterization and ligation, through which chemotherapy was administered.37 For rapidly growing mesenchymal hamartomas, hepatic resection is also the treatment of choice. The most important preoperative examination is hepatic arteriography (Fig. 79.5) that indicates which branch of the hepatic artery should be ligated and divided. It is important to know of any abnormalities of the hepatic arteries preoperatively. Selective hepatic arteriography (depending on the size of the patient) is usually performed retrogradely via the femoral artery. In newborns, the umbilical artery may be used for aortography. In the operating theatre, monitoring via an arterial line and central venous pressure line is essential. Two central venous lines are needed for the infusion of red blood cells, fresh-frozen plasma, platelets, and ﬂuid.

742 Hepatic tumors Table 79.1 Chemotherapeutic regimens in clinical trials for hepatoblastoma Group

Stage and regimen

Paediatric oncology group

Stage I, favorable histology: no further treatment Stage I, unfavorable histology and stage II: Course 1: cisplatin 90 mg/m2 alone Course 2–5: cisplatin 90 mg/m2 on day 1, and vincristine 1.5 mg/m2 and ﬂuorouracil 600 mg/m2 on day 3, every 3 weeks Stage III and IV: Course 1–5 same as stages I and II After tumor resection, two courses of cisplatin, vincristine, and ﬂuorouracil are added

Children’s Cancer Group

Unresectable or incompletely resected hepatoblastoma: cisplatin 100 mg/m2 on day 1 and doxorubicin 20 mg/m2/day continuously infused on days 1–4, every 3–4 weeks

German Cooperative Paediatric Liver Tumor Study HB-89

Unresectable or incompletely resected hepatoblastoma: Ifosphamide 0.5 g/m2 bolus and 3.0 g/m2 over 72 hours on days 1–3, cisplatin 20 mg/m2 5 times on days 4–8, and doxorubicin 60 mg/m2 over 48 hours on days 9–10, 2– 4 courses every 3 weeks

International Society of Paediatric Oncology (SIOPEL) Japanese Study Group for Paediatric Liver Tumour (J-PLT)

Cisplatin 80 mg/m2 over 24 hours on day 1 and doxorubicin 60 mg/m2 over 48 hours on days 2–3, every 3 weeks Resectable hepatoblastoma: Cisplatin 40 mg/m2 and THP-Adriamycin 30 mg/m2 on day 1, six courses every 4 weeks Unresectable hepatoblastoma: Cisplatin 80 mg/m2 over 24 hours on day 1, and THP-Adriamycin 60 mg/m2 over 48 hours on days 2–3, six courses every 4 weeks

Figure 79.5 Hepatic arteriograph in hepatoblastoma is shown. The right hepatic artery, nourishing the tumor, arises from the superior mesenteric artery in this case. Subsequent selective arteriography demonstrated that the left hepatic artery was from the coeliac artery. Preoperative angiography is important not only for diagnosis but also for surgery

SURGICAL TECHNIQUE Preoperative systemic or intra-arterial chemotherapy is recommended in the case of large tumors. The resectability of a hepatic tumor depends not only on the

tumor size and location in the liver, but also on the skill of the pediatric surgeon. An equally important factor in the success of hepatic resection is the skill and ability of the ﬁrst assistant to the surgeon. Observation of donor hepatectomy for living related liver transplantation may beneﬁt the surgeon where appropriate, because the technique of donor hepatectomy is much more meticulous than simple hepatectomy for hepatoblastoma.38,39 Hepatic resection should ideally be based on the concept of anatomical, systematic resection and be performed with the aid of an ultrasonic surgical aspirator (e.g., CUSA or Sonop, Aroka, Tokyo). The liver is exposed through a larger transverse incision of the abdomen (Fig. 79.6). An additional vertical skin incision is unnecessary in the newborn. Dissection begins in the porta hepatis, which is made visible by hepatic mobilization through cutting the falciform and triangular ligaments on both sides. In the right hepatic resection, the cystic duct and cystic artery are ﬁrst ligated and divided. Then the right hepatic duct is identiﬁed, ligated, and sectioned (Fig. 79.7). After this separation, the right hepatic artery is also identiﬁed, ligated, and divided. Care must be taken to dissect the right portal vein, because it is short, big, and thin walled. It must be suture ligated with atraumatic 3-0 silk sutures and severed. After the dissection at the porta hepatis has been completed, ideally the right hepatic vein, with or without the middle hepatic vein, is identiﬁed, suture ligated, and divided. Extreme care must be taken in the identiﬁcation of the hepatic veins: dissection should

Treatment results 743

Figure 79.6 Operative ﬁndings of the case whose arteriograph is shown in Fig. 79.5 are shown. The right hepatic lobe was exposed through a large transverse incision to the abdomen and by hepatic mobilization. The tumor was in the anterior segment of the right lobe. The gallbladder is in the right lower edge of the liver and the inferior vena cava is visible beneath the diaphragm

First, the section line is marked on the liver surface using an electrocauterizer; then an ultrasonic surgical aspirator is applied gently while the assistant surgeon holds the hepatic lobes tightly in order to minimize blood loss. Hemostatic forceps are used for vessels and ducts, which remain like bridges between the cut surfaces. The bridgelike vessels and ducts are then severed and ligated or cauterized (Fig. 79.8). The large hepatic veins are sometimes ﬁrst identiﬁed during the use of the ultrasonic surgical aspirator. After removal of the right hepatic lobe, hemostasis of the raw surface is carried out using atraumatic 3-0 silk sutures, with or without the use of hemostatic sponges. An argon-laser coagulater is of great help in achieving hemostasis, and ﬁbrin glue may be applied on the raw cut surface whenever appropriate. Two drainage tubes are left in place. Left hepatic trisegmentectomy or extended right hepatic lobectomy (right hepatic trisegmentectomy) is indicated and feasible in infants, depending on the localization of the hepatoblastoma.40 For such extended hepatic resection, careful evaluation of the hepatic arteriogram and intraparenchymal dissection/ligation of the branch of the right or left hepatic artery are often of value.41,42 Postoperatively, the infant should be carefully monitored in an intensive care unit, where oxygen, water, and electrolytes are provided and replacement of red blood cells, fresh-frozen plasma, and/or platelets is possible. For tumors unresectable by any means, hepatic transplantation may be considered in the absence of remote metastases.43

Figure 79.7 Dissection of the right hepatic duct, right hepatic artery, and right portal vein at the porta hepatis. The cystic duct and cystic artery are also ligated and divided

progress softly and downward intraparenchymally. Sometimes the identiﬁcation of these structures is not possible, especially in older patients. An ischemic color change on the liver surface may be helpful in identifying the anatomical section line, but the line should primarily be based upon the site of the tumor rather than the anatomical line. A relatively narrow free margin may be justiﬁed, if one can predict that the hepatoblastoma is of the fetal (well-differentiated) type.

Figure 79.8 Schema of hepatic resection with an ultrasonic surgical aspirator is shown. Hemostatic forceps are used for vessels and ducts, which remain like bridges between the cut surfaces. The bridge-like vessels and ducts are then severed and ligated or cauterized

TREATMENT RESULTS Very few patients with hepatoblastoma are expected to survive after incomplete excision or biopsy alone; in

744 Hepatic tumors

those in whom the hepatoblastomas are completely resected, however, up to 70% or more can be expected to survive.44 Cases of survivors whose tumors were initially unresectable but were resected at second-look surgery after chemotherapy have also been recently reported.32–34 Long-term survivors should be monitored for the occurrence of familial adenomatous polyposis of the colon.

PROGNOSTIC FACTORS Recently, several study groups have evaluated prognostic factors on a clinical basis in order to identify different risk groups among patients with hepatoblastomas.45,46 In parallel, several genetic alterations have been identiﬁed in hepatoblastomas such as LOH on chromosomes 11p, 1p, and 1q, activating mutations of the b-catenin gene, and overexpression of the c-met gene.47–51

REFERENCES 1. Isaacs H Jr. Congenital and neonatal malignant tumors: a 28 year experience at Children’s Hospital of Los Angeles. Am J Pediatr Hematol Oncol 1987; 8:121–9. 2. Campbell AN, Chan HSL, O’Brien A et al. Malignant tumors in the neonates. Arch Dis Childh 1987; 62:19–23. 3. Davis CF, Carachi R, Young DG et al. Neonatal tumours Glasgow 1955–86. Arch Dis Childh 1988; 63:1075–8. 4. Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a chance? J Pediatr 1997; 130:557–60. 5. Tanaka K, Uemoto S, Asonume K et al. Hepatoblastoma in a two year old girl with trisomy 18. Eur J Pediatr Surg 1997; 2:298. 6. Garber JE, Li FP, Kingston JE et al. Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 1988; 80:1626–8. 7. Grosfeld JL. Hepatoblastoma and hepatocellular carcinoma. In: Carachi R, Azmy A, Grosfeld JL, editors. The Surgery of Childhood Tumors. London: Arnold, 1999 178–98. 8. Napoli V, Campbell W. Hepatoblastoma in infant sister and brother. Cancer 1977; 39:2647–50. 9. Aoyama K, Takada Y, Mori S et al. Hepatoblastoma in two infant sisters. J Jpn Soc Pediatr Surg 1979; 15:1213–17. 10. Albrecht S, von Schweinitz D, Waha A et al. Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res 1994; 54:5041–4. 11. Parada LA, Limon J, Iliszko M et al. Cytogenetics of hepatoblastoma: further characterization of 1q rearrangements by ﬂuorescence in situ hybridization. Med Pediatr Oncol 2000; 34: 165–70. 12. Liu HC, Chang MH, Lue HE et al. Hepatic haemangioma in infancy and early childhood. J Formosan Med Assoc 1988; 87:288–96.

13. Davenport M, Hanson L, Haton ND et al. Haemangioendothelioma of liver in infants. J Pediatr Surg 1995; 30:44–8. 14. Tsuchida Y, Terada M, Honna T et al. The role of subfractionation of alpha-fetoprotein in the treatment of pediatric surgical patients. J Pediatr Surg 1997; 32:514–17. 15. Tsuchida Y. Malignant liver and bile duct tumors. In: Balistreri WF, Ohi R, Todani T et al., editors. Hepatobiliary, Splenic and Pancreatic Disease in Children: Medical and Surgical Management. Amsterdam: Elsevier, 1977: 331–47. 16. Haas JE, Muczynski KA, Krailo M et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989; 64:1082–95. 17. Craig JR, Peters RL, Edmondson HA et al. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinicopathologic features. Cancer 1980; 46:372–9. 18. Lack EE, Neave C, Vawter GF. Hepatoblastoma: a clinical and pathologic study of 54 cases. Am J Surg Pathol 1982; 6:693–705. 19. Chen WJ, Lee JC, Hung WT. Primary malignant tumor of liver in infants and children in Taiwan. J Pediatr Surg 1988; 23:457–61. 20. Stocker JT, Ishack KG. Mesenchymal hamartoma of the liver: report of 30 cases and review of the literature. Pediatr Pathol 1983; 1:245–67. 21. Dickinson JE, Knowles S, Phillips JM. Prenatal diagnosis of hepatic mesenchymal hamartoma. Prenat Diagn 1999; 19:81–4. 22. Sakai M, Ikeda H, Suzuki N et al. Inﬂammatory pseudotumor of the liver: a case report and a review of the literature. J Pediatr Surg 2001; 36:663–6. 23. Mahmoubi S, Sunaryo FP, Glassman MS et al. Computed tomography, management and follow-up in infantile hemangioendothelioma of the liver in infants and children. J Comput Tomogr 1987; 11:370–5. 24. Miller JH. Technetium-99m-labelled red blood cells in the evaluation of hemangiomas of the liver in infants and children. J Nucl Med 1987; 28:1412–18. 25. Urbach AH, Zitelli BJ, Blant J et al. Elevated ?-fetoprotein in a neonate with a benign hemangioendothelioma of the liver. Pediatrics 1987; 80:596–7. 26. Tsuchida Y, Endo Y, Saito S et al. Evaluation of alphafetoprotein in early infancy. J Pediatr Surg 1978; 13:155–6. 27. Tsuchida Y. Markers in childhood solid tumours. In: Hays DH, editor. Pediatric Surgical Oncology. New York: Grune and Stratton, 1986:47–62. 28. Tsuchida Y, Honnna T, Fukui M et al. The ratio of fucosylation of alpha-fetoprotein in hepatoblastoma. Cancer 1989; 63:2174–6. 29. Hazebroek FW, Tibboel D, Robben SGF et al. Hepatic artery ligation for hepatic vascular tumours with arteriovenous and arterioportal venous shunts in the newborn. J Pediatr Surg 1995; 30:1127–30.

References 745 30. Lister J. Abdominal tumours. In: Rickman PP, Lister J, Irving IM, editors. Neonatal Surgery. 2nd edn. London: Butterworths, 1978:101–14. 31. Pierro A, Langevin AM, Filler RM et al. Preoperative chemotherapy in ‘unresectable’ hepatoblastoma. J Pediatr Surg 1989; 24:24–9. 32. Langevin AM, Pierro A, Lieu P et al. Adriamycin and cisplatinum administered by continuous infusion preoperatively in hepatoblastoma unresectable at presentation. Med Pediatr Oncol 1990; 18:181–4. 33. Douglass EC, Reynolds M, Finegold M et al. Cisplatin, vincristine and ﬂuorouracil therapy for hepatoblastoma: a Pediatric Oncology Group Study. J Clin Oncol 1993; 11:96–9. 34. Ortega JA, Douglass EC, Feusner JH et al. Randomized comparison of cisplatin/vincristine/ﬂuorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: a report from the Children’s Cancer Study Group and the Pediatric Oncology Group. J Clin Oncol 2000; 18:2665–75. 35. von Schweinitz D, Hecker H, Harms D et al. Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma: a report from the German Cooperative Paediatric Liver Tumour Study HB-89. J Pediatr Surg 1995; 30:845–52. 36. Plaschkes J, Perilongo G, Shafford E et al. SIOP trial report: childhood hepatocellular carcinoma: preliminary results of the SIOPEL-1 study of preoperative chemotherapy: continuous infusion of cisplatin and doxorubicin (PLADO). Med Pediatr Oncol 1994; 23:287. 37. Tsuchida Y, Bastos JC, Honna T et al. Treatment of disseminated hepatoblastoma involving bilateral lobes. J Pediatr Surg 1990; 25:1253–5. 38. Makuuchi M, Kawasaki S, Noguchi T et al. Donor hepatectomy for living related partial liver transplantation. Surgery 1993; 113:395–402. 39. Colombani PM, Lau H, Prabhakaran K et al. Cumulative experience with pediatric living related liver transplantation. J Pediatr Surg 2000; 35:9–12. 40. Starzl TE, Iwatsuki S, Shaw BW Jr et al. Left hepatic trisegmentectomy. Surg Gynecol Obstet 1982; 155:21–7.

41. Glick RD, Nadler EP, Blumgart LH et al. Extended left hepatectomy (left hepatic trisegmentectomy) in childhood. J Pediatr Surg 2000; 35:303–7. 42. Tsuchida Y, Hashimoto H, Iwanaka T et al. Left hepatic trisegmentectomy for interlobar hepatoblastoma located close to the hepatic hilum. J Pediatr Surg 1989; 24:1167–8. 43. Reyes JD, Carr B, Dvorchik I et al. Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 2000; 136:795–804. 44. Exelby PR, Filler RM, Grosfeld JL. Liver tumours in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey 1974. J Pediatr Surg 1975; 10:329–37. 45. von Schweinitz D, Hecker H, Schmidt-von Arndt G et al. Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer 1997; 74:593–9. 46. Brown J, Perilongo G, Shafford E et al. Pretreatment prognostic factors for children with hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) Study SIOPEL 1. Eur J Cancer 2000; 36:1418–25. 47. Hu J, Wills M, Baker BB et al. Comparative genomic hybridization analysis of hepatoblastoma. Gene Chromosomes Cancer 2000; 27:196–201. 48. Albrecht S, von Schweinitz D, Waha A et al. Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res 1994; 54:5041–4. 49. Kraus JA, Albrecht S, Wiestler OD et al. Loss of heterozygosity on chromosome 1 in human hepatoblastoma. Int J Cancer 1996; 67:467–71. 50. Koch A, Denkhaus D, Albrecht S et al. Childhood hepatoblastoma frequently carry a mutated degradation targeting box of the b-catenin gene. J Clin Oncol 1999; 11:96–9. 51. von Schweinitz D, Faundez A, Teichmann B et al. Hepatocyte growth factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 2000; 85:151–9.

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80 Congenital mesoblastic nephroma and Wilms’ tumor ROBERT CARACHI

INTRODUCTION Congenital mesoblastic nephroma (CMN) ﬁrst described by Kastner in 1921,1 is the most common renal tumor in the neonate, although rare cases present in later childhood. It is also known as a fetal renal hamartoma, mesenchymal hamartoma of infancy, or lipomyomatous hamartoma. It has an incidence of 2.8% of all renal tumors of childhood, with a mean age of presentation of 3.4 months in contrast to an average age of 3 years in Wilms’ tumors.2 It has been documented as being 22.8% of all primary tumors in children 1-year-old or younger.3 A neoplasm in the kidney of a child less than 3 months old is usually a CMN. The majority of renal neoplasms originating in the fetus and found during the ﬁrst weeks of life differ in structure and biological behavior from nephroblastomas. In contrast to cystic lesions of the kidney, solid renal neoplasms are rare in the newborn and account for only 8% of neonatal tumors. In the Children’s Cancer Group Neonatal Study there were 25 neonatal renal neoplasms, of which 17 were CMNs and the rest were Wilms’ tumors.4 A review of neonatal Wilms’ tumors in the national Wilms’ tumor register identiﬁed 15 cases out of 6832 patients with an incidence of 0.16%, demonstrating how rare malignant renal neoplasms are in neonates. Although prenatal ultrasound is capable of detecting renal neoplasms in utero, there are no speciﬁc sonographic characteristics that can differentiate a CMN from a Wilms’ tumor. Both tumors present as a palpable abdominal mass in the neonate. Affected males outnumber females by 2 to 1 with CMN, and both sexes are equally affected by Wilms’ tumors.

PATHOLOGY Bolande and associates, in 1967, recognized CMN as a unique lesion that could be distinguished clinically

and pathologically from true congenital Wilms’ tumor by its benign clinical behavior, a preponderance of mesenchymal derivatives and lack of the malignant epithelial components typical of Wilms’ tumor.5 A deﬁnite inﬁltrative tendency distinguishes CMNs from hamartomas with more limited growth potential. CMNs are usually solid, unilateral and can attain a very large size like a uterine ﬁbroid. Histologic differentiation is that of a spindle-cell neoplasm with interlacing bundles of ﬁbroblasts and myoﬁbroblasts. Tumor types have irregular interdigitating margins in the perirenal fat and wide margins of excision are desirable for complete removal. Incomplete removal results in tumor recurrence, which happens within a year of resection in most instances. No chemotherapy or radiotherapy is indicated here and a wide surgical resection is the treatment of choice.6 Atypical and more aggressive mesoblastic nephromas tend to be soft, ﬂeshy tumors with areas of gross hemorrhage and necrosis, and are more cellular without recognizable normal glomeruli or tubules. Another variant is a congenital cystic mesoblastic nephroma (cellular variant), which can present as a unilocular hemorrhagic cyst. This can be detected antenatally and misdiagnosed as a hemorrhage into the kidney. The lining of the wall of this cyst shows a typical cellular rim comprising of mitotically active small round and spindle-shaped cells giving the diagnosis of CMN.7 The treatment for this tumor is surgical. Gaillard et al. recently reported pathological and molecular characteristics of CMN in 35 cases.8 Based on cellular criteria, 14 were classiﬁed as classical, four as partly cellular and 17 as cellular CMN. The mean ages were 24, 11 and 70 days, respectively. There were 13 intrarenal tumors (stage I), but nine classical, three partly cellular and ﬁve cellular CMNs extended to the perirenal fat (stage II) and ﬁve cellular tumors ruptured (stage III). In order to assess cellular proliferative activity, silver staining of nucleolar organizer region

748 Congenital mesoblastic nephroma and Wilms’ tumor

(Ag-NOR) proteins was performed on 19 CMNS. The number of Ag-NOR dots per cell was signiﬁcantly lower in classical and partly cellular CMN than in cellular CMN, whatever the stage. Within the cellular CMNs, the mean number of Ag-NOR dots was statistically higher in the single case that recurred with a fatal outcome. The number of Ag-NOR dots, DNA content measurements, the histologic subclassiﬁcation, and the presence or absence of tumor at the surgical margins may be useful features in selecting those patients who will beneﬁt from further treatment after nephrectomy. It has been reported that abnormal renin production and hypertension are common features of CMN. Several investigators have reported distinctive patterns of immunoreactive renin staining, suggesting that mesoblastic nephromas are a source of increased renin production, producing hypertension.9,10 The most intense staining for renin was observed within areas of recognizable cortex trapped within the tumor. Renin was localized in cells in the walls of vessels running up to the glomeruli.

(a)

CLINICAL FEATURES The newborn usually presents with a large, non-tender abdominal mass. Maternal polyhydramnios and prematurity are frequently seen although the reason for this is unclear. The male-to-female ratio ranges from 1.8:1 to 3:1.6,10 Hypertension has been recognized as a presenting feature and there is an association between preoperative hypertension and cardiac arrest during surgery.6 Some patients present with hematuria. In the congenital cystic mesoblastic nephroma variant, the patient may present with a hemorrhagic problem. Detailed antenatal ultrasound scans may pick up a solid tumor of the kidney. Plain ﬁlms of the abdomen show a large, soft-tissue abdominal mass that is rarely calciﬁed. Sonography demonstrates the solid nature and renal origin of the mass and most commonly shows a mixed echogenic intrarenal mass (Fig. 80.1a). CMN should easily be distinguished from more common renal masses in the newborn11 – hydronephrosis or multicystic kidney – which are sonolucent. Magnetic resonance imaging (MRI) scans give detailed imaging of the renal tumor and its surrounding structures.

TREATMENT Nephrectomy of this benign tumor is curative without the need for supplementary radiation or adjuvant chemotherapy. Even when there has been intraoperative rupture, excisional surgery is curative and local recurrence is rare. Distant metastasis has been reported but is extremely uncommon.12 A review of 38 patients with the

(b) Figure 80.1 (a) Sonography demonstrates a mixed echogenic mass. (b) 99mTc-DTPA renal scintigraphy shows function within the mass in the kidney

cellular variant of mesoblastic nephroma showed that seven children had recurrence and three died. According to them, pathologically positive surgical margins were the only statistically signiﬁcant predictor of recurrent disease. Frozen section analysis may help in obtaining tumor-free margins during surgery. Recent studies on molecular biology may shed further light on tumor behavior and add criteria for further therapy after surgery.

PREOPERATIVE PREPARATION Blood samples are obtained for a full blood count, group and cross-match. Tumor markers renin, active renin, and inactive renin should also be assayed because these tumors have been documented as producing high levels of these hormones.10 Erythropoietin levels should also be assayed. Careful monitoring and control of blood pressure is required to prevent dangerous perioperative ﬂuctuations. A central venous cannula for i.v. infusion is inserted into the neck vein or subclavian vein as well as an arterial cannula to monitor blood pressure.

Operative technique 749

OPERATIVE TECHNIQUE

Laparotomy and exposure of the renal pedicle

Position The patient is placed in the supine position with a roll under the lumbar spine to create a lordosis.

Incision An upper transverse muscle-cutting incision from the blank across the midline provides adequate exposure (Fig. 80.2a).

(a)

(d)

(b)

The abdomen is entered, taking care not to cut into the tumor while incising the abdominal wall muscles. The small intestine is displaced toward the opposite side and covered with moist packs. The liver and the opposite kidney are inspected for the presence of any other disease; this is very rare in this condition. Free ﬂuid is sampled and sent for cytology. The colon overlying the tumor is retracted medially and the posterior peritoneum lateral to the colon is incised and reﬂected forward to the midline (Fig. 80.2b).

(c)

(e)

Figure 80.2 Resection of left mesoblastic nephroma. (a) Incision. (b) Colon retracted medially and posterior peritoneum incised. (c) Ureter, gonadal vessels and renal vessels identiﬁed. (d) Ureter and gonadal vessels ligated and divided – this is followed by ligation and division of renal vein and artery. (e) Tumor is removed from the posterior abdominal wall using sharp and blunt dissection

750 Congenital mesoblastic nephroma and Wilms’ tumor

Tumor handling should be minimized in hypertensive patients to prevent excessive release of renin. The inferior vena cava and renal veins are both palpated for the presence of tumor. The ureter is identiﬁed (Fig. 80.2c) and a tape is passed around it. It is traced as far down into the pelvis as possible, ligated with 3-0 chromic catgut sutures and divided. Next the gonadal vessels are ligated and divided. Before mobilization of the tumor, abdominal packs are used to isolate the operative site from the rest of the abdominal cavity. This is to prevent any dissemination of tumor if there is spillage during the time of surgery. The renal vein is doubly ligated and divided (Fig. 80.2d). The renal artery is exposed and transﬁxed with non-absorbable sutures. The para-aortic lymph glands, together with surrounding tissue, are dissected off the aorta and inferior vena cava and labelled carefully. The tumor is removed from the posterior abdominal wall using ﬁnger dissection (Fig. 80.2e). The excised specimen should contain kidney, Gerota’s fascia, fat from the lumbar fossa and para-aortic lymph glands. After removal of the tumor, hemostasis is obtained with diathermy coagulation or suture ligatures. No drainage is usually required.

POSTOPERATIVE CARE Postoperative recovery following resection of mesoblastic nephroma is rapid. Nephrectomy of this benign tumor is curative. If on histology the tumor is found to be Wilms’, it should be treated in accordance with the degree of involvement as outlined in the National Wilms’ Tumor Study Programs.

COMPLICATIONS The main complication of CMN is rupture of the tumor during surgery. Howell et al. reported intraoperative rupture in 20% of their cases.6 In practice this is

extremely rare despite intraoperative rupture; excellent subsequent relapse-free survival has been reported within tumor.

REFERENCES 1. Kastner K. Nierensarckon ber einem siebenmonatlichen. Fotus Ztschn Path 1921; 25:1. 2. Crom DB, Wilimas HA, Green AA et al. Malignancy in the neonate. Med Pediatr Oncol 1989; 17:101–4. 3. Campbell AN, Chan HSL, O’Brien A et al. Malignant tumours in the neonate. Arch Dis Childh 1987; 62:19–23. 4. Ritchey ML, Azizkhan RG, Beckwith JB et al. Neonatal Wilms’ tumour. J Pediatr Surg 1995; 30:856–9. 5. Bolande RP, Brough AJ, Izant RJ. Congenital mesoblastic nephroma of infancy. A report of 8 cases and the relationship to Wilms’ tumour. Pediatrics 1967; 40:272–8. 6. Howell CG, Otherson HB, Kiviat NE et al. Therapy and outcome in 51 children with mesoblastic nephroma. A report of the National Wilms’ Tumour Study. J Pediatr Surg 1982; 17:826–31. 7. Murthi S, Carachi R, Howatson A. Congenital cystic mesoblastic nephroma (cellular variant), (unilocular, haemorrhagic). Personal communication. 8. Gaillard D, Bouvier R, Sonsino E et al. Nucleolar organizer regions in congenital mesoblastic nephroma. Pediatr Pathol 1992; 12:811–21. 9. Yokomori K, Hori T, Takemura T et al. Demonstration of both primary and secondary reninism in renal tumours in children. J Pediatr Surg 1988; 23:403–9. 10. Malone PS, Duffy PG, Ransley PG et al. Congenital mesoblastic nephroma, renin production and hypertension. J Pediatr Surg 1989; 24:599–600. 11. Kirks DR, Kaufman RA. Function with mesoblastic nephroma: imaging – pathologic correlation. Pediatr Radiol 1989; 19:136–9. 12. Heidelberger KP, Ritchy ML, Dauser RC et al. Congenital mesoblastic nephroma metastatic to brain. Cancer 1993; 72:2499–505.

81 Neonatal ovarian tumors JEAN GAUDIN

INTRODUCTION The ovarian cyst is the commonest ovarian tumor in the newborn. This pathology, rarely discovered before the advent of antenatal sonographic detection, now frequently confronts the surgeon. Ultrasound permits the assessment of antenatal development and examination of the newborn. These elements allow the best opportunity for treatment. Possible complications justify treatment being carried out in a surgical unit.

EMBRYOLOGY AND PATHOPHYSIOLOGY The gonad remains undifferentiated until the 50th day of gestation. The process of the ovarian differentiation is then marked by the proliferation and migration of the coelomic epithelium in the underlying mesenchyme. The presence of crypts bordered by the surface epithelium and then of cystic inclusions of the coelomic epithelium in the ovarian cortex seems almost constant in the 12th gestational week. The follicles appear in the 4th gestational month and evolve toward the antral follicle stage. From the 21st week onward, antral follicles with crowns of granulosa cells are present. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) trigger development of the follicles and then human chorionic gonadotrophin (HCG) stimulates this development up to the diploid stage. The pathophysiology of the neonatal ovarian cyst is not fully understood. It is probably the result of hyperstimulation of fetal ovary by maternal hormones, for example: • A precocious FSH peak between the 20th and 30th weeks of gestation • An abnormal HCG peak, for example in maternal diabetes and placental senescence with an increase in HCG transplacental movements (these factors have not been found in recent reports)

• An abnormal ovarian follicle or a disorder of enzyme activity in the internal theca could be the cause.

PATHOLOGICAL EXAMINATION Small follicular cysts (< 2 cm in diameter) are found in up to 33% of female stillbirths and neonatal deaths.1 Large cysts (> 3 cm in diameter) are much less common, although more cases have been detected in recent years by routine antenatal ultrasonography.2–4 The pathological examination conﬁrms the benign nature and clariﬁes the nature of the cyst as follicular or simple. Malignant tumors in the newborn are extremely rare. If torsion of the cyst occurs, necrosis of the cyst makes classiﬁcation impossible, but calcium deposits and signs of resorption (giant cells) are found, indicating the age of the torsion. The ovarian parenchyma is damaged and the histopathologist may ﬁnd some more or less wellpreserved follicles. The absence of an identiﬁable follicle would prove that ischemia has not appeared recently. The presence of normal identiﬁable ovarian stroma in the lining of cysts that are not in torsion indicates conservative surgery.

ANTENATAL DIAGNOSIS Antenatal diagnosis is most often made during a systematic ultrasound scan. It depends on the detection of a rounded, intra-abdominal liquid mass in a female fetus (Fig. 81.1). The time of the discovery is always after the 28th week. The sonographic aspect is that of a liquid mass of homogeneous content, often found in the hypochondrium or mid-abdomen. It is ﬂexible and mobile on examination, or from one examination to the next. A cyst is considered to be pathological when it measures

752 Neonatal ovarian tumors

TORSION

Figure 81.1 Sonographic aspect of ovarian cyst: rounded intra-abdominal liquid mass; (K = cyst, E = stomach, R = kidney)

Torsion of these ovarian cysts mostly occurs antenatally, with a frequency of about one in two.5,9–19 In utero torsion is diagnosed sonographically by the presence of intracystic ﬂocculation, in which the sediment is deposited in the most dependent part of the cyst, giving a characteristic liquid interface (Fig. 81.2). At the end of the development, a rare image is that of a solid mass, moderately echogenic and homogeneous or that of a double level aspect, if the cystic cavity is divided (Fig. 81.3). Flocculation is pathognomonic of the complications (torsion occurs in the great majority of cases, and sometimes hemorrhage without torsion occurs). Frequently these signs of torsion are present when the cyst is discovered,17 whereas some torsion does not reﬂect ultrasonic beams. Torsion may develop secondary to complications: either pericystic adhesion (causing obstruction, perforation of the digestive tube, adhesions to the opposite fallopian tube etc.) or cystic rupture (causing peritonitis and hemoperitoneum).

> 20 mm in diameter, and can be as large as 120 mm in diameter. The quantity of amniotic liquid is normal. The image of a divided cyst may also sometimes be found. Ultrasonography can also determine the normality of the urinary tract, where antenatal abnormalities are most frequently found.

EVOLUTION Sonographic follow-up of these cysts will determine their antenatal development, which may be toward regression, with no sign of complications, or may develop in utero complications or be characterized by stability of the sonographic image.

Figure 81.2 Torsion is indicated by intracystic ﬂocculation

REGRESSION Spontaneous regression of these cysts seems to be quite common;5,6 it can occur in one-quarter to half of cysts and is most often encountered in cysts measuring < 40 mm in diameter, and is not the result of complications. This regression often begins at the end of a pregnancy or sometimes during the ﬁrst days of life.

STABILITY OF THE CYST The cyst changes neither in size nor in its ultrasonic structure during pregnancy.

Figure 81.3 Double level aspect of a divided cyst

Treatment 753

The discovery of bilateral cysts is infrequent and is an acute problem, as it may affect ovarian function later.

DIFFERENTIAL DIAGNOSIS Generally speaking, with the use of sonography, it is easy to exclude a renal or vesical abnormality, endopelvic sacrococcygeal teratoma, anterior meningocele or encysted meconial peritonitis. A diagnosis of an intraabdominal liquid mass can be made. The infrequent antenatal cyst of the bile duct, pancreatic cysts and digestive duplications are usually identiﬁed by postnatal assessment. The identiﬁcation of a cystic lesion of the mesentery is more difﬁcult.

MANAGEMENT In utero therapy In utero therapy must only be practised in a prenatal center, with a pediatric intensive care unit, and by a practitioner skilled in using this technique. Puncture is only carried out for uncomplicated cysts, with a risk of torsion and infrequent bilateral cysts. As torsion is more frequent in larger cysts (≥ 50 mm) some authors reserve in utero puncture for these cysts.17–19 Torsion can also occur in smaller cysts and justiﬁes the extended use of puncture for all anechoic cysts.20 The beneﬁts of avoiding torsion and risk of aspiration after the 30th week of gestation are to allow a comparison with natural evolution and possibility of regression of the cyst.

Delivery The delivery should take place according to obstetric criteria only. Close collaboration between obstetricians and pediatric surgeons ensures that neonatal assessment will be carried out in the ﬁrst few days of life and under optimal conditions.

Neonatal assessment Clinical examination detects the mass in only one case out of two. Without antenatal ultrasonographic diagnosis, such cysts only come to the practitioner’s notice through the discovery of an abdominal mass during systematic clinical examination or when there are complications (obstruction, peritonitis, hemorrhage and ascites).10 Plain abdominal X-rays can show the mass displacing the intestinal gases and allowing the pneumatization of the digestive tube to be checked.

The neonatal ultrasound scan allows a better appreciation of the size, mobility and echogenicity of the cyst. A modiﬁcation of the echostructure (ﬂocculation and intracystic level) should indicate a complication. I.v. pyelography is not needed if the ultrasound diagnosis is certain. On rare occasions sonography reveals a tumor by a heterogeneous image, the presence of intracystic vegetation, the discovery of a non-liquid mass and/or the presence of calciﬁcation on plain X-rays.

TREATMENT The type of treatment depends on the benign nature of the cyst, its possible evolution (to regression or complications) or a doubt about the exact nature of the tumor. The aim for treatment of cysts is to avoid torsion and preserve as much parenchyma as possible, and for antenatal cystic torsion, the aim is to avoid digestive, peritoneal or gynecological complications. The choice of treatment will depend on the progress, aspect and size of the cyst. The treatment is simple for cysts which regress or are in torsion, whereas it is more difﬁcult for simple, unchanged cysts.

Regressive cysts A cyst which diminishes signiﬁcantly in size before birth (spontaneously or after puncture) or during the ﬁrst few days of life must be followed up by ultrasonography to check its return to a normal size (< 20 mm).

Torsion Cysts with torsion can resolve after several months; the complications are infrequent but serious. Many authors consider surgery necessary for asymptomatic cysts in order to prevent secondary complications5,7,11,13 but for others conservative management seems appropriate when cysts tend to involute after birth.19 When cysts exhibiting symptoms of torsion require surgery,5–7,11–13 puncture may be dangerous (e.g. in cases of frequent multiple pericystic adhesions) or impossible (e.g. when the cyst content is of an organized coagulum type, or has mummiﬁed and uncollapsible walls). The state of the ovary and fallopian tubes often leave no choice other than salpingo-oophorectomy (Fig. 81.4).

Unchanged cysts These cysts must be kept under close observation, as a surgical decision may have to be made early, since they are liable to postnatal torsion. Most authors consider that the size of cysts determines surgical management.5,7,8,12,14,15

754 Neonatal ovarian tumors

Rare malignant tumors will be resected more extensively by salpingo-oophorectomy according to their nature and extent.

SURGICAL TECHNIQUES Preoperative preparation

Figure 81.4 Torsion of ovarian cyst with necrosis of ovary and tube: surgical specimen

The exact location of a cyst to the right or left can only be determined by the correct identiﬁcation of the healthy ovary on the opposite side. The vascular pedicle and tube are stretched, which makes the ovarian cyst very mobile. Prudence demands that a lateral approach is avoided.

Laparotomy Small cysts of < 40 mm in diameter are considered to be less liable to torsion and we suggest a period of observation for 1 week is undertaken under the guidance of pediatric surgeons, as during this period regression has been noted in a number of cases. In the absence of regression, laparotomy or puncture is performed. Ultrasound-guided puncture of the cyst is carried out either by the transperitoneal or transvesical route.16 Hormonal analysis of the aspirated liquid should enable the assessment of the ovarian origin of the punctured cyst. The presence of blood in the aspirated cyst ﬂuid is the sign of a complicated cyst). Failure to collapse the cyst is an indication for surgery. Puncturing avoids laparotomy, but there may be recurrence. Laparotomy allows evaluation of the ovaries and permits the performance of conservative surgery, if there is no torsion. Cysts > 40 mm must be punctured or operated on before complications occur. Laparotomy allows enucleation of the cyst with maximum preservation of the parenchyma; this occasionally reveals torsion not detected by ultrasound.

Abdominal palpation under general anesthetic is carried out prior to laparotomy. A urethral catheter is inserted and a curved transverse mark is made in the inferior abdominal crease, before the incision is made (Fig. 81.5a). Subcutaneous tissues are divided to the anterior rectus sheath. Dissection is made between subcutaneous tissues and the anterior rectus sheath in the avascular plane, up to the umbilicus, and then down to the symphysis pubis.

(a)

Tumors Doubt after a scan about the functional nature of a neonatal ovarian mass leads to laparotomy and measurement of carcinoembryonic antigen (CEA) and alphafetoprotein in the blood. Frozen-section analysis should be carried out if the benign status is uncertain. Benign tumors ought to beneﬁt from enucleation, preserving the fallopian tube and normal compressed parenchyma. A plane of dissection is generally found. If no ovarian parenchyma is identiﬁable, oophorectomy is performed. These benign tumors can also have torsion, and ischemic lesions make a salpingo-oophorectomy necessary.

(b)

Figure 81.5 (a) Incision in the inferior abdominal crease. (b) Dissection between subcutaneous tissues and anterior rectus sheath

Surgical techniques 755

This dissection is facilitated by traction on the superﬁcialis fascia, using two retractors (Fig. 81.5b). Cauterization, notably of the superﬁcial epigastric veins, must be meticulous. A vertical incision is made between the two recti, then an opening of the peritoneum above the bladder dome, which is located and retracted downwards. The use of two retractors and abdominal towels allows upward displacement of the small intestine and exposure of the pelvis. Examination of the affected side for the state of the ovarian parenchyma and cyst (to determine whether or not necrosis is present) and the state of the fallopian tube (whether or not necrosis of the distal part, atrophy, or pedicle rupture with wandering tumor is present) follows. The opposite ovary frequently contains minor cysts and must be examined. This examination may necessitate the release of pericystic adhesions between the necrosed cyst and the opposing fallopian tube and ovary, small intestine or colon.

Delivery of the cyst through the incision is usually easy due to the pedicle’s length, however, large cysts can be punctured after protecting the abdominal cavity and determining the benign nature of the cyst. The surgical maneuver therefore depends on the state of the ovary. The discovery of torsion, frequently old and with necrosis of the distal part of adnexa, demands a salpingo-oophorectomy. A cyst without signs of ischemia requires excision, with maximum preservation of compressed parenchyma. Closure is carried out in layers, with a suction drain between the anterior rectus sheath and subcutaneous tissues.

Salpingo-oophorectomy Salpingo-oophorectomy is carried out on necrotic cysts (Fig. 81.6) as follows:

Figure 81.6 (a) Salpingo-oophorectomy: ligature of anterior round ligament and posterior ligament of ovary and resection of intramural part of the tube. (b) Resection of cyst: Compressed parenchyma is opened at the top of the cyst. (c) The ‘capsule’ of parenchyma is stripped from the cyst. (d) Resuturing the ovary: the cavity is closed. (e) Hemostasis of the edges

756 Neonatal ovarian tumors

• Dissection of the adnexa, ligature of anterior round ligament and posterior ligament of the ovary • Resection of the proximal part of the tube, including the intramural part, by a cuneiform incision to avoid later risk of extrauterine pregnancy; then the uterus is closed with a continuous suture • Thrombosis and atrophy of the pedicle frequently facilitate surgery.

Resection of the cyst This procedure is carried out by enucleating the cyst and resuturing the ovary, in order to preserve as much parenchyma as possible. The cyst is delivered, then the compressed parenchyma appearing as a capsule is opened at the top of the cyst, well away from the ovarian pedicle (Fig. 81.6a,b). By combined sharp and blunt dissection, the capsule (parenchyma) is stripped from the cyst. Applying traction sutures on both sides of the incision and compressing the underlying cyst with a small sponge facilitates this maneuver (Fig. 81.6c). During this dissection, stretched ﬁbrous tracts between the cyst and capsule are cauterized. It may be necessary to resect the most compressed part of the parenchyma on both sides of the incision. This resection should be minimized; the parenchyma is usually thicker near the hilum. The resulting cavity is obliterated by absorbable sutures and a continuous absorbable suture is used for hemostasis of the edges (Fig. 81.6d,e). When division of the cyst from the parenchyma is impossible and its benign nature is ascertained, the roof of the cyst is excised (the unrooﬁng technique).

Oophorectomy This procedure is used when the adnexa is healthy and no parenchyma is identiﬁable. Most often it is possible to preserve a sheet of parenchyma at the hilum of the ovary. Oophorectomy will be carried out only for large cystic or benign tumors.

Laparoscopy and minimally invasive surgery The aims and indications of laparoscopic operations are the same as carried out by the open route. Laparoscopy necessitates the monitoring of intra-abdominal pressure (levels of < 8 mmHg should be maintained) and carbon dioxide. An open laparoscopy is performed: a blunt trocar for a camera is introduced under the umbilicus through a small incision. Once lesions have been evaluated and the side of the cyst identiﬁed, two other operative ports are inserted. The intraperitoneal procedure (resection of the cyst, salpingo-oophorectomy, etc.) is then performed.22 For minimally invasive surgery, the cyst is punctured under direct vision and then a lateral incision in front of

the cyst is made.The length of the pedicle allows the cyst to be extirped, and out of the abdomen the surgical procedure is carried out depending on the state of the ovary.21

POSTOPERATIVE ASSESSMENT The long-term prognosis is difﬁcult to predict and subsequent examination of the child, using ultrasound scans, is necessary to detect recurrence during infancy and the pre-pubertal period. Doubt about the future of these patients is another reason to perform conservative surgery at all costs.

REFERENCES 1. deSa DJ. Follicular ovarian cysts in stillbirths and neonates. Arch Dis Child 1975; 50(1):45–50. 2. Bourgeot P, Cockenpot P. Les kystes de l’ovaire du nouveau-né. Aspects échographiques pré et post nataux. A propos de neuf observations. JEMU 1985; 6:285–92. 3. Henrion R, Helardot PG. Le diagnostic des kystes de l’ovaire in utéro. Ann Ped (Paris) 1987; 34:65–9. 4. Vaillant F, Ganichaud P, Denis A et al. Neonatal ovarian cysts. (Apropos of 4 cases). J Gynecol Obstet Biol Reprod (Paris) 1984; 13(6):663–9. 5. Fremond B, Guibert L, Jouan H et al. Prenatal diagnosis of ovarian cysts. Chir Pediatr 1986; 27(3):128–33. 6. Gaudin J, Le Treguilly C, Parent P et al. Neonatal ovarian cysts.Twelve cysts witn antenal diagnosis. Pediatr Surg Int 1988; 3:158–64. 7. Grapin C, Montagne JP, Sirinelli D et al. Diagnosis of ovarian cysts in the perinatal period and therapeutic implications (20 cases). Ann Radiol (Paris) 1987; 30(7):497–502. 8. Ikeda K, Suita S, Nakano H. Management of ovarian cyst detected antenatally. J Pediatr Surg 1988; 23(5):432–5. 9. Mc Keever PA, Andrews H. Fetal ovarian cyst: a report of ﬁve cases. J Pediatr Surg 1988; 23:354–5. 10. Ahmed S. Neonatal and childhood ovarian cysts. J Pediatr Surg 1971; 6(6):702–8. 11. Calisti A, Pintus C, Celli S et al. Fetal ovarian cyts: post natal evolution and indications for surgical treatment. Pediatr Surg Int 1989; 4:431–6. 12. Brandt ML, Luks FI, Filiatrault D et al. Surgical indications in antenatally diagnosed ovarian cysts. J Pediatr Surg 1991; 26(3):276–81. 13. Croitoru DP, Aaron LE, Laberge JM et al. Management of complex ovarian cysts. J Pediatr Surg 1991; 26:1366–8. 14. Zachariou Z, Roth H, Boos R et al. Three years’ experience with large ovarian cysts. J Pediatr Surg 1989; 24:478–82. 15. Bagolan P, Rivosecchi M, Giorlandino C. Prenatal diagnosis and clinical outcome of ovarian cysts. J Pediatr Surg 1992; 27(7):879–81.

References 757 16. Debeugny P, Huillet P, Cussac L et al. Systematic nonsurgical treatment of ovarian cysts in newborn infants. (Apropos of 8 cases). Chir Pediatr 1989; 30(1):30–6. 17. Giorlandino C, Bilancioni E, Bagolan P et al. Antenatal ultrasonographic diagnosis and management of fetal ovarian cysts. Int J Gynaecol Obstet 1994; 44(1):27–31. 18. Sapin E, Bargy F, Lewin F et al. Management of ovarian cyst detected by prenatal ultrasounds. Eur J Pediatr Surg 1994; 4(3):137–40. 19. Luzzatto C, Midrio P, Toffolutti T, Suma V. Neonatal ovarian cysts: management and follow-up. Pediatr Surg Int 2000; 16(1–2):56–9.

20. Perrotin F, Roy F, Potin J, Lardy H, Lansac J, Body G. Diagnostic échographique et prise en charge prénatale des kystes ovariens du fœtus. J Gynecol Obstet Biol Reprod 2000; 29:161–9. 21. Van der Zee DC, van Seumeren IG, Bax KM, Rovekamp MH, ter Gunne AJ. Laparoscopic approach to surgical management of ovarian cysts in the newborn. J Pediatr Surg 1995; 30(1):42–3. 22. Esposito C, Garipoli V, Di Matteo G, De Pasquale M. Laparoscopic management of ovarian cysts in newborns. Surg Endosc 1998; 12(9):1152–4.

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9 Spina biﬁda and hydrocephalus

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82 Spina biﬁda and encephalocele PREM PURI AND RAJENDRA SURANA

INTRODUCTION The term ‘neural tube defect’ (NTD) refers to any defect in the morphogenesis of the neural tube, ranging from anencephaly to spina biﬁda occulta. Spina biﬁda is one of the commonest congenital anomalies encountered. However, the incidence of NTDs is now on decline.1,2 The precise reason for this change is unclear. The declining rates of neural tube defects can be partially explained by increased widespread prenatal diagnostic techniques, declining birth rates, and an improved standard of living with dietary improvements. Nevertheless spina biﬁda when it occurs can have devastating consequences. Its management has stirred a great deal of medical, ethical and legal controversy over the past 3 decades. This management requires a team approach involving medical specialists, e.g. surgeons, neonatologists, neurologists, urologists, radiologists along with physiotherapists, social workers, psychologists, nursing staff and most of all the patient, family and society so as to enable the patient to live a meaningful life.

HISTORY The ﬁrst accurate description of spina biﬁda was given by Caspar Baulinin early 17th century.3 The term ‘spina dorsi biﬁda’ was coined by Nicholas Talpius (Tulp) in 1641.4,5 Virchow in 1875 introduced the term ‘spina biﬁda occulta’.6 The association of hydrocephalus and spina biﬁda was recognized by Morgagni in 1761. He also described anencephaly and spina biﬁda as expressions of the same pathological process and attributed bladder, rectal and limb abnormalities to the neuronal damage in the defective spinal cord.3 Various classiﬁcations of spina biﬁda were based on the pathological descriptions of von Recklinghausen.7 Aspiration of the lesion was the time honored method of management but had catastrophic consequences. Forestus ligated the sac.8 Excisions of the sac were

attempted by Tulp with fatal results.4 The Clinical Society of London8 recommended the use of a local sclerosing technique as the preferred method of treatment, which was initially advocated by Morton.9 Excision of the sac was again popularized by Bayer10 and Frazier.11 However, the mortality rate remained high. With the advent of antibiotics and introduction of CSF shunts in the 1950s, the operative results encouraged more surgeons to introduce comprehensive, aggressive management. In 1963 Sharrad, Zachary and Lorber proposed emergency operative closure of the back lesion to decrease mortality and improve muscle function.12 This provided new hope for these patients. However in the latter part of the decade it became evident that the mortality remained high and those who survived had major handicaps. Lorber,13 who was one of the supporters of aggressive policy of the Shefﬁeld group, reviewed 524 cases of myelomeningocele treated actively and concluded that there were four main criteria associated with a poor prognosis: gross hydrocephalus, severe paraplegia, kyphosis, associated gross congenital anomalies or major birth injury. He suggested that a patient with one or a combination of these adverse criteria should be selected for conservative management as very few patients with such adverse criteria would live and those who live would be severely mentally and physically handicapped. In recent years, the reliability and ‘predictive value’ of these four criteria has been questioned. It has been suggested that the management of these infants should be individualized and changed whenever necessary in the best interest of the patient.14,15

EMBRYOLOGY NTDs are the results of an abnormality in the process of neurulation. The primitive streak and Hensen’s nodes are present in the embryo of 2 weeks’ gestation (c.r. length 0.2 mm). The notochord starts extending rostrally from Hensen’s node. This induces the process of neural tube formation. Thickening of the ectoderm cephalic to

762 Spina biﬁda and encephalocele

Hensen’s node occurs and forms the neural plate. Folding and later fusion of these folds forms the neural tube. This process continues caudally up to the recent developed somites, which have started to appear from the third week (c.r. length 1.5–2.5 mm). Other ectodermal tissue closes over this and buries the tube. The unfused rostral and caudal neural folds are called anterior and posterior neuropores. These are closed at about 25 days (c.r. length 2.5–4.5 mm) and 30 days (c.r. length 3–5 mm), respectively. The process of neurulation is then completed. At this stage there are about 21–29 somites. Four somites are incorporated into the occipital bone and 20 for the cervical and thoracic vertebrae. Caudal to this, the remainder of the tube forms the caudal cell mass. During the next 4–5 weeks (crown length 28–53 mm) canalization of this cell mass occurs; this is followed by the regression of the most caudal part of the neural tube, which forms the ﬁlum terminale. The notochord separates from the neural tube dorsally and the gut ventrally forming sub and epichordal spaces.

PATHOGENESIS All developmental defects of the central nervous system are NTDs while neurulation defects in a strict sense make up a sub-group of NTDs. These defects can involve: 1 Brain • Anencephaly: a result of persistence of the anterior neuropore. This allows some part of the developing brain to remain in contact with the amniotic cavity. The types are: holocrine, if the defect extends to involve foramen magnum, and mesoacrania, if the foramen is not involved16 • Encephalocele: the result of defective neurulation in cephalic part. 2 Spinal cord • Meningocele: a post-neurulation defect • Myelomeningocele: Defective caudal neurulation results in myelomeningocele, which can occur anywhere from cervical to lumbar sites. There are various theories put forward to explain the precise mechanism of the defective neurulation. These are either due to failure of neural folds to fuse or a reopening of the normally fused neural tube. Defective neuroepithelium itself may be responsible for the failure of neural folds to fuse17 or the defect may lie in mesoderm, which deters the closure of neural folds.18 The normally fused neural tube may reopen because of increased intraluminal pressure19 or a primary defect in the neuroepithelium.20 Associated Arnold Chiari malformation may be secondary to failure of ascent of the cord within spinal column because of tethering or as a result

of descent secondary to increased pressure of hydrocephalus. 3 Brain and spinal cord • Craniorachischisis is the defect involving brain and spinal cord. 4 Other defects occur secondary to various postneurulation abnormalities involving the neural tube or mesoderm, or because of persistence of totipotent cells. These lesions are: diastematomyelia, complete anterior and posterior spina biﬁda, butterﬂy vertebrae, lipoma, hemangioma, dermoid cyst, and sacrococcygeal teratoma. A partial duplication and separation of the notochord can result in herniation of the endoderm of the yolk sac, called split notochord syndrome. If the hernia ruptures it may result in ectopic bowel, sinus or ﬁstula.21

ETIOLOGY The etiology of NTDs is not known. Genetic as well as environmental factors may be involved in the causation of these abnormalities.

Genetics Though the exact mode of inheritance is not known, ethnic variation, sex difference (females are more commonly affected than males), increased incidence with parental consanguinity and familial tendency, suggest a multifactorial hereditary predisposition. An individual’s risk of having other children with spina biﬁda increases to one in 20–25 if there is one child with spina biﬁda in the family.22,23 This risk is one in eight to ten if there are two children with NTDs.23 The risk of having an affected child is of lesser magnitude (one in 200) if one of the parents had spina biﬁda than if a sibling had spina biﬁda.22

Environmental factors Dietary factors have long been suspected in causation of NTDs. Recently substantial data have been accumulated to suggest that myelomeningocele and other neural defect recurrences may be reduced by improved maternal nutritional status. Deﬁciencies of folic acid and zinc have been incriminated. Mothers of spina biﬁda patients were found to have an increased incidence of folate metabolism abnormalities24,25 and it has since been suggested that folic acid might be involved. Several studies have reported a beneﬁcial role of folic acid or other vitamins or both.26–29 Recently, the Medical Research Council conducted a randomized double-blind prevention trial with factorial design at 33 centers in

Prenatal diagnosis 763

seven countries to determine whether supplementation with folic acid or a mixture of seven other vitamins (A, D, B1, B2, B6, C and nicotinamide) around the time of conception could prevent NTDs.30 The women at risk were randomly allocated to various groups including a control group to avoid bias. This study found a signiﬁcant reduction in the number of children born with NTDs to high-risk mothers who have taken folic acid in the periconceptional period. Periconceptional use of folic acid has been recommended to all women with or without risk. A concern that large doses of folic acid may delay the diagnosis of pernicious anemia has led to the fortiﬁcation recommendations being limited to a level that may add on average, only about 0.1 mg folic acid/day.31 However, others feel that a daily dose of 0.4 mg/day should be continued.32

Table 82.1 Classiﬁcation of neural tube defects Site

Lesion

Pathology

Craniospinal

Craniorachischisis

NTD involving both the brain and spinal cord

Cranial

Anencephaly

Brain and skull poorly developed Exposed brain without skin and bone cover Brain herniation through a congenital opening of the skull and covered by meninges and skin. Can be occipital, parietal, frontal, nasal and nasopharyngeal

Exencephaly Encephalocele

Spinal

Teratogens Many agents have been blamed as possible teratogens responsible for the occurrence of NTDs. Exposure to antiepileptic agents valproate33,34 and carbamazepine35 in utero carries a 1.2% risk of the occurrence of NTDs, which is more than the risk involved with the disease itself, and the NTDs caused are usually more severe open defects with a high incidence of hydrocephalus.36 Certain viruses37 and hyperthermia have also been held responsible as the cause of NTDs. Exposure to heat in the form of a hot tub, sauna or fever in the ﬁrst trimester of pregnancy was also associated with an increased risk of causing NTDs.38–40

CLASSIFICATION The types of NTDs vary, from anencephaly to spina biﬁda occulta. These lesions can be classiﬁed as shown in Table 82.1. Myelomeningocele is one of the most common congenital malformations.

Spina biﬁda cystica a) Myelomeningocele Open cord defect. Cervical, thoracic, thoracolumbar, lumbar, sacral, lumbosacral, thoracolumbosacral b) Meningocele Sac formed of meninges. Through incomplete posterior arch. Skin covered Spina biﬁda occulta Absence of spinous process and varying amounts of associated lamina. May be with normal skin or associated lesions, e.g. lipoma, hemangioma, dermoid, dimple, sinus, etc.

PRENATAL DIAGNOSIS Prenatal diagnosis of myelomeningocele allows both improved obstetric care and, conversely, termination of an affected fetus if desired.45

INCIDENCE AND EPIDEMIOLOGY Chorionic villous sampling There are geographic variations in the incidence of spina biﬁda and NTDs in the world. The ﬂuctuations in the incidence of spina biﬁda in the same region are reported.1 The incidence of spina biﬁda cystica varies between 0.3 (Finland) to 4.5 (Ireland) per 1000 live births,41 while spina biﬁda occulta incidence varies greatly between 1–50% depending upon the age group.42 Caucasians are at higher risk than black people of developing spina biﬁda43 and lower socioeconomic groups also seem to have a higher incidence of the defect.44

In early pregnancy, after eight weeks of conception, a chorionic villous sample can be obtained either perabdominally or per-vaginally. Cells are then cultured. This is a quite safe and reliable method for the diagnosis of NTDs.46

Alphafetoprotein in maternal serum Maternal serum alphafetoprotein (MSAFP) is a good method for mass screening as it helps to identify

764 Spina biﬁda and encephalocele

pregnancies requiring further evaluation. Elevated levels after 16 weeks pregnancy are suspicious; the test is repeated a week later to conﬁrm the presence or absence of NTDs. The sensitivity of this test is about 97% for anencephaly and 72% for spina biﬁda.47 This second test requires further conﬁrmation by amniocentesis and prenatal ultrasonography.

Amniocentesis In this test, the amniotic ﬂuid is obtained abdominally under ultrasound guidance at about 16 weeks’ gestation. Alphafetoprotein and acetylcholinesterase (ACHE) levels are estimated to conﬁrm the presence of NTDs in the fetus. Alphafetoprotein was ﬁrst noted in the serum of fetuses in 1956,48 however, the usefulness of amniotic ﬂuid levels of alphafetoproteins in detection of NTDs was not reported until 1972.49 The risk of an open NTD is 60% if the levels are > +3SD. The risk rises to 86% if the levels are > +5SD. Recently ACHE levels in amniotic ﬂuid have been reported to be an effective adjunctive test.50 The combined analysis of alphafetoprotein and ACHE in amniotic ﬂuid provide a high degree of accuracy in the diagnosis of NTDs. However, specimens contaminated with fetal or maternal blood still cause problems in relation to interpretation of results. In such situations repeat amniocentesis or ultrasonography is necessary. This prenatal ultrasonography may be used as a primary screening procedure or in those pregnancies where the amniotic ﬂuid specimen is contaminated with blood. It is a safe and effective method of antenatal screening if the ultrasonographer is experienced.51 Levels of up to 98% speciﬁcity and 94% sensitivity have been reported.52

SPINA BIFIDA OCCULTA The term ‘spina biﬁda occulta’ refers to the form of spinal dysraphism not accompanied by the extrusions of the contents of the vertebral column.

Figure 82.1 Spina biﬁda occulta. A large tuft of hair over lumbosacral region in this baby was associated with spina biﬁda occulta and a tethered cord

ulceration. All these patients warrant careful examination and investigation. Spinal X-ray will show evidence of spina biﬁda and other spinal abnormalities. Ultrasonography can be useful in the newborn period to diagnose diastomyelia.53

SPINA BIFIDA CYSTICA: MENINGOCELE Meningocele is an epithelial lined sac ﬁlled with cerebrospinal ﬂuid (CSF) and is in the communication with the spinal subarachnoid space. The site of predilection is usually the lumbar region. Meningocele, which comprises about 5% of all spina biﬁda cystica cases, is usually not associated with neurological deﬁcit and hydrocephalus.

Management Clinical features Spina biﬁda occulta, without any external evidence, is rarely diagnosed in the newborn. Occasionally it may cause neurological deﬁcit because of a tethering of the cord, or some patients may have external evidence of spina biﬁda occulta. These lesions include a small dimple, sinus, tuft of hair (Fig. 82.1), or harmartomatous lesions such as hemangioma, lipoma, nevi etc. Neural involvement may be manifested by urinary problems, e.g. recurrent urinary infection or enuresis, motor deﬁcit with pedal deformity, pelvic tilt and muscle weakness, and sensory involvement in the form of trophic

After careful evaluation, early operation is recommended to prevent infection, restore continuity of the back and avoid psychological trauma. The prognosis for normal development is good in patients with meningocele.

SPINA BIFIDA CYSTICA: MYELOMENINGOCELE Myelomeningocele is the commonest form of NTD (Fig. 82.2). A neural plaque is centrally placed, around which there is a cystic lesion with attenuated meninges and skin (Fig. 82.3). Although the pathological changes are

Spina biﬁda cystica: myelomeningocele 765

ment of an infant presenting with spina biﬁda is complex, whatever the approach. It begins with careful assessment of the infant, not only of the local lesion and neurological involvement, but also of the general condition to determine if there are any other congenital anomalies.

Perinatal management It still remains controversial whether cesarian section should be carried out if the prenatal diagnosis of myelomeningocele has been made. Some authors54 report that cesarian section offers advantages to those born by this route as compared to those born by vaginal delivery, although other authors do not support this.55 Luthy et al.54 reported that delivery by cesarian section for the fetus with uncomplicated myelomeningocele before onset of labor may result in better subsequent motor function than vaginal delivery or cesarian section after labor has commenced. Figure 82.2 Dorsolumbar myelomeningocele. This infant had normal movement in both lower limbs

Clinical assessment LOCAL EXAMINATION The sites affected are the lower thoracic, lumbar, sacral, cervical and upper thoracic regions. In about 80% of infants with myelomeningocele, the defect includes the lumbar region because this is the last region of the neural tube to close. Occasionally more than one lesion can be found56 and there is often marked kyphosis or scoliosis present. Most myelomeningoceles contain an enlarged subarachnoid space ventrally, with the neural tissue displaced dorsally; in combination this creates a herniated sac on the infant’s back.

NEUROLOGICAL DISTURBANCES These defects are almost always associated with some degree of paralysis, sensory loss and bladder, and bowel abnormalities. Though it is largely dependent on the site of the lesion, it may vary because of abnormalities in the cord beyond the lesion. Figure 82.3 Myelomeningocele. Lesion showing neural plaque in the center, covered by a thin membrane

obvious at the site of the lesion, additional changes involve the whole of the nervous system and other systems, especially genitourinary and skeletal.

Management The management of myelomeningocele has stirred a great deal of controversy over the past 3 decades, varying from early detection and aggressive management of all patients to the highly selective conservative approach. The manage-

MOTOR FUNCTION Varying degrees of paralysis below the level of the lesion are common, except in rarer cervical and upper thoracic lesions, which are usually spared. The paralysis is usually ﬂaccid, indicating a complete neural lesion, but sometimes it may be spastic as in the upper motor neuron lesion. It must be borne in mind that there are some abnormal reﬂux activities in the lower extremities that have no bearing on volitional motor function.

SENSORY LOSS Sensory loss is determined by pinprick test and the producing of an upper extremity or facial response

766 Spina biﬁda and encephalocele

characteristic of those experiencing a pain sensation. The level at which anesthesia starts is the indicator of myotome level of the lesion and predictor of handicap.57 Proper care is necessary to avoid trophic changes in anesthetized areas.

BLADDER AND BOWEL INVOLVEMENT Over 90% of patients with myelomeningocele have a form of neurogenic bladder. The vast majority of these patients have disturbances of detrusor and sphincter balance resulting in a large, trabeculated bladder with urinary stasis. The anal external sphincter and puborectalis are often involved, resulting in patulous anus and sometimes rectal prolapse. It is difﬁcult to ascertain bladder involvement in the newborn but steps should be taken to ensure the bladder is kept empty. The upper urinary tract is usually normal but some affected patients will experience changes in the upper urinary tract at birth.58 All of these patients need careful followup of the renal systems.

lined some adverse criteria for conservative management of these patients, including gross paraplegia, hydrocephalus exceeding the 90th centile by 2 cm or more, severe kyphosis, thoracolumbar lesions and other associated congenital anomalies (Fig. 82.4). These criteria are based on the belief that these patients will die early in infancy; this type of management will also give some time for discussion with the parents, enabling them to make rational decisions. In some units these patients are managed with demand feeding with heavy sedation, while other units differ in managing these patients with normal feeding, sedation only when indicated and full nursing care except use of antibiotics and resuscitation.62 If these infants show signs of survival, this policy should be reviewed. Delaying surgery to the back lesion does not seem to alter the prognosis.63–65

HYDROCEPHALUS Approximately 85–95% of patients with myelomeningocele have some degree of hydrocephalus, which is almost always associated with the Arnold Chiari malformation.59

SKELETAL ABNORMALITIES Club foot is the most commonly occurring abnormality with spina biﬁda. Other deformities include dislocation of the hip, genu recurvatum and kyphoscoliosis.

Investigations A full blood count is obtained and blood is crossmatched with maternal serum. A plain X-ray of the spine will reveal the extent of the bony lesion and associated kyphoscoliosis. An ultrasound scan of the head and renal tract are carried out as baseline investigations.

Postnatal management Babies born with NTDs deserve an ethical, humane program of management based on accurate background data involving the parents fully in the decision-making process.14 Most parents want to be involved in the decision-making process about the care of their child.60 The management of each child should be individualized and reviewed regularly.

Conservative management It was observed that in spite of early closure and application of all measures available, there is still a signiﬁcant rate of handicap and mortality.57,61 Lorber therefore out-

Figure 82.4 Large dorsolumbar myelomeningocele. This baby had bilateral lower limb paralysis, hydrocephalus and bilateral dysplastic kidneys. The baby was managed conservatively

Operative treatment All spina biﬁda patients managed in units where the policy is for active intervention and those patients who survive beyond 3 months or so with conservative management should also be moved to receive active management.

Timing of operation It was suggested that the closure of the back lesion within the ﬁrst 24 hours of life resulted in some improvement in neurological status,11 but this has not been supported by others.65,66 Patients with open myelomeningocele and good power in lower limbs should be operated on as soon as possible to prevent infection and further damage to exposed tissue. The lesion is covered with a non-stick

Spina biﬁda cystica: myelomeningocele 767

dressing or swabs soaked with 2% chlorhexidine. Hypothermia should be avoided. The aim of the operation is to preserve motor and sensory function, to prevent infection thereby limiting deterioration in intellectual ability and to restore the normal contour of the back.

Position

General anesthesia with endotracheal intubation is given.

The patient is placed in the prone position with a soft roll under the hips and shoulder, and with the head turned to the right through 90o (Fig. 82.5a). Swabs are taken from the lesion for microbial examination and culture. An antiseptic soak is placed over the anus. The lesion is covered with a warm chlorhexidine swab and the surrounding skin is cleansed and draped.

Operation

Incision

The principle of surgery is to reconstruct the spinal cord by ﬁve-layer closure of the pia and arachnoid dura, iliocostalis fascia, subcutaneous tissue and skin. The vascular supply to neuroplaque is maintained and unnecessary neural injury is avoided.

The skin is incised at the junction of the arachnoid membrane and skin (Fig. 82.5b). The membrane between the edge of the skin defect and neural plaque is removed carefully to avoid inclusion cysts (Fig. 82.5c).

Anesthesia

(b) (a)

(c)

(d)

(e)

(f)

Figure 82.5 Closure of myelomeningocele. (a) Position of the patient on the operating table. (b) An elliptical incision at the junction of the arachnoid membrane and the skin. (c) Membrane is excised and neural plaque freed. (d) Dura is dissected laterally from the underlying muscle. (e) Dura is closed with an interrupted or continuous 5-0 monoﬁlament absorbable sutures. (f) Skin is closed with interrupted 5-0 nylon sutures

768 Spina biﬁda and encephalocele

DURAL LAYER The dura is freed laterally and then superiorly and inferiorly to normal intact dura (Fig. 82.5d). Dura is then sutured in the midline with continuous monoﬁlament absorbable sutures (Fig. 82.5e). A suction drain may be placed extradurally.

FASCIAL LAYER The lumbodorsal fascia is incised laterally and dissected free from the posterior lilac crest. These are folded medially and sutured over the dorsal dural layer. The subcutaneous tissue is closed with absorbable interrupted sutures and then the skin is closed with interrupted nylon stitches (Fig. 82.5e).

POSTOPERATIVE CARE The infant is nursed in a prone position. Feeding is commenced once the bowel starts working. The wound is periodically inspected. The suction drain is removed 24–48 hours after operation.

Postoperative complications

Results The results of myelomeningocele operations vary considerably because of differences in approach to management. In the units where a highly selective approach is taken, all 100% conservatively managed patients died, while only 14.3% of actively managed patients died.69 The authors reviewed the results of the patients managed over the last 5 years. Of the 104 patients in their institution, 55 were managed actively with a mortality rate of 7.8% and 49 were managed conservatively, with a mortality rate of 46.9%. In the centers where patients were managed unselectively, a 41% mortality rate has been reported.57

PROGNOSIS Whether patients are managed conservatively or actively, the quality of life is an important factor in those who survive. Recently, Hunt57 published a long-term followup study of 117 patients treated unselectively, who were followed up for 16–20 years. It was found that 41% of these patients had died before 16-years of age. Of the survivors, almost 31% were mentally retarded and 48% were unable to live without help or supervision, while only about one-quarter of the survivors were capable of open employment.

WOUND INFECTION Infection is common67 and treatment is with appropriate antibiotics and local drainage.

WOUND DEHISCENCE Wound dehiscence is secondary to undue tension on the skin edges or skin necrosis. If the involvement is deep to the lumbodorsal fascia, it may cause meningitis or ventriculitis. These are vigorously treated with local dressings, systemic antibiotics and external ventricular drainage if hydrocephalus is present.

CSF FISTULA With meticulous closure of the dura, CSF ﬁstula should be rare. However if it does occur, immediate repair is the preferred treatment rather than conservative treatment.

HYDROCEPHALUS Hydrocephalus may be present in about 15% of patients with myelomeningocele at birth, while it eventually develops in 85.96% of these patients. The exact reason for this is not clear. It may be aggravated by a shift in the brainstem after repair, which produces changes in the aqueduct or the Arnold Chiari malformation leading to a further alteration in the CSF ﬂow pathways. It is doubtful that the sac serves as a site of absorption and with removal the hydrocephalus is aggravated.68

INTELLIGENCE Patients who have associated hydrocephalus and episodes of ventriculitis have lower intelligence than those who only have myelomeningocele. Patients though severely physically handicapped but who are not mentally retarded can be self-supporting and live quality lives.

AMBULATION Ambulatory potential and capacity are related to intelligence, orthopedic deformity, level of lesion, obesity and motivation. Most of the patients with lesions below L5 are ambulators, those with lesions at L4 are functional ambulators, and those with lesions above L3 are wheelchair-bound.70

URINARY INCONTINENCE Only 10% of the myelomeningocele patients have a normal bladder; the rest of the patients have a neurogenic bladder. Introduction of clean intermittent catheterization, pharmacological agents, external devices, biofeedback and innovative surgical procedures for the neurogenic bladder have altered the management so as to permit the development and social relationship while preserving the renal function.71 Up to 75% of these patients could be socially continent of urine. Urodynamic studies in the newborn period are useful in identifying ‘at-risk’ children, with high bladder pressure and detrusor sphincter.72,73

Encephalocele 769

PSYCHO-SOCIAL PROBLEMS Educational mainstreaming, special counselling, improved understanding of the patient’s potential and increased public awareness of spina biﬁda contribute to a reduction in stress through psycho-social problems originating within themselves, their families and society.

PREVENTION In spite of improvement in surgical techniques, modern intensive care facilities, and newer investigative modalities, myelomeningocele remains a condition with devastating results. Prevention of this condition is therefore the most important aspect of the management. This involves identiﬁcation of high-risk patients, genetic and prenatal counselling, avoiding known teratogens such as valproate and carbamazepine, supplementation of folic acid in the periconception period, and prenatal screening with termination of pregnancy where it is acceptable.

content and location are variable, though the occipital type is the most common (Fig. 82.6). There may be a hamartomatous lesion overlying the encephalocele. Anterior lesions may present airway obstruction. Sometimes diagnosis may be delayed and may only become evident because of a CSF leak and recurrent meningitis. A full neurological examination is necessary. The common abnormalities are spasticity, focal motor weakness and visual impairment. Physical examination will reveal association anomalies.

ENCEPHALOCELE Encephalocele constitutes 10–20% of all NTDs.1 Cranial malformations are more common in the eastern world than the West.74

Pathology With this anomaly, there is a defect in the cranial vault which is either oval or circular in shape, with variable degrees of abnormality, ranging from skin-covered meningocele to gross herniation of abnormal brain. These abnormalities can occur in different locations and are classiﬁed as occipital, parietal, frontal, nasopharyngeal, nasal, frontoethmoid and basal encephalocele. Occipital encephalocele is the most common type. The contents of the encephalocele vary according to its location and size. Brain tissue has been described in 25–80% of cases, usually in occipital encephalocele. In addition to the brain tissue in the sac, the rest of the brain, especially the optic pathway, is distorted and may be associated with microgyria, holoprosencephaly, heterotopia, agenesis, hydrocephalus, cerebellar aplasia, pyramidal tract aplasia (causing spasticity) and spinal cord distortion. Encephaloceles are also commonly associated with other congenital anomalies like spina biﬁda, Klippel-Feil syndrome, facial cleft, and renal, cardiac and pulmonary anomalies.

Figure 82.6 Occipital encephalocele

Clinical features

Treatment

Most of the encephaloceles are obvious at birth and some may have been diagnosed prenatally. The size,

Conservative treatment may be justiﬁed for patients with microcephaly and large amounts of brain within the

Differential diagnosis The anterior lesion can be difﬁcult to diagnose and may need to be differentiated from the nasal polyp, glioma, dermoid cyst, teratoma, neuroﬁbroma, meningioma and hamartoma. A pulsatile mass that increases in size with crying is the sign of encephalocele.

Investigations Plain X-rays and tomogram will establish the size, location and cranial defect (Fig. 82.7). Ultrasound, computed tomography and magnetic resonance imaging will give information regarding brain deformity, identiﬁcation of bony defects and associated hydrocephalus. Visually evoked response will establish the presence of the occipital cortex within the sac, which may be helpful in planning the contemplated surgery.

770 Spina biﬁda and encephalocele

(a)

Figure 82.7 Encephalocele. Lateral radiograph shows the mass arising from occipital region with intact cervical spine

encephalocele, where death is inevitable. Most of the patients are treated by surgical repair of the encephalocele. The aims of the surgery are excision of the extracranial nonfunctioning brain tissue, closure of the dura at the level of the cranium and restoration of cranial contour with good skin coverage. Taking these steps to treatment also helps to prevent infection and preserve function.

PROCEDURE The patient is anesthetized with endotracheal intubation. A prone position is adopted if the patient has occipital or parietal encephalocele, with the head resting on a soft head rest. The lesion is painted and draped as usual, supporting the encephalocele. If the lesion is too large, it could be aspirated for easier handling and dissection. A sample of CSF is sent for microbiological examination and cultures.

INCISION Usually a transverse ellipse incision is made near the base of the lesion, planned so as to enable closing it without causing undue tension (Fig. 82.8).

OPENING OF THE SAC The incision is then deepened until the dura is seen, which is traced up to the bony defect. The sac is opened where the cerebral tissue is not adhered. If the cerebral tissue is too large, necrotic and if no visual evoked potentials are demonstrated, it is excised. Every effort should be made to preserve brain tissue without causing acute rise in intracranial pressure. Bony defects may sometimes need to be enlarged. While dissecting the dura and brain tissue, care must be taken to avoid abnormal venous sinuses and venous connections.

(b)

(c)

Figure 82.8 Closure of encephalocele. (a) Diagrammatic representation of occipital encephalocele. (b) Incision around the base of the encephalocele. (c) Skin closure

EXCISION OF THE SAC AND REPAIR The distal sac is then excised. The dura is closed with continuous monoﬁlament absorbable sutures. Dural grafting may usually be used to bridge the gap; this can be further strengthened with a musculofascial ﬂap or aponeuro-pericranial ﬂaps. Meticulous hemostasis is achieved carefully. A small suction drain is occasionally used.

CLOSURE OF SKIN Subcutaneous tissue is approximated with ﬁne, absorbable interrupted sutures, and the skin is closed with interrupted nylon or continuous absorbable subcuticular stitches (Fig. 82.3). A dressing and bandage is applied.

POSTOPERATIVE CARE The infant is nursed in a prone position and watched carefully for an acute rise in intracranial pressure or development of hydrocephalus.

References 771

POSTOPERATIVE COMPLICATIONS Meningitis is common with anterior encephalocele, where contamination is more likely because of the proximity to the nose, mouth, sinuses etc. An intracranial approach may help to avoid this.

CSF FISTULA A CSF ﬁstula can occur and proper closure of the dura is important. A dural graft may be used to achieve a watertight closure.

RISE IN INTRACRANIAL PRESSURE AND HYDROCEPHALUS Postoperatively infants are watched for a sudden acute rise in intracranial pressure. Most infants develop hydrocephalus, subsequently requiring CSF shunts.

RESULTS Encephalocele carries a high rate of mortality (up to 50%).35 These deaths may be due to cerebral anomalies, associated congenital abnormalities, an acute rise in intracranial pressure and shunt malfunction and complications.

PROGNOSIS The prognosis is worse if the lesion is encephalcele rather than meningocele, associated with microcephaly, a large encephalocele, an anterior encephalocele rather than a posterior one, and in those who develop hydrocephalus.

REFERENCES 1. Anonymous. Prevalence of neural tube defects in twenty regions of Europe and the impact of prenatal diagnosis 1980–1986. EUROCAT Working Group. J Epidemiol Community Health 1991; 45(1):52–8. 2. Yen IH, Khoury MJ, Erickson JD, James LM, Waters GD, Berry RJ. The changing epidemiology of neural tube defects. United States. 1968–1989. Am J Dis Child 1992; 146:857–61. 3. Morgagni JB. Je sedibus et causis morborum per indagatis. Naples: Typographia Simoniana, 1762:1962. 4. Tulp N. Observationes medicae. Amsterdam: Elsevier, 1672. 5. Doran PA, Guthkelch AN. Studies in spina biﬁda cystica I. General surgery and reassessment of the problem. J Neurol Neurosurg Psychiat 1961; 24:331–45. 6. Virchow R. Ein Fall von hypertrichosis circumscripta mediana kornbiniert mit spina biﬁda. Ztschaz Ethnol 1875; vii:279. 7. von Recklinghausen FD. Untersuchungen uber die spina biﬁda. Arch Pathol Anat 1886; 105:243.

8. Report. Report of a committee of the society nominated to investigate spina biﬁda. Trans Chir Soc Lond 1882; 18:339. 9. Morton J. Case of spina biﬁda cured by injection. Br Med J 1872; 1:364. 10. Bayer C. Zur technik der operation der spina biﬁda and encephalocoele. Prag Med Wochenschr 1892; 17:317. 11. Frazier CH. Surgery of the spine and spinal cord. New York: D. Appleton & Co., 1918. 12. Sharrad JW, Zachary RB, Lorber J et al. A controlled trial of immediate and delayed closure of spina biﬁda cystica. Arch Dis Child 1963; 38:18–22. 13. Lorber J. Results of treatment of myelomeningocoele: An analysis of 524 unselected cases with special reference to possible selection for treatment. Dev Med Child Neurol 1971; 13:279–303. 14. Surana RH, Quinn FMJ, Guiney EJ, Fitzgerald RJ. Are the selection criteria still applicable in the management of spina biﬁda? Eur J Ped Surg 1991; Suppl 1:35–7. 15. McCarthy GT. Treating children with spina biﬁda. An individual programme for each child. Br Med J 1991; 302:65–6. 16. Lemire RJ, Beckwith JB, Warkny J. Anencephaly. New York: Raven Press, 1978. 17. Patten BM. Overgrowth of the neural tube in young human embryos. Anat Rec 1952; 113:381–93. 18. Martin-Padilla M, Fern WH. Somite necrosis and developmental malformations induced by Vitamin A in the golden hamster. J Embryol Exp Morphol 1965; 13: 1–8. 19. Gardner WJ. Rupture of the neural tube the cause of myelomeningocoele. Arch Neurol 1961; 4:1–7. 20. Pledget DM. Spina biﬁda and embryonic neurochisis. A causal relationship. Johns Hopkins Med J 1961; 4:1–7. 21. Bentley JL, Smith JR. Developmental posterior enteric remnants and spinal malformations. Arch Dis Child 1960; 35:76–86. 22. Angerpointner TA, Pockrandt L, Schroer K. Course of pregnancy, family history and genetics in children with spina biﬁda. Z fur Kinderchirurgie 1990; 45(2):72–7. 23. Carter CO. Clues to the aetiology of neural tube malformations. Develop Med Child Neurol 1974; 16(Supp 32):3–15. 24. Hibbard ED, Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1965; I:1254. 25. Smithells RW, Cuinn ER. Spina biﬁda in Liverpool. Develop Med Child Neurol 1965; 7:258–68. 26. Obrey RS, Mulinare J. Trends in neural tube defect prevalence, folic acid fortiﬁcation, and vitamin supplement use. Semin Perinatol 2002; 26:277–85. 27. Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. Br Med J 1981; 282:1509–11. 28. Anonymous. Folate supplements prevent recurrence of neural tube defects. Nutrition Reviews 1992; 50:22–4. 29. Willett WC. Folic acid and neural tube defects. Can’t we come to closure? Am J Public Health 1992; 82:666–8.

772 Spina biﬁda and encephalocele 30. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131–7. 31. US campaign for women to take folic acid to prevent birth defects. Br Med J 1994; 208:223. 32. Wald NJ, Boewr C. Folic acid, pernicious anaemia and prevention of neural tube defects. Lancet 1994; 343:307. 33. Anonymous. Valproate, spina biﬁda and birth defect registries. Lancet 1988; ii:1404–5. 34. Anonymous. Valproate: A new cause of birth defects – Report from Italy and follow-up from France. MMWR 1983; 32:438–9. 35. Rosa FW. Spina biﬁda in infants of women treated with carbamezepine during pregnancy. N Engl J Med 1991; 324:674–7. 36. Lindhout D, Omtzigt JG, Cornel MC. Spectrum of neural tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992; 42(4 Suppl 5): 111–18. 37. Janerich DT. Inﬂuenza and neural tube defects. Lancet 1971; ii:551–2. 38. Layde PM, Edmonds LD, Erickson JD. Maternal fever and neural tube defects. Teratology 1980; 21:105–8. 39. Sandford MK, Kissling GE, Joubert PE. Neural tube defect etiology: new evidence concerning maternal hyperthermia health and diet. Develop Med Child Neurol 1992; 34:661–75. 40. Milunsky A, Ulcickas M, Rothman KJ, Willet HW, Jicks SS, Jick H. Maternal heat exposure and neural tube defects. JAMA 1992; 268:882–5. 41. Leck I. The geographic distribution of neural tube defects and oral clefts. Br Med Bull 1984; 40:390–5. 42. Boone D, Parsons D, Lachmann SM, Sherwood T. Spina biﬁda occulta: Lesion or anomaly? Clin Radiol 1985; 36:159–61. 43. Wiswell TE, Tuttle DJ, Northam RS, Simonds GR. Major congenital neurological malformations. A 17 year survey. Am J Dis Child 1990; 144(1):61–7. 44. Leek I. The aetiology of human malformations and insights from epidemiology. Teratology 1972; 5:303. 45. White Van Mourik MC, Connor JM, Ferguson Smith MA. Patient care before and after termination of pregnancy for neural tube defects. Prenatal Diag 1990; 10(8):497–505. 46. Reussner L, King CR. Chorionic villous sampling: First trimester fetal diagnosis. Kansas Medicine 1989; 90(4):109–12. 47. Wald NJ, Cuckle H, Brock JH, Peto R, Polani PE, Woodford FP. Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina biﬁda in early pregnancy. Report of UK Collaborative Study on alpha fetoprotein in relation to neural tube defects. Lancet 1977; 1:1323–32. 48. Bergstrand CG, Czar B. Demonstration of a new protein fraction in serum from the human fetus. Scand J Clin Lab Invest 1956; 108:174–9. 49. Brock DJH. Amniotic ﬂuid tests for fetal neural tube defects. Br Med Bull 1983; 39:373–7.

50. Aitken DA, Morrison NM, Fergusson Smith MA. Predictive value of acetylcholinesterase analysis in the diagnosis of fetal abnormality in 3700 pregnancies. Prenat Diagn 1984; 4:329–40. 51. Takeuchi H. Prenatal ultrasound diagnosis of central nervous system anomalies: NO to Hattatsu 1991; 23(2):183–8. 52. Romero R, Mathisen M, Ghidini A, Sirtori M, Hobbins JC. Accuracy of ultrasound in the prenatal diagnosis of spinal anomalies. Am J Perinatol 1989; 6(3):320–3. 53. McConnell JR, Holder JC, Menik JR, Alexander JE. Spina biﬁda: The radiology of neural tube defects. In: Keats TF, Bragg NA, Evens RG, Singleton EB, Tegtmeier CH, editors. Diagnostic Radiology. Vol. XV. No. 4. 1986:246–76. 54. Luthy DA, Wardinsky T, Shurtleff DB, Hollenbach KA, Hickok DE, Nyberg DA, Benedetti TJ. Cesarean section before the onset of labour and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991; 324:662–6. 55. Sakala EP, Andree I. Optimal route of delivery for meningomyelocele. Obstet Gynecol Surg 1990; 45(4):209–12. 56. Tryfonas G. Three spina biﬁda defects in one child. J Pediatr Surg 1973; 8:75–6. 57. Hunt GM. Open spina biﬁda. Outcome for a complete cohort treated unselectively and followed into adulthood. Develop Med Chid Neurol; 1990; 32:108–18. 58. Greig JD, Young DG, Azmy AF. Follow-up of spina biﬁda children with or without upper renal tract changes at birth. Eur J Paed Surg 1991; 1(1):5–9. 59. Steinbok P, Irvine B, Cochrane DD, Irwin BJ. Long-term outcome and complications of children born with meningomyelocele. Child’s Nervous Systems 1992; 8:92–6. 60. Charney EB. Parental attitudes toward management of newborns with myelomeningocoele. Dev Med Child Neurol 1990; 32:14–19. 61. Fitzgerald RJ, Healy B. The spina biﬁda problem. A longer term review with special reference to the quality of survival. Ir Med J 1974; 67(21):565–7. 62. Guiney EJ, Fitzgerald RJ, Mehigan D, Puri P, Sundar B. Surgical closure of myelomeningocoele: Problems and consequences of the introduction of a policy of selection. Ir J Med Sci 1977; 146:260–2. 63. Guiney EJ, Fitzgerald RJ, Blake NS, Goldberg C. Status of a group of spina biﬁda children not managed by early surgery. Zeitschrift fur Kinderchir 1986; (Suppl. 1)41:16–17. 64. Deans GT, Boston VE. Is surgical closure of the back lesion in open neural tube defects necessary? Br Med J 1988; 296:1441–2. 65. Charney EB, Weller SC, Sutton LN, Bruce DA, Schut LB. Management of the newborn with myelomeningocoele. Time for a decision-making process. Pediatrics 1985; 75:58–64. 66. Robards MF, Thomas CG, Rosenbloom L. Survival of infants with unoperated myelocoeles. Br Med J 1975; 4:12–13.

References 773 67. Rickwood AMK. Infective problems encountered in neonatal closure of the neural tube defects. Dev Med Child Neurol 1976 ; (Suppl. 37)18:164–5. 68. Reigel DH. Spina biﬁda in paediatric neurosurgery. Surgery of the developing nervous system. New York: Grune and Stratton, 1982:23–47. 69. Lorber J, Salﬁeld SAW. Results of selective treatment of spina biﬁda cystica. Arch Dis Child 1981; 56:822–30. 70. Asher M, Olson J. Factors affecting the ambulatory status of patients with spina biﬁda cystica. J Bone Joint Surg 1983; 65(3):350–6. 71. Rudy DC, Woodside JR. The incontinent myelodysplastic patient. Urol Clin N Am 1991; 18(2):295–308. 72. Kasabian NG, Bauer SB, Dyro FM, Colodny AH, Mandell J,

Retik AB. The prophylactic value of clean intermittent catheterisation and anticholinergic medication in newborns and infants with myelodysplasia at risk of developing urinary tract deterioration. Am J Dis Child 1992; 146:840–3. 73. Stoneking BJ, Brock JW, Pope JC, Adams MC. Early evolution of bladder after myelomeningocele closure. Urology 2001; 58:767–71. 74. Suwanwela C. Craniomeningocoele and encephalomeningocoele. In: Sanok, Ishii S, editors. Recent Progress in Neurological Surgery. Proceedings of the Symposium of the Fifth International Congress of Neurological Surgery, Tokyo, October 7–13, 1973. Amsterdam: Excerpta Medica, 1974:49–55.

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83 Hydrocephalus RAYMOND J. FITZGERALD

INTRODUCTION The term ‘hydrocephalus’ denotes the presence of an excessive amount of cerebrospinal ﬂuid (CSF), which is usually under increased pressure with abnormal enlargement of the cerebral ventricles. It results from an imbalance between the production and absorption of CSF. It is most frequently caused by an intraventricular or extraventricular blockage in the normal circulation and absorption of CSF. Hydrocephalus may be classiﬁed as communicating and non-communicating. In noncommunicating hydrocephalus, the obstruction is in the ventricular system and may be caused by the Arnold– Chiari malformation, aqueductal stenosis, neoplasm, hemorrhage or obstruction of the fourth ventricular outlet (Dandy–Walker malformation). The term ‘communicating hydrocephalus’ is used for situations where there is a free ﬂow of CSF into the subarachnoid space; this may rarely be due to a choroid plexus papilloma, sometimes with the Arnold–Chiari malformation or more commonly following inﬂammatory conditions. The overall incidence of hydrocephalus may be as high as two in 1000 births.1 The incidence of hydrocephalus, excluding hydrocephalus associated with myelomeningocele, is estimated to be 0.1–1 in 1000 births.2,3

CAUSES OF HYDROCEPHALUS Posthemorrhagic hydrocephalus Posthemorrhagic hydrocephalus can be deﬁned as signiﬁcant progressive dilatation of the ventricular system that develops as a complication of neonatal intraventricular hemorrhage (IVH). The continuous improvement in perinatal care has led not only to an increased survival rate in preterm infants, but also the greater risk of developing IVH in these infants. Fernall et al. reported that an infant born very preterm has a 60 times higher

risk of developing infantile hydrocephalus than an infant born at term.4 The markedly increased risk is correlated to a high frequency of IVH in very preterm infants.5 Most of these hemorrhages are small and resolve spontaneously, but the more severe hemorrhages are associated with an increased risk of developing posthemorrhagic hydrocephalus.

Congenital malformations ARNOLD–CHIARI MALFORMATION Approximately 95% of patients with myelomeningocele involving thoracolumbar, lumbar and lumbosacral regions have some degree of hydrocephalus, which is almost invariably associated with the Arnold–Chiari malformation.6 The major features of this lesion include: caudal displacement of the fourth ventricle into the upper cervical canal, elongation and thinning of the upper medulla and lower pons with persistence of the embryonic ﬂexure of these structures, caudal displacement of the medulla and lower cerebellum through the foramen magnum and various bony defects of the upper cervical vertebrae and occiput.7 In this anomaly, the aqueduct of Sylvius also may be elongated and thus vulnerable to blockage within the overly small posterior fossa. Such a process probably occurs in 40–75% of cases of myelomeningocele and is the most common explanation for overt hydrocephalus at birth.6

AQUEDUCT STENOSIS This accounts for about 15% of cases of hydrocephalus and occurs in several different anatomical forms.8 There may be multiple channels instead of a single one, most of them ending blindly. Aqueductal obstruction may be caused by gliosis, which is a progressive condition due to overgrowth of dense ﬁbrillary subependymal neuroglia. In the vast majority of cases, aqueduct stenosis cases are sporadic and non-genetic but rarely X-linked cases occur.8

776 Hydrocephalus

DANDY–WALKER SYNDROME This malformation, a rare cause of hydrocephalus in the newborn period, results from obstruction of the foramina of Luschka and Magendie. There is a small hypoplastic cerebellum with a greatly distended fourth ventricle, elevation of the lateral sinuses and tentorium, and an enlarged posterior fossa.

MALFORMATION OF VEIN OF GALEN This may result in hydrocephalus and a need for endovascular treatment.9

Infection Intrauterine infection by cytomegalic inclusion disease, mumps, toxoplasmosis and syphilis may cause congenital hydrocephalus. Postnatally following meningitis and/or ventriculitis, hydrocephalus may form from either adhesions in the subarachnoid space or internal obstruction. Meningitis in the newborn may result from amniotic infection where the membranes have been ruptured for a prolonged period. In the ﬁrst 2 weeks of life, the organism is usually that of Escherichia coli and other Gram-negative enteric bacilli. In the second 2-week period, the pathogens are more likely to be Gram-positive cocci and Pseudomonas.

Neoplasm Tumors such as medulloblastomas in the posterior fossa, astrocytoma or ependymomas are rare in the newborn period. Hydrocephalus results from obstruction at various points in the circulation of CSF.

CLINICAL FEATURES An increase in head size is the major feature of hydrocephalus in the newborn, with an increasing deviation of head circumference from the normal centiles for age. Incremental plotting of head circumference is useful in this regard, using a centile chart such as that produced by Gairdner and Pearson, allowing for gestational age at birth.10 It should be noted that there are causes for head enlargement other than hydrocephalus (e.g. a familial tendency for a large head, osteoﬁbromatosis, macrocephaly or intracranial cysts). The shape of the head will also be abnormal, with greater expansion in the region of the occiput when aqueductal stenosis is the cause. If the fourth ventricle foramina are obstructed with enlargement of the fourth ventricle, the occipital protuberance is pushed cranialward with enlargement of the posterior fossa. In patients with communicating hydrocephalus, the head is more symmetrically enlarged.

Other clinical features of hydrocephalus in the infant include vomiting, failure to thrive, irritability, a shrill cry and delayed motor development. The most common features directly attributable to Arnold–Chiari malformation are feeding disturbances with reﬂux and aspiration, laryngeal stridor secondary to vocal cord paralysis and apnea. The anterior fontanelle is wide and may bulge with a variably open posterior fontanelle, separation of the suture lines and dilatation of superﬁcial scalp veins. A ‘cracked pot’ sound is evident on percussion. The ‘sunset’ appearance, with the superior sclera visible, is a later sign and is due to pressure on the soft orbital plates. Internal strabismus due to palsy of the sixth cranial nerve is not uncommon. The hydrocephalic infant’s vision may be affected either from pressure atrophy of the optic nerve or damage to the occipital cortex. Brainstem signs are more common if the hydrocephalus is rapid and bulbar palsy occurs occasionally. Papilloedema is more likely with rising pressure in communicating hydrocephalus.

INVESTIGATIONS An antibody screen should be carried out if intrauterine infection is considered. Transillumination of the head may conﬁrm the diagnosis of general enlargement of the ventricles. Unilateral translucency or localized areas of illumination may indicate subdural collections or cysts. In practice, this mode of investigation is not very helpful. Radiology with skull X-rays will show the separation of sutures and the digital markings (lacunar skull) as well as intracerebral claciﬁcation, which is seen in cases of toxoplasmosis. Ultrasonography is extremely useful as a non-invasive technique and will usually indicate the anatomical arrangement and often the cause of the hydrocephalus (Fig. 83.1). Antenatal sonography can detect hydrocephalus in utero. In the newborn, the anterior fontanelle provides a window. Measurement of both the ventricle size and the cortical mantle is possible. Serial ultrasonography not only has improved the ability to detect hydrocephalus, but has also resulted in more prompt treatment of this condition and has proved extremely useful in detecting IVH and hydrocephalus in premature infants. It is considered the initial investigation of choice for neonates with hydrocephalus (Fig. 83.1). Computed topography (CT) is used where greater detail is required (Fig. 83.2) and is particularly useful if a tumor in the posterior fossa is suspected. Magnetic resonance imaging (MRI) is proving even more useful and certainly has shown up posterior fossa tumors not detected by CT. MRI can show up such causative processes as aqueductal stenosis and Chiari malformation with remarkable clarity.11

Treatment 777

studies may prove to be useful in the management of hydrocephalus.14 Furthermore, there is a problem of normotensive chronic hydrocephalus where the CSF has returned to a physiological range but a slight pressure gradient exists between the ventricles and the brain.

TREATMENT Fetal therapy

Figure 83.1 Aqueduct stenosis. Coronal section on sonography showing dilated lateral ventricles and foramina of Monro passing into a dilated third ventricle

Hydrocephalus is detectable in utero and the question of prenatal intervention arises. In spite of extensive experimental work and indeed some human intervention, the results in general, so far, are not good and this method of management is not currently recommended.15

Postnatal therapy Not all cases of hydrocephalus require treatment, since some may arrest. This is more likely in those patients with hydrocephalus caused by hemorrhage or infection, though some cases associated with spina biﬁda also arrest. However, these patients need long-term follow-up because some may have normal pressure hydrocephalus and slow progressive neurologic impairment, and indeed an acute decompensation requiring surgical management.

Pharmacological treatment

Figure 83.2 CT scan of head showing dilated lateral ventricles

Air, other contrast, isotope and angiographic studies are no longer routine, but may be indicated in rare instances. CSF analysis is indicated where infection or hemorrhage are suspected, since these will inﬂuence the way that the hydrocephalus is managed. A raised protein level, or indeed bloodstained CSF, is not necessarily a contraindication to shunting. Routine tapping of the ventricle is not recommended since this may result in ventriculitis or intraventricular hemorrhage. Furthermore, the introduction of a commensal into the ventricular ﬂuid may result in shunt colonization if shunting is carried out a short time afterwards. Invasive pressure measurements are less often justiﬁed with modern methods of imaging and fontonmetry is unreliable.12 Transcranial Doppler ultrasound studies of blood ﬂow12,13 and tympanic membrane displacement

Isosorbide (1,4:3,6-dianhydro-D-glucital) has been used, but is difﬁcult to administer and is not without serious complications. It is likely to be more successful where the hydrocephalus is moderate with a reasonable thick cerebral mantle.16 In the current author’s personal experience, it only uncommonly obviates surgery, although it may delay it. Isosorbide may be more valuable where infection or hemorrhage are the primary causes and may help control hydrocephalus until surgery is more likely to be successful. Other drugs such as acetazolamide have been used, particularly in premature babies, again without great success.

Surgery Tumors, as a cause of hydrocephalus, are rare in the neonate, but the surgical management will lead to a rapid decompression in most cases. Most other cases will require drainage from the ventricle to some other part of the body. As a means of holding a situation temporarily in a premature baby, for example with hydrocephalus complicating intraventricular hemorrhage, CSF may be drained intermittently either by lumbar puncture in

778 Hydrocephalus

communicating hydrocephalus or ventricular taps. Drainage of CSF via a shunt to the peritoneal cavity is now favored, with good reason, although some still favor drainage to the atrium. The latter is particularly problematical in the neonate because of the need to lengthen the lower end as the child grows and the catheter pulls up out of the atrium.

VALVE SYSTEMS With regard to the pressure of systems to be used, it has generally been found that the low-pressure systems are satisfactory in most cases of neonatal hydrocephalus. An anti-siphon device may be included in the system to prevent over-drainage with low-pressure, high-resistive valves, e.g. silicone rubber slit valves, or with any pressure low-resistive valves, e.g. the Hakim.17 If an antisiphon device is being introduced, it is placed just distal to the valve and therefore is not suitable when the valve is terminally placed on the distal catheter. Siphoning can be minimized by increasing the resistance of the shunt through the use of small tubing and a high-resistive slit valve. There are many valves on the market and some are now pressure programmable externally. In the premature child, in whom the skin and aponeurosis are thin, the use of a system without a reservoir avoids the possible complication of skin necrosis over it. Some low-proﬁle reservoirs are also satisfactory in this situation. The current author’s policy is to use the simplest and most economical system that has been shown to be effective in a particular set of circumstances. Reservoirs are less necessary with a low infection rate.

OPERATION Preoperative management Hemoglobin estimation and cross-matching of 1 unit of blood is recommended, although transfusion will rarely be needed. General anesthesia with endotracheal intubation is usual with an i.v. line in situ. A single dose of cloxacillin is given intravenously at this point as prophylaxis against wound infection. An overhead radiant heater is useful in the prevention of heat loss during the preparative stages of surgery and the patient is placed in the supine position on the operating table covered with a heating mattress. Traditionally the right ventricle is used as a source of the CSF in the shunting procedure, although either lateral ventricle may be used. The side of the body being used is raised slightly with gamgee and the head rotated so that the occiput is available for surgery (Fig. 83.3).

Figure 83.3 The dotted line represents the course of the ventricular catheter. The patient is positioned with a roll of gamgee under the shoulders to straighten out the neck and allow easier passage of the cannula. The skin is marked, predisinfection, with a pen, showing the curved incision site behind the posterior parietal eminence. The transverse abdominal incision site is also marked with a dark line

The head, neck and upper abdomen are prepared. The head is carefully shaved with a safety razor using soap and water. Incisions are marked on the skin using pen and dye. The head incision is a semicircle with a radius of approximately 3 cm, lying well behind the posterior parietal eminence. The abdominal transverse incision is approximately 1.5 cm in length, is made just inferior to the rib cage and lies on a line running just medial to the nipple. The skin is prepared using aqueous povodone– iodine 10% at body temperature. Two applications are made and then with a chlorhexidine solution, 1.5%, just over the incisions. The surgeon rescrubs and regowns. The gloves of the surgeon and the assistant are put on by the scrub nurse using a technique that will ensure no contamination of the outside of the gloves. The wound areas are draped with natural ﬁber drapes which are doubled over for 6 cm and the edges which will be adjacent to the working areas soaked in warm chlorhexidine solution. Great care is taken not to touch the skin with the gloves at any stage. The area between the upper and lower incision is covered with a small hand towel to allow access if need be and all unnecessary skin is covered. The proximal catheter, reservoir and distal catheter are ﬂushed through with gentamicin solution (80 mg in 100 ml saline) after testing, depending on the recommendations of the manufacturer. A ‘no touch’ technique is used as far as is practicable. ‘Rubber shod’ tissue forceps are useful for manipulating the shunt system without damaging it. Both sides of the marked skin incision are covered with chlorhexidine-soaked swabs and the incision made (Fig. 83.4a). The aponeurosis is divided at the same time as the skin. The assistant applies pressure on the chlorhexidine swabs to reduce hemorrhage. The edges of the aponeurosis are caught with a series of artery forceps and rotated back over the soaked swab; further soaked swabs are then used to cover the wound so that no skin is visible (Fig. 83.4b). In choosing the site for the craniotomy, care must be taken that when the operation is complete no part of the

Operation 779

shunt system will be under or very near the skin incision. The periosteum is divided using diathermy in a cross and rasped peripherally, leaving bare bone. A small burr hole may then be made using a suitable burr and can be enlarged as necessary using a bone nibbler. Bone wax may be used to arrest bony hemorrhage. Alternatively, a disc of bone can be cut out using a bone-cutting instrument to the size suitable for the reservoir. Clearly the size of the bony defect should only be big enough to accept the drainage system being used. A right-angled catheter or a ‘unishunt’ system will require a hole slightly bigger than the catheter itself.

The abdominal incision is treated in a similar fashion to that with the scalp, except that the muscle layers are split at each layer. The peritoneum is caught in a forceps and a small incision made in it. At this point the distal catheter is tunnelled down from the upper wound to the abdominal incision (Fig. 83.4c). If a long trocar and stylet with a removable handle is used, the catheter with reservoir or valve can be left in situ and the trocar removed through the abdominal incision. The dura is now lightly diathermied to reduce risk of hemorrhage and a small incision made approximately 2 mm in diameter to accommodate the proximal catheter

(b)

Chlorhexidine-soaked swabs

(a)

(c) Ventricular catheter

Peritoneal catheter

Metal cannular

(d)

Reservoir

Figure 83.4 (a) Wound drapes surrounding the scalp incision with edges soaked in chlorhexidine. Upper incision to pericranium with chlorhexidine-soaked swabs surrounding the wound. (b) Further soaked swabs cover the edge of the wound (not shown for clarity). The pericranium is diathermied and rasped peripherally and a burr hole made. (c) Following incision in the abdomen, treated similarly with chlohexidine-soaked swabs, a long trocar and cannula are passed percutaneously to exit at the lower incision. The long trocar is removed, allowing passage of the peritoneal catheter along the metal cannula. The trocars in some prepared shunt sets have a device for attaching the distal catheter and allowing it to be pulled through distally. (d) Having lightly diathermied the dura, a small hole is made in it and the ventricular catheter introduced and connected to a reservoir. With free ﬂow from the distal end, the catheter is placed in the peritoneal cavity and the peritoneum closed snugly around it

780 Hydrocephalus

tightly and minimize leakage around the catheter. A catheter is introduced, mounted on a stilet or as recommended by the makers, e.g. a ‘Unishunt’ system is provided with a special trocar and cannula. The catheter is run forward in the ventricle so that the tip lies in the anterior horn away from the choroid plexus; however, Bierbrauer et al. concluded that this offers no advantage over posteriorly placed shunts.18 Intraoperative ultrasonography may be used to position the catheter. Pressure may be measured at this point and a sample of CSF taken for biochemical and microbiological examinations. The proximal catheter is connected to the distal catheter or valve system, depending on what is being used. The distal end is examined to ensure that there is free ﬂow of CSF and this is then placed into the peritoneal cavity (Fig. 83.4d). The peritoneum is closed using absorbable sutures, e.g. polyglycolic acid, the muscle closed over this to ensure as watertight a closure as possible, and the catheter is run obliquely through the muscle layers. The skin is closed with a polyglycolic acid subcuticular suture. Some reservoir/valve systems have a few holes at their perimeter which can be used to anchor the system with ﬁne sutures to the periosteum; others have a plastic anchoring device. The maker’s recommendations should be followed. The upper wound is closed with an absorbable suture to the aponeurosis and the skin with a ﬁne nylon or subcuticular absorbable suture. The wound dressing is ‘non-stick’ and horseshoe shaped to avoid pressure over the reservoir and a crepe bandage is used. The abdominal wound is covered with an adhesive dressing. The nylon sutures are removed in 5–6 days. The rationale for the detailed preparation of the patient for surgery is discussed in detail elsewhere.19 It should be emphasized that the resident ﬂora in the pilosebaceous units deep in the skin of the patient is the source of the organisms in most infected shunts.20 Every effort must be made to prevent this infection. It is necessary to use an agent active through the course of the surgery to kill the organisms, as they egress from the deep units to the surface. The system outlined earlier has been shown to be effective in this regard in reducing infection.

VENTRICULAR ATRIAL SHUNTS These may be performed in similar fashion to ventriculoperitoneal shunts except that the lower incision is made by a skin crease over the lower sternomastoid muscle. The ﬁbers of the sternomastoid muscle are split to give access to the internal jugular vein. This is mobilized and a sling passed around it, above, and below. A pursestring suture of ﬁne material (e.g. 6-0 polydioxanone

monoﬁlament) is made in the wall of the vein and light traction applied to the upper and lower slings to prevent hemorrhage. The distal catheter is passed and a small incision made in the center of the pursestring. The catheter is inserted until it is lying freely in the right atrium and this can be conﬁrmed radiologically or by other methods. The pursestring suture is closed around the catheter sufﬁciently to prevent hemorrhage, but not tight enough to cause obstruction to the catheter. Some systems have an intraluminal piece to prevent obstruction and this can be moved internally to a suitable site in the catheter.

Postoperative care With peritoneal shunts, an ileus is not uncommon for a day or so and feeding is not re-established until this period is complete. I.v. ﬂuid is reduced for at least 24 hours because of the extra ﬂuid being absorbed from the peritoneal cavity. The pumping of shunt systems is not necessary and may actually encourage blockage by creating unnecessary negative pressure. Even where shunt blockages are suspected, pumping often gives erroneous information.21 In an endeavor to pick up any colonized shunts early, all my patients with ventriculoperitoneal shunts, have Creactive protein estimations at 6 weeks post surgery, and this has been shown to be effective.22 If the C-reactive protein is raised then a cause must be found and if there is no other explanation, then shunt infection must be excluded by tapping the system. If an atrial shunt has been inserted, then antibody titers to coagulase negative staphylococci should be estimated as well as C-reactive protein levels. If there is any suggestion in this situation of a shunt infection, then blood cultures should be taken. Careful follow-up with measurement of head circumference, clinical neurology and assessment of valve function are vital. The valve and system should be palpated for any collection of ﬂuid, disconnection or breakage and an assessment of the infant’s psychological development made regularly.

Complications CSF shunting is fraught with possible complications; mechanical failure and infection remain serious problems.23,24

CATHETER BLOCKAGE In all reported series, catheter blockage is a signiﬁcant problem. Various catheters have been devised in an attempt to reduce this, but none has been totally successful. Symptoms and signs of raised intracranial pressure may be evident, but when this occurs in the neonate the

Other surgical treatments: endoscopy 781

original clinical signs of hydrocephalus may recur with an enlargement of the head. If doubt exists about blockage, imaging may be helpful. A period of observation may be warranted, but in general when shunt blockage has become established surgery will be required. Peritoneal blockage is less common and in our experience rare unless there is shunt colonization.19 Therefore, any patient with a peritoneal blockage or collection of ﬂuid should be suspected of having a shunt infection and investigated as such. The distal catheter may perforate a hollow viscus such as the bowel, in which case infection is extremely likely and the whole shunt system will need revision.

CATHETER DISCONNECTION AND BREAKAGE This may result in blockage or a leak may be evident as a local collection of CSF around the shunt system (a temporary leak around the shunt system may occur for a few days shortly after insertion until the tissues close around the proximal end). Routine examination may indicate a lack of continuity. Usually a breakage will result in the catheter falling down into the peritoneal cavity.

INFECTION Infection is a serious problem when it occurs, but the incidence can be reduced to less than 2% provided that great care is taken during the initial insertion.25 If the CSF is sterile on insertion, the usual organisms causing shunt infection are skin commensals such as Staphylococcus epidermidis (albus). However, pathogenic organisms may cause ventriculitis or shunt colonization with subsequent generalized infection where there has been a breakdown in operative technique. In general, infection with this kind of organism will result in clinical features of greater magnitude than if commensal colonization has occurred. Also, the clinical features in patients with ventriculoatrial (VA) colonization will be greater than those with ventriculoperitoneal (VP) colonization. Tapping of the ventricular CSF is important in diagnosis, but this may be clear while the shunt system is infected and frequently it is necessary to tap the system. Neither of these should be undertaken lightly, since infection or colonization of a system may occur from the tapping procedure. A tap would only be carried out, using a Huber needle, when there is clinical evidence of infection and none has been found elsewhere, or where there is serological evidence that the system is infected with no evidence of infection elsewhere. The C-reactive protein estimation has been of great importance in the diagnosis of coagulase-negative Staphylococcus infections in the VP shunts. In VA shunt infection, Staphylococcus antibody estimations have been useful. Shunt nephritis, caused by deposition of immune complexes and complement on the glomerular basement membranes in the kidneys, is associated with chronic

colonization of the VA shunt systems and has not been found in VP shunts. It is preventable by careful surveillance. Where infection has been proven, the removal of the entire system is necessary.26,27 Ventricular infection must be treated with antibiotics and this will usually mean ventricular placement, possibly with external drainage of CSF, although this is fraught with difﬁculties and is better avoided. If only the shunt is colonized, then removal of the entire shunt system, insertion of ventricular catheter, systemic antibiotics and replacing the shunt in a new site, i.e. the other ventricle, has been proven successful. I have waited for a day or more before putting in the new shunt, to allow complete clearance of organisms. The child will need to be very carefully monitored for rising CSF pressure during this time and it may prove necessary to reinsert a shunt as an emergency. The treatment of shunt infections has been reviewed extensively by Bayston.28

OVER-DRAINAGE The slit ventricle syndrome, craniosynostoses and subdural hematomas or effusions may result from excessive drainage of CSF. These occur sequentially at different age groups, but approximate averages of incidence and time of occurrence after ﬁrst shunt reveal an overall incidence of 10–12% for at least one of these appearing 6.5 years after shunting.29 The insertion of an anti-siphon device will not necessarily prevent subdural hematomas,29 but the insertion of an anti-siphon device has been successful in treating slit ventricle syndrome.30

ISOLATED VENTRICLE A rise in intracranial pressure with an apparently functioning shunt should raise the possibility of an isolated ventricle. The shunt continues to drain, but the other lateral ventricle or the fourth ventricle31 is not in communication with it. This will become evident on imaging and the patient will require a further shunt to drain it.

OTHER SURGICAL TREATMENTS: ENDOSCOPY Rigid or ﬂexible neuroendoscopy has been developed over many years buts its place in the management of neonatal hydrocephalus has yet to be proven.

Endoscopic choroid plexus coagulation There may be a limited place for endoscopic choroid plexus coagulation for the control of hydrocephalus and it would seem best suited to those patients with the communicating type with a slow to moderate rate of increase.32 Use of electrocautery has also been described

782 Hydrocephalus

for the unblocking of obstructed ventricular catheters using a ﬁber endoscope.33

Neuroendoscopic third ventriculostomy One method of carrying out neuroendoscopic third ventriculostomy (NTV) has been described recently in detail by Kurpad and Cohen, but no results are given.34 Essentially the right lateral ventrical is cannulated with a rigid endoscopic sheath. Extracorporeal monitoring is used to orientate the intraventricular anatomy and the third ventricle is entered. The ﬂoor of the third ventricle is identiﬁed and punctured anterior to the location of the basilar artery complex. A blunt probe is ﬁrst used followed by a Fogarty balloon catheter which is sequentially inﬂated. Jones et al. in 1996 reported 25 patients who had an NTV for hydrocephalus associated with spinal dysraphism. In the patients younger than 6 months of age, only one out of 11 had a successful long-term result. They conclude that third ventriculostomy is not a suitable procedure in the newborn associated with spina biﬁda.35 More recently, Buxton et al.36 report on 27 patients who had primary NTV at an age of younger than 1 year. The mean age was 3.7 months (range 0.25–10 months). The operation worked in about onequarter of these patients and the authors called for a randomized, controlled trial.

REFERENCES 1. Jackson PL. Primary care needs of children with hydrocephalus. J Pediatr Hlth Care 1990; 4:59–71. 2. Stein S, Feldman H, Kohl S et al. The epidemiology of congenital hydrocephalus: a study in Brooklyn NY 1968–1976. Child’s Brain 1981; 8:253–62. 3. Cudmore RE, Tam PKH. Hydrocephalus. In: Lister J, Irving IM, editors. Neonatal Surgery. London: Butterworths, 1990: 589–612. 4. Fernall E, Hagberg G, Hagberg B. Infantile hydrocephalus – the impact of enhanced preterm survival. Acta Paediatr Scand 1990; 79:1080–6. 5. Ahmann PA, Lazzara A, Dykes FD et al. Intraventricular haemorrhage in the high risk preterm infant: incidence and outcome. Ann Neurol 1980; 7:118–24. 6. Noetzel MJ. Myelomeningocele: current concepts of management. Clin Perinatol 1989; 16:311–29. 7. Laroche JC. 1984 Malformations of the nervous system. In: Adams JH, Corsellis JAN, Duchen LW, editors. Greenﬁelds Neuropathology. 4th edn. New York: Wiley, 1984:385–450. 8. Brett EM. Hydrocephalus and congenital anomalies of the nervous system other than myelomeningocele. In: Paediatric Neurology. 2nd edn. Brett EM editor. London: Churchill Livingstone, 1991:467–509.

9. Zerah M, Garcia-Monaco R, Rodesch G et al. Hydrodynamics in vein of Galen malformations. Childs Nerv Sys 1992; 8:111–17. 10. Gairdner D, Pearson J. A growth chart for premature and other infants. Arch Dis Childh 1971; 46:783–7. 11. Bradshaw JR. Magnetic resonance imaging of the CNS. Br J Hosp Med 1989; 42:472–9. 12. Quinn MW. The Doppler characteristics of hydrocephalus. MD thesis, Trinity College, Dublin University, 1991. 13. Goh D, Minns RA, Pye SD. Transcranial Doppler ultrasound as a non-invasive means of monitoring cerebrohaemodynamic change in hydrocephalus. Eur J Paediatr Surg 1991; 1(Suppl. I):14–17. 14. Reid A, March Banks RJ, Bateman DE et al. Mean intracranial pressure monitoring by a non-invasive audiological technique: a pilot study. J Neurol Neurosurg Psychiatr 1989; 52:610–12. 15. Harrison MR. The fetus as a patient. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, editors. Pediatric Surgery. St Louis: Mosby, 1998:38. 16. Lorber J. Isosorbide in the medical treatment of infantile hydrocephalus. Arch Dis Childh 1975; 20:431–6. 17. Portnoy HD, Shulte RR, Fox J et al. Antisiphon and reversible occlusion valves for shunting in hydrocephalus and preventing post-shunt subdural hematoma. J Neurosurg 1973; 38:729–38. 18. Bierbrauer KS, Storrs BB, McLone JG et al. A prospective randomised study of shunt function and infections as a function of shunt placement. Ped Neurosurg 1990–91; 16:287–91. 19. Fitzgerald R, Connolly B. An operative technique to reduce valve colonisation. Z Kinderchir 39(Suppl. 11):107–8. 20. Bayston R, Lari J. Study of the sources of infection in colonised shunts. Dev Med Child Neurol 1974; 32(Suppl.):16–22. 21. Piatt JH Jr. Physical examination of patients with cerebrospinal ﬂuid shunts: is there useful information in pumping the shunt? Pediatrics 1992; 89:470–3. 22. Bayston R. Serum C-reactive protein in diagnosis of septic complications of cerebrospinal ﬂuids shunts for hydrocephalus. Arch Dis Childh 1979; 54:545–8. 23. Hayashi T, Hashimoto TO, Fukuda S et al. Clinical analysis of shunted hydrocephalic neonates and sucklings – observation on obstruction and infection of shunting system. No To Shinkei (Brain and Nerve) 1990; 42:1049–54. 24. Pople IK, Quinn MW, Bayston R. Morbidity and outcome of shunted hydrocephalus. Z Kinderchir 1990; 45(Suppl.I):29–31. 25. Tabera Z, Forrest D. Colonisation of C.S.F. shunts, preventative measures. Z Kinderchir 1982; 37:156–7. 26. Connolly B, Guiney EJ, Fitzgerald RJ. C.S.F/shunt infections – the bane of our lives. Z Kinderchir 1987; 42(Suppl. I):13–14. 27. Forrest DM, Tabara ZB, Towu E et al. Management of colonised shunt. Z Kinderchir 1987; 42(Suppl. I):21–2. 28. Bayston R. Hydrocephalus Shunt Infections. London: Chapman and Hall, 1989.

References 783 29. Pudenz RH, Foltz EL. Hydrocephalus: over-drainage by ventricular shunts. A review and recommendations. Surg Neurol 1991; 35:200–12. 30. Jaskolska E, Mackinnon AE. Experience with antisiphon devices: successes and complications. Z Kinderchir 1988; 43(Suppl. II):22–3. 31. James HE. Spectrum of the syndrome of the isolated fourth ventricle in posthemorrhagic hydrocephalus of the premature infant. Ped Neurosurg 1990–91; 16:305–8. 32. Pople I. The role of endoscopic choroid plexus coagulation in the management of hydrochephalus. Eur J Pediatr Surg 1994; 4(1):46 (Abstract). 33. Pattisapu J, Trumble E, Taylor K et al. Percutaneous endoscopic recanalisation of catheter: A minimally

invasive technique to maintain shunt function. Society for Research into Hydrocephalus and Spina Biﬁda. 44th Annual Scientiﬁc Meeting, Atlanta, 2000. 34. Kurpad SN, Cohen AR. Endoscopic ventriculostomy. Pediatr Endosurg Innovative Techniques 1999; 3:117–21. 35. Jones RFC, Kwok BCT, Stening WA, Vonau M. Third ventriculostomy for hydrocephalus associated with spinal dysraphism: Indications and contraindications. Eur J Pediatr Surg 1996; 6(Suppl. I):5–6. 36. Buxton N, Macarthur D, Mallucci C et al. Primary neuroendoscopic third ventriculostomy in patients less than one year old. Eur J Pediatr Surg 1998; 8(Suppl. I):75 (Abstract).

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10 Genitourinary

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84 Imaging of the renal tract in the neonate ISKY GORDON

INTRODUCTION

ABDOMINAL ULTRASOUND EXAMINATION

Clinical attention may be drawn to the renal tract in a number of different ways in the neonate. With better ultrasound equipment, and more prenatal ultrasound (US) examinations, a large group of neonates are presenting with an antenatal diagnosis of a nephrourological abnormality. The neonate may also present ill with septicemia and/or a urinary tract infection (UTI), with a metabolic upset due to renal failure, or simply vomiting. Occasionally the ill neonate may have hematuria due to renal venous thrombosis, especially if the infant was subjected to any hypoxic event, i.e. prolonged labor. A well neonate may present with an abdominal mass found on routine examination or with an unrelated congenital abnormality, e.g. esophageal atresia. Once the renal tract has been brought to the attention of the clinician, the role of the radiologist/ imager is to establish the number and size of the kidneys. Further, it needs to be established if the infant was born with a normal tract and is suffering from an acquired condition, e.g. renal vein thrombosis, or whether there is an underlying congenital developmental abnormality. The questions posed by the clinical team are: ﬁrst, how many kidneys are present; second, is there dilatation of the collecting system; third, is the bladder normal or is there a thick bladder wall; and ﬁnally, what is the state of individual renal function? The answers come from a combination of abdominal US examination, micturating cystourethrography (MCU), technetium-99m dimercaptosuccinic acid (99mTc-DMSA) scan and/or Tc-99m mercato acetyl triglycine (99mTc-MAG3) scan. A logical approach to these imaging techniques should be established in an attempt to reach the diagnosis using the lowest radiation dose and least invasive technique. There is almost no indication for intravenous urography (IVU) or computerized tomography (CT) in the neonatal period; the role of magnetic resonance imaging (MRI) has yet to be established.

The ﬁrst imaging examination of the urinary tract should always be an abdominal US. With modern realtime ultrasound equipment and well trained personnel, it is possible to obtain anatomical detail of the entire urinary tract. This equipment is mobile, so that a comprehensive US examination can be undertaken even in the ill neonate in an incubator on intensive care. The results of this US examination set the framework of the anatomical state and frequently permit the nephrourological team to begin therapy with either a shortlist of differential diagnoses or a presumed single diagnosis. In the majority of cases, the US examination will identify how many kidneys are present and the renal size, as well as the presence of dilation of the collecting systems. The bladder should be examined at the beginning of the US, as micturition may occur at any moment and a full bladder is useful when searching for dilated ureters behind the bladder (Fig. 84.1). Bladder wall thickness is easy to identify; the proximal posterior urethra may be dilated in the male with posterior urethral valves, and this can be identiﬁed during micturition if looked for. The normal appearance of the kidneys includes an echolucent medulla and a relatively echodense cortex. A small kidney with loss of the corticomedullary differentiation suggests renal dysplasia, which may be associated with cysts to varying degrees (Fig. 84.2a,b). The presence of dilatation of the collecting system must raise the possibility of obstruction. If the dilatation is bilateral, then bladder outlet pathology must be excluded. However, vesico-ureteric reﬂux (VUR) may give a very similar appearance (Fig. 84.3a,b). In polycystic disease it is not always possible to distinguish autosomal recessive polycystic kidney disease (ARPKD) from autosomal dominant polycystic kidney disease (ADPKD). One problem encountered is that, in both ARPKD and ADPKD, the kidneys in the fetus and young infants may have the typical appearance of ARPKD (i.e. big kidneys which are hyper-echogenic). On

788 Imaging of the renal tract in the neonate

Figure 84.1 Ultrasound (top image) demonstrates full bladder with dilated ureter behind the bladder. The dilated posterior urethra is clearly seen, as is the bladder neck hypertrophy. The orientation of the MCU (lower) is the same as the bladder, and correlation between the anatomical detail is provided by these two examinations. The MCU further demonstrates the posterior urethral valve as the cause of the dilated posterior urethra

follow-up in later infancy and childhood the appearance of the recessive form may change to that of the dominant polycystic form (big kidneys with hypoechogenic areas of different sizes throughout the kidneys). For these reasons the so-called typical appearance of either ARPKD or ADPKD on US may be misleading. In those neonates suspected of having ADPKD because of transonic lesions in both kidneys, the important differential diagnosis is tuberous sclerosis (TS). Imaging of the kidneys will not allow these two conditions to be separated and typical cranial features of TS may not be visible until the child is much older (approximately 5 years). TS is more common than ADPKD and many young children with the diagnosis of ADPKD end up with a ﬁnal diagnosis of TS. Echogenic areas within the kidney on US may suggest nephrocalcinosis, the commonest cause in the neonate following furosemide diuretic therapy. There are two important pit falls which must be stressed with US. The ﬁrst is in the presence of a sick neonate who is either anuric or oliguric when US may not reveal any dilation, but an obstructive uropathy may be present. In this clinical situation, a repeat US must be carried out once the infant starts to produce urine. The

(a)

(b) Figure 84.2 (a) The US images show that the kidney has lost its corticomedullary differentiation and that the entire kidney is bright compared to the liver. Minimal dilatation of the collecting system can be seen on the lower image. The kidney is also noted to be small. (b) The MCU shows bilateral VUR, the calyces are abnormal, as are the renal pelves, and these appearances strongly support the US suggestion that renal dysplasia is present

Micturating cystourethrogram 789

(a)

(b)

Figure 84.3 (a) The US images demonstrate signiﬁcant hydronephrosis involving the calyces and the pelvis of the kidney (lower image). The bladder is full of urine and the dilated ureter can be seen behind the bladder (upper image). (b) The MCU clearly demonstrates bilateral VUR. No bladder neck hypertrophy could be demonstrated and the urethra appeared normal (not shown). This child had bilateral VUR with no evidence of any bladder outﬂow obstruction, yet the US appearances of the kidneys and the ureters strongly suggested an outﬂow obstruction. This demonstrates the need for the MCU early on

second pitfall is in the case of antenatally diagnosed unilateral hydronephrosis – here the US may fail to show signiﬁcant dilation during the ﬁrst 48 hours of life and US should be done on the third postnatal day or later.

MICTURATING CYSTOURETHROGRAM A micturating cystourethrogram (MCU) gives invaluable anatomical information about the bladder, and the bladder outﬂow tract in the male, and if VUR is detected then details of the ureters, pelvis, and calyces are well outlined. Contrast showing calyceal detail may suggest renal dysplasia.

INDICATIONS FOR MICTURATING CYSTOURETHROGRAM Antenatal diagnosis of certain renal tract abnormalities, postnatal detection of hydro-ureteronephrosis on US, a UTI, or the presence of renal failure in the neonate requires an MCU. Bilateral hydronephrosis on US raises the possibility of an obstructive uropathy either in the

urethra (posterior urethral vale) (Fig. 84.1), at the bladder base (ureterocele), at the vesico-ureteric junctions bilaterally, or bilateral pelvi-ureteric junction obstruction. Bilateral VUR may give identical images. In this context (Fig. 84.3), an MCU should be carried out as soon as the baby is in a good clinical state. Those neonates with an antenatal diagnosis of hydronephrosis who require an MCU include all those with postnatal conﬁrmation of either a dilated ureter, bilateral hydronephrosis or an abnormal bladder. Unilateral hydronephrosis with a normal opposite kidney and bladder on US in a well neonate does not require an MCU. Because renal failure due to bilateral renal dysplasia has an increased incidence of VUR, an MCU may be helpful in conﬁrming this diagnosis (Fig. 84.2); there is, however, no urgency in obtaining the MCU if no hydronephrosis is seen on US examination. The combination of US and MCU allows adequate evaluation of all kidneys and collecting systems shortly after birth and permits appropriate management to be instituted immediately in all cases, especially if an obstructive uropathy is present, e.g. posterior urethral valves. The timing of the MCU will depend on clinical presentation and clinical state of the baby.

790 Imaging of the renal tract in the neonate

WHAT NEXT? Further imaging may be planned when the neonate is stable and full discussion of the clinical, laboratory and radiological ﬁndings have been evaluated by the clinical team. This is even more important if there are other congenital abnormalities unrelated to the urinary tract. Anatomy is frequently fully understood and information relating to the individual kidney function is now required. This requires use of radioisotopes. Transitional nephrology must be borne in mind, since this governs the way both 99mTc-DTPA and contrast for an IVU as well as 99mTc-DMSA and 99mTc-MAG3 are handled by the kidney.

Renal isotope scans 99m

Tc-DTPA as well as the contrast used for IVU are pure glomerular ﬁltrates, being neither reabsorbed nor excreted by the tubules. Because the neonate has a relatively large extracellular ﬂuid space and a low glomerular ﬁltration rate (GFR), the normal 99mTc-DTPA is characterized by a high background activity and a rapid renal transit time with poor delineation of the kidney. The time taken for the injected dose to reach 50% of its original plasma value in a normal full-term neonate using either 99mTc-DTPA or contrast for IVU is approximately three times longer than that of adolescence. These physiological reasons suggest that a GFR agent should not be used. 99mTc-MAG3 is proteinbound so is distributed mainly in the intravascular space and also has a higher renal extraction than 99mTc-DTPA thus providing clearer images of the kidneys with lower background activity than 99mTc-DTPA. In many institutions 99mTc-MAG3 has replaced 99mTc-DTPA in the assessment of the renal tract, especially in patients under 2 years of age. 99m Tc-DMSA is actively taken up by the proximal tubules and, as tubular function is slightly more mature than GFR in the neonatal kidney, this agent has a role to assess individual renal function but not focal defects in the neonatal period. 99mTc-DMSA is characterized in the newborn period by a high background activity, excess excretion of isotope in the urine and relatively low ﬁxation of the isotope in the renal tubules (Fig. 84.4). The detection of scars requires a 99mTc-DMSA scan when the kidneys have matured signiﬁcantly, e.g. at age 3–6 months. Two questions can be answered by renal radioisotope studies, the ﬁrst is individual renal function and the second is information about drainage of the kidneys. There is only one clinical situation when this information is required during the neonatal period – this is the neonate in renal failure with either bilateral hydronephrosis or asymmetrical kidneys on US. The question posed is are both kidneys functioning equally or is there

Figure 84.4 This neonate had an antenatal diagnosis of a unilateral pelvi-ureteric junction obstruction. The 99mTc-DMSA scan shows one normal kidney, while the opposite kidney shows decreased function with the dilated renal pelvis seen as a negative defect. Note the high background and the relatively poor kidney-to-background ratio seen in the neonatal period. The isotope of choice in this clinical context is not 99mTc-DMSA but rather 99mTc-MAG3

one kidney which contributes most of the function, albeit poor function, so that treatment can focus on the better kidney. Either 99mTc-DMSA or 99mTc-MAG3 can be used, although in this institution we prefer 99mTc-DMSA. In most neonates with a prenatal diagnosis of hydronephrosis, the assessment of function and drainage can be undertaken when renal maturation has progressed and so undertaken at between 4 and 8 weeks of age. In the neonate who presents with either UTI, renal failure of whatever cause (without hydronephrosis), or prenatal diagnosis of an abnormally bright/small kidney the question of renal scarring arises. In these clinical situations a 99mTc-DMSA scan is required at about the age of 3 months or older if clinically acceptable. When posterior urethral valves are present, the ﬁrst 99m Tc-MAG3 scan is carried out 2 weeks after valve ablation and follow-up scans are done regularly at 3, 12, and 24 months. In renal failure with asymmetrical kidneys on US an early scan may be undertaken to ensure that both kidneys are functioning (Fig. 84.5). With a duplex kidney and an obstructed upper moiety, function in the upper moeiety must be assessed using either 99mTc-MAG3 (Fig. 84.6) or 99mTc-DMSA.

Intravenous urogram The IVU is reserved to answer speciﬁc problems. Low osmolar contrast, with a maximum dose of 3 ml/kg, should be used. The use of contrast with a high osmolar load may seriously damage the kidneys of the neonate by causing renal venous thrombosis. The X-ray room should be preheated to help preserve the temperature of the ill neonate. There is no ‘routine’ IVU in the neonate, as speciﬁc questions remain unanswered and therefore each

What next? 791

Figure 84.5 99mTc-DMSA scan in a 8-week-old infant in renal failure due to posterior urethral valves. The US showed marked left hydronephrosis with a ureterocele (not shown). The 99mTc-DMSA scan shows that both kidneys are functioning, with the right doing better than the left

Figure 84.6 99mTc-MAG3 of the pelvi-ureteric junction at 3 weeks of age in a neonate with an obstructed upper moiety due to a ureterocele. 99mTc-MAG3 diuretic renogram showing only moderate function in the displaced left lower moiety, but with good drainage. The upper moiety is functioning very poorly with poor drainage

IVU is tailored to the particular clinical problem. The commonest indication is to provide certain anatomical detail essential for further management. This occurs most frequently when a ureterocele has been identiﬁed but the US has failed to diagnose from which kidney this arises; the IVU may be undertaken at 3–6 months of age especially if there is no gross hydronephrosis on US. In the presence of gross bilateral hydronephrosis, when the US cannot determine the level of the possible obstruction and there is no VUR or MCU, then an IVU is indicated.

In suspected recessive or dominant polycystic disease, an IVU is indicated when the infant is older, e.g. 6–9 months of age. Delayed images are mandatory, even as late as 12–24 hours after the administration of the contrast. Early ﬁlms, in the presence of signiﬁcant hydronephrosis, are frequently of little value. Any neonate who has suffered acute renal failure must have an IVU at about 3 months of age, in order to outline the calyces to allow the diagnosis of the medullary necrosis to be made.

792 Imaging of the renal tract in the neonate

Computerized tomography In the presence of a transonic lesion on US there is no indication for CT. The neonate has little fat and is thus not the ideal patient for CT. There is also a high radiation burden from CT. The role for CT in neonatal renal disease is in the presence of a unilateral renal mass which is echogenic on US. The major differential diagnosis is that of a mesoblastic nephroma as Wilms’ tumors are rare in the neonatal period. The US is usually sufﬁcient but most surgeons request a CT in this rare disorder to ensure that there is no other pathology. This tumor shows reduced uptake of 99mTc-DMSA if there is doubt about the nature of the mass.

use of radioisotopes to obtain information about individual kidney function and urinary drainage. This should be carried out as late as possible in the neonatal period. The IVU is indicated only to provide speciﬁc answers and should never be undertaken in the neonatal period. The only indications for further imaging in the neonatal period are, ﬁrst, if the US reveals two different kidneys and there is renal failure when a radioisotope scan is indicated. Second, if the dilatation is gross and persistent with renal failure, then following the radioisotope scan a drainage procedure with a nephrostogram may be indicated.

REFERENCES Magnetic resonance imaging The availability of MRI is still limited in virtually all parts of the world and the major demand for this equipment is in neurology and neurosurgery. Current MRI machines require the child to remain very still for periods of up to 15 minutes, which in a neonate/infant is difﬁcult, and respiratory movement will degrade the images of the kidneys. For these reasons its full potential in renal pathology is yet to be explored. Its major use in the neonate lies in congenital abnormalities of the pelvic organs, i.e. ano-rectal, cloacal, and bladder abnormalities.

CONCLUSIONS The US examination should always be the ﬁrst imaging examination. The ﬁnding of one normal kidney, especially in those well neonates who only have an abnormal antenatal ultrasound as the presenting feature, allows the clinical team time to evaluate the neonate fully at a later age and ensure close mother/infant contact with good binding. The combined use of US and MCU in the presence of either bilateral hydronephrosis, or the ill neonate, permits an accurate diagnosis and allows therapy to begin. There is rarely a need to proceed with further imaging while the neonate remains unwell, especially if the bladder catheter is left in place and on open drainage when bladder outﬂow obstruction is present, e.g. posterior urethral valves. Further imaging requires the

1. Scott JES, Renwick M. Antenatal diagnosis of congenital abnormalities in the urinary tract. Br J Urol 1988; 62:295–300. 2. Ransley PG, Dhillon HK, Gordon I et al. The postnatal management of hydronephrosis diagnosed by prenatal ultrasound. J Urol 1990; 144:584–7. 3. Homsy YL, Saad F, Laberge I et al. Transitional hydronephrosis of the newborn and infant. J Urol 1990; 144:579–83. 4. Najmaldin AS, Burge DM, Atwell JD. Outcome of antenatally diagnosed pelviureteric junction hydronephrosis. Br J Urol 1991; 67:96–9. 5. Gordon I, Dhillon HK, Peters AM. Antenatal diagnosis of renal pelvic dilatation – the natural history of conservative management. Pediatr Radiol 1991; 21:272–3. 6. Koff SA, McDowell GC, Byard M. Diuretic radionuclide assessment of obstruction in the infant: guidelines for successful interpretation. J Urol 1988; 140:1167–8. 7. de Bruyn R, Gordon I. Imaging in cystic renal disease. Arch Dis Child 2000; 83:401–7. 8. McHugh K, de Bruyn R, Gordon I. Paediatric uroradiology. In: Grainger RG, Alison DJ, editors. Diagnostic Radiology, 3rd edn. Edinburgh: Churchill Livingstone, 2001: 1717–64. 9. Ulman I, Javanthi VR, Koff SA. The long-term followup of newborns with severe unilateral hydronephrosis initially treated nonoperatively. J Urol 2000; 164(3 Pt 2):1101–5. 10. Koff SA. Neonatal management of unilateral hydronephrosis. Role for delayed intervention. Urol Clin North Am 1998; 25:181–6.

85 Management of antenatally detected hydronephrosis JACK S. ELDER

INTRODUCTION Maternal ultrasonography is used to determine fetal gestational age, well-being of the fetus in high-risk pregnancies, and as a screening tool in those with a family history of congenital abnormalities, as well as normal mothers. In 1% of pregnancies, a structural fetal anomaly is detected, and often the urinary tract is involved.1–4 The probability of detecting a structural anomaly by prenatal ultrasound depends on the experience and skill of the sonographer and usually is better late in gestation when the fetus is larger and an abnormality is easier to image. An anomaly involving the genitourinary tract is present in as many as one in 50 to one in 100 pregnancies, depending on the sonogram criteria.2,5 Improved ultrasound equipment and greater experience have resulted in increasing accuracy of sonography in detecting and identifying these lesions. Prenatal ultrasound allows the identiﬁcation of urological abnormalities that otherwise would be unrecognized until later in life when symptoms of pyelonephritis, stone disease, or abdominal pain or renal colic occur. Anomalies of the urinary tract detectable by prenatal ultrasonography include obstructive lesions, conditions that mimic obstruction (such as vesicoureteral reﬂux, VUR), cystic disease and renal agenesis (Table 85.1). Most obstructive anomalies occur more commonly in males. The timing and type of evaluation necessary in the newborn period depend on the nature of the abnormality visualized on ultrasound.

blastema, an area of undifferentiated mesenchyme on the nephrogenic ridge. The ureteral bud undergoes a series of approximately 15 generations of divisions and by 20 weeks’ gestation forms the entire collecting system, that is, the ureter, renal pelvis, calices, papillary ducts, and collecting tubules. Under the inductive inﬂuence of the ureteral bud, nephron differentiation begins during the seventh week. By 20 weeks, when the collecting system is completely developed, approximately one-third of the nephrons are present. Nephrogenesis continues at a nearly exponential rate and is complete by 36 weeks. Throughout normal gestation, the placenta functions as the fetal hemodialyser, and the fetal kidneys play a minor role in the maintenance of fetal salt and water homeostasis. Formation of urine begins between the ﬁfth and ninth weeks of gestation. The rate of urine production increases throughout gestation and, at term, urine output is 28–50 ml/h (Fig. 85.1).6,7 Normally, fetal urine is hypotonic.8 The glomerular ﬁltration rate (GFR)

DEVELOPMENT OF THE KIDNEY AND RENAL FUNCTION The human kidney is derived from the ureteral bud and the metanephric blastema. During the ﬁfth week of gestation, the ureteral bud arises from the mesonephric (Wolfﬁan) duct and penetrates the metanephric

Figure 85.1 Changes in GFR and urine output during fetal development and infancy (from Glick et al.,8 by permission)

794 Management of antenatally detected hydronephrosis Table 85.1 Genitourinary anomalies detectable by prenatal ultrasonography Condition

Sex (Ratio)

Frequency

Kidney(s)

Ureter(s)

Bladder

Amniotic ﬂuid

Prognosis

Ureteropelvic junction obstruction (unilateral)

M/F (3–4:1)

1:2000

Hydronephrosis

Not seen

Normal

Normal

Good after surgical correction

Multicystic kidney (unilateral)

M/F (1:1)

1:3000

Large with cysts of variable size

Not seen

Normal

Normal

Normal

Primary obstructive megaureter

M/F (3:1)

1:10 000

Hydronephrosis

Dilated

Normal

Normal

Good after surgical correction

Ectopic ureterocele or ureter

M/F (1:6)

1:10 000

Large cyst; possible Dilated duplex kidney

Normal or enlarged

Normal

Good after surgical correction

Posterior urethral valves

Male

1:8000

Bilateral hydroDilated nephrosis; possible cortical cysts

Enlarged

Variable; diminished or absent in severe obstruction

Usually good after surgical correction or drainage; poor if oligohydramnios is present

Prune belly syndrome

Nearly always 1:40 000 male

Bilateral hydroDilated nephrosis; possible cortical cysts

Enlarged

Variable; diminished or absent if severely affected

Usually fair to good; may need surgical drainage; poor if oligohydramnios is present

Vesico-ureteral reﬂux

M/F (1:5)

1:100

Hydronephrosis if reﬂux high grade

Variable

Normal; dilated Normal if reﬂux high grade

Good; may need surgical correction

Infantile polycystic kidney disease

M/F

1:6000– 1:14 000

Large, echogenic

Not seen

Small or not seen

Usually absent or severely diminished

Poor

Renal agenesis

M/F (2.0–2.5:1)

1:4000 (bilateral)

Not seen

Not seen

Not seen

Stillbirth

1:1500 (unilateral)

Not seen

Not seen

Normal

Severely diminished or absent Normal

May have hydroNot seen nephrosis Normal (cyst may Not seen be confused with kidney or bladder)

Normal

Normal

Normal

Normal

Hydrocolpos

Female

Ovarian cyst

Female

has been measured at 6 ml/min/1.73 m2 at 28 weeks’ gestation, increasing to 25 ml/min/1.73 m2 at term, and thereafter triples by 3 months of age. The main factors responsible for this rise in GFR include an increase in the capillary surface area available for ﬁltration, changes in intrarenal vascular resistance, and redistribution of renal blood ﬂow to the cortical nephrons, in which the majority of nephrons are located.9 A congenital obstructive lesion of the urinary tract may have a deleterious effect on renal function.

SONOGRAPHY OF THE FETAL URINARY TRACT In a normal fetus, the bladder is visualized as early as 14 weeks’ gestation. Although the kidneys also may be seen at 14 weeks, they should always be visualized by 18 weeks. Identiﬁcation of a ﬁlled bladder provides

Normal Good after surgical correction Good after surgical correction

evidence of renal function. Conversely, nonvisualization of the urinary bladder, particularly in association with oligohydramnios, suggests that renal function is poor. There are standards for normal fetal renal size10 and kidney circumference remains constant at approximately one-fourth of the abdominal circumference throughout gestation. Normally, the fetal ureter is not seen. Fetal sex may be determined early in gestation and requires the unequivocal visualization of the penis or scrotum, or both, or the labia majora. In one study, 40% of fetuses under 24 weeks’ gestation were deﬁnitely identiﬁed as to sex, with misdiagnosis occurring in only 3%.11 Assessment of the amniotic ﬂuid is important as well. During the ﬁrst trimester, amniotic ﬂuid represents a transudate of maternal plasma. Beyond 18 weeks, nearly all of the amniotic ﬂuid is the result of voided urine. Thus, with high-grade bladder outlet obstruction or bilateral renal agenesis, the volume of amniotic ﬂuid is severely diminished (oligohydramnios or anhydram-

Management 795

nios). Prolonged oligohydramnios results in impairment of fetal lung development and pulmonary hypoplasia, which is fatal. Consequently, the identiﬁcation of obstructive uropathy in association with oligohydramnios often is predictive of a poor outcome. Because visualization of the fetal kidneys may be marginal until 18–20 weeks’ gestation, and fetal urine output does not contribute signiﬁcantly to amniotic ﬂuid during the ﬁrst trimester, it is not uncommon for a newborn with obstructive uropathy to have a normal fetal ultrasound during the ﬁrst or second trimester. In order to be certain that renal development is normal, an ultrasound at or beyond 30 weeks’ gestation is necessary. A potentially obstructive anomaly is recognized by demonstrating a dilated renal pelvis or calyces, ureter, and/or bladder. The later the sonogram is performed, the more likely an existing anomaly will be detected, because the renal pelvis enlarges throughout gestation. In one study, only one-third of a series of women carrying babies with a urologic anomaly had an abnormal sonogram at 15–21 weeks’ gestation.12 Fetal renal dimensions measured by ultrasound are important in diagnosing lesions that may affect renal functional development. Obstructive lesions are almost always characterized by a fetal renal pelvic diameter more than 10 mm after 24–26 weeks’ gestation.2,13,14 In addition, false-positive sonograms have been noted in 9% to 22% of prenatally suspected uropathies.15,16 Furthermore, there have been anecdotal reports of progression of fetal hydronephrosis and obstructive dilatation of the upper urinary tract in fetuses with a renal pelvic diameter less than 10 mm.17,18 Although hydronephrosis is the most common urological abnormality detected by prenatal ultrasonography, a multicystic kidney or distended loop of bowel may be mistakenly identiﬁed as hydronephrosis. Furthermore, dilatation of the renal collecting system may occur in the absence of obstruction. This phenomenon may result from high fetal urine volume, reﬂux of urine from the bladder to the kidney, folds of the superior aspect of the fetal ureter, or simply from a dysmorphic urinary tract. One must keep in mind that antenatal sonography is only able to allow detection of a urinary abnormality and that a deﬁnitive diagnosis cannot be made until after birth (Table 85.2). Table 85.2 Evaluation of hydronephrosis Prenatal

Postnatal

Serial ultrasound Urinary electrolytes (fetal bladder)

Serial ultrasound Voiding cystourethrogram 99m Tc-MAG3 diuretic renogram DMSA renal scan Serial serum creatinine and electrolytes Cystoscopy; retrograde pyelogram Antegrade pyelogram Whitaker test Intravenous urogram

Urinary B2 microglobulin

MANAGEMENT Fetus with suspected hydronephrosis When a genitourinary anomaly is discovered prenatally, it is essential that the obstetrician, neonatologist, and pediatric urologist or pediatric surgeon work together to maximize the chances for a successful outcome. The knowledge that the fetus has a potential renal abnormality is extremely anxiety-provoking to the parents, and a team approach is helpful in providing not only optimal medical care but emotional support as well. In the fetus with bilateral hydronephrosis and a distended bladder, the most important prognostic feature is the volume of amniotic ﬂuid. If there is a normal amniotic ﬂuid volume, then renal function should be sufﬁcient to allow normal pulmonary development. Usually the renal cortex is visualized and may be demonstrated to be normal, whereas in other cases macroscopic renal cysts may be seen, which are strongly suggestive of dysplasia. The fetus should be monitored every 2 weeks to ascertain that the volume of amniotic ﬂuid remains normal. If oligohydramnios develops, the cause should be determined. Early delivery is not advised, except for the rare cases in which the amniotic ﬂuid volume diminishes signiﬁcantly, which may have an adverse effect on pulmonary development. In the fetus with unilateral hydronephrosis, plans should be made to evaluate the infant following delivery, and early delivery of the baby is not necessary. Because of the adverse consequences of oligohydramnios on the developing airway, it seems logical that survival might be improved if amniotic ﬂuid could be restored by bypassing the obstructive lesion with a vesicostomy or placement of a shunt between the bladder and amniotic space. In fetuses with a urologic anomaly, associated anomalies are common. For example, in one series of fetuses with bilateral hydronephrosis and oligohydramnios, 16 of 31 (55%) had an associated structural or chromosomal abnormality.19 Congenital heart disease and neurologic deformities often can be detected. In contrast, large bowel abnormalities, such as imperforate anus, usually are difﬁcult to detect by antenatal sonography, but recognition of small bowel anomalies, such as atresia, usually is straightforward.20 The main considerations in determining fetal management include overall fetal well-being, gestational age, whether the hydronephrosis is unilateral or bilateral, amniotic ﬂuid volume, and absence of other structural and chromosomal abnormalities. If hydronephrosis is unilateral, usually no fetal interventional therapy is necessary, unless there is dystocia from the mass, which is rare. In addition, if there is suspected bilateral uretero-

796 Management of antenatally detected hydronephrosis

pelvic junction (UPJ) obstruction or uretero-vesical junction (UVJ) obstruction, if the amniotic ﬂuid volume is normal, then pulmonary function should be normal as well. Because the neonatal kidney has a tremendous capacity for recovery following drainage, percutaneous drainage of the fetal kidney to improve function or early delivery to allow immediate urologic surgery are unwarranted. The primary life-threatening congenital urologic anomalies include posterior urethral valves, urethral atresia, and prune belly syndrome, which usually are characterized by bilateral hydroureteronephrosis and a distended bladder that does not empty. Approximately 40% of infants with urethral valves develop end-stage renal disease or chronic renal insufﬁciency.21,22 Although prune belly syndrome is considered non-obstructive, neonates with this condition frequently have renal insufﬁciency.23 Urethral atresia is nearly always fatal, because the kidneys are dysplastic. A severe adverse prognostic factor is oligohydramnios, which prevents normal pulmonary development. In fetuses with severe obstructive uropathy and renal dysplasia, neonatal demise usually results from pulmonary hypoplasia rather than chronic renal failure. Intuitively, it would seem that treatment of the obstructed fetal urinary tract by diverting the urine into the empty amniotic space might allow normal renal development to occur and restore amniotic ﬂuid dynamics, stimulating lung development. Indeed, percutaneous placement of a vesico-amniotic shunt, creation of a fetal vesicostomy or pyelostomy, and even percutaneous urethral valve ablation through a miniscope have been performed.24–26 Unfortunately, the complication rate has been signiﬁcant, including shunt migration, urinary ascites, stimulation of preterm labor, and chorioamnionitis.24 In addition, often there is signiﬁcant renal dysplasia, such that even if a satisfactory shunt has been placed, the baby might have severe renal insufﬁciency or end-stage renal disease. Nevertheless, some fetuses may beneﬁt from aggressive intervention. Selection has been based on the assessment of serial fetal urinary electrolytes. The concept is that normally fetal urine is hypotonic. In an obstructed system with dysplasia, the fetal urinary electrolytes often include a sodium > 100 mEq/L, chloride > 90 mEq/L, and osmolarity > 210 mOsm/L. If the fetal urine shows levels in these ranges, then a repeat fetal urinary drainage procedure should be performed in 48–72 hours and 48–72 hours after that. A downward trend to a more normal range suggests that fetal renal function may be satisfactory, and suggests that the fetus should be considered for antenatal intervention.27 Another important urinary parameter is B2 microglobulin.28 A thorough review of this controversial area is beyond the scope of this chapter, but several recent reviews are available.27, 29–31

Newborn with suspected obstructive uropathy At birth, the abdomen is inspected to detect the presence of a mass, which often is secondary to a multicystic kidney or UPJ obstruction. In addition, the newborn should be evaluated for anomalies involving other organ systems. Renal function should be monitored with periodic serum creatinines, particularly if the baby has bilateral hydronephrosis. At birth, the serum creatinine reﬂects maternal renal function. However, by 1 week of age, the creatinine should decrease to 0.4 mg/dL. The exception is the premature infant, in whom the creatinine may not decrease until the child reaches 34–35 weeks’ conceptional age, because of the immaturity of renal function prior to that time. Neonates with hydronephrosis may be at risk for urinary tract infections (UTIs) and should be placed on antibiotic prophylaxis with either amoxicillin 50 mg daily or cephalexin 50 mg daily. At 2 months, the prophylaxis usually is changed to trimethoprim–sulfamethoxazole. In addition, circumcision should be considered in male neonates to minimize the likelihood of UTI. A prompt radiological evaluation should be performed to delineate the abnormality responsible for changes on prenatal ultrasound (see Table 85.2). Serial renal sonograms, a voiding cystourethrogram (VCU) and, on occasion, a diuretic renogram usually provide the diagnosis. A renal and bladder ultrasound should be obtained ﬁrst. If the fetus has bilateral hydronephrosis, the sonogram should be obtained shortly after birth, whereas with unilateral hydronephrosis, the evaluation may be delayed for several days, because neonates may have transient oliguria and a dilated or obstructed collecting system may appear normal for the ﬁrst 24–48 hours of life.32 Renal length, degree of caliectasis and parenchymal thickness, and presence or absence of ureteral dilation should be assessed. Ideally, the severity of the hydronephrosis should be graded from 1 to 4 using the Society for Fetal Urology (SFU) scale33 (Fig. 85.2). Most signiﬁcant urologic anomalies are associated with higher grades of hydronephrosis. In one report of 464 infants with 582 prenatally detected hydronephrotic kidneys, 80% of those who underwent surgical correction of a structural abnormality of the upper urinary tract had grade 3 or 4 hydronephrosis.34 More sophisticated analyses, such as the ultrasound renal resistive index, have not been useful. The bladder should be imaged by ultrasound to detect a dilated posterior urethra (urethral valves), thickening of the bladder wall, inadequate bladder emptying, a ureterocele, or ureteral dilatation. Next, a VCU should be performed. This study may demonstrate posterior urethral valves, a bladder diverticulum or VUR. Even if the neonatal ultrasound is normal, a VCU should be performed, because reﬂux may be the cause of fetal hydronephrosis.35,36

Management 797

0

1

2

3

4

Figure 85.2 Grading system for hydronephrosis (by permission of the Society for Fetal Urology)

If the ultrasound and VCU are normal, then only a follow-up ultrasound in 6–8 weeks is necessary. In some cases, although the renal ultrasound was normal on initial evaluation, subsequent evaluation has shown a signiﬁcant upper tract anomaly. In one study of 10 newborns with prenatal hydronephrosis and a normal initial ultrasound, four were found to have obstruction, two had VUR, two remained normal and two were lost to follow-up.32 If the postnatal sonogram shows grade 1 or 2 hydronephrosis and the VCU is normal, then it may be presumed that the pelvo-caliectasis is physiologic or secondary to mild narrowing or the UPJ. The likelihood of obstruction is quite low, and no further immediate evaluation is necessary, but a follow-up renal sonogram in 3–6 months is necessary. If the postnatal sonogram shows grade 3 or 4 hydronephrosis and there is no reﬂux, the upper urinary tracts must be evaluated further. In a newborn, the best method of evaluation is to perform a renal scan (diuretic renogram) using technetium-99m MAG3 (99mTcMAG3), which is ﬁltered and also secreted by the renal tubules. The renal scan provides an excellent method of

objectively assessing the relative function of each kidney. Differential renal function is computed by measuring the uptake over each kidney during the ﬁrst 2–3 minutes, before the radionuclide enters the collecting system. In addition, the efﬁciency of upper urinary tract drainage may be measured. On the diuretic renal scan, upper urinary tract obstruction is assessed by injecting furosemide when the renal pelvis is full, which stimulates washout of the radionuclide from the renal pelvis. If no obstruction is present, then normally half of the radionuclide is cleared from the renal pelvis within 15 minutes, termed the ‘half-time’. In the presence of signiﬁcant upper tract obstruction at the level of the UPJ or UVJ, the half-time is longer than 20 minutes, and typically the drainage curve is ﬂat. In some cases, the half-time is an indeterminate 15 to 20-minute range. If VUR is present, a catheter must be inserted into the bladder at the beginning of the study. Numerous factors affect the interpretation of the diuretic renogram, including renal maturity, renal function, hydration status, dose of radiopharmaceutical, dose of diuretic, timing of diuretic administration, presence of VUR, volume of urine in the bladder, outlined regions of interest, patient position, patient movement, capacity of the upper urinary tract, severity of obstruction, site of obstruction, and method of data interpretation.9 Recognizing the limitations of the diuretic renogram in the newborn with hydronephrosis, and because the methodology of diuretic renography varies substantially among nuclear medicine specialists, the Society for Fetal Urology and the Pediatric Nuclear Medicine Club jointly developed a standardized method for the diuretic renogram in infants, termed the ‘well-tempered renogram’.37 Patients should be older than 1 month in order to reduce the likelihood that renal function is immature, and prematurely born infants should be even older. Oral hydration is offered ad libitum, beginning 2 hours prior to the study. The bladder is catheterized to ensure it is empty, and the catheter is left to continuous open drainage or intermittent syringe evacuation. The infant receives prophylactic antibiotics during the study. Saline solution is administered intravenously at a rate of 10 ml/kg for 15 minutes prior to the injection of the radiopharmaceutical, 99mTc-MAG3, and is continued for 15 minutes after injection. The renogram is recorded with the infant in a supine position. The region of interest encompasses the entire kidney including the dilated renal pelvis, with a region of interest for background subtraction deﬁned as 2 pixels wide around the entire outer perimeter of the kidney. The percentage differential function and renal function is computed by measuring the total counts of the renogram curve for each kidney minus background between 90 and 150 seconds after the appearance of the abdominal aorta. Furosemide is administered in a dose of 1 mg/kg after

798 Management of antenatally detected hydronephrosis

20–30 minutes or when the dilated renal pelvis or ureter is thought to be ﬁlled on the scintigram images. In a baby with unilateral hydronephrosis, the diuretic renogram should be performed at 6–8 weeks to allow for maturation of renal function, whereas if there is bilateral hydronephrosis or a solitary hydronephrotic kidney, prompt evaluation is important, particularly if the hydronephrosis is severe.

(a)

URETEROPELVIC JUNCTION OBSTRUCTION The most common cause of hydronephrosis in the newborn is an anomalous UPJ, which usually is secondary to an intrinsic ﬁbrotic narrowing between the ureter and renal pelvis (Fig. 85.3a–d). The diagnosis of UPJ obstruction in the infant is based upon the ﬁnding of SFU grade 3 or 4 hydronephrosis on ultrasonography

(b)

(c)

(d)

Figure 85.3 Bilateral UPJ obstruction detected prenatally in a female. (a) Prenatal ultrasound demonstrates dilated right kidney (RT), left kidney (LT) and bladder (UB). The perinatologist suspected outlet obstruction, although this is extremely rare in a female. At birth, there was a severe bilateral hydronephrosis. Renal scan showed nonfunction on the left. Bilateral ﬂank exploration was performed. On the right, a UPJ obstruction was found and dismembered pyeloplasty was done. On the left, there was essentially no parenchyma and a small-caliber ureter. A renal biopsy showed dysplasia and a nephrectomy was performed. (b) Postoperative IVP, 10-minute ﬁlm, demonstrated excellent function on the right side. (c) DTPA diuretic renal scan, 30 minutes shows accumulation of radionuclide in right kidney. Furosemide administered. (d) Forty-ﬁve minute image demonstrates excellent drainage. T1⁄2 was 6.5 minutes. Arrow points to accumulation of urine in nappy

Management 799

and poor drainage on a 99mTc-MAG3 diuretic renogram. Often the differential function of the involved kidney is relatively normal.38 The degree of renal pelvic and calyceal dilatation and alteration in renal function depends on the severity of the obstruction and the compliance of the renal pelvis. In 20% of older children and adults there is an accessory renal artery supplying the lower pole of the kidney, which may impede urinary ﬂow and cause stasis. However, this ﬁnding is rare in neonates with a UPJ obstruction. In 10% of infants with UPJ obstruction, both kidneys are involved. In addition, 10–15% of infants with a UPJ obstruction have ipsilateral VUR. A UPJ obstruction usually is managed by excising the stenotic segment and anastomosing the ureter to the renal pelvis, termed a dismembered pyeloplasty. The procedure is performed either through a ﬂank or dorsal lumbotomy incision. In the neonate the success rate is over 90%.9,39 Often a temporary stent is placed through the UPJ and some prefer to place a nephrostomy tube as well. If there is a solitary kidney, bilateral UPJ obstruction, or if there is an abdominal mass resulting from the obstructed kidney, the pyeloplasty should be performed shortly after the diagnosis is made, even before the baby leaves the hospital. Otherwise, the procedure can be delayed until the baby is 3 or 4 months of age. Lesser degrees of UPJ stenosis may cause mild hydronephrosis, which is almost always non-obstructive, and typically these kidneys function normally. The spectrum of UPJ abnormalities is termed anomalous UPJ. Another cause of mild hydronephrosis is fetal ureteral folds, which also are non-obstructive. Hydronephrosis in many newborns gradually diminishes or resolves over months to years. The goal of early evaluation is to determine whether a true anatomic obstruction is present that should be repaired or whether it is safe to follow the infant non-operatively. Several studies have demonstrated that many infants with severe hydronephrosis may be followed non-operatively. Cartwright and associates studied 97 newborns with suspected UPJ obstruction.40 Of 39 with at least 35% differential renal function followed non-operatively, only six (15%) underwent pyeloplasty, with average follow-up of 18 months (range of 6–48 months). All three of the patients with differential renal function of less than 40% who underwent pyeloplasty because of decreasing renal function returned to their initial levels. One might question whether early pyeloplasty in these three patients would have allowed renal function to improve to 50%, which would have been ideal. In those followed non-operatively, all maintained differential functions greater than 40% with follow-up as late as 48 months. Takla and associates studied 51 patients with SFU grades 2, 3, and 4 hydronephrosis initially managed nonoperatively and found that 4% of those with grade 2,

56% with grade 3, and 71% with grade 4 hydronephrosis ultimately underwent pyeloplasty.41 In the remaining patients, the hydronephrosis resolved, usually by 18 months of age. In contrast, Ulman and co-workers reported 104 infants with SFU grade 3 or 4 hydronephrosis initially managed non-operatively followed for a mean of 6.5 years.42 Of the patients followed non-operatively, hydronephrosis resolved in 69% and improved in 31%. However, 33% still had a T1⁄2 greater than 20 minutes on their most recent diuretic renogram. Of the infants, 23% underwent pyeloplasty. All were younger than 18 months of age and showed progressive hydronephrosis and/or reduction in differential renal function. In these kidneys, postoperative differential renal function exceeded the predeterioration level in all kidneys. Palmer and colleagues reported the initial results of a prospective randomized trial comparing observation to pyeloplasty in infants with SFU grade 3 or 4 hydronephrosis.43 All had differential renal function greater than 40% on their initial renal scan and a prolonged T1⁄2. Of the 32 infants studied in the observation group, 25% had signiﬁcant deterioration in renal function and underwent pyeloplasty. The remaining observation patients were stable. Those undergoing pyeloplasty had less hydronephrosis and a shorter T1⁄2 drainage curve at follow-up compared with the observed group. These observations may seem inconsistent and can be interpreted in several ways. First, it may be that some partially obstructed kidneys have signiﬁcant functional impairment at birth but that the capacity for renal maturation, with increasing GFR secondary to redistribution of blood ﬂow to cortical nephrons, during the ﬁrst year of life is maintained. Another explanation is that the early diuretic renogram is erroneous and that during the period of transitional nephrology the differential renal function and capacity for washout in these kidneys is different than in older children. Finally, it must be remembered that all of these studies base ‘renal function’ on the results of the differential renal function, which has signiﬁcant potential for variability. This author’s approach to neonates with a perinatal diagnosis of suspected UPJ obstruction is as follows. In children with unilateral hydronephrosis, no abdominal mass, and a normal contralateral kidney, the hydronephrosis is graded (1–4). Those with grade 3 and 4 hydronephrosis are most likely to require pyeloplasty. A VCU is obtained during the ﬁrst few weeks of life, the child is placed on prophylactic amoxicillin or cephalexin, and circumcision is recommended for boys. At 6 weeks, a well-tempered renogram is performed. If differential renal function is greater than 35–40% and any signiﬁcant drainage is noted after administration of furosemide, even if the T1⁄2 is greater than 20 minutes, the child is managed non-operatively and kept on prophylaxis with trimethoprim–sulfamethoxazole, which is safe to administer after 2 months of age. A follow-up renal

800 Management of antenatally detected hydronephrosis

sonogram and diuretic renogram are performed 3 months later. If there is deterioration in differential function, worsening of the diuretic washout curve, or worsening hydronephrosis, pyeloplasty is recommended. If these parameters remain stable or improved, however, follow-up 3–6 months later with another diuretic renogram is performed and management is individualized. If there is an abdominal mass, a solitary kidney, bilateral hydronephrosis, or impaired renal function, pyeloplasty is performed.

MULTICYSTIC KIDNEY An entity that may be confused with a UPJ obstruction is a multicystic dysplastic kidney (Fig. 85.4a–c). Although a multicystic kidney is the most common cause of an abdominal mass in a neonate, many smaller multicystic kidneys are being detected incidentally by prenatal ultrasound. These kidneys are completely replaced by multiple cysts of varying sizes, and the stroma is composed of dysplastic parenchyma. Occasionally, the cysts may be orientated in such a way as to resemble a severe UPJ obstruction with minimal parenchyma, termed the hydronephrotic variant.44 A renal scan should be performed to conﬁrm the diagnosis. Approximately 10% have a contralateral UPJ obstruction, and 15% have VUR.45 Consequently a VCU also should be obtained. Many clinicians inaccurately assume that multicystic kidney and polycystic kidney are synonymous terms. Polycystic kidney disease is an inherited disorder and has an adult form (autosomal dominant) and an infantile form (autosomal recessive) and affects both kidneys. In contrast, a multicystic kidney is almost always unilateral and is not an inherited disorder. The management of an infant with a multicystic kidney is controversial. If there is an abdominal mass that is symptomatic, early nephrectomy is indicated. However, the anesthetic risk is slightly higher in a newborn and many prefer to wait until the infant is 3–6 months of age before performing nephrectomy. Most multicystic kidneys are detected by prenatal ultrasonography and are not apparent on physical examination. Serial sonographic examinations demonstrate that many of these regress during the ﬁrst 2 years of life. In the American Academy of Pediatrics multicystic kidney registry, 23% of those managed non-operatively demonstrated complete cyst regression by 3 years of age.46 With a mean observation period of 4.9 years, John et al. reported that 48% showed complete regression, 33% were reduced in size, 15% showed no change, and 4% increased in size.47 Consequently, one can argue that nephrectomy is unnecessary.48 However, there have been numerous reports of childhood hypertension (generally curable by nephrectomy)49 as well as malignancy, including Wilms tumor,50,51 transitional cell carcinoma,52 and renal cell carcinoma.53 Tumors do not arise from the cystic, but rather from the stromal component of the

(a)

(b)

(c) Figure 85.4 Newborn with prenatal diagnosis of right cystic mass. (a) Ultrasound of right kidney demonstrates multiple cysts of varying sizes without parenchyma, suggestive of multicystic kidney. Renal scan showed nonfunction, conﬁrming this diagnosis. (b) Ultrasound of left kidney demonstrates good cortex and slight hydronephrosis. (c) VCU demonstrates grade V reﬂux into left kidney. The urethra was normal. This demonstrates that there may be high-grade reﬂux even if the renal ultrasound only shows mild hydronephrosis

Management 801

multicystic kidney. Consequently, even if the cysts regress completely, the likelihood that the kidney could develop a neoplasm is not altered. If a decision is made not to remove a multicystic kidney, annual renal ultrasonography is necessary, but there is no agreement on the duration of follow-up. Over the past 12 years, this author has been removing selected multicystic and hydronephrotic kidneys in children between 6 and 18 months of age through a 25 mm (1 inch) incision as an outpatient procedure.54 Morbidity has been nil and the families have been able to avoid long-term follow-up. If there is any question regarding whether the affected kidney is multicystic or hydronephrotic, renal exploration is recommended. Hydronephrosis and an enlarged ureter If unilateral hydronephrosis and a dilated ureter are identiﬁed, the etiology may be a ureterocele, an ectopic ureter, primary obstructive megaureter, VUR or a nonobstructive megaureter. A ureterocele is a cystic dilatation of the distal end of the ureter and is obstructive. In children they usually extend through the bladder neck, termed ectopic, but may remain entirely within the bladder, termed intravesical. In girls, at least 90% are associated with a duplicated upper urinary tract, and the ureterocele drains the upper pole ureter. In boys, however, approximately half drain a single system and half drain the upper pole of a duplicated upper urinary tract. Early evaluation consists of: • Sonography – shows hydroureteronephrosis with a cystic mass visible within the bladder. Renal parenchymal atrophy is variable. • VCU – shows whether there is reﬂux into the lower pole ureter or into the contralateral system; the study will not demonstrate reﬂux into the ureterocele unless the ureterocele is inadvertently punctured during urethral catheterization, which is rare. • DMSA renal scan – shows whether the moiety drained by the ureterocele functions. In some cases the upper pole shows nonfunction and the lower pole also has minimal function, either from reﬂux nephropathy or extrinsic obstruction by the ureterocele. This study may be done at 1–2 weeks of age because the result does not change with functional maturity. The DMSA scan is much more sensitive than an IVP in demonstrating whether the obstructed system has signiﬁcant function. Treatment of the ureterocele is controversial. Transurethral puncture of the ureterocele usually provides satisfactory decompression of the upper tract with a 30% risk of postoperative reﬂux into the upper pole moiety through the decompressed ureterocele.55 If there is an ectopic ureterocele, both the urethral extension as well as the intravesical portion must be punctured, whereas if the ureterocele is entirely intravesical, inferomedial

puncture is sufﬁcient. If the renal scan shows signiﬁcant upper pole function, transurethral puncture is performed during the ﬁrst few weeks of life. If there is nonfunction and there is no lower pole reﬂux, however, the infant is maintained on antibiotic prophylaxis and deﬁnitive treatment may be planned at 6 months of age. Interval laparoscopic upper pole nephrectomy can be done safely at 6 months of age.56 Total urinary tract reconstruction in neonates and infants is not recommended because of the high complication rate caused by the small size of the infant bladder. An ectopic ureter refers to a ureter that drains outside the bladder. In girls, one-third drain into the bladder neck, one-third into the urethro-vaginal septum, and one-third into the vagina. In boys, ectopic ureters may drain into the bladder neck, prostate, or seminal vesicle. Ectopic ureters occur more commonly in girls and usually are associated with the upper pole of a completely duplicated collecting system. These conditions are bilateral in 10–15% of patients. Evaluation is identical to that noted above for ureteroceles. If the ectopic ureter drains into the bladder neck, usually there is reﬂux into the affected ureter, which also is obstructed. Frequently, a cyclic cystogram is necessary. If the upper pole moiety is dysplastic and nonfunctional, interval heminephrectomy (which can be performed laparoscopically56) at 6 months of age generally is the initial treatment (Fig. 85.5a–c). However, if the upper pole demonstrates signiﬁcant function on renal scan, then a ureteropyelostomy (suturing the upper pole ureter to the lower pole renal pelvis) or ureteral reimplantation is indicated. A nonreﬂuxing megaureter results from an aperistaltic segment of the distal ureter that does not allow normal propulsion of urine. In this condition, sonography shows a dilated ureter and renal pelvis with variable renal parenchymal atrophy. VCU shows no reﬂux in most cases. Before the era of antenatal ultrasound, most patients with this condition presented with ﬂank pain, a ﬂank mass, pyelonephritis, hematuria, or stone disease. Approximately 70% of individuals with this condition are male and two-thirds of the megaureters present on the left side. Although severe hydronephrosis may be present, the natural history of this condition is that there is a tendency to gradual reduction in hydronephrosis over a period of several years. For example, in one series of 35 neonates with a primary nonreﬂuxing megaureter, 10 underwent early repair, whereas 25 were followed nonoperatively.57 With a mean follow-up of 7.3 years, none of the 25 exhibited deterioration in differential function or demonstrated signs of obstruction. In another series of 21 patients with nonreﬂuxing megaureters with obstruction on the initial scan, six underwent early reconstruction, whereas 15 were observed.58 Of the patients who were managed non-operatively, two showed functional deterioration and three, who were not receiving antimicrobial prophylaxis, developed

802 Management of antenatally detected hydronephrosis

(a)

(b)

(c) Figure 85.5 Obstructing ectopic ureter. (a) Transverse section at 30 weeks’ gestation, dilated ureter (large arrows) and lower pole, right kidney (small arrow). (b) Longitudinal view demonstrating dilated ureter in abdomen (arrows). (c) Postnatal IVP, 15-minute ﬁlm. Drooping lily deformity, right kidney with deviation of lower pole ureter. The obstructed upper pole segment is not visualized and causes displacement of the lower pole of the kidney and ureter. The left kidney is normal. A right upper pole heminephrectomy was performed, with removal of the dysplastic segment (from Cendron and Elder,9 by permission)

UTIs. Liu and colleagues found that 11 of 67 (17%) neonatal megaureters managed non-operatively ultimately needed repair because of deteriorating renal function in eight and breakthrough UTIs in three.59 Consequently, it appears that most of these patients may be followed non-operatively on antibiotic prophylaxis and serial monitoring of renal function and drainage. In these neonates, a VCU and renal sonogram should be obtained before discharge. Early management is identical to that of neonates with a suspected UPJ obstruction. If an abdominal mass, solitary kidney, or bilateral hydroureteronephrosis is present, a well-

tempered diuretic renogram should be obtained promptly. Otherwise, the study is deferred until 6–8 weeks of age. If the differential renal function is at least 35–40%, the child is managed non-operatively and follow-up diuretic renograms and/or renal sonograms are obtained every 3–6 months. Circumcision is recommended for boys, and all are administered antimicrobial prophylaxis. As long as the child remains asymptomatic and the severity of hydronephrosis remains stable or decreases, non-operative management may continue. On the other hand, if the differential renal function is low or diminishing, the T1⁄2 is prolonged, the child is sympto-

Management 803

matic, or the hydronephrosis worsens, repair is indicated (Fig. 85.6a–d). When repairing a megaureter, one must be certain to remove the narrowed distal ureteral segment and part of the redundant ureter. Although Hendren’s60 technique of extensive ureteral excisional tapering has stood the test of time, ureteral plication has been demonstrated to be a reliable method of repair if the ureter is not too wide, with a low incidence of postoperative obstruction. Tailoring needs to be performed only up to a few

(a)

centimeters proximal to the intramural segment. In general, we have stented these tailored ureters for 3 weeks with a small double-J stent that is connected to a small suture that is brought out through the urethra and taped to the lower abdomen. Early repair of megaureter has a higher complication rate than in older children. For example, Peters and associates reported on megaureter repair in 42 infants operated on at a mean age of 11.8 months.61 In that series, early complications occurred only in those

(b)

(c)

(d)

Figure 85.6 A symptomatic male newborn with left hydroureteronephrosis demonstrated by prenatal ultrasound. (a) IVP, 5 weeks old, 30-minute ﬁlm demonstrates left primary obstructive megaureter. VCU was normal. DTPA scan showed 25% function on left and T1⁄2 greater than 30 minutes. (b) DTPA diuretic renal scan shows poor drainage from left kidney. (c) At 2 months, left ureteral reimplantation with Starr plication and transtrigonal advancement performed. IVP, 6 months old, 6-minute ﬁlm demonstrates marked improvement in caliectasis. (d) DTPA diuretic renal scan, 9 months old. Fifteen- and 30-minute images shown. Furosemide given at 15 minutes. Left kidney on right side, T1⁄2 on left, 10 minutes. Differential function on left, 50%

804 Management of antenatally detected hydronephrosis

younger than 6 weeks of age and included transient apnea in three, UTI in one, hyponatremia in one, and meningitis in one. Six had postoperative reﬂux, and none had obstruction. Greenﬁeld et al. reported on repair of 11 megaureters in infants younger than 6 months old.62 Of these children, two had transient ureteral obstruction immediately after stent removal and persistent grades I and II reﬂux in two children. Bilateral hydronephrosis and a distended bladder In a newborn with bilateral hydronephrosis and a distended bladder, the most common conditions are posterior urethral valves, prune belly syndrome, and VUR. The most common cause of bladder outlet obstruction is posterior urethral valves (PUV), which are obstructing tissue leaﬂets fanning distally from the prostatic urethra to the external urinary sphincter (Fig. 85.7a,b). The degree of functional renal impairment depends on the severity of the obstruction. Because of the high-grade bladder outlet obstruction throughout gestation, many children with PUV have severely compromised renal function secondary to renal dysplasia. Frequently, the diagnosis of PUV is suggested by prenatal ultrasonography. Prognosis is signiﬁcantly better if ultrasound studies performed before 24 weeks of gestation were normal; more than half detected by 24 weeks died or were in chronic renal failure.63 The newborn with PUV may have an abdominal mass (48%), failure to thrive (10%), urosepsis (8%), or urinary ascites (7%). When the bladder is empty, most will have a walnut-size ﬁrm mass in the pelvis, which corresponds to the trabeculated bladder muscle. In addition, dyspnea at birth associated with pneumothorax or pneumomediastinum may be the initial sign of severe urethral obstruction. When the diagnosis of urethral valves is suspected, a VCU should be performed. A thick trabeculated bladder with a very distended posterior urethra and valve leaﬂets is seen. Other ﬁndings include detrusor hypertrophy, often with cellules or diverticula; bladder neck hypertrophy; and a thin stream distal to the valve leaﬂets. Half of these patients have VUR, with 25% having bilateral and 25% having unilateral reﬂux. The radiographic appearance of PUV is not confused with prune belly syndrome, although both of these conditions can cause signiﬁcant bladder and upper urinary tract dilatation. The other important radiographic study is a renal and bladder sonogram. It is important to obtain baseline views of the renal collecting systems to assess pelvic and calyceal dilatation, as well as cortical echogenicity, which may be indicative of the presence of dysplasia. Sonographic presence of the corticomedullary junction in newborns with urethral valves is an important prognostic indicator of good renal function following drainage of the urinary tract. Conversely, if the corticomedullary junction is not visualized and does not appear

(a)

(b) Figure 85.7 Prenatal ultrasound in a male with ascites and unilateral hydronephrosis with urethral valves. (a) Prenatal ultrasound demonstrates massive ascites and unilateral hydronephrosis. (b) VCUG demonstrating posterior urethral valves and massive left VUR. The left kidney was nonfunctioning. The child was managed with transurethral valve ablation with the Whitaker hook and drainage of the urinoma. Serum creatinine at 1 month of age, 0.4 mg%

on subsequent ultrasound examinations, most develop renal insufﬁciency.64 Suprapubic or perineal ultrasound may demonstrate the dilated posterior urethra, and thus one might establish the diagnosis of PUV on the basis of ultrasound before the VCU is performed. After the diagnosis of PUV is made, the bladder should be drained with a 5- or 8-Fr pediatric feeding

Management 805

tube. A Foley balloon catheter may not drain satisfactorily because the balloon has a tendency to occlude the ureteral oriﬁces or it may cause severe bladder spasm and prevent normal drainage of the upper urinary tracts. When passing the urethral catheter, there is a tendency for the tip of the tube to bump on the bladder neck and coil in the dilated posterior urethra, compromising effective drainage. In this circumstance, most of the urine tends to drain around the feeding tube. Broadspectrum antibiotics are given to minimize the chance of developing a nosocomial bacterial infection. The serum creatinine is monitored, and electrolyte abnormalities, including acidosis and hyperkalemia, need to be managed before surgical treatment of the lesion is undertaken. In addition, repeat sonography of the upper tracts may be performed to assess the response to bladder drainage. Initial treatment of PUV depends on the size and condition of the child. The goal of therapy is to provide optimal upper tract drainage and preserve bladder cycling to allow satisfactory bladder growth with maximal compliance.22,65 In the past, use of an inappropriately large endoscopic instrument for valve ablation resulted in urethral stricture. With improvement in the optics of the infant cystoscope, fulguration can be performed in most small infants safely. In most cases, the 3-Fr Bugbee electrode may be inserted through the operating channel of the infant cystoscope. The valve leaﬂets should be ablated at the 5 and 7 o’clock positions, and on occasion at the 12 o’clock position. Complications with transurethral valve ablation are rare; the most common is incomplete valve ablation. Urethral stricture may occur if the cystoscope is too large for the urethra or if the diathermy current comes into contact with the metal of the cystoscope.66 If the urethra is too small to accommodate the pediatric cystoscope and miniature Bugbee electrode, cutaneous vesicostomy is an alternative form of management. The dome of the bladder should be brought to the skin at a level such that the posterior bladder wall will not prolapse into the stoma. The vesicostomy should calibrate to 24 Fr. Following deﬁnitive therapy, the child should be monitored closely by ultrasound to be certain that the upper urinary tracts are decompressed satisfactorily. A high serum creatinine should decrease gradually. In a newborn who has undergone valve ablation, if the serum creatinine remains unchanged or does not decrease at least to 1.0–1.2 mg/dL, proximal diversion by vesicostomy should be considered. In the past, cutaneous pyelostomy was thought by some to be a superior form of upper tract diversion compared with cutaneous vesicostomy. However, supravesical diversion does not seem to prevent progression to end-stage renal disease in many of these children because of underlying renal dysplasia. Furthermore, proximal diversion results in the absence of urine going to the bladder and thereby

prevents bladder cycling, which may result in poor bladder compliance (the ‘valve bladder’). An alternative is to insert a percutaneous nephrostomy tube for temporary diversion and identify those few patients who might beneﬁt from cutaneous pyelostomy.67 An alternative is the Sober-en-T temporary high diversion for urethral valves, in which a cutaneous ureterostomy is performed, and the distal ureter is sutured to the upper ureter just distal to the renal pelvis.68 The advantage of this approach is that the upper urinary tract is diverted, but some of the urine drains to the bladder, which preserves long-term bladder cycling. In select cases, cutaneous pyelostomy may be necessary if a child has urosepsis secondary to pyonephrosis. If upper urinary tract diversion is performed, concurrent renal biopsy should be done to assess renal morphology. The long-term prognosis for infants with PUV depends on multiple factors. Among the most important are the serum creatinine level following urinary drainage and whether a pop-off valve, such as unilateral VUR associated with a nonfunctioning kidney (VURD syndrome), a large bladder diverticulum, or urinary ascites is present. If the serum creatinine level is less than 0.8 mg/dL 4–5 days after bladder drainage, renal function usually remains sufﬁcient to prevent the need for dialysis, particularly if the renal corticomedullary junction is intact on sonography.64,69 In patients with unilateral VUR associated with nonfunction, the prognosis has been quite good. It has been called the VURD (valves, unilateral reﬂux, and dysplasia) syndrome. The reﬂuxing ureter acts as a pop-off valve, preventing the deleterious effects of high vesical pressure on the opposite kidney. Finally, the presence of urinary ascites in newborns with PUV has been recognized as another protective factor, with an upper or lower urinary tract leak allowing the kidneys to develop without the deleterious effects of high pressure. The risk of end-stage renal disease in boys with PUV is signiﬁcant. In a series of 98 boys with follow-up between 11 and 22 years, Parkhouse and colleagues reported that 31 (32%) had poor renal function: 10 (10%) had died of renal failure, 15 (15%) had endstage renal failure, and six (6%) had chronic renal failure but were not yet receiving dialysis.21 Adverse prognostic factors included presentation before 1 year of age, bilateral VUR, and diurnal incontinence after 5 years of age, the last being the most important factor. The association of diurnal incontinence and poor renal function in these patients most likely is related to detrusor instability and detrusor sphincter dyssynergia, which many of these boys develop, resulting in elevated upper urinary tract pressures and gradual deterioration in renal function. When PUV is discovered in the newborn, it is likely that the infant will have high urine output resulting from a renal-concentrating defect. Consequently, the parents of these infants should be advised that their child is

806 Management of antenatally detected hydronephrosis

much more likely than other infants to become severely dehydrated with viral gastroenteritis or other febrile infections that might increase the child’s ﬂuid requirements. Although prune belly syndrome has an identical appearance to urethral valves on prenatal ultrasonography, the phenotypic appearance of the wrinkled abdomen and the ﬁndings of a distended bladder, bilateral hydroureteronephrosis, and bilateral cryptorchidism are characteristic. The etiology of prune belly syndrome is uncertain, although it has been attributed to a generalized mesenchymal abnormality involving the urinary tract. Another possible explanation is a transient embryologic urethral obstruction. In contrast to posterior urethral valves, signiﬁcant bladder outlet obstruction usually is not present. Immediate urological evaluation is necessary to determine whether cutaneous vesicostomy or urinary reconstruction is required to improve drainage of the urinary tract. A signiﬁcant proportion of these babies have renal insufﬁciency.23 Many neonates with medium- and high-grade vesicoureteral reﬂux are detected by the ﬁnding of hydronephrosis on prenatal sonography. Approximately 80% of such patients are boys. The male predominance is thought to be secondary to transient urethral valve-like urethral obstruction in utero that resolves before birth. The high intravesical pressures generated seem to destabilize the UVJ. Infants with reﬂux have had abnormal urodynamic patterns including low bladder capacity in combination with extremely high detrusor pressure levels (hypercontractility) and high-capacity bladder with normal or low detrusor pressure levels.70 A complication of bilateral high-grade reﬂux is the megacystis-megaureter syndrome (Fig. 85.7). Most of the voided urine reﬂuxes into the upper urinary tracts, resulting in a weak urinary stream, a large bladder, and signiﬁcant residual urine mimicking bladder outlet obstruction. However, the bladder is smooth-walled, and no obstructive component is demonstrated on VCU. This pattern of constant recycling of large volumes of reﬂuxing urine has been termed aberrant micturition. Ureteral reimplantation with tapering is necessary to correct the condition, although cutaneous vesicostomy is a temporizing procedure that may allow the ureters to diminish in caliber, which may facilitate later ureteral reimplantation. Reduction cystoplasty is not necessary or effective. If the neonate has grade III or higher reﬂux, a DMSA renal scan should be obtained to determine the baseline differential renal function and assess whether there is congenital reﬂux nephropathy. Often the affected kidney shows signiﬁcant reduction in differential renal function, even though no infection has occurred.71 Initially, neonates with reﬂux are usually managed medically. They are placed on antimicrobial prophylaxis with amoxicillin or cephalexin for 2 months and then switched to trimethoprim–sulfamethoxazole or nitro-

furantoin. Circumcision is recommended for male neonates to decrease the risk of UTI. They undergo a follow-up sonogram every 6–12 months and follow-up cystography every 12–18 months. Neonates with reﬂux are more likely to show spontaneous resolution than older children with similar reﬂux grades. For example, 20–35% of ureters with grade IV and V reﬂux have reﬂux resolution with 2 years.72,73 However, as many as 25% have a breakthrough UTI, and ureteroneocystostomy is recommended in these cases. The success rate for surgical correction of reﬂux in infants can be high.74,75 Although these patients have been reported to have abnormal urodynamic patterns, late follow-up of operated patients demonstrates that nearly all have a normal voiding pattern and bladder capacity.75

REFERENCES 1. Hobbins JC, Grannum PAT, Berkowitz RL et al. Ultrasound and the diagnosis of congenital anomalies. Am J Obstet Gynecol 1979; 134:331. 2. Johnson DE, Elder JS, Judge NE et al. The accuracy of antenatal ultrasonography in identifying renal abnormalities. Am J Dis Child 1992; 146:1181. 3. Hill IN, Breckele R, Gehrking WC. Prenatal detection of congenital malformations by ultrasonography: Mayo clinic experience. Am J Obstet Gynecol 1985; 151:44. 4. Grisoni ER, Gauderer MWL, Wolfson RN et al. Antenatal ultrasonography: the experience in a high risk perinatal center. J Pediatr Surg 1986; 21:359. 5. Corteville JE, Gray DL, Crane JP et al. Congenital hydronephrosis: Correlation of fetal ultrasonographic ﬁndings with infant outcome. Am J Obstet Gynecol 1991; 165:384. 6. Campbell S, Wladimiroff JW, Dewhurst CJ. The antenatal measurement of fetal urine production. J Obstet Gynecol Br Commonw 1973; 80:680. 7. Rabinowitz R, Peters MT, Vyas S et al. Measurement of fetal urine production in normal pregnancy by real-time ultrasonography. Am J Obstet Gynecol 1989; 161:1264. 8. Glick PI, Harrison MR, Golbus MS et al. Management of the fetus with congenital hydronephrosis. II: Prognostic criteria and selection for treatment. J Pediatr Surg 1985; 20:376. 9. Cendron M, Elder JS. Perinatal urology. In: Gillenwater JY, Howards SS, Grayhack JT et al., editors. Adult and Pediatric Urology, 4th edn. St. Louis: Mosby Year Book. 10. Jeanty P, Dramaix-Wilmet M, Elkhazen N et al. Measurement of fetal kidney growth on ultrasound. Radiology 1982; 144:159. 11. Birnholz JC. Determination of fetal sex. N Engl J Med 1983; 309:942. 12. Fugelseth D, Lindemann R, Sande HA et al. Prenatal diagnosis of urinary tract anomalies: The value of two ultrasound examinations. Acta Obstet Gynec Scand 1994; 73:290.

References 807 13. Cendron M, D’Alton ME, Crombleholme M. Prenatal diagnosis and management of the fetus with hydronephrosis. Semin Perinatol 1994; 18:2047. 14. Mandell J, Blyth B, Peters CA et al. The natural history of structural genitourinary defects detected in utero. Radiology 1991; 178:194. 15. Noe NH, Magill HL. Progression of mild ureteropelvic junction obstruction in infancy. Urology 1987; 30:348. 16. Reznick VM, Kaplan GW, Murphy G et al. Follow-up of infants with bilateral renal disease detected in utero. Am J Dis Child 1988; 142:453. 17. Morin L, Cendron M, Crombleholme TM et al. Minimal hydronephrosis in the fetus: clinical signiﬁcance and implications for management. J Urol 1996; 155:2047. 18. Flashner SC, Mesrobian HG, Flatt JA et al. Nonobstructive dilatation of upper urinary tract may later convert to obstruction. Urology 1993; 42:569. 19. Reuss A, Wladimiroff JW, Steward PA et al. Noninvasive management of fetal obstructive uropathy. Lancet 1988; ii:949. 20. Corteville JE, Gray DL, Langer JC. Bowel abnormalities in the fetus – correlation of prenatal ultrasonographic ﬁndings with outcome. Am J Obstet Gynecol 1996; 175:724. 21. Parkhouse HR, Barratt TM, Dillon MJ et al. Long-term outcome of boys with posterior urethral valves. Br J Urol 1988; 62:59. 22. Smith GHH, Canning DA, Schulman SL et al. The long-term outcome of posterior urethral valves treated with primary valve ablation and observation. J Urol 1996; 155:1730. 23. Noh PH, Cooper CS, Winkler AC et al. Prognostic factors for long-term renal function in boys with the prune belly syndrome. J Urol 1999; 162:1399. 24. Elder JS, Duckett JW, Snyder HM. Intervention for fetal obstructive uropathy: has it been effective? Lancet 1987; ii:1007. 25. Cromblehome TM, Harrison MR, Langer JC et al. Early experience with open fetal surgery for congenital hydronephrosis. J Pediatr Surg 1988; 23:1114. 26. Quintero RA, Johnson MP, Romero R et al. In utero percutaneous cystoscopy in the management of fetal lower obstructive uropathy. Lancet 1995; 346:537. 27. Freedman AL, Bukowski TP, Smith CA et al. Fetal therapy for obstructive uropathy: Speciﬁc outcomes diagnosis. J Urol 1996; 156:720. 28. Lipitz S, Ryan G, Samuell C et al. Fetal urine analysis for the assessment of renal function in obstructive uropathy. Am J Obstet Gynecol 1993; 168:174. 29. Adzick NS, Harrison MR. Fetal surgical therapy. Lancet 1994; 343:897. 30. McLorie G, Farhat W, Khoury A et al. Outcome analysis of vesicoamniotic shunting in a comprehensive population. J Urol 2001; 166:1036. 31. Elder JS. Antenatal surgical intervention for urinary obstruction: a critical analysis. In: Smith AD, editor. Smith’s Textbook of Endourology. St Louis: Quality Medical Publishing, 1996:1464.

32. Dejter SW Jr, Gibbons MD. The fate of infant kidneys with fetal hydronephrosis but initially normal postnatal sonography. J Urol 1989; 142:661. 33. Maizels M, Reisman M, Flom LS et al. Grading nephroureteral dilatation detected in the ﬁrst year of life: correlation with obstruction. J Urol 1992; 148:609. 34. Maizels M, Mitchell B, Kass E et al. Outcome of nonspeciﬁc hydronephrosis in the infant: a report from the registry of the Society for Fetal Urology. J Urol 1994; 152:2324. 35. Tibballs JM, De Bruyn R. Primary vesicoureteral reﬂux: how useful is postnatal ultrasound? Arch Dis Child 1996; 75:444. 36. Elder JS. Antenatal hydronephrosis: Fetal and neonatal management. Ped Clin North Am 1997; 44:1299. 37. Society for Fetal Urology and Pediatric Nuclear Medicine Council. The ‘well tempered’ diuretic renogram: a standard method to examine the asymptomatic neonate with hydronephrosis or hydroureteronephrosis. J Nucl Med 1992; 33:2047. 38. Elder JS, Stansbrey R, Dahms BB et al. Renal histologic changes secondary to ureteropelvic junction obstruction. J Urol 1995; 154:719. 39. Perez LM, Friedman RM, King LR. The case for relief of ureteropelvic junction obstruction in neonates and young children at time of diagnosis. Urology 1991; 28:195. 40. Cartwright PC, Duckett JW, Keating MA et al. Managing apparent ureteropelvic junction obstruction in the newborn. J Urol 1992; 148:1224. 41. Takla NV, Hamilton BD, Cartwright PC et al. Apparent unilateral ureteropelvic junction obstruction in the newborn: expectations for resolution. J Urol 1998; 160:2175. 42. Ulman I, Jayanthi VR, Koff SA. The long-term follow-up of newborns with severe unilateral hydronephrosis initially treated nonoperatively. J Urol 2000; 164:1101. 43. Palmer LS, Maizels M, Cartwright PC et al. Surgery versus observation for managing obstructive grade 3 to 4 unilateral hydronephrosis: a report from the Society for Fetal Urology. J Urol 1998; 159:222. 44. Felson B, Cussen IJ. The hydronephrotic type of unilateral congenital multicystic disease of the kidney. Semin Roentgenol 1975; 10:113. 45. Selzman AA, Elder JS. Vesicoureteral reﬂux in children with a multicystic kidney. J Urol 1995; 153:1252. 46. Wacksman J, Phipps L. Report of the multicystic kidney registry: preliminary ﬁndings. J Urol 1993; 150:1870. 47. John U, Rudnik-Schoneborn S, Zerres K et al. Kidney growth and renal function in unilateral multicystic dysplastic kidney disease. Pediatr Nephrol 1998; 12:567. 48. Gordon AC, Thomas DFM, Arthur RJ et al. Multicystic dysplastic kidney: is nephrectomy still appropriate? J Urol 140:1231. 49. Snodgrass WT. Hypertension associated with multicystic dysplastic kidney in children. J Urol 2000; 164:472. 50. de Oliveira-Filho AG, Carvalho MH, Sbragia-Neto L et al. Wilms’ tumor in a prenatally diagnosed multicystic kidney. J Urol 1997; 158:1926.

808 Management of antenatally detected hydronephrosis 51. Oddone M, Marino C, Sergi C et al. Wilms tumor arising in a multicystic kidney. Pediatr Radiol 1994; 24:236. 52. Mingin GC, Gilhooly P, Sadeghi-Nejad H. Transitional cell carcinoma in a multicystic dysplastic kidney. J Urol 2000; 163:544. 53. Rackley R, Angermeier KW, Levin H et al. Renal cell carcinoma arising in a regressed multicystic dysplastic kidney. J Urol 1994; 152:1543. 54. Elder JS, Hladky D, Selzman AA. Outpatient nephrectomy for non-functioning kidneys. J Urol 1995; 154:712. 55. Cooper CS, Passerini-Glazel G, Hutcheson JC et al. Longterm followup of endoscopic incision of ureteroceles: intravesical versus extravesical. J Urol 2000; 164:1097. 56. Horowitz M, Shah SM, Ferzli G et al. Laparoscopic partial upper pole nephrectomy in infants and children. BJU Int 2001; 87:514. 57. Baskin LS, Zderic SA, Snyder HM et al. Primary dilated megaureter: long-term follow-up. J Urol 1994; 152:618. 58. Rickwood AMK, Jee LD, Williams MPL et al. Natural history of obstructed and pseudo-obstructed megaureters detected by prenatal ultrasonography. Br J Urol 1992; 70:322. 59. Liu HYA, Dhillon HK, Yeung CK et al. Clinical outcome and management of prenatally diagnosed primary megaureters. J Urol 1994; 152:614. 60. Hendren WH. Operative repair of megaureter in children. J Urol 1969; 101:491. 61. Peters CA, Mandell J, Lebowitz RL et al. Congenital obstructed megaureters in early infancy. J Urol 1989; 142:641. 62. Greenﬁeld SP, Griswold JJ, Wan J. Ureteral reimplantation in infants. J Urol 1994; 150:1460. 63. Hutton KAR, Thomas DFM, Davies BW. Prenatally detected posterior urethral valves: quantitative assessment of second trimester scans and prediction of outcome. J Urol 1997; 158:1022. 64. Hulbert WC, Rosenberg HK, Cartwright PC et al. The

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predictive value of ultrasonography in evaluation of infants with posterior urethral valves. J Urol 1992; 148:122. Duckett JW. Are ‘valve bladders’ iatrogenic? Br J Urol 1997; 79:271. Shapiro E, Elder JS. Complications of surgery for posterior urethral valves. In: Taneja SS, Smith RB, Ehrlich RM, editors. Complications of Urologic Surgery: Prevention and Management. Philadelphia: WB Saunders, 2001:563. Ghali AM, el Malki T, Sheir KZ et al. Posterior urethral valves with persistent high serum creatinine: the value of percutaneous nephrostomy. J Urol 2000; 164:1340. Liard A, Seguier-Lipszyc E, Mitrofanoff P. Temporary high diversion for posterior urethral valves. J Urol 2000; 164:145. Denes ED, Barthold JS, Gonzalez R. Early prognostic value of serum creatinine levels in children with posterior urethral valves. J Urol 1997; 157:1441. Sillen U, Hellstrom AL, Hermanson G et al. Comparison of urodynamic and free voiding pattern in infants with dilating reﬂux. J Urol 1999; 161:1928. Polito C, La Manna A, Rambaldi PF et al. High incidence of a generally small kidney and primary vesicoureteral reﬂux. J Urol 2000; 164:479. Farhat W, McLorie G, Geary D et al. The natural history of neonatal vesicoureteral reﬂux associated with antenatal hydronephrosis. J Urol 2000; 164:1057. Herndon CDA, McKenna PH, Kolon TF et al. A multicenter outcomes analysis of patients with neonatal reﬂux presenting with prenatal hydronephrosis. J Urol 1999; 162:1203. Liu C, Chin T, Wei C. Surgical treatment of vesicoureteral reﬂux in infants under 3 months of age. J Pediatr Surg 1998; 33:1716. Upadhyay J, Shekarrriz B, Fleming P et al. Ureteral reimplantation in infancy: evaluation of long-term voiding function. J Urol 1999; 162:1209.

86 Multicystic dysplastic kidney DAVID F. M. THOMAS AND AZAD S. NAJMALDIN

INTRODUCTION Before the introduction of routine antenatal ultrasound scan, multicystic dysplastic kidney (MDK) was regarded as an uncommon anomaly which generally presented as an abdominal mass in the newborn period. Nephrectomy was the standard form of management. However, it is now clear that the prevalence of asymptomatic unilateral multicystic kidneys in the general population is far higher than was previously suspected, with one recent study indicating a ﬁgure of 1:2500–3000 live births. The majority of MDKs are small, clinically undetectable and would have remained undetected in the neonatal period if they had not been identiﬁed prenatally on the maternal ultrasound scan. Opinion remains divided on the rationale for removing asymptomatic, prenatally detected MDKs. The arguments center principally on the perceived magnitude of the risks of hypertension and malignant change in later life.

86.1). Other causes of a renal mass in the neonatal period, such as mesoblastic nephroma or infantile polycystic kidney, can readily be excluded from the differential diagnosis. The principal diagnostic difﬁculty arises in making the distinction between a multicystic dysplastic kidney and gross hydronephroses due to pelvi-ureteric junction obstruction. The initial ultrasound examination should also include careful visualization of the bladder, ureters and contralateral kidney to exclude dilatation associated with vesico-ureteric reﬂux, contralateral pelvi-ureteric obstruction or some other urological abnormality.

Isotope imaging The main aim of isotope scanning lies in distinguishing between a multicystic dysplastic kidney and a grossly hydronephrotic kidney. Multicystic kidneys are characteristically nonfunctioning, with zero differential isotope uptake. In contrast, even grossly hydronephrotic kidneys

PRESENTATION Patterns of presentation include: 1 Prenatal ultrasound scan detection (the majority). 2 Clinical presentation. Large multicystic kidneys generally present as a ﬁrm abdominal mass which is evident at delivery or early in the neonatal period. Classically the surface of a multicystic kidney is irregular and ‘knobbly’ on palpation – unlike the smooth surface of a hydronephrotic kidney. 3 Incidental ﬁnding during the investigation of some unrelated illness. 4 Symptomatic complications (very rare).

INVESTIGATIONS Ultrasound The ultrasonographic characteristics of the MDK are now well deﬁned in the radiological literature1,2 (Fig.

Figure 86.1 Typical ultrasonographic appearance of neonatal multicystic dysplastic kidney, i.e. noncommunicating cysts of varying size, demonstrable septa between cysts, no visible rim or cortical tissue

810 Multicystic dysplastic kidney

are usually capable of some isotope uptake, corresponding to a small percentage differential function. However, this distinction is not absolute. For example, hydronephrotic kidneys may occasionally demonstrate total absence of function whilst rare variants of multicystic kidney may retain a demonstrable level of isotope uptake.3 In such situations there may be no alternative to nephrectomy to establish a precise diagnosis. Static imaging with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) is the most reliable modality for demonstrating low levels of function (Fig. 86.2a,b). Technetium-99m mercapto acetyl triglycine (99mTcMAG3) is a suitable alternative and may be preferable if there is any suggestion of contralateral pelvi-ureteric junction obstruction (which is present in 5–10% of cases). Ideally, imaging should be deferred until after the fourth week of life. The indications for further investigation will depend on the ﬁndings of the ultrasound and isotope scans, and the following may be required.

Other investigations VOIDING CYSTOURETHROGRAM

(a)

The role of voiding cystourethrography (VCU) as a routine investigation remains controversial. A 15–30% incidence of coexisting contralateral or ipsilateral vesicoureteric reﬂux (VUR) has been reported from centers that routinely investigate infants with prenatally detected MDK by VCU.4 However, such VUR is generally low grade, self-limiting and rarely of clinical signiﬁcance. A VCU is certainly advisable if postnatal ultrasonography reveals upper tract dilatation. But if the ultrasonographic appearances of the urinary tract are otherwise normal it may be reasonable to omit the VCU. If the decision is taken to omit the VCU, parents and primary care physicians should, nevertheless, be aware that normal ultrasonographic appearances do not exclude the presence of low-grade reﬂux and the consequent risk of urinary infection.

INTRAVENOUS UROGRAPHY This investigation is now seldom used for the routine evaluation of infants with MDK. However, for surgeons who do not have access to reliable nuclear medine facilities, it may still play a role in the assessment of coexisting upper tract anomalies. In addition, for medicolegal reasons, a limited intravenous urography (IVU) may be a prudent precaution to ascertain the side of the functioning kidney with certainty before embarking on nephrectomy.

INDICATIONS FOR SURGERY The following are widely accepted as deﬁnite indications for nephrectomy:

(b) Figure 86.2 (a) 99mTc-DMSA scan demonstrating normal isotope uptake and renal morphology on the left, and no uptake or isotope in the right (multicystic) kidney. (b) A focus of poor but discernible uptake of 99mTc-DMSA in a grossly hydronephrotic right kidney. Ultrasound could not distinguish with certainty between gross hydronephrosis and multicystic kidney

1 Large multicystic kidney giving rise to an obvious, visible and readily palpable abdominal mass. In this situation there is usually considerable parental anxiety. In addition, there may be apparent discomfort or other symptoms attributable to the size of the mass.

Indications for surgery 811

2 Diagnostic uncertainty. Despite the combination of ultrasound and isotope imaging, it may occasionally be impossible to distinguish with certainty between a multicystic kidney and a poorly functioning hydronephrosis. As the latter are in communication with the lower urinary tract, there is a risk of urinary infection and pyonephrosis. The presence of demonstrable function in an otherwise typical multicystic kidney or an obvious mass should also be regarded as a valid indication for nephrectomy. Isotope function equates with perfusion and it can be reasonably argued that perfused tissue imparts a greater risk of renal hypertension. Surgical opinion remains divided on the indications for the ‘prophylactic’ nephrectomy – the surgical removal of small, asymptomatic prenatally detected MDKs. Indeed, the two authors of this chapter adopt differing approaches to management. A comprehensive literature review is beyond the scope of this chapter but the arguments raised by the published evidence on the risks of hypertension and malignancy can be brieﬂy summarized as follows:

tumor attributed to MDK in children and ﬁve cases of renal cell carcinoma and one of mesothelioma in adults aged 15–68 years. At least three further cases have been reported subsequently. As with hypertension there may also be a degree of under-reporting of cases of malignant transformation. But, as with hypertension, the scale of risk can also be assessed from a different perspective by asking, ‘how frequently does MDK ﬁgure in published series of Wilms tumor?’ In the United States, Beckwith11 analyzed data relating to 7500 Wilms tumors reported to the National Wilms Tumour Study Pathology Centre over 18 years. During that period, ﬁve Wilms tumors arose in MDKs. On the basis of the NWTS data, Beckwith calculated that MDK carries an individual lifetime risk of Wilms tumor of 1:2000. (As Wilms tumor is a largely treatable malignancy this translates into corresponding lifetime risk of death of the order 1:15 000–20 000.) It is possible that this calculation may over state the risk as it is based on an outdated ﬁgure for the prevalence of MDK in the general population.

Conclusion Hypertension A 30-year literature review published by Manzoni and Caldamone in 19985 uncovered 24 cases of hypertension linked to MDK, of which at least 13 were reported to have responded to nephrectomy, thus implicating the MDK as the cause of hypertension. Closer analysis of three of these cases (comprising one of the published reports)6 reveals, however, that the diagnosis of MDK was clearly incorrect in one case and the diagnosis of hypertension was of questionable validity in the remaining two cases.7 From the number of published cases it would appear that the risk of hypertension is low in relation to the true prevalence of MDK, however, it must also be acknowledged that the literature may understate the true extent of the risk. Do the published cases simply represent the tip of the iceberg? Some degree of under-reporting almost certainly occurs. Nevertheless, if hypertension were occurring on any appreciable scale it would feature prominently as a course of renal hypertension in later childhood. This is not the case. In a series of 454 children with renal hypertension treated at Great Ormond Street Childrens Hospital London, Deal and associates (JE Deal, personal communication, 1997) did not encounter a single MDK.8 Similarly published series from Boston and Glasgow totalling 64 children undergoing nephrectomy for ‘surgical’ forms of renal hypertension did not include a single MDK.9,10

Malignancy In the same 30-year literature review, Manzoni and Caldamone5 identiﬁed ﬁve published cases of Wilms

Long-term prospective studies are needed to document the natural history of conservatively managed MDK and to establish the true scale of the risks of hypertension and malignancy. Until then surgeons will continue to differ in their interpretation of the available evidence and their perception of the magnitude of risk. In particular they are likely to arrive at different conclusions when balancing the cost of follow-up and the risk of complications against the morbidity of surgery and general anesthesia. In reality, the order of risk on both sides of the equation is likely to be very low. Parents, too, differ in their attitudes to conservative management versus ‘prophylactic’ nephrectomy. At a time when parents are increasingly well informed perhaps the role of the surgeon in the management of asymptomatic, prenatally detected MDKs is to summarize the conﬂicting evidence as objectively as possible and then be guided largely by the parents’ decision. The need for lifelong annual monitoring of blood pressure applies equally to individuals managed conservatively and those who have undergone nephrectomy in view of the emerging evidence which points to an increased long-term risk of hypertension associated with a solitary kidney.

Timing of surgery Large multicystic kidneys associated with a sizeable mass should be removed electively in the ﬁrst few weeks of life. Smaller lesions for which surgery is nevertheless thought to be appropriate can safely be left until 6–12 months of age or later.

812 Multicystic dysplastic kidney

SURGICAL OPTIONS Nephrectomy can be performed as a conventional open procedure or laparoscopically, depending upon such factors as the surgeon’s expertise in minimally invasive surgery, availability of suitable paediatric instrumentation and the preference of the parents.

Open nephrectomy Dorsal or posterior lumbotomy has the advantage of simplicity, good cosmesis, reduced postoperative pain and shortened hospital stay. The major drawback is the more limited exposure of the kidney offered by this incision and difﬁculty in extending it if the surgeon is faced with an unforeseen problem. With the small MDK, the dorsal lumbotomy incision is ideal and even for larger lesions nephrectomy should not pose problems, provided that the bulk of the multicystic kidney is reduced by cyst aspiration. Dorsal lumbotomy would now be the favored approach to the MDK in many pediatric urological centers. For an account of operative technique and an assessment of the place of the dorsal lumbotomy in pediatric renal surgery, readers are referred to the articles of Orland et al.12 and Wise and Snow.13 Pediatric surgeons may prefer the more familiar loin approach, described in detail below.

OPERATIVE DETAILS

should be taken to base the incision on the twelfth rib (Fig. 86.4a), as an inadvertent supra-eleventh rib incision often results in the pleura being breached. Once the skin and subcutaneous fat have been incised, cutting diathermy is used to deepen the incision to the tip of the twelfth rib. The muscles attached to the superior border of the twelfth rib (latissimus dorsi, intercostal muscles) are divided along their insertion. The rib, thus mobilized, is deﬂected caudally to allow the surgeon to insert a ﬁnger which can be advanced anteriorly in the line of the rib to sweep the peritoneum medially and anteriorly from the overlying abdominal wall muscles (Fig. 86.4b). The incision can then be extended forwards in the line of the rib using the diathermy to divide the external oblique, internal oblique, and transversus abdominis muscles. Care is needed to avoid damaging the neurovascular bundles, as this can result in an obvious (but usually reversible) postoperative weakness of the relevant segmental abdominal musculature. When the incision has been completed, a self-retaining retractor can be inserted. A bent or ‘offset’ ring retractor is suitable for this purpose, but a conventional ﬂat ring is not usually effective as it does not correspond to the marked curvature of the loin. Mobilization of the kidney Small multicystic kidneys (particularly in older infants) are sometimes difﬁcult to locate in the retroperitoneum. In this situation it is best to dissect through the retroperitoneal and perirenal fat, maintaining proximity to the posterior abdominal wall until the multicystic kidney is identiﬁed. In the usual situation, however, a large or

Position of the patient A full lateral position is employed (Fig. 86.3). Lateral ﬂexion of the spine is best achieved in this age group by the use of a sandbag under the contralateral loin rather than by a bridge or ‘break’ in the table. Once the required position and the degree of inclination has been achieved, adhesive strapping is used to maintain this position. The strapping is ﬁxed ﬁrst to one side of the operating table, is taken across the abdomen at the level of the iliac crests and then is secured ﬁrmly on the other side of the table. The incision The twelfth rib is identiﬁed by palpation. A preoperative plain X-ray (or the control ﬁlm of an IVU series) is helpful in determining the length of the twelfth rib. A supratwelfth rib incision of modest length nevertheless affords good access for nephrectomy if the procedure is combined with intraoperative cyst aspiration. Care

Figure 86.3 Lateral position of the patient

Figure. 86.4 (a,b) The incision

Surgical options 813

moderate-sized multicystic kidney is encountered without difﬁculty in the renal fossa. A combination of blunt and scissor dissection is commenced to develop a plane between the most superﬁcial cysts and adjacent tissues (Fig. 86.5). It should be noted that the peritoneum is usually applied to an extensive area of the anteromedial aspect of a large multicystic kidney. The part of the dissection which is intended to identify and develop a plane around the multicystic kidney is best achieved with the cysts intact. Aspiration of cysts Once a portion of the kidney has been exposed and mobilized in this fashion, it is helpful to aspirate the visible cysts with a syringe and needle (Fig. 86.6). The decompressed cyst wall can then be grasped, e.g. with Allis tissue forceps, so that gentle traction can be applied to deliver the kidney out of the incision. By sequence of

dissection around the intact cysts followed by aspiration and mobilization through the incision, it is possible to remove a multicystic kidney through a smaller incision than would have been required if the cysts were left intact. Dissection of hilum As the dissection is deepened, a malleable copper retractor is inserted to retract the peritoneum and to expose the ureter and hilar vessels in the depth of the incision. A vascular sling or tape is placed around the ureter and gentle traction is applied to facilitate the ﬁnal dissection of the hilum (Fig. 86.7). The ureter is then ligated with 3-0 absorbable suture and divided. While it is accepted practice to ligate the renal arteries and veins individually (to prevent the risk of arteriovenous ﬁstula formation), this may prove impossible with a multicystic kidney. The renal vessels are usually small and frequently nonpatent. Once identiﬁed, the vessels are ligated in continuity with 3-0 silk and the vessels then divided between ligatures. At this stage, mobilization of the decompressed multicystic kidney is usually complete and the kidney can then be removed following division of any remaining attached tissue. The renal bed is inspected carefully and further diathermy hemostasis is performed if required. Likewise the peritoneum is inspected and any defect closed with a continuous suture of 3-0 or 4-0 absorbable suture. Drainage of the renal fossa is not necessary. This incision is closed either in two layers using continuous 3-0 PDS or Vicryl, or alternatively by a series of interrupted mass sutures encompassing the rib. The skin is then closed with a subcuticular suture of 5-0 Vicryl.

Figure 86.5 Mobilization of the kidney

Figure 86.6 Aspiration of cysts

Figure 86.7 Dissection of the hilum

814 Multicystic dysplastic kidney

Postoperative care Postoperative recovery is usually rapid. Feeding is reestablished within 24 hours and the child generally leaves hospital within 1–2 days.

M1 A2

An

Laparoscopic nephrectomy

T

Laparoscopic nephrectomy can be performed either transperitoneally14 or extraperitoneally,15 with the former being more widely practised.

M2

N S A1

EQUIPMENT AND INSTRUMENTS In addition to a set of instruments for open technique laparosocopy16 and laparotomy in case of emergency or conversion to open surgery, the following equipment and instruments are required: • Camera, light source, insufﬂator, and one or preferably two monitors with appropriate attachments. • Diathermy unit (monopolar and bipolar) with appropriate cables and hand probes. Ultrasonic scalpel/shears may be used as an alternative. • Three or four, 3.5–12 mm cannulae and trocars with appropriate converters. • A 30o or 45o, 5–10 mm, angled telescope (0o scope may be adequate). • An appropriate retractor may prove helpful. Often a simple instrument such as a grasper may be used as a retractor. • Two atraumatic, preferably insulated, relatively ﬁne curved or angled double action jaw grasping forceps (an additional forceps with ratchet can be useful). • One traumatic grasping forceps with ratchet to retrieve the specimen. • One insulated, curved, double action jaw scissors with appropriate diathermy lead. • Suction/irrigation apparatus and probe. • A single-load or multi-load automatic clip applicator and clips (alternatively suture ligatures may be used). • One long needle to compress cysts if necessary. • Balloon dissector may be required for extraperitoneal approach only.

PREPARATION AND POSITION OF THE PATIENT General anesthesia with endotracheal intubation and full muscle relaxation are essential. A small nasogastric tube and a urinary catheter only if the bladder is palpable, may improve access. The child is placed and strapped securely in the semilateral position with a sandbag/ towels under the contralateral loin/lower chest or a break in the table to allow lateral ﬂexion and the bowel to fall medially under gravity (Fig. 86.8).

(a) C B

B1 A

(b) Figure 86.8 Laparoscopic transperitoneal right nephrectomy for multi-cystic dysplastic disease. (a) Theater layout. Note how the patient is fully supported and strapped in a semilateral position. S=surgeon, A1/A2=assistants, N=scrubbed nurse, An=anesthetic apparatus, M1/M2=monitors, T=instrument trolley. (b) Position of cannulae. A=periumbilical or lateral abdominal wall site for the primary cannula, B=working cannula 1, B1=working cannula 2 in the lower abdominal skin crease which may be extended to retrieve the specimen if necessary, C=an accessory cannula for hand instruments and/or retractor if necessary

TECHNIQUE FOR TRANSPERITONEAL NEPHRECTOMY Theatre layout, position of the surgeons, and the placement of the cannulae are illustrated in Fig. 86.8. A pneumoperitoneum is created (CO2 ﬂow 0.5–1 L/min, pressure 8–10 mm mercury) through the primary cannula inserted using an open technique laparoscopy.16 The sites and sizes of two or three working ‘secondary’ cannulae are dependent on the size of the patient, the size of the instruments to be used, and the surgeons’ preference. Often, two, 3.5–5 mm, working cannulae in addition to the primary cannula provide adequate access to remove multi-cystic dysplastic kidneys. An opening (a few centimeters long) in the peritoneum, lateral to the upper border of the colon and directly over the lower part of the kidney allows adequate exposure.14 A true mobilization of the colon is not necessary in pediatric patients. The kidney is then mobilized by blunt and sharp dissection and traction on the cyst may facilitate exposure

References 815

(Fig. 86.9). The vessels, which are small and attenuated, are exposed usually close to the kidney and divided between two proximal and one distal clip or ligatures. Alternatively, bipolar diathermy or ultrasonic shears may be used to secure hemostasis. A non-atretic ureter is clipped or ligated and divided at a convenient level. If necessary, the size of the specimen can be reduced by needle aspiration. The specimen is then removed via the largest access cannula or the site of a cannula with or without 1–2 cm extension. A retrieval bag is usually not required. A change of telescope and/or instruments from one cannula to another may facilitate viewing and dissection during the procedure. Cannula sites greater than 4 mm are closed with absorbable sutures. The peritoneal opening is covered by the colon as the patient is returned to the supine position at the end of the procedure thus leaving very little, if any, raw surface that might promote adhesion formation.

POSTOPERATIVE CARE At the end of the procedure the nasogastric tube and/or urinary catheter are removed. Local inﬁltration of the cannulae sites with an appropriate anesthetic agent with or without a single-shot epidural or opiate analgesia provide adequate pain relief. The patient is usually ready to go home within 8–24 hours.

APPROACH FOR RETROPERITONEAL NEPHRECTOMY This technique provides access and avoids the morbidity that may be associated with traversing the peritoneal cavity. However, its major drawback is the more limited exposure of the kidney offered by this approach and difﬁculty in extending the operative space if the surgeon

B1

A B

Figure 86.9 Laparoscopic transperitoneal nephrectomy. A=Five- or 10-mm angled or 0o telescope. B and B1=Two working grasping forceps. Note how a few centimeter-long high para-colic peritoneal incision directly over the cystic kidney without colon mobilization allows full mobilization of the specimen and hemostasis

is faced with complications. Other disadvantages include peritoneal tear and extension pneumoperitoneum that makes extraperitoneal surgery difﬁcult to achieve, and avulsion of small retroperitoneal vessels that causes minor bleed sufﬁcient to reduce laparoscopic viewing. Extraperitoneal nephrectomy may be performed effectively within a space created by breaking up the connective tissue binding the extraperitoneal space with either direct CO2 insufﬂation or a balloon dissector.15,17 Follow-up is determined by the nature of any coexistent abnormalities. In an otherwise normal child who has undergone nephrectomy for a multicystic kidney, follow-up consists of precautionary ultrasound scans of the solitary remaining kidney. For reasons outlined above, lifelong annual blood pressure measurement may also be advisable for any individual with a solitary kidney.

REFERENCES 1. Sanders RC, Hartman DS. The sonographic distinction between neonatal multicystic kidney and hydronephrosis. Radiology 1984; 151:621–5. 2. Stuck KJ, Koff SA, Silver TM. Ultrasonographic features of multicystic dysplastic kidney: expanded diagnostic criteria. Radiology 1982; 143:217–21. 3. O’Casey P, Howards SS. Multicystic dysplastic kidneys and diagnostic confusion on renal scan. J Urol 1988; 139:83–4. 4. Thomas DFM, Fitzpatrick MM. Cystic renal disease in childhood. In: Thomas DFM, editor. Urological Disease of the Fetus and Infant. Oxford: Butterworth Heinemann, 1997:237–49. 5. Manzoni GM, Caldamone AA. Multicystic kidney. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER, editors. Paediatric Surgery and Urology: Long-term Outcome. London: WB Saunders, 1998:632–41. 6 . Webb NJA, Lewis MA, Bruce J, Gouch DCS et al. Unilateral multicystic dysplastic kidney: the case for nephrectomy. Arch Dis Child 1997; 76:31–4. 7. Thomas DFM, Fitzpatrick MM. Unilateral multicystic dysplastic kidney [letter]. Arch Dis Child 1997; 77:368. 8. Deal JE, Sever PS, Barratt TM, Dillon MJ. Phaeochromocytoma – investigation and management of 20 cases. Arch Dis Child 1990; 65:269–74. 9. Hendren WH, Kim SH, Herrin JT, Crawford JD. Surgically correctable hypertension of renal origin in childhood. Am J Surg 1982; 143:432–41. 10. Taylor RG, Azmy AF, Young DG. Long-term follow-up of surgical renal hypertension. J Pediatr Surg 1987; 22:228–30. 11. Beckwith JB. Wilms tumor and multicystic kidney disease [editorial comment]. J Urol 1997; 158:2258–9. 12. Orland SN, Synder HM, Duckett JW. The dorsal lumbotomy incision in pediatric urological surgery. J Urol 1987; 138:963–6.

816 Multicystic dysplastic kidney 13. Wise WR, Snow BW. The versatility of the posterior lumbotomy approach in infants. J Urol 1989; 141:1148–50. 14. Najmaldin AS. Transperitoneal laparoscopic nephrectomy. In: Bax NMA, Georgeson KE, Najmaldin A, Valla JS, editors. Endoscopic Surgery in Children. Berlin: Springer-Verlag, 1999:371–8. 15. Valla JS. Video surgery of the retroperitoneal space in

children. In: Bax NMA, Georgeson KE, Najmaldin A, Valla JS, editors. Endoscopic Surgery in Children. Berlin: Springer-Verlag, 1999:379–92. 16. Humphrey GME, Najmaldin A. Modiﬁcation of the Hasson technique in paediatric laparoscopy. Br J Surg 1994; 81:1320–3. 17. Najmaldin A, Guillou P, editors. A Guide to Laparoscopic Surgery. London: Blackwell Sciences, 1998:56–9.

87 Upper urinary tract obstructions PREM PURI AND BORIS CHERTIN

INTRODUCTION With the widespread use of maternal ultrasound, the incidence of hydronephrosis has increased, signiﬁcantly altering the practice of urology. Pelvi-ureteric junction (PUJ) obstruction is the most common cause of hydronephrosis detected antenatally.1,2 Next most common cause of prenatally detected hydronephrosis is obstruction at the uretero-vesical junction (UVJ).1 Management of these patients after birth remains controversial. The decision to intervene surgically in these infants has become more complex because spontaneous resolution of antenatal and neonatal upper urinary tract dilatations is being increasingly recognized.1,3–5 The recognition and relief of signiﬁcant obstruction is important to prevent irreversible damage to the kidneys.6 Differentiating urinary tract dilatations that are signiﬁcantly obstructive and require surgery from those that represent mere anatomical variants with no implications for renal function is not a simple task, especially in the newborn. Recently, interest has developed using the function in involved kidney as a measure of degree of obstruction.3,4

PELVI-URETERIC JUNCTION OBSTRUCTION The overall incidence of PUJ obstruction approximates one in 1500 births. The ratio of males to females is 2 : 1 in the neonatal period, with left-sided lesions occurring in 60%. In the newborn period, a unilateral process is most common, but bilateral PUJ obstruction was found in 10–49% of neonates in some reported series.7 PUJ obstruction is classiﬁed as intrinsic, extrinsic, or secondary. Intrinsic obstruction results from failure of transmission of the peristaltic waves across the PUJ with failure of urine to be propulsed from the renal pelvis into the ureter, which results in multiple ineffective peristaltic waves that eventually cause hydronephrosis by incompletely emptying the pelvic contents.8–10 Tainio et al. have

shown the abnormalities of peptidergic innervation with dense innervation of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) and proposed that these may have a role in intrinsic obstruction.11 Absence or reduction of smooth muscle with replacement by collagen ﬁbers has been demonstrated histologically.12,13 Extrinsic mechanical factors include aberrant renal vessels, bands, adventitial tissues and adhesions that cause angulation, kinking or compression of the PUJ. Extrinsic obstruction may occur alone but usually coexists with intrinsic uretero-pelvic junction (UPJ) pathology. Secondary PUJ obstruction may develop as a consequence of severe vesico-ureteric reﬂux (VUR) in which a tortuous ureter may kink proximately.7 Previous reports have described VUR in 9–15% of children who have PUJ obstruction, although the number that are secondary to reﬂux is difﬁcult to determine.7,14

Prenatal diagnosis The bladder is visualized by 14 weeks of gestation. The presence of full bladder provides evidence of renal function. The ureters are usually not seen in the absence of distal obstruction or reﬂux. The fetal kidney may be visualized at the same time as bladder. If not, they are always visualized by the 16th week of gestation. However, it is not until 20–24 weeks’ gestation, when the fetal kidney is surrounded by fat, that the internal renal structures appear distinct.15 Renal growth can then be assessed easily.16 Beyond 20 weeks, fetal urine production is the main source of amniotic ﬂuid. Therefore, major abnormalities of the urinary tract may result in oligohydramnios. Because of the distinct urine tissue interface, hydronephrosis can be detected as early as 16 weeks’ gestation. An obstructive anomaly is recognized by demonstrating dilated renal calyces and pelvis. A multitude of measurement and different gestational age cut-off points have been recommended in the assessment of fetal obstructive uropathy.17 Harrison et al.18 suggest that proportion of more than 1 : 2 of the pyelon width to the kidney width

818 Upper urinary tract obstructions

is pathological and may be diagnosed as fetal hydronephrosis. Grignon et al.19 graded the fetal hydronephrosis into ﬁve grades: Grade I, detectable renal pelvic dilatation; Grade II, dilatation greater than 1 cm; Grade III–IV, further degrees of pyelactesis with dilatation greater than 1.5 cms; Grade V, associated with atrophic cortex. Dilatation of the collecting system can occur in the absence of obstruction and is termed as physiological hydronephrosis. Recently, as a result of 10 large studies involving more than 46 000 screening patients, the standards regarding renal pelvic measurement have been summarized.17,20 These studies have utilized routine estimation of anteroposterior (AP) diameter of renal pelvis in fetus with hydronephrosis; AP renal pelvis threshold values ranged between 2.3 and 10 mm. Positive predictive values for pathological dilatation conﬁrmed in the neonate ranged between 2.3 and > 40% for AP renal measurements of 2–3 mm and 10 mm respectively. This study concluded that only fetuses exhibiting third-trimester AP renal pelvis dilatations > 10 mm would merit postnatal assessment.21 In case of severe prenatal bilateral hydronephrosis, severe hydroureteronephrosis or severe impairment of the solitary kidney, fetal bladder aspiration for urinary proteins and electrolytes is recommended in order to predict the renal injury secondary to obstructive uropathy.17 Fetal urinary sodium level less than 100 mmol/L, chloride level of less than 90 mmol/L and an osmolality of less than 210 mOsm/kg are considered as prognostic features for good renal function.22

Clinical presentation The clinical presentation of PUJ obstruction has dramatically changed since the advent of maternal ultrasonographic screening.23 Before the routine fetal ultrasonography, the commonest presentation was with abdominal ﬂank mass. Fifty percent of abdominal masses in newborns are of renal origin, with 40% being secondary to PUJ obstruction. Some patients present with urinary tract infection.24 Other clinical presentations include irritability, vomiting, and failure to thrive. Ten to 35% of PUJ obstructions are bilateral, and associated abnormalities of urinary tract are seen in about 30%.25 PUJ problems are often associated with other congenital anomalies, including imperforated anus, contralateral dysplastic kidney, congenital heart disease, VATER syndrome, and esophageal atresia. In patients with such an established diagnosis, a renal ultrasound examination should be performed.26 Although the majority of cases occur sporadically, familial cases have been reported. Hereditary pelvi-ureteric obstruction is an autosomal dominant trait with variable penetrance, and Izquierdo et al. proposed one of the loci as the short arm of chromosome 6.27 Recently, the importance of angiotensin II and its type 2 receptor (AT2) in the

development of congenital urinary tract abnormalities has begun to be appreciated.27–29 Nishimura et al. reported an association of a polymorphism of intron 1 of the AT2 gene (the A-1332G transition, which perturbed AT2 mRNA splicing) in patients with multicystic dysplastic kidneys and/or PUJ obstruction.30

Diagnosis With the increasing number of antenatally diagnosed hydronephroses, it is difﬁcult to interpret the underlying pathology and its signiﬁcance. Severe obstructive uropathies are detrimental to renal function. However, hydronephrosis without ureteral or lower tract anomaly is common. The important aspect of postnatal investigations is to identify the groups of patients who will beneﬁt from early intervention and those who need to be carefully followed up.

Ultrasound Follow-up ultrasound examination is necessary in the postnatal period in antenatally detected hydronephrosis. If bilateral hydronephrosis is diagnosed in utero in a male infant, postnatal evaluation should be carried out within 24 hours primarily because of the possibility of posterior urethral valves. If the ultrasound scan is negative in the ﬁrst 24–48 hours in any patient with unilateral or bilateral hydronephrosis, a repeat scan should be performed after 5–10 days, recognizing that neonatal oliguria may mask a moderately obstructive lesion. If hydronephrosis is conﬁrmed on the postnatal scan, further careful scan of the kidney, ureter, bladder, and in boys the posterior urethra, is essential. Ultrasonography depicts the dilated calyces as multiple intercommunicating cystic spaces of fairly uniform size that lead into a larger cystic structure at the hilum, representing the dilated renal pelvis (Fig. 87.1a). Peripheral to the dilated calyces, the renal parenchyma is usually thinned with the normal or increased echogeneicity. In order to standardize postnatal evolution of prenatal hydronephrosis, a grading system of postnatal hydronephrosis was implemented in 1993 by the Society for Fetal Urology (SFU). In the SFU system, the status of calices is paramount, while the size of the pelvis is less important. In SFU grading of hydronephrosis, there is no hydronephrosis in Grade 0. At Grade 1, the renal pelvis is only visualized. Grade 2 hydronephrosis is diagnosed when a few (but not all) renal calices are identiﬁed in addition to the renal pelvis. Grade 3 hydronephrosis requires that virtually all calices are depicted. Grade 4 hydronephrotic kidneys will exhibit similar caliceal status with the involved kidney exhibiting parenchymal thinning.31 Typically, the ureter is of normal caliber and is not seen.25 But if it dilated, the size of ureter is also assessed

Pelvi-ureteric junction obstruction 819

ultrasonographically and graded 1–3 according to ureteral width < 7 mm, 7–10 mm, > 10 mm respectively.31

Radionucleide scans Diuretic renograms using technetium-99m-DTPA (99mTc-DTPA) augmented with furesemide were useful in the diagnosis of urinary tract obstructions for a long time.32,33 DTPA is completely ﬁltered by the kidneys, a maximum concentration of 5% being reached in 5 minutes, falling to 2% at 15 minutes. Recently it has been reported that use of the tracers that rely on tubular extraction such as 123I-Hippuran and 99mTc-mercato acetyltriglyceride (MAG3) (Fig. 87.1b) may improve the diagnostic accuracy.33 The kidney of the young infant is immature; renal clearance, even when corrected for body surface, progressively increases until approximately 2 years of age. Therefore the renal uptake of tracer is

particularly low in infants, and there is a high background activity. Thus the traces such as 123I-Hippuran and 99mTc-MAG3 with a high extraction rate provide reasonable images, enabling estimation of the differential kidney function during the ﬁrst few weeks of life. It is also helpful in assessing the size, shape, location, and function of the kidney. Diuretic augmented renogram is a provocative test and is intended to demonstrate or exclude obstructive hydronephrosis by stressing an upper urinary tract with a high urine ﬂow. Obstruction usually is deﬁned as a failure of tracer washout after diuretic stimulation. If unequivocal, it eliminates the need for further investigations. In equivocal cases, F15 (in which furosemide is given 15 minutes before the test) provides a better assessment of the drainage of upper urinary tract.34 Forced hydration prior to scan increases predictive value of non-obstructed pattern up to 94%.35 As glomerular ﬁltration and glomerular blood ﬂow are still low in the newborn, the handling of isotype is unpredictable and can be misleading. Koff et al.,36 therefore, feel that the risk of making a misdiagnosis of obstruction in this age group far outweighs the potential damage to renal function that might result from delaying

(a)

(b)

(c)

Figure 87.1 (a) A coronal plane scan through the obstructed left kidney conﬁrms obstruction at the level of the pelvi-ureteric junction. (b) 99mTc-MAG3 scan in the above patient. Clearance curve for left kidney conﬁrming the high-grade obstruction on this side. (c) A 20-minute full-length ﬁlm from an IVU series showing left-sided high-grade pelvi-ureteric junction obstruction in the same patient

820 Upper urinary tract obstructions

surgery for a few weeks until the diagnosis can be made more accurately. Diagnosis of PUJ obstruction can be made by intravenous urography (Fig. 87.1c). This investigation, however, shows that a dilated renal pelvis with clubbed calyces is often not helpful as concentration of contrast is unreliable.25

Pressure-ﬂow study In the equivocal cases and in the presence of impaired function, the pressure-ﬂow study (Whitaker test) and antegrade pyelography may be necessary to conﬁrm or exclude obstruction.37 The Whitaker test is based on the hypothesis that if the dilated upper urinary tract can transport 10 ml/min without an inordinate increase in pressure, the hydrostatic pressure under physiological conditions should not cause impairment of renal function, and the degree of obstruction if present is insigniﬁcant. However, it is an invasive test and is seldom required. Antegrade pyelography may be performed with ultrasound guidance in patients where diagnosis is difﬁcult.38 Retrograde pyelography is seldom required to determine the status of ureters. The disadvantages include difﬁculty in ureteral catheterization in neonates, and that trauma and oedema may change partial obstruction to the complete one. In patients where diagnosis is equivocal, serial examinations may be necessary.

TREATMENT A considerable controversy exists regarding the management of newborn urinary tract obstructions. Some authors advocate early surgical intervention to prevent damage to maturing nephrons,39,40 while others feel that early surgery carries no speciﬁc beneﬁt.3,4 During late prenatal and early postnatal life, there is progressive increase in glomerular ﬁltration rate (GFR).4 Additionally, this transition is associated with an abrupt decline in urine output from what appears to be a quite high in utero output to a rather low early neonatal level of urine production. These physiological observations may explain the common observation of hydronephrosis detected antenatally, which on postnatal follow-up reverts to an unobstructed pattern.1,4 In 1990, Ransley et al. reported results of non-operative treatment in newborns with nonreﬂuxing hydronephrosis and differential renal function > 40%.3 At 6-year follow-up, only 23% needed surgical correction. The most common indication for surgery in this group of children was deterioration of renal function. Subsequently, Koff and Cambell reported that, out of 104 neonates with prenatally diagnosed unilateral hydronephrosis who have been followed conservatively, only 7% required pyeloplasty in long-term follow-up.4 Recently, the same group reported results of

initial conservative management of children with severe unilateral hydronephrosis due to PUJ obstruction.41 Only 22% of these children required pyeloplasty. All children who required surgery were younger than 18 months and had progressive hydronephrosis and/or reduction in renal function. Therefore immediate postnatal surgical intervention is unnecessary in the majority of newborn children with PUJ obstruction. These babies should be followed up with serial examinations to observe anatomical and functional improvement. Surgery is undertaken in infants with deteriorating renal function.3,4,41–43

Pyeloplasty Pathological variations in PUJ obstruction necessitate the surgeon to be conversant with the various techniques of the pyeloplasty. The objective of the pyeloplasty is to achieve dependent, adequate calibered watertight PUJ. There are different approaches for open pyeloplasty. The classical traditional approach is an extraperitoneal approach via lateral ﬂank incision. The infant is placed on the operating table in a supine position with the affected side elevated on a roll (Fig. 87.2a). Muscles are either cut or split (Fig. 87.2b–d). Gerota’s fascia is opened (Fig. 87.2e). Usually it is easy to ﬁnd the site of obstruction, but if there is a doubt, the site of obstruction is determined by distending the renal pelvis with normal saline. Intraoperatively, an appropriate size silicone tube is passed from the opened PUJ down the ureter to the bladder to check for distal obstruction. Recently the posterior lumbotomy has gained wide popularity.44 The use of muscle splitting rather than muscle cutting makes it almost a minimally invasive procedure. The location of the incision just under and parallel to the 12th rib has a cosmetic advantage. The bilateral procedure is possible if indicated under the same anesthesia without position changes. This approach should not be used in older or signiﬁcantly obese children. The various techniques of pyeloplasty are divided into dismembered and nondismembered pyeloplasty.

DISMEMBERED PYELOPLASTY Anderson-Hynes pyeloplasty: The renal pelvis, PUJ and proximal ureter are freed of perirenal fat. Three stay sutures are placed (1) at supero-medial aspect of the pelvis, (2) at inferolateral aspect of pelvis and (3) on the ureter about 5 mm below pelvi-ureteric junction. The ureter is divided obliquely above the ureteric stitch and the redundant pelvis trimmed (Fig. 87.3a). The superior two-thirds of the pelvis is closed by using continuous 6-0 Maxon stitch (Fig. 87.3b). An ovalshaped anastomosis between the ureter and lower part of the pelvis is carried out from posterior to anterior layer over a silastic stent using a 6-0 maxon continuous stitch

Treatment 821

Figure 87.2 (a) Position of the infant on operating table and line of skin incision. (b) Incision through skin and subcutaneous tissue. (c) Incision through external and internal oblique muscles. (d) Renal facia exposed. (e) The renal fascia has been opened

(Fig. 87.3c,d). A Cummin’s tube may be used. After the anastomosis is completed a radivac drain is placed. Gerota’s fascia is closed with interrupted 3-0 chromic catgut sutures. Muscles are approximated in layers and skin by using subcuticular 5-0 Dexon. Postoperatively, the patient is kept fasting for 24 hours for possible ileus. Antibiotics are given preoperatively and continued postoperatively. The drain is removed after 48 hours. The Cummin’s tube, if used, is removed after 7–10 days.

NONDISMEMBERED PYELOPLASTY The Y plasty (Foley) This is based on the principle of a Y–V ﬂap. This operation is suitable when the ureter inserts high on the pelvis. A V-shaped incision is made on the pelvis on the anterior and posterior surface. The tail of the incision is on the lateral surface of the ureter, well below the

obstruction. The ﬂap of the pelvis is brought down, and posterior and anterior anastomosis of the ﬂap and ureter performed using 6/0 maxon. The spiral ﬂap (Culp) This is suitable for long, dependent, stenotic ureteropelvic obstruction. The incision on the ureter must be adequate, covering the stenotic area. The ﬂap of equal length is based on a broad base (Fig. 87.4a). The posterior layer of ureter and ﬂap is sutured using 6-0 maxon (Fig. 87.4b). The anterior layer is crossed over the stent and anastomosed using 6-0 maxon (Fig. 87.4c). Endoscopic and laparoscopic techniques have gained some popularity in the surgical treatment of PUJ obstruction.

ENDOPYELOTOMY Endopyelotomy can be done utilizing either a percutaneous antegrade approach or endoscopic retrograde

822 Upper urinary tract obstructions

(a)

(b)

(a)

(b)

(d)

(c)

Figure 87.3 Anderson-Hynes pyeloplasty. (a) Vertical en bloc resection of the pelvis, pelvi-ureteric junction with oblique division of the ureter. (b) Superior part of the pelvis is closed and start of the posterior layer anastomosis between ureter and pelvis. (c) Posterior layer anastomosis completed and anterior layer anastomosis commenced over a stent. (d) An oval-shaped anastomosis completed between ureter and renal pelvis

(c)

Figure 87.4 The spiral ﬂap (Culp) pyeloplasty. (a) Spiral fashioning of the ﬂap. (b) The ﬂap brought down and the ﬁrst suture positions the rounded tip of the ﬂap distally to the ureter. (c) Anterior layer closed over a stent

LAPAROSCOPIC PYELOPLASTY 45

procedure. However, even experienced surgeons do not recommend this procedure in neonates, infants, or young children.26 Percutaneous endopyelotomy is performed by making an incision on the posterolateral wall using a smaller endoscope and using a 3F or 5F electrocautery probe and followed by separating the cut edges by using balloon. A ureteral stent is placed for drainage for 6 weeks and a nephrostomy tube for 3 days to 6 weeks. Kavausi et al.46 have shown this procedure is safe and effective also in treating secondary PUJ obstruction. Figenshau and Clayman used the retrograde technique for older children and a combined antegrade– retrograde approach for younger children.47 The incision in PUJ segment was done using an Accucise balloon with ﬂuoroscopic control. They concluded that the technique has an 86% success rate and should be offered to pediatric patients with PUJ obstruction. Balloon dilatation of PUJ has also been reported in infants and young children.26 This consists of dilatation of PUJ segment using a dilating balloon catheter (12–24 Fr), which is positioned, conﬁrmed, and inﬂated for 3 minutes under ﬂuoroscopic control. The success rate has been reported as 63%, with a follow-up to 23 months.

There are few reports of laparoscopic Anderson-Hynes dismembered pyeloplasty in infants and children.48 Recently, Yeung et al. reported the results of initial experience with retroperitoneal dismembered pyeloplasty in 13 infants and children.49 The authors concluded that laparoscopic Anderson-Hynes dismembered pyeloplasty is feasible and safe in infants, but the longterm results are awaited.

NEPHRECTOMY Because the recovery potential of the kidney is greater in neonates, extreme conservation is justiﬁed. Salvage pyeloplasty should be considered as renal function shown on renal scintigraphy can recover.50 At operation, an assessment should be made of the renal cortex after emptying the pelvis. Severe cystic dysplasia is an indication for nephrectomy, otherwise every effort be made to salvage the kidney.

Bilateral pelvi-ureteric obstruction Surgical correction of the symptomatic side or side with better function should take precedence. If a nephrectomy

Uretero-vesical junction obstruction 823

is considered on one side, the pyeloplasty should precede this. Postoperative complications include infection, adhesive obstruction (transperitoneal approach), temporary obstruction at the anastomosis resulting in excessive urine leakage, and failures due to postoperative stricture at anastomotic sites. An overall reoperation rate of 8.2% was reported in an early series.44 However, in the latest series, when temporally double-J stents were utilized, the reoperation rate was negligible.26 Follow-up ultrasound may be performed 3–6 months after operation when maximum improvement can be seen.51 Radionuclide scans are useful to monitor the post-pyeloplasty function and drainage. Pyeloplasty in the neonatal period when indicated gives excellent results.

MEGAURETER Megaureter is a ureter that is dilated out of proportion to the rest of the urinary tract and above the norms. Cussen52 and later Hellstrom et al.53 have established the normal measurement of the ureteral diameter in infants and children from 30 weeks of gestation to 12 years of age. Normal ureteral diameter in children is rarely greater than 5 mm, and ureters larger than 7 mm can be considered megaureters.

Classiﬁcation The Paediatric Urology Society in 197654 adopted a standard nomenclature for categorizing megaureters, which is useful guide for management. There are three types described: 1 Reﬂuxing ureter, which may be primary or secondary to distal obstruction or pathology 2 Obstructive, which may be primary and include intrinsic obstruction, or secondary due to distal obstruction or extrinsic causes 3 Nonreﬂuxing or non-obstructed, which may be primary-idiopathic type or secondary to diabetes insipidus or infection. In 1980, King subsequently modiﬁed this classiﬁcation by adding a fourth group comprising the reﬂuxing, obstructed megaureters.55

URETERO-VESICAL JUNCTION OBSTRUCTION The presence of an adynamic distal ureteral segment is the most common cause of primary obstructive megaureter. The presence of a narrowed terminal portion of ureter will not convey the peristaltic wave or dilate

enough to permit free passage of urine. This results in excess boluses of urine coalesce and causes ureteral dilatation. The contraction waves become smaller and are unable to coapt the walls of dilated ureters.10 This, along with infection, could damage the renal parenchyma. The proposed etiologies include: 1 Alteration in muscular orientation: Tanagho56,57 noted in fetal lamb that the muscle coats of the distal ureter develops last and that late arrest in the development results in absence of longitudinally oriented musculature that conducts the peristaltic wave. This results in hypertrophy of the circular ﬁbers causing obstruction. 2 Muscular hypoplasia with ﬁbrosis: McLoughlin et al.58 found that 69% of narrowed terminal ureteric segments showed muscular hypoplasia which were separated by ﬁbrotic sheets thus affecting the transmission of peristalsis. This ﬁbrotic ring prevents expansion and free urinary drainage. 3 Excessive collagen deposition resulting in a discontinuity of muscular coordination is another hypothesis.59 Lee et al. examined the histology of ureteric smooth muscle and collagen in obstructive employing computer-assisted color image analysis. They have found that the tissue matrix collagen ratios (collagen : smooth muscle) were signiﬁcantly higher in patients with megaureters compared to controls.60 4 Disturbance in the electric syncytium along with the nexus injury has been suggested to precede pathological innervation.61 Recently, Dixon showed dense non-adrenergic innervation in a smooth muscle collar surrounding the terminal ureter in cases of obstructed megaureter associated with ectopic ureteric insertion.62

Prenatal diagnosis Usually ureter is not seen in fetal scans. Visualization of dilated ureter to the level of vesico-ureteric junction without abnormal bladder may suggest obstruction or reﬂux. However, this may be a transient phenomenon. Fetal urine ﬂow is four to six times greater before birth than after and is due to differences in renal vascular resistance, glomerular ﬁltration, and concentrating ability. This high outﬂow contributes to ureteral dilatation. Another contributing factor is increased compliance of the fetal ureter.63

Clinical features The widespread use of maternal ultrasound has changed the age of presentation of congenital uropathies, including megaureter. Currently about half of the cases are asymptomatic and discovered on prenatal ultrasound.

824 Upper urinary tract obstructions

The commonest mode of clinical presentation is urinary tract infection.64,65 Microscopic hematuria is frequent and may occur in the absence of infection. This is presumably caused by the disruption of mucosal vessels of the ureter secondary to ureteric distension.66 Primary obstructive megaureter is more common in males than females, and the left ureter is more likely to be involved than the right. Seventeen to 34% of patients have bilateral megaureters. Contralateral renal agenesis is found in 10% of patients.64–69

the Whitaker test and antegrade pyelography may be required to establish the diagnosis. Recently, Fung et al. explored ureteral opening pressure as a novel parameter for evaluating pediatric ureterohydronephrosis.72 Renal pelvic pressure is assessed while simultaneously documenting the passage of contrast material from the distal ureter into the bladder. A pressure increase of 14 cmH2O within renal pelvis is consistent with distal ureter obstruction.

Management Diagnosis Antenatally diagnosed ureteral dilatation needs further evaluation to conﬁrm or exclude obstruction, reﬂux or both. Clinicians are confronted with the two basic problems in assessing the dilated ureter in a neonate.66,70 First, there is no diagnostic modality that allows the reliable differentiation between obstructive and nonobstructive urinary tract dilatations. Second, there is no study that can determine accurately the potential of the kidney to recover after relief of obstruction.

Ultrasound In antenatally detected cases, ultrasonography should be performed between 3 and 5 days after birth. If no dilatation is seen, repeat ultrasound should be performed after a few weeks, as neonatal oliguria can mask dilatation. If dilatation persists on a repeat ultrasound, further workup can be postponed for a few weeks unless bilateral disease or a serious abnormality such as obstruction in a solitary kidney or urethral valves is suspected.70 Such an approach allows for the expected changes of transitional renal function in the newborn period that might otherwise cause inaccuracies with many diagnostic studies. Ultrasonography classically shows hydroureter and variable hydronephrosis, with hyperperistalsis of a lower ureter that terminates shortly above the bladder in a narrow, adynamic segment71 (Fig. 87.5a). However, the narrow segment may not always be visualized, and therefore MCU is necessary to exclude VUR.

Renal scintigraphy Radionuclide scan is required to assess the urinary ﬂow and stasis along with determining the differential function and GFR. For the evaluation of neonatal hydronephrosis and hydroureter, 99mTc-DTPA diureteric scan (Fig. 87.5b) or 99mTc-MAG3 are the most frequently used. Intravenous urography may be necessary in equivocal cases to establish the diagnosis. It delineates the anatomy showing dilated, obstructed ureter (Fig. 87.5c). However, it is better to wait for a few weeks for renal maturation to allow concentration of contrast reliability. Occasionally,

It is being increasingly recognized that many antenatal and neonatal ureteral dilatations improve with time.5,65,66 Surgery is indicated in patients with progressive ureteral dilatation and deterioration in renal function.

Operation There are various techniques of reimplanting the ureter in a nonreﬂuxing manner after excision of an adynamic, narrow segment. The initial approach to the ureter can be either intravesical, extravesical or combined.73 The most commonly used techniques for intravesical approach are Cohen’s transtrigonal reimplantation and Politano–Leadbetter operation.

INTRAVESICAL APPROACH Position Patient is anesthetized and placed in a supine position (Fig. 87.6a). Incision A low transverse suprapubic skin crease incision is made (Fig. 87.6a). Exposure The skin ﬂaps are raised by diathermy dissection (Fig. 87.6b). The rectus sheath is cut and two recti are separated in the midline. Peritoneum is pushed upwards. The bladder is opened vertically between two stay sutures. Denis Brown retractor is placed over the gauze inside the bladder to improve exposure. The ureter openings are inspected. A 3- or 5-Fr infant feeding tube is passed into the ureter and a stay suture is placed around the tube. This facilitates the handling of the ureter during dissection. An incision is made circumferentially along the ureter opening and the distal ureter dissected from mucosa and trigonal muscle. The ureter is freed, keeping away from adventitia and mesentery to avoid damage to blood supply (Fig. 87.6c). Bladder opening is narrowed with interrupted Dexon sutures.

COHEN’S METHOD This method is simple and easier to perform and is an especially useful technique in infants in whom the

Uretero-vesical junction obstruction 825

(a) Max=6277.63

Left BKG SUB

100

Percentage

80 60 40 20 0 0.166 3.666

10.000

Rel clearance curve

17.333

25.000 5/ 1/90 11:49

(b)

(c)

Figure 87.5 (a) Longitudinal scan to the left of the midline through the bladder demonstrates dilatation of the left lower ureter to the level of the vesico-ureteric junction. Similar appearances were seen in the right side of this infant. (b) A 99mTc-DTPA scan. Clearance curve for left kidney demonstrating obstructive pattern. Similar appearances were seen on the right side. (c) A 30-minute full-length ﬁlm from intravenous urogram series showing bilateral hydronephrosis and hydroureter

bladder is small. An incision is made in the mucosa above and a little lateral to the opposite ureteric oriﬁce. A submucous tunnel is made by inserting the closed blades of scissors and making an opening and cutting movement. The ureter is threaded through the tunnel (Fig. 87.6d). The tunnel should be adequately wide for the ureter and two to three times the ureteric diameter in length to prevent reﬂux. The terminal narrow portion of the ureter is excised and sent for histology. If the ureter is very dilated, remodeling is necessary which may be performed by one of the following methods: 1 Non-excisional tapering technique has advantage of avoiding a suture line with potential urinary leakage. However, it is inappropriate for very dilated ureter as it reduces the diameter by only 50% and in neonates it can become too bulky for the tunnel. a. Folding (Kalikinski) where a 10–12 Fr catheter is placed into the ureter and a running mattress suture placed proximally and continued distally.

The lateral excluded segment is folded posteriorly and its edge ﬁxed to the medial wall with another running suture. b. Plication (Starr) of ureteral wall is achieved by multiple mattress suture in antimesenteric border. 2 Excisional tapering technique, where part of ureteral wall is excised by using knife and scissors or Hendren clamps. The remaining ureteral strip is tubularized by 5-0 catgut for mucosa and muscularis, and 5-0 Dexon for adventitia. The cuff of the ureter is then sutured in position. First a 4-0 Dexon suture is inserted laterally through the full thickness of the ureter and also through the full thickness of bladder muscle so as to prevent the ureter retracting. Next, bladder and ureteral mucosa are approximated using interrupted 5-0 Dexon. The stents are placed in the ureter (Fig. 87.6e). In bilateral reimplantation, the second ureter has its tunnel below and parallel to the ﬁrst ending in the oriﬁce of the opposite side (Fig. 87.6b).

826 Upper urinary tract obstructions

(a)

(b)

(c)

(d)

(e)

(f)

Figure 87.6 Reimplantation of the ureter. (a) Position of patient on the operating table and line of incision. (b) Skin ﬂaps being raised. (c) Opened bladder is retracted by Denis Browne retractor and the stented ureter is dissected free. (d) The tunnel is commenced just above and lateral to the opposite ureteric oriﬁce and continued to the original oriﬁce. The ureter is threaded through the tunnel. (e) Cuff of the ureter is sutured in position. The original oriﬁce in the bladder is closed. (f) In bilateral reimplantation, the second separate tunnel is parallel to the ﬁrst and ends in the opposite oriﬁce

POLITANO–LEADBETTER TECHNIQUE The ureter is further freed up to the dome of the bladder. The new opening for entrance of the ureter is made on postero-lateral aspect of the bladder. The new submucosal tunnel formed from there to old ureteric oriﬁce.

Then the stay suture of the ureter passed and gently threaded through the new tunnel. The narrow terminal portion of ureter is excised and ureter narrowed by one of the above techniques if needed and neo-ureter opening ﬁxed at the old opening with 5-0 Dexon. Stents are placed.

References 827

Suprapubic cather is left in the bladder and bladder closed in two layers: mucosa with 4-0 plain catgut and muscles with 4-0 Dexon. The retropubic drain is brought out through a separate incision. Muscles are approximated with 3-0 Dexon. Rectus sheath is sutured with 3-0 Dexon and skin approximated with a 5-0 Dexon subcuticular stitch.

ENDOSCOPIC REPAIR OF URETER Recent progress in endoscopic tools (such as miniscopes, balloons, and guidewires) has led to widespread use of endoscopy for ureteral repair.74 Barat et al. recently reported preliminary results with endoureterotomy for congenital megaureter.75 The technique consists of incision of the obstructive segment of ureter via a ureteroscope inserted into the ureteral oriﬁce. All of the layers of the ureter are incised in the long axis through the entire obstructive segment, to expose the peri-ureteral areolar tissue. A double-J stent is inserted for 3 weeks after the procedure. The risk of secondary reﬂux, which is a main concern after this type of procedure, has not been systematically checked. The role of endoureterotomy in the treatment of megaureters in children has not yet been established. Postoperative course Patients are fasted for 24 hours in case of development of ileus. In the cases of intravesical approach, the drain is removed after 24–48 hours. Stents are removed after 7–10 days, followed by suprapubic catheter. Ureteral reimplantation using extravesical approach can be performed without stenting.76,77 Indwelling urethral catheter is placed usually for 3–5 days to avoid urinary retention. Complications include wound infection, VUR due to short tunnel with no effective ﬂap valve mechanism, or obstruction due to a ﬁbrotic distal end secondary to ischemia. Follow-up and results Radiologic studies are used to assess initial and longterm surgical results and to monitor renal growth. These include ultrasound, intravenous urography or radionuclide scans. The success is measured by normal urinary drainage with no reﬂux and control of urinary infections.

REFERENCES 1. Blachav A, Blachav Y, Livne PM, Zurkowski L, Pelet D, Mogilner B. Clinical outcome and follow-up of prenatal hydronephrosis. Pediatr Nephrol 1994; 8:30–5. 2. Najmaldin AS, Burge DM, Atwell JD. Outcome of antenatally diagnosed pelviureteric junction hydronephrosis. Br J Urol 1991; 67:96–9.

3. Ransley PG, Dhillon HK, Gordon I, Duffy PG, Dillon MJ, Barratt TM. The postnatal management of hydronephrosis diagnosed by prenatal ultrasound. J Urol 1990; 144:584–7. 4. Koff SA, Campbell K. Non-operative management of unilateral neonatal hydronephrosis. J Urol 1992; 148:525–31. 5. Keating MA, Escala J, McC Snyder H III, Heyman S, Duckett JW. Changing concepts in management of primary obstructive megaureter. J Urol 1989; 142:636–40. 6. Allen TD. The swing of the pendulum. (editor) J Urol 1992; 148:534–5. 7. Peters CA, Roth JA. Congenital urine ﬂow impairments of the upper urine tract: pathophysiology and experimental studies. In: Gearhart JP, Rink RC, Mouriguand PDE, editors. Pediatric Urology. Philadelphia: WB Saunders, 2001: 303–17. 8. El-Dahr SS, Lewy JE. Urinary tract obstruction and infection in the neonate. Clin in Perinatol 1992; 19:213–22. 9. Koff SA. Pathophysiology of ureteropelvic junction obstruction. Clinical and experimental observations. Urol Clin North Am 1990; 17:263–72. 10. Weiss RM. Obstructive uropathy: Pathophysiology and diagnosis. Kelalis PP, King LR, Barry Belman A, editors. 3rd edn, Philadelphia: WB Saunders, 1992: 664–82. 11. Tainio H, Kylmala T, Heikkinen A. Peptidergic innervation of the normal and obstructed human pyelo-ureteral junctions. Urol Int 1992; 48:31–4. 12. Krueger RP, Ash JM, Silver MM, Kass EJ, Gilmour RF, Alton DJ, Gilday DJ, Churchill BM. Primary hydronephrosis assessment of diureteric renography pelvis perfusion pressure, operative ﬁndings and renal and ureteral histology. Urol Clin North Am 1980; 7:231–42. 13. Starr NT, Maizels M, Chou P, Brannigan R, Sharpio E. Microanatomy and morphometry of the hydronephrotic ‘obstructed’ renal pelvis in asymptomatic infants. J Urol 1992; 148:519–24. 14. Kim YS, Do SH, Hong CH, et al. Does every patient with ureteropelvic junction obstruction need voiding cystourethrography. J Urol 2001; 165:2305–7. 15. Bowie JD, Rosenberg ER, Andreotti RF, Fields SI. The changing sonographic appearance of fetal kidneys during pregnancy. J Ultrasound Med 1983; 2:505–7. 16. Jeanty P, Dramaix-Wilmet M, Elkhazen N, Hubinont C, Van Regemorter N. Measurement of fetal kidney growth on ultrasound. Radiol 1982; 144:159–62. 17. Sherer DM. Is fetal hydronephrosis overdiagnosed? Ultrasound Obstet Gynecol 2000; 16:601–6. 18. Harrison MR, Filly RA. The fetus with obstructive uropathy. Pathophysiology, Natural History, Selection and treatment in the unborn patient: Prenatal diagnosis and treatment. Harrison MR, Gollous MS, Filly RA, editors. Philadelphia: WB Saunders, 1990: 238–402. 19. Grignon A, Filion R, Filiatrault B, Robitaille P, Homsy Y, Boutin H, Leblond R. Urinary tract dilatation in utero, classiﬁcations and clinical applications. Radiol 1986; 160:645–7.

828 Upper urinary tract obstructions 20. Fasolato V, Poloniato A, Bianchi C et al. Feto-neonatal ultrasonography to detect renal abnormalities: evaluation of 1-year screening program. Am J Perinatol 1998; 15:161–4. 21. Langer B, Simeoni U, Schiader G. Prognostic criteria for fetal pyelectasis. Ultrasound Obstet Gynecol 1998; 11:82–3. 22. Roth JA, Diamond DA. Prenatal hydronephrosis. Cur Opin in Pediatr 2001; 13:138–41. 23. Shokeir A, Nijman R. Antenatal hydronephrosis: changing concepts in diagnosis and subsequent management. BJU Int 2000; 85:987–94. 24. Johnston JH, Evans JP, Glassberg KI, Shapiro SR. Pelvic hydronephrosis in children. A review of 219 personal cases. J Urol 1977; 117:97–101. 25. Shackelford GD, Kees-Folts W, Cole BR. Imaging the urinary tract. Clin in Perinatol 1992; 19:85–119. 26. Churchill BM, Feng WC. Ureteropelvic junction anomalies: congenital UPJ problems in children. In: Gearhart JP, Rink RC, Mouriguand PDE, editors. Pediatric Urology. Philadelphia: WB Saunders, 2001: 318–46. 27. Izquierdo L, Porteous M, Paramo PG, Connor JM. Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p. Human Genetics 1992; 89:557–60. 28. Pope JC, Brock JW III, Adams MC et al. Congenital anomalies of the kidney and urinary tract-role of the loss of function mutation in the pluripotent angiotensin type 2 receptor gene. J Urol 2001; 165:196–202. 29. Woolf AA. A molecular and genetic view of human renal and urinary tract malformations. Kidney Int 2000; 58:500–12. 30. Nishimura H, Yerkes E, Hohenfellner K et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell 1999; 3:1–10. 31. Fernloach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. Pediatric Radiol 1993; 23:278–80. 32. O’Reilly PH. Diuresis renography. Recent advances and recommended protocols. Br J Urol 1992; 69:113–20. 33. Piepsz A, Blaufox MD, Gordon I et al. Consensus on renal cortical scintigraphy in children with urinary tract infection. Scientiﬁc Committee of Radionuclides in Nephrourology. Semin Nuc Med 1999; 2:160–74. 34. Upsdell SM, Testa HJ, Lawson RS. The F-15, diuresis renogram in suspected obstruction of the upper urinary tract. Br J Urol 1992; 69:126–31. 35. Nauta J, Pot DJ, Kooij PPM, Nijman JM, Wolff ED. Forced hydration prior to renography in children with hydronephrosis. An evaluation. Br J Urol 1991; 68:93–7. 36. Koff SA, McDowell GC, Byard M. Diureteric radionuclide assessment of obstruction in the infant. Guidelines for successful interpretation. J Urol 1988; 140:1167–8.

37. Whitaker RH. Methods of assessing obstruction in dilated ureters. Br J Urol 1973; 45:15–22. 38. Rohatagi M, Bajpai M, Gupta DK, Gupta AK. Role of ultrasound guided percutaneous antegrade pyelography (USPCAP) in the diagnosis of obstructive uropathy. Indian Pediatrics 1992; 29:425–31. 39. King LR, Coughlin PW, Bloch EC et al. The case for immediate pyeloplasty in the neonate with ureteropelvic junction obstruction. J Urol 1984; 132:725–7. 40. Chevalier RL, Gomez RA, Jones CE. Developmental determinants of recovery after relief of partial ureteral obstruction. Kidney Int 1988; 33:775–81. 41. Ulman I, Jayanthi VR, Koff SA. The long-term followup of newborns with severe unilateral hydronephrosis initially treated nonoperatively. J Urol 2000; 164(3 Pt 2):1101–5. 42. Elder JS, Duckett JW. Perinatal Urology. In: Gillenwater JY, Grayhack JT, Harwards SS et al. editors. Adult and Pediatric Urology, vol. 2, Chicago, Il. Yearbook, 1987: 1512–1603. 43. Thorup J, Mortensen T, Diemer H, Johnsen A, Nielsen OH. The prognosis of surgically treated congenital hydronephrosis after diagnosis in utero. J Urol 1985; 134:914–17. 44. Sheldon CA, Duckett JW, Snyder HM. Evolution in the management of infant pyeloplasty. J Pediatr Surg 1992; 27:501–5. 45. Motola JA, Badlani GH, Smith AD. Results of 212 consecutive endopyelotomies: an 8-year followup. J Urol 1993; 149:453–6. 46. Kavoussi LR, Meretyk S, Dierks SM et al. Endopyelotomy for secondary uretero-pelvic junction obstruction in children. J Urol 1991; 145:345–9. 47. Figenshau RS, Clayman RV. Endourologic options for management ureteropelvic junction obstruction in the pediatric patient. Urol Clin North Am 1998; 25:199–209. 48. Tan HL. Laparoscopic Anderson–Hynes dismembered pyeloplasty in children using needlescopic instrumentation. Urol Clin North Am 2001; 28(1):43–51. 49. Yeung CK, Tam YH, Sihoe JD et al. Retroperitoneoscopic dismembered pyeloplasty for pelvi-ureteric junction obstruction in infants and children. BJU Int 2001; 87(6):509–13. 50. Bassiouny IE. Salvage pyeloplasty in non-visualising hydronephrotic kidney secondary to ureteropelvic junction obstruction. J Urol 1992; 148:685–7. 51. Konda R, Orikassa S, Ioritani N, Sakai K, Kuji S, Ota S, Abe Y, Ikeda S. The effect of pyeloplasty on renal function in children with unilateral ureteropelvic junction obstruction. Investigation of the split renal function using DMSA renal uptake rate. Japanese J Urol 1991; 82:1576–82. 52. Cussen LJ. The morphology of congenital dilatation of ureter: intrinsic ureteral lesions. Aust NZJ Surg 1971; 41:185–94. 53. Hellstrom M, Hajlmas K, Jacobsson B et al. Normal ureteral diameter in infancy and childhood. Acta Radiol 1985; 26:433–5.

References 829 54. Smith ED, Cussen LJ, Glenn J et al. Report of working party to establish an international nomenclature for the large ureter. Birth Defects 1977; 13:3–5. 55. King LR. Megaloureter: Deﬁnition, diagnosis and management. (editor) J Urol 1980; 123:222–3. 56. Tanagho EA. Intrauterine fetal ureteral obstruction. J Urol 1973; 109:196–203. 57. Tanagho EA, Smith DR, Guthrie TM. Pathophysiology of functional ureteral obstruction. J Urol 1970; 104:73–8. 58. McLaughlin AP IIIrd, Pﬁster RC, Leadbetter WF, Salzstein SL, Kessler WO. The pathophysiology of primary megaloureter. J Urol 1973; 109:805–11. 59. Hanna MK, Jeffs RD, Sturgess JM, Barkin M. Ureteral structure and ultrastructure. Part II. Congenital ureteropelvic junction obstruction and primary obstructive megaureter. J Urol 1976; 116:725–30. 60. Lee BR, Partin AW, Epstein JI et al. A quantitative histological analysis of the dilated ureter of childhood. J Urol 1992; 148:1482–6. 61. Fridrich U, Schreiber D, Gottschalk E, Dietz W. Ultrastructure of the distal ureter in congenital malformations in childhood. Z Fur Kinderchirurgie 1987; 42:94–102. 62. Dixon JS, Jen PYP, Yeung CK et al. The vesico-ureteric junction in three cases of primary obstructive megaureter associated with ectopic ureteric insertion. BJU Int 1998; 81:580–4. 63. Keating MA, Escala J, Mc C Snyder HM III, Heyman S, Duckett JW. Changing concepts in management of primary obstructive megaureter. J Urol 1989; 142:636–40. 64. Seeds JW, Mittlestaedt CA, Mandell J. Prenatal and postnatal ultrasonographic diagnosis of congenital obstructive uropathies. Urol Clin North Am 1988; 13:131–54.

65. Helin I, Persson P. Prenatal diagnosis of urinary tract abnormalities by ultrasound. Pediatr 1986; 78:879–83. 66. Shokeir AA, Nijman RJM. Primary megaureter: current trends in diagnosis and treatment. BJU Int 2000; 86:861–8. 67. Hanna MK, Jeffs RD. Primary obstructive megaureter in children. Urol 1975; 6:419–27. 68. Retik AB, McEvoy JP, Bauer SB. Megaureters in children. Urol 1978; 11:231–6. 69. Williams DI, Hulme-Moir I. Primary obstructive megaureter. Br J Urol 1970; 42:140–9. 70. Keating MA, Retik AB. Management of the dilated obstructed ureter. Urol Clin N Am 1990; 17:291–306. 71. Wood BP, Ben-Ami T, Teele RL, Rabinowitz R. Ureterovesical obstruction and megaloureter: Diagnosis by real time US. Radiol 1985; 156:79–81. 72. Fung LCT, Churchill BM, Mc Lorie GA et al. Ureteral opening pressure: A novel parameter for the evaluation of pediatric hydronephrosis. J Urol 1998; 159:1326–30. 73. Koo HP, Bloom DA. Lower ureteral reconstruction. Urol Clin North Am 1999; 26(1):167–73. 74. Desgrandchamps F. Endoscopic and surgical repair of the ureter. Cur Opin Urol 2001; 11:271–4. 75. Barat S, Barat M, Kirpekar D. Endoureterotomy for congenital primary obstructive megaureter: preliminary report. J Endourol 2000; 14:263–7. 76. Wacksman J, Gilbert A, Sheldon CA. Results of the renewed extravesical reimplant for surgical correction of vesicoureteral reﬂux. J Urol 1992; 148:359–61. 77. Burbige KA, Miller M, Connor JP. Extravesical ureteral reimplantation: results in 128 patients. J Urol 1996; 155:1721–2.

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88 Duplication anomalies PREM PURI AND HIDESHI MIYAKITA

INTRODUCTION Duplication of the renal pelvis and ureter is the commonest anomaly of the upper urinary tract.1 It occurs in approximately 0.8% of the population,2 and in 1.8–4.2% of pyelograms.3–5 Commonly these are asymptomatic. However, they can challenge the diagnostic acumen with a wide variety of manifestations. Complete duplication of the ureter may manifest as a result of reﬂux into the lower pole ureter, obstruction of the upper pole with an ectopic ureterocele or narrowed distal ureter with an ectopic oriﬁce or, in females, dribbling of urine because of infrasphincteric insertion of the upper pole ureter.

EMBRYOLOGY The ureteric bud appears at 5 weeks’ gestation from the place where the Wolfﬁan duct bends centrally and medially to the cloaca and pushes into the pelvic metanephrogenic mass and eventually forms the ureter and renal pelvis. Premature division of the ureteral bud gives rise to incomplete duplication. If two ureteral buds arise from the Wolfﬁan duct and if both are incorporated into the urogenital sinus, then complete duplication occurs. The upper pole ureter is more closely associated with the Wolfﬁan duct, while the lower pole ureteric bud is closest to the urogenital sinus and incorporated ﬁrst. The upper pole ureter is carried medially and caudally along with the Wolfﬁan duct. Therefore, the upper pole ureter opens more medially and inferiorly than the lower pole ureter, according to the Weigert–Mayer law.6–8 Sometimes this upper pole ureter has an abnormally prolonged or close attachment to the Wolfﬁan duct which will migrate into the segment of urogenital sinus that is destined to become the urethra. Occasionally in males, a separate opening into the urogenital sinus is not established and the bud continues to be linked to the Wolfﬁan duct much longer and the

ureter comes to insert in the male genital tract such as in seminal vesicles, vas deferens or even epididymis. Stephens proposed that, in females, the fused Mullerian ducts after penetrating the urogenital sinus undergo signiﬁcant epithelial activity and incorporate any Wolfﬁan duct remnants, and thus the ureteral bud along with the Wolfﬁan duct may be carried along as part of caudal Mullerian migration and this in turn would lead to drainage sites into the vestibule, vagina, cervix, and uterus.9

CLASSIFICATION A standard set of deﬁnitions used to describe ureteral duplications anomalies now exists. These deﬁnitions were established by the Urologic Section of the American Academy of Pediatrics Committee on Terminology, Nomenclature and Classiﬁcation.10 Following are the different types of uretero-pelvic duplications, the recognition of which is important in understanding the pathophysiology, clinical manifestations, and management. 1 Incomplete ureteral duplication, where two ureters unite and enter the bladder through a common oriﬁce. 2 Complete ureteral duplication a Intravesical: Two ureters drain separately into the bladder. The upper pole opens caudal and medial to lower pole ureter and has a longer ureterovesical course and therefore less risk of reﬂux. b Extravesical: where the ureter opens into the urethra or genital tract. 3 Inverted Y ureteral duplication. Two distal ureters fuse to drain a single kidney; one of the limbs may be ectopic, blind-ending or atretic. 4 Blind biﬁd ureter. One branch ends blindly and this is thought to be because one ureteral bud does not join the metanephrogenic mass. 5 Ureteral triplication and even quadruplication has been reported and is due to formation and/or division into three or four buds.11–13

832 Duplication anomalies

CLINICAL MANIFESTATION Most often, ureteral duplication anomalies are discovered incidentally unassociated with any symptoms. Infants may come to medical attention because of the complications of obstruction of the upper moiety or infection. Vesico-ureteric reﬂux (VUR) is common, occurring much more frequently in the lower segment. Duplication affects both sides equally, while 15% of patients have bilateral duplications. It is more common in females, who are more likely to exhibit pathological complications. There is a familial tendency with the risk of duplication in a sibling up to one in eight and is suggestive of autosomal dominant inheritance with incomplete penetration.3,14 Ureterocele, a cystic dilatation of the terminal intramural segment of the distal ureter, is classiﬁed as either simple or ectopic.10 The ectopic variety is symptomatic in infants far more commonly than simple ureterocele and is nearly always with an obstructed upper segment of a duplex kidney. The bulging ureterocele protrudes into the intravesical space and terminates ectopically at the bladder neck or in the urethra. Whether associated with single or duplex systems, the problems of ureterocele are much more common in girls than boys. Ureteral duplication can present with diverse clinical manifestations and include: • Urinary tract infection, which may be due to reﬂux or obstruction. This can vary from overwhelming sepsis to asymptomatic bacteria. • Epididymo-orchitis as a result of an ectopic ureter opening into the male genital tract or • Incontinence, which is due to an ectopic ureter opening beyond the sphincter and is thus more common in females or because of infection causing urge incontinence. • Urinary retention. An ureterocele occupying the bladder neck can cause urinary retention and overﬂow incontinence. Rarely, it may prolapse through the urethra (Fig. 88.1). • Abdominal mass. Hydronephrosis secondary to obstruction may present with abdominal mass. • Failure to thrive, because of chronic persistent urinary infection.

Figure 88.1 Ureterocele prolapsing through the urethra in a newborn

outﬂow obstruction. In order to be certain that renal development is normal, ultrasound at or beyond 20 weeks of gestation is necessary. An obstruction anomaly is recognized by demonstrating a dilated renal pelvis, calyces or ureter. However, it is not possible to detect an uncomplicated duplex anomaly prenatally.15

Postnatal diagnosis Ultrasonography, which does not visualize the excretory pathway, may be unable to differentiate between kidneys with and without pyeloureteral duplication, but is able to recognize thick transverse intermediate cortical mass (1 cm) in the latter group and also on the basis of the ratio between the longitudinal and transverse diameter which is greater than in kidneys without duplication.16 An obstructed or reﬂuxing system and ureteroceles can be visualized on the ultrasound scans (Fig. 88.2).

Prenatal diagnosis The kidneys can be imaged at the 12th gestational week by abdominal ultrasound. With the increased availability and use of maternal ultrasonography, the incidence of urinary tract disorders diagnosed in utero has increased considerably. Oligohydramnios or anhydramnios in the mother is usually due to diminished amniotic ﬂuid. Because amniotic ﬂuid after 18 weeks of gestation is voided urine, it suggests bilateral renal agenesis or

Figure 88.2 Sonographic appearance of a ureterocele within the bladder

Management 833

Micturating cystograms will delineate reﬂux and ureteroceles. Intravenous urography remains the most accurate and easily available modality of investigation.17 It accurately deﬁnes the anatomy, while in the nonfunctioning segment the remaining pole will exhibit the ‘drooping lily’ sign (Fig. 88.3). Radionuclide scans are useful in determining the differential function.18 Computerized tomography and magnetic resonance imaging scans may be used if available, as a last resort, to deﬁne the lesion. Diagnosis is usually conﬁrmed by cystoscopy and endoscopic visualization of the ureteric oriﬁces. It also helps to assess the extent of ureterocele.

Figure 88.3 Twenty-minute ﬁlm from urogram showing ‘drooping lily’ sign on the left as a consequence of an obstructed non-functioning upper moiety on this side due to a large ureterocele

MANAGEMENT Asymptomatic uncomplicated ureteral duplications do not require active clinical management.

Vesico-ureteric reﬂux VUR is the most common problem associated with ureteral duplication and is more common in lower poles than in upper poles. Until recently, reﬂux into completely duplicated ureters was considered a surgical problem. Most of the recent reports suggest that there is no difference in the rate of spontaneous resolution of minor grades of reﬂux into single ureters or lower pole ureters in duplex systems.18–21 Medical surveillance

should be continued in these patients to prevent renal scarring. Lee and colleagues feel that the reﬂux into both moieties has a much lower likelihood of spontaneous resolution and recommend a surgical approach.19 The reported rates of spontaneous resolution of grades I and II reﬂux in duplex systems vary from 22% to 85%.19–21 In the newborn period conservative antimicrobial treatment combined with full urological investigations is the management of choice. Infants with grades I–III reﬂux should continue on chemoprophylaxis. High grades of reﬂux in infants associated with ureteral duplication, breakthrough infections in spite of prophylaxis and progressive renal scarring and poor function constitute indications for antireﬂux operation22,23 or endoscopic correction.24 In patients with lower pole reﬂux only in complete ureter duplication, Ahmed and Boucout23 and Bivens and Palken25 recommend ipsilateral uretero-ureterostomy when there is no abnormality on the contralateral side, or there is history of bladder operation or abnormality thickened bladders. They propose that this operation has fewer complications, requires shorter hospitalization, no postoperative bladder catheters are required and, as the nonreﬂuxing ureteral oriﬁce and submucosal tunnel are not disturbed, there is no risk of creating reﬂux. This can be undertaken either by suprapubic incision or extraperitoneal iliac fossa incision. Recently, Lashley et al. reported excellent results of uretero-ureterostomy in 94 children with complete ureteral duplication associated with VUR, obstructing ureterocele, and ectopic ureters.26 The signiﬁcant discrepancy in ureteral size did not preclude uretero-ureterostomy. Another surgical option is reimplantation of ureters. Only a reﬂuxing ureter may be undertaken if it can be safely separated. In patients with reﬂux into both ureters and those where the reﬂuxing ureter cannot be safely separated, common sheath ureteric reimplantation is undertaken. Recently, Ellsworth et al. reported 10-year experience with common sheath reimplantation in 54 reﬂuxing units.27 Common sheath reimplantation yields a 98% success rate with minimal morbidity. Some authors have raised concern in regards to high incidence of recurrence of VUR after common sheath reimplantation.28 Kalicinski and colleagues have described a method to separate the distal ends of the ureter by cutting this avascular membrane and preserving the adventitia and mesentery supplying the blood to the ureter and then reimplanting them as single ureters in separate submucous tunnels.28 They believe that the recurrence with this method is less as compared to common sheath reimplantation and is due to less effective valve mechanism as the duplex ureter is thicker and not as susceptible to external pressure as a single ureter. Polar nephro-ureterectomy is performed in patients who have one pole ureter reﬂux with poorly functioning segment of kidney, while nephro-uterectomy may be necessary if both poles are involved. Recently, the role of

834 Duplication anomalies

laparoscopic heminephroureterectomy in pediatric patients has begun to be appreciated.29 Janetschek et al. reported their experience with laparoscopic heminephrectomy in 14 consecutive patients.29 The advantages of the procedure are decreased morbidity and that total ureterectomy may be performed without a second incision. The main disadvantage is the long operative time (3–5.5 hours). In incompletely duplicated ureters, surgical options include reimplantation of the common distal ureter if the junction is proximal or when junction is close to bladder excision of the common segment, with reimplantion of both ureters in the bladder or ureteroureterostomy with reimplantation of one ureter. However, if the function is poor, nephro-ureterectomy is necessary to avoid a diverticulum-like defect. Endoscopic subureteric Teﬂon or Deﬂux injection is effective in treating duplex reﬂux of higher grade in complete and incomplete systems.24 The technique of endoscopic injection of Polytef paste or Deﬂux is simple and straighforward.24 With an incomplete duplex system, the technique is the same as in a single system. To inject the paste, a disposable Puri catheter 4-Fr gauge (Storz, Tuttlingen, W. Germany) is ﬁrst ﬁlled with paste with a 1-ml tuberculin syringe with a metallic sheath and piston (Storz). The catheter is then introduced through the cystoscope. A 4-Fr catheter can easily be introduced through a 10-Fr cystoscope without removing the telescope. Under direct cystoscopic vision, the needle is introduced under the bladder mucosa 2–3 mm below the affected ureteric oriﬁce at the 6 o’clock position (Fig. 88.4). The needle is advanced about 4–5 mm into the lamina propria in the submucosal portion of the ureter and the injection started slowly. As the paste is injected, a bulge appears in the ﬂoor of the submucosal ureter. During injection, the needle is slowly withdrawn until a ‘volcanic’ bulge of paste is seen. The needle should be kept in position for about 30–60 s after injection to avoid extrusion. When injection is completed, the ureteric oriﬁce should look slit-like (Fig. 88.4) and (Fig. 88.5).

(a)

(b) Figure 88.5 (a) Micturating cystogram in an 8-week-old boy shows grade IV vesico-ureteric reﬂux into the lower moiety of the right duplex system. (b) Micturating cystogram in the same boy following endoscopic correction of reﬂux

Figure 88.4 Technique of subureteric injection in an incomplete duplex system

In the case of a complete ureteral duplication, the needle is introduced 2–3 mm below the lower ureteric oriﬁce at the 6 o’clock position, but the entire length of the needle (8 mm) is advanced behind the two ureters. During injection, the needle is slowly withdrawn until a ‘volcanic’ bulge of paste is seen and the two ureteric oriﬁces look slit-like (Fig. 88.6).

References 835

Figure 88.6 Technique of subureteric injection in a complete duplex system

Uretero-pelvic obstruction In the biﬁd system, obstruction commonly involves the lower pole.30–33 Upper pole uretero-pelvic junction obstruction is uncommon (Fig. 88.7a,b). In patients with low bifurcations and who have long ureteral segments, a standard pyeloplasty can safely be performed. If the lower pole ureteral segment is short, an end-to-end anastomosis of the lower pole pelvis to the upper pole ureter, eliminating the short lower pole ureter, may be necessary. Alternatively, the short lower pole ureter is retained and incorporated into a wider anastomosis.31 In patients with incomplete duplications, it is possible to widen the narrowed junction of the lower pole segment to the upper pole ureter by making a vertical incision in the anterior wall and suturing it transversely.32 If there is nonfunction of the obstructed segment, a heminephroureterectomy to the level of the bifurcation is necessary to avoid leaving a ureteral stump into which ureteroureteral reﬂux can occur.32 The management of ureterocele is complex.34–39 Consideration of ureterocele as intravesical or extravesical is important because the technique of surgical reconstruction can be different. If the function is good, endoscopic incision of the ureterocele may be tried. The advantages of this procedure are that this is straightforward management, especially in septic babies. The obstruction can be solved by simple puncture of ureterocele rather than endoscopic incision. The reﬂux rate to the ureterocele moiety following endoscopic puncture is negligible. We have used in all our babies a stylet of the 3-Fr ureteral catheter. The puncture hole is made high enough and lateral on the ureterocele in order to avoid reobstruction and to create postpuncture ﬂap sufﬁcient to preserve the ﬂap-valve antireﬂux mechanism. If the reﬂux developed after endoscopic puncture it is usually a low grade and does not require any treatment. If the child develops breakthrough infections or high-grade reﬂux endoscopic correction of reﬂux can be easily performed.38

(a)

(b) Figure 88.7 (a) Bilateral duplex system. Urogram showing obstructed upper moiety on the left due to pelvic-ureteric junction obstruction. (b) Longitudinal sonographic scan through the left kidney in the coronal plane in the same patient, demonstrating pelvi-ureteric junction obstruction to upper moiety and normal lower moiety

The other option is a staged approach to the ureterocele and includes partial ureterectomy with or without heminephrectomy and decompression of the ureterocele.38,39

REFERENCES 1. Nordmarck B. Double formations of the pelvis of the kidney and ureters: embryology, occurance and clinical signiﬁcance. Ann Rad 1948; 30:276.

836 Duplication anomalies 2. Nation FF. Duplication of the kidney and ureter: a statistical study of two hundred thirty new cases. J Urol 1944; 51:456–65. 3. Atwell JD, Cook PL, Howell CJ. Familial incidence of biﬁd and double ureters. Arch Dis Childh 1974; 49:390–3. 4. Hartman GW, Hodson CJ. The duplex kidney and related abnormalities. Clin Radiol 1969; 20:387. 5. Privett JTJ, Jeans WD, Roylance J. The incidence and importance of renal duplication. Clin Radiol 1976; 27:521–30. 6. Churchill BM, Abovea EO, McLorie GA. Ureteral duplication, ectopy and ureterocele. Ped Clin N Am 1987; 34:1273–89. 7. Mayer R. Development of the ureter in the human embryo: a mechanistic consideration. Anat Rec 1946; 96:355. 8. Weigert C. Uebeteinige bildunsfetster der Ureteren. Virch Arch 1877; 70:490. 9. Stephens FO. Congenital Malformations of the Urinary Tract, Prager, New York, 1983:186–363. 10. Glassberg KI, Braren V, Duckett JW. Suggested terminology for duplex systems, ectopic ureters and ureteroceles. Report of the Committee on Terminology, Nomenclature and Classiﬁcation. American Academy of Pediatrics. J Urol 1986; 132:1153–5. 11. Gosalbes R Jr, Gosalbes R, Piro C et al. Ureteral triplication and ureterocoele. Report of three cases and review of the literature. J Urol 1991; 145:105–8. 12. Luque Mialdea R, DeThomas E, Aprojo F et al. Ureteral triplication: double extravesical ureteral ectopic. J Urol 1991; 145:109–11. 13. Soderahl DW, Shivaki LW, Sabamber DT. Bilateral ureteral quaduplication. J Urol 1976; 116:255. 14. Whitaker J, Banks DM. A study of the inheritance of duplication of the kidneys and ureters. J Urol 1966; 95:176. 15. Bronshtein M, Yoffe N, Brandes JM et al. First and early second trimester diagnosis of fetal urinary tract anomalies using transvaginal sonography. Prenat Diag 1990; 10:653–66. 16. Dalla Palma L, Bazzocchi M, Cressa C et al. Radiological anatomy of the kidney revisited. Br J Radiol 1990; 63:680–90. 17. Fernbach SK, Feinstein KA, Spencer K, Lindstrom CA. Ureteral duplication and its complications. Radiographics 1997; 17(1):109–27. 18. Pattaras JG, Rushton HG, Majd M. The role of 99mtechnetium dimercapto-succinic acid renal scan in the evaluation of the occult ectopic ureters in girls with paradoxical incontinence. J Urol 1999; 162(3 Pt 1):821–5. 19. Lee PH, Diamond DA, Duffy P et al. Duplex reﬂux: a study of 105 children. J Urol 1991; 146:657–9. 20. Hausmann DA, Allen TD. Resolution of vesico-ureteral reﬂux in completely duplicated systems: fact or ﬁction? J Urol 1991; 145:1022–3. 21. Ben-Ami T, Gayer G, Hertz M et al. The natural history of

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reﬂux in the lower pole of duplicating collecting systems: a controlled study. Pediatr Radiol 1989; 19:308–10. Amar AD, Chabra K. Reﬂux in duplicated ureters. J Pediatr Surg 1970; 5:419–30. Ahmed S, Boucout HA. Vesicoureteral reﬂux in complete ureteral duplication: surgical options. J Urol 1988; 140:1092–4. Miyakita H, Ninan GK, Puri P. Endoscopic correction of vesicoureteric reﬂux in duplex systems. Eur Urol 1993; 24:111–15. Bivens A, Palken M. Ureteroureterostomy for reﬂux in duplex systems. J Urol 1971; 106:290. Lashley DB, McAleer IM, Kaplan GW. Ipsilateral ureteroureterostomy for the treatment of vesicoureteral reﬂux or obstruction associated with complete ureteral duplication. J Urol 2001; 165:552–4. Ellsworth PI, Lim DJ, Walker RD et al. Common sheath reimplantation yields excellent results in the treatment of vesicoureteral reﬂux in duplicated collecting system. J Urol 1996; 155(4):1407–9. Kalincinski ZH, Joszt W, Perdzynski W et al. Completely duplicates ureters: a new concept of reimplantation. J Pediatr Surg 1992; 27:70–3. Janetschek G, Seibold J, Radmayr C, Bartsch G. Laporoscopic heminephrectomy in pediatric patients. J Urol 1997; 158:1928–30. Fernbach SK, Zawin JK, Lebowitz RL. Complete duplication of the ureter with uteropelvic junction obstruction of the lower pole of the kidney: imaging ﬁndings. Am J Roentgenol 1995; 164:701–4. Caldamore AA. Duplication anomalies of the upper tract in infants and children: symposium on advances in paediatric urology. Urol Clin N Am 1985; 12:75–91. Amar AD. Congenital hydronephrosis of lower segment in duplex kidneys. Urology 1976; 7:480–5. Ulchaker J, Ross J, Alexander F, Kay R. The spectrum of ureteropelvic junction obstruction occurring duplicated collecting systems. J Pediatr Surg 1996; 31(9):1221–4. Monofort G, Guys JM, Roth CK et al. Surgical management of duplex ureters. J Pediatr Surg 1992; 27:634–8. King LR, Kozlowski JM, Schacht MJ. Ureterocoeles in children. A simpliﬁed successful approach to management. J Am Med Ass 1983; 249:1461. Cobb LM, Desai PG, Price SF. Surgical management of infantile (ectopic) ureterocoele. Report of a modiﬁed approach. J Pediatr Surg 1982; 17:745. Cooper CS, Passerini-Glasel G, Hutcheson JC et al. Longterm followup of endoscopic incision of ureteroceles: intravesical versus extravesical. J Urol 2000; 164:1097–9. Chertin B, Fridmans A, Hadas-Halpren I, Farkas A. Endoscopic puncture of ureterocele as a minimally invasive and effective long-term procedure in children. Eur Urol 2001; 39:332–6. Coplen DE, Barthold JS. Controversies in the management of ectopic ureteroceles. Urology 2000; 56:665–8.

89 Vesico-ureteric reﬂux PREM PURI

INTRODUCTION Primary vesico-ureteric reﬂux (VUR) is the most common urological problem in children and has been reported in 30–50% of children who present with urinary tract infection.1–3 Reﬂux nephropathy is a cause of end-stage renal failure in about 10% of all patients and is the most common cause in children and adolescents.4,5 It is also the most common cause of severe hypertension in children.6,7 Siblings of patients with reﬂux have a much higher incidence of reﬂux than that seen in the general population, the reported incidence being 8–46%.8–11 Primary VUR is due to congenital absence or deﬁciency of the longitudinal muscle of the submucosal ureter, which results in upward and lateral displacement of the ureteric oriﬁce, and hence reduction in length and obliquity of the submucosal ureter.

Mechanism of renal scarring The association between VUR and renal scarring is now widely recognized.12,13 Scarring is directly related to the severity of reﬂux. Belman and Skoog assessed renal scarring in 804 reﬂuxing units and found renal scars in 5% of those with grade I reﬂux, 6% of those with grade II reﬂux, 17% of those with grade III reﬂux, 25% of those with grade IV reﬂux, and 50% of those with grade V reﬂux.12 The mechanism by which reﬂux produces renal scars is still not clear. It is essential to distinguish between the commonly acquired segmental scarring associated with VUR and infection, and the primary scarring seen congenitally, in which the etiology is very different and linked to abnormal metanephric development.7 There is no doubt that bacterial pyelonephritis produces renal scars experimentally and clinically.13–17 Dimercaptosuccinic acid (DMSA) scans have allowed us to follow sequentially the evolution of a scar from an area of decreased blood ﬂow during the acute inﬂammatory

phase to a parenchymal defect indicative of a mature scar.17 Yet only half of patients with acute pyelonephritis will have such a scar.17 What converts an acute inﬂammatory process into a scar in some patients and not in others is not clearly understood. Factors implicated in the formation of a mature scar include magnitude of the pressure driving the organisms into the tissues, the intrinsic virulence of the organism itself, and the host defence mechanisms.18 Furthermore, some of the worst examples of renal injury associated with VUR are those that are present at birth. As renal damage at that time cannot be the consequence of infection, such injury is assumed to be developmental in origin, but the pathophysiology of this is not entirely clear. It has been suggested that the transient bladder outﬂow obstruction with elevated intravesical pressure might damage the kidneys during development.18–20 Sillen and colleagues performed cystometry in 18 consecutive infants with gross bilateral VUR and found elevated detrusor pressures in all but one.18,19 Recently, Willemsen reported a 5-year follow-up of 102 patients with VUR.21 Bladder instability was identiﬁed in 40% of patients. In terms of reﬂux resolution, 57% of patients resolved with bladder instability compared to 67% without bladder instability. A breakthrough urinary tract infection (UTI) occurred in 34% of patients with bladder instability compared to 18% without voiding dysfunction. Elevated intravesical pressures are known to be able to produce renal scars indistinguishable from those caused by bacterial infection, especially in the young patient.7,25

DIAGNOSIS Antenatally diagnosed reﬂux Prenatal ultrasonography has resulted in a dramatic increase in the number of infants detected with signiﬁcant asymptomatic uropathology, allowing treatment before the potential devastating consequences of UTI

838 Vesico-ureteric reﬂux

occur.26 An incidental anomaly is detected by antenatal ultrasonography in about 1% of studies and 20–30% involving the urinary tract.27 By far the commonest abnormal ﬁnding is hydronephrosis, comprising over 90% of the urological abnormalities detected. Underlying diagnosis include pelvic-ureteric junction obstruction, vesico-ureteric junction obstruction, posterior urethral valves and VUR. Although antenatal hydronephrosis is generally considered to represent an obstructive lesion, VUR is a common cause. Najmaldin and colleagues performed micturating cystography in the ﬁrst 6 months of life in 97 of 102 patients with renal abnormalities detected in utero and found that 18 males and 12 females had VUR. 28 In the series of Gordon and associates, of 25 cases of primary VUR suspected in utero and conﬁrmed in the neonatal period, 21 (84%) were males.29 In another series, prenatal hydronephrosis was due to VUR in 34 of 309 cases (11%).30

Natural history of prenatally diagnosed VUR The vast majority of infants found to have VUR following detection of antenatal hydronephrosis are males. The male preponderance is reported to range from 2 : 1 to 5 : 1 in various series.31–33 This is in total contrast to the female preponderance that has been consistently reported in later childhood. In approximately two-thirds of the cases, the reﬂux is bilateral. VUR diagnosed prenatally tends to be of high grade.31–33 It also has been reported that boys are more vulnerable to UTI, especially in the ﬁrst 6 months of life, where different factors play a signiﬁcant role.34 Host factors such as the inner nonkeratinized epithelium of the foreskin create a moist reservoir for uropathogens and contribute to the ﬁrst contact between the host and the bacteria. Once the prepuce has been colonized, the bacteria can ascend the urinary tract, causing cystitis or pyelonephritis. Rushton et al. showed a clear predominance of males among infants less than 6 months old with febrile UTI, and a disproportionately high frequency of uncircumcised male infants.34 Cascio et al. showed a pure growth of an uropathogen in 48% of uncircumcised infants with VUR despite the use of prophylactic antibiotics.35 At birth, between one-third and a half of reﬂuxing kidneys may have reduced renal function on DMSA scintigraphy, even in the absence of UTI.36,37 In the series of Anderson and Rickwood, 75% of the kidneys with grade V reﬂux, 80% with grade IV reﬂux, 46% with grade III reﬂux, and 0% with grade I or II reﬂux exhibited reduced isotope uptake with an overall 18% of renal function.30 Yeung et al. studied 155 infants with prenatal hydronephrosis and postnatally diagnosed VUR. They observed renal parenchymal damage in 42% of the 135

infants (101 male and 34 female) without history of UTI.36 Furthermore, Nguyen et al. reported renal parenchymal abnormalities in 65% of predominantly male infants with sterile high-grade reﬂux.37 The resolution rate of antenatally diagnosed high-grade VUR (grade IV or V) is approximately 20% by the age of 2 years.26,27 However, in approximately 25% of boys followed non-operatively, UTIs developed by the age of 2 years, despite antimicrobial chemoprophylaxis.27

CLINICAL PRESENTATION It is obviously important to diagnose VUR at the earliest possible age, preferably in infancy. There are a number of clinical presentations, which should raise the suspicion of VUR in an infant. As antenatal ultrasound becomes increasingly routine, many cases will be suspected before birth and should be investigated within the ﬁrst month of life. Infants with a poor urinary stream as in posterior urethral valves or infants with spina biﬁda have a high incidence of VUR, while early investigations are indicated in the ﬁrst-degree relatives of patients with high-grade VUR. An infant with a UTI usually presents with obvious sepsis. If there is signiﬁcant renal damage, failure to thrive often accompanied by polyuria and polydipsia may be a clue to reﬂux nephropathy. Moderate damage is often associated with polyhydramnios, while oligohydramnios suggests severe damage.32 When an infant with such damage develops a UTI, the common presentation is acute metabolic acidosis with profound hyponatremia and hyperkalemia with varying degrees of renal failure.

RADIOLOGICAL INVESTIGATIONS Ultrasound Sonography should be performed in any infant with suspicion of VUR. The kidneys and upper ureters should be examined both in B-mode and real time. The bladder and lower ureters are assessed by real-time examination at each uretero-vesical junction for dilatation, conﬁguration, peristalsis, and continuity with the bladder base. VUR is suspected in the presence of a dilated pelvicaliceal system, upper or lower ureter, unequal renal size, or cortical loss and increased echogenicity (Fig. 89.1d). Sonography is not sufﬁciently sensitive or speciﬁc for diagnosing VUR.33 The intermittent and dynamic nature of VUR probably contributes to the insensitivity of routine renal sonography in the detection of even higher grades of reﬂux.

Radiological investigations 839

(a)

(b)

(c)

(d)

Figure 89.1 (a, b) Ultrasound shows bilateral hydronephrosis in a 6-week-old infant. (c) Micturating cystography in the same infant shows bilateral high-grade vesico-ureteric reﬂux. Note intrarenal reﬂux on the left side. (d) DMSA scan demonstrates signiﬁcant left renal scarring, particularly in upper and lower poles

Micturating cystography VUR is a dynamic process. Bladder ﬁlling and voiding are necessary for its elucidation which requires catheterization for adequate documentation. Micturating cystogram remains the gold standard for detecting VUR (Fig. 89.2). Despite the high radiation dose and unpleasant nature of the procedure, it has a low false-negative rate and provides accurate anatomical detail, allowing grading of the VUR (Fig. 89.3a–c). It is commonly performed as a ﬁrst-line investigation, together with ultrasound.

Some investigators employ nuclear cystography for diagnosing VUR. This can be either direct or indirect using technetium-labelled diaminotetra-ethyl-pentaacetic acid (DTPA). In direct nuclear cystography, DTPA is instilled into the bladder by urethral catheter or suprapubic injection and the ureters and kidneys are observed on camera during bladder ﬁlling and voiding. In indirect nuclear cystography, DTPA is injected intravenously. After the bladder is ﬁlled, the patient is instructed to void and the counts taken over the ureters and kidneys are used to assess the presence of VUR. Indirect nuclear cystography requires a co-operative patient and therefore is of no value

840 Vesico-ureteric reﬂux

(a) Figure 89.2 Four-week-old male infant with bilateral grade V vesico-ureteric reﬂux. Note normal urethra and bladder wall

in infants. The main disadvantage of nuclear cystography is that it does not give anatomical detail and VUR cannot be graded according to international classiﬁcation. According to the international classiﬁcation of reﬂux,1 there are ﬁve grades of reﬂux: • grade I, ureter only • grade II, ureter, pelvis, and calices – no dilatation, normal caliceal fornices • grade III, mild dilatation and/or tortuosity of the ureter and mild dilatation of the renal pelvis – minor blunting of the fornices • grade IV, moderate, dilatation and/or tortuosity of the ureter and moderate dilatation of the renal pelvis and calices – complete obliteration of the sharp angle of fornices but maintenance of the papillary impressions in the majority of calices • grade V, gross dilatation of the renal pelvis and calices (Fig. 89.4).

(b)

DMSA scan DMSA is the most sensitive technique for detecting renal scarring. When performed in the course of acute urinary tract infection, the DMSA scan is currently the most reliable test for the diagnosis of acute pyelonephritis. The scan, when performed within 4 weeks of the UTI, detects transient areas of abnormality that may not develop into scars on long-term follow-up.38 To avoid misleading results of the DMSA scan, it is mandatory to establish under what clinical condition the test was undertaken.

(c) Figure 89.3 (a) Male infant showing grade V left vesico-ureteric reﬂux; (b) ultrasound in the same patient. Transverse scan through the full bladder demonstrates dilated left ureter. (c) DMSA scan in the same patient demonstrates small left kidney

Management 841

Figure 89.4 International classiﬁcation of vesico-ureteric reﬂux (grades I–V)

MANAGEMENT The management of VUR in children has been controversial.39 During the last three decades there have been over 5000 reports on this subject. There have been a number of studies that prospectively compared medical and surgical management of VUR. The Birmingham Reﬂux Study showed that more than one-half of the patients continued to show severe reﬂux after 5 years of medical treatment.40 A study from Toronto showed that 93% of the patients with grade IV and 83% of those with grade III VUR had persistent reﬂux after 2 years of observation therapy, and 70% with grade IV and 50% of those with grade III VUR had persistent reﬂux after 5 years of this therapy.41 The International Reﬂux Study in Children (European section of the study) showed that 128 (84%) out of the 153 children with grade II and IV reﬂux randomly allocated to medical treatment still had reﬂux after 5 years.42 In those with bilateral reﬂux, 91% of the patients had persistence of the reﬂux after 5 years. The American Urological Association (AUA) reported a reﬂux resolution of 9.9% in bilateral grade IV VUR after 5 years of medical therapy.43 All of these studies further showed that the observation therapy does carry an ongoing risk of renal scarring. In the literature, at least a quarter of neonates and infants with reﬂux have experienced a UTI while on antimicrobial prophylaxis. A question that is often asked in relation to these patients is: how long should they be followed? Is there a role for surgical treatment? Ureteral reimplantation certainly is an option, but it has a higher risk for complication in infants compared to older children with similar grades of reﬂux. In 1984, Puri and O’Donnell demonstrated the effectiveness of an endoscopic approach for the treatment of VUR by injecting a small bead of Teﬂon paste behind the reﬂuxing ureteric oriﬁce to provide support and partial closure of the abnormal ureteric oriﬁce.44,45 Endoscopic treatment of VUR is safe, is a simple daycare procedure, and is effective in correcting all grades of

reﬂux.46 The author treats high-grade reﬂux (grade IV–V) in infants older than 3 months by endoscopic subureteric Teﬂon injection (STING) and more recently by Deﬂux injection.47 Recently, Puri and Granata reported the results of a multicenter survey of endoscopic treatment of VUR using polytetraﬂuoroethylene (PTFE) in 8332 children (12 251 reﬂuxing ureters).48 A total of 53 pediatric urologists and pediatric surgeons at 41 centers worldwide answered an enquiry regarding experience with STING in treatment of VUR. The authors reported that the reﬂux resolved after one subureteral Teﬂon injection in 75.3%, after two in 12.1%, and after three or four injections in 2% of the patients, respectively. The ureteral reimplantations were performed in 4.5% of patients who failed to correct the reﬂux by Teﬂon injection. No clinically untoward effects were reported in any patient from the use of Teﬂon as an injectable material. Teﬂon paste has been used in vocal and cord surgery and for stress incontinence for over 30 years, and has not been associated with signiﬁcant complications.49 Most urologists acknowledge the success of STING, a 15-minute outpatient endoscopic procedure to correct reﬂux.39 However, some have been concerned by the use of PTFE paste as the implanted substance because distant migration of PTFE particles after periurethral, periureteral, and intravenous injection has been reported in animal studies.50,51 Distant particle migration has been reported more often with solid plastic implants, such as breast prosthesis, artiﬁcial sphincters, hemodialysis tubing and even intravenous line tubing than with injectable biomaterials. Miyakita and Puri performed a detailed experimental study in two animal species to determine whether polytetraﬂuoroethylene particles migrate to the lungs and brain after subureteral injections of PTFE paste.52,53 They showed that the subureteral injection of PTFE paste in minimal doses that are accurately placed in the subureteral region is not associated with the distant migration of particles. In another study, Miyakita and co-workers injected PTFE paste intravascularly in dogs in order to investigate its effects on brain parenchyma.53 They found that, after intravenous injection, there was no evidence of migration of PTFE to the brain. Small quantities of PTFE injected into the carotid arteries were associated with a local foreign body reaction, but no brain parenchymal damage was found. In recent years a number of other tissue-augmenting substances have been used endoscopically for the subureteral injection in the correction of VUR. Cross-linked bovine collagen has been used as an injectable material for the endoscopic treatment of VUR. Initially collagen appeared promising for the correction of low-grade reﬂux in short-term studies. However, long-term studies have shown that collagen is not an ideal tissue-augmenting substance; it has a documented tendency to disappear with time, resulting in recurrence of reﬂux.

842 Vesico-ureteric reﬂux

Recently, polydimethylsiloxane and dexranomer in sodium hylauronan (Deﬂux) were used in endoscopic correction of reﬂux. Their physical properties are similar to those of Teﬂon. However, there are no long-term follow-up studies available with these injectable materials for the treatment of VUR. Recently, Caldamone and Diamond reported endoscopic injection of autologous chondrocytes to correct VUR in children during a greater than 1-year follow-up.54 Reﬂux correction was maintained in 70% of ureters and 65% of patients. There were no signiﬁcant complications. These initial results with cultured chondrocytes appear promising. The long-term results are awaited. The technique of endoscopic injection of Poyltef paste is simple and straightforward. A disposable 4 Fr gauge Puri catheter (Storz, Tuttlingen, W. Germany) is ﬁrst ﬁlled with Polytef paste (Mentor Inc., Hingham, MA, USA) with a 1 ml tuberculin syringe with a metallic sheath and piston (Storz). The catheter is then introduced through a cystoscope. The 4 Fr catheter can easily be introduced through a 10 Fr cystoscope without removing the telescope. Under direct cystoscopic vision, the needle is introduced under the bladder mucosa 2–3 mm below the affected ureteric oriﬁce at the 6 o’clock position (Fig. 89.5a). The needle is advanced about 4–5 mm into the lamina propria in the submucosal position

Figure 89.5 Technique of endoscopic subureteric injection: (a) the site of insertion of needle; (b) appearance of ureteric oriﬁce at completion of injection

of the ureter and the injection started slowly. As the paste is injected, a bulge appears in the ﬂoor of the submucosal ureter. During injection, the needle is slowly withdrawn until a ‘volcanic’ bulge of paste is seen. The needle should be kept in position for about 30–60 s after injection to avoid extrusion. When injection is complete, the ureteric oriﬁce should look slit-like (Fig. 89.5b). In recent years the author has used Deﬂux as an injectable material and found it to be an effective tissue – augmenting substance in the endoscopic treatment of all grades of VUR.55 The patient is usually discharged from the hospital on the day of the procedure. Cotrimoxazole of the preoperative antibiotic is prescribed for 12 weeks after the procedure. Patients undergo micturating cystography and ultrasonography 3 months after discharge. If negative, ultrasonography and DMSA scan are repeated a year after STING and annually thereafter. Micturating cystogram is again performed 3 years after STING.

REFERENCES 1. Report of the International Reﬂux Committee Medical versus surgical treatment of primary vesicoureteral reﬂux. Pediatrics 1981; 67:392–400. 2. Gleeson FV, Gordon I. Imaging in urinary tract infection. Arch Dis Childh 1991; 66:1282–3. 3. Sweeney B, Cascio S, Velayudham M, Puri P. Reﬂux nephropathy in infancy: A comparison of infants presenting with and without urinary tract infection. J Urol 2001; 166:648–50. 4. Bailey RR. End-stage reﬂux nehropathy. Nephron 1981; 27:302–6. 5. Bailey RR. Vesico-ureteric reﬂux and reﬂux nephropathy. In: Schrier RW, Gottschalr VCW, editors. Diseases of the kidney, 4th edn. Boston: Little, Brown, 1988: 747–83. 6. Holland NH, Kotchen R, Bhathenn D. Hypertension in children with chronic pyelonephritis. Kidney Int 1975; S242–51. 7. Goonasekera CDA, Dillon MJ. Hypertension in reﬂux nephropathy. BJU Int 1999; 83:1–12. 8. de Vargas A, Evans K, Ransley P et al. A family study of vesicourfeteric reﬂux. J Med Genet 1978; 15:85. 9. Peeden JN, Noe HN. Is it practical to screen for familial vesicoureteral reﬂux within a private pediatric practice? Pediatrics 1992; 89:758. 10. Noe HN. The long-term results of prospective sibling reﬂux screen. J Urol 1992; 148:1739–2742. 11. Puri P, Cascio S, Lakshmandass G, Colhoun E. Urinary tract infection and renal damage in sibling vesicoureteral reﬂux. J Urol 1998; 160:1028–30. 12. Belman AB, Skoog SJ. Nonsurgical approach to the management of vesicoureteral reﬂux in children. Pediatr Infect Dis J 1989; 8:556–9. 13. Roberts JA. Etiology and pathophysiology of pyelonephritis. Am J Kidney Dis 1991; 17:1.

References 843 14. Rushton HG, Majd M. Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J Urol 1992; 148:1726. 15. Winberg J, Bollgren I, Kallenius G et al. Clinical pyelonephritis and focal renal scarring. A selected review of pathogenesis, prevention and prognosis. 1982. 16. Berg UB. Long-term follow-up of renal morphology and function in children with recurrent phyelonephritis. J Urol 1992; 148:1715. 17. Allen TD, Arant BS Jr, Roberts JA. Commentary: vesicoureteral reﬂux – 1992. J Urol 1992; 148:1758–60. 18. Sillen U, Hjalmax K, Aili M et al. Pronounced detrusor hypercontractility in infants with gros bilateral reﬂux. J Urol 1992; 148:598. 19. Sillen U. Bladder dysfunction in children with vesicoureteric reﬂux. Acta Paediatr 1999; Suppl. 88:40–7. 20. Yeung CK, Godley MI, Dhillon HK et al. Urodynamic patterns in infants with normal lower urinary tracts or primary vesico-ureteric reﬂux. Br J Urol 1998; 81:461–7. 21. Willemsen J, Nijman RJ. Vesicoureteral reﬂux and videourodynamic studies: results of a prospective study. Urology 2000; 55:939–43. 22. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reﬂux and urinary tract infections in children. J Urol 1998; 160:1019–22. 23. Sillen U. Vesicoureteral reﬂux in infants. Pediatr Nephrol 1999; 13:355–61. 24. McKenna PH, Herndon A. Voiding dysfunction associated with incontinence, vesicoureteral reﬂux and recurrent urinary tract infections. Curr Opinion in Urol 2000; 10:599–606. 25. Greenﬁeld SP, Wan J. The relationship between dysfunctional voiding and congenital vesicoureteral reﬂux. Curr Opinion in Urol 2000; 10:607–10. 26. Elder JS. Commentary: importance of antenatal diagnosis of vesicoureteral reﬂux. J Urol 1992; 148:1750–4. 27. Elder JS. Guidelines for consideration for surgical repair of vesicoureteral reﬂux. Cur Opin Urol 2000; 10:579–85. 28. Najamaldin A, Burge DM, Atwell JD. Fetal vesicourteric reﬂux. Br J Urol 1990; 65:403–6. 29. Gordon AC, Thomas DFM, Arthur RJ et al. Prenatally diagnosed reﬂux, a follow-up study. Br J Urol 1990; 65:407–12. 30. Anderson PAM, Rickwood AMK. Features of primary vesicoureteric reﬂux detected by prenatal sonography. Br J Urol 1991; 67:267–71. 31. Steele BT, Robintalle P, Demaria J et al. Follow-up evaluation of prenatally recognized vesicoureteric reﬂux. J Pediatr 1989; 115:95–6. 32. Jureidine KF, Hogg RJ, Cocklington RA et al. Screening for early detection of renal damage in children. Kidney Int 1988; 33:137. 33. Blane CE, DiPietro MA, Zerin JM et al. Renal sonography is not a reliable screening examination for vesicoureteral reﬂux. J Urol 1993; 150:752–5.

34. Rushton HG, Majd M. Pyelonephritis in male infants: how important is the foreskin? J Urol 1992; 148:733–6. 35. Cascio S, Colhoun E, Puri P. Bacterial colonization of the prepuce in boys with vesicoureteral reﬂux who receive antibiotic prophylaxis. J Pediatr 2001; 139:1, 160–2. 36. Yeung CK, Godley ML, Dhillon HK et al. The characteristics of primary vesico-ureteric reﬂux in male and female infants with pre-natal hydronephrosis. Br J Urol 1997; 80:319–27. 37. Nguyen HT, Bauer SB, Peters CA et al. 99mTc technetium dimercapto-succinic acid renal scintigraphy abnormalities in infants with sterile high grade vesicoureteral reﬂux. J Urol 2000; 164:1674–9. 38. Goldraich NP, Ramos OL, Goldraich IH. Urography versus DMSA scan in children with vesicoureteric reﬂux. Pediatr Nephrol 1989:3:1–5. 39. Puri P. Endoscopic correction of vesicoureteral reﬂux. Cur Opin Urol 2000; 10:593–7. 40. Birmingham Reﬂux Study Group. Prospective trial of operative versus nonoperative treatment of severe vesicoureteric reﬂux in children: ﬁve years observations. Br Med J 1987; 295:237–41. 41. McLorie GA, McKenna PH, Jumper BM et al. High grade vesicoureteric reﬂux: analysis of observation therapy. J Urol 1990; 144:537–40. 42. Tamminen-Mobius T, Burnier E, Ebel KD et al. on behalf of the International Reﬂux Study in Children. Cessation of vesicoureteral reﬂux for 5 years in infants and children allocated to medical treatment. J Urol 1992; 148:1662–6. 43. American Urological Association. Report on the management of primary vesicoureteral reﬂux in children. American Urological Association, Baltimore, Maryland, 1997. 44. Puri P, O’Donnell B. Correction of experimentally produced vesico-ureteric reﬂux in the piglet by intravesical injection of Teﬂon. Br Med J 1984; 289:5–9. 45. O’Donnell B, Puri P. Treatment of vesicoureteric reﬂux by endoscopic injection of Teﬂon. Br Med J 1984; 289:7–9. 46. Puri P, Ninjan GK, Surana R. Subureteric Teﬂon injection (STING): Results of a European Survey. Eur Urol 1995; 27:71–5. 47. Puri P, Palanimuthu M, Dass L. Endoscopic treatment of primary vesicoureteric reﬂux in infants by subureteric injection of polytetraﬂuorethylene: a nine year follow-up. Eur Urol 1995; 27:67–70. 48. Puri P, Granata C. Multicenter survey of endoscopic treatment of vesicoureteral reﬂux using polytetraﬂuoroethylene. J Urol 1998; 160(3 Pt 2):1007–11 discussion 1038. 49. Becmeur F, Geiss S, Laustriat S et al. History of Teﬂon. Eur Urol 1980; 17:229–231. 50. Kershen RT, Atala A. New advances in injectable therapies for the treatment of incontinence and vesicoureteral reﬂux. Urol Clin North Am 1999; 26(1):81–6. 51. Peters CA. Why use Teﬂon® in Children? Dialog Ped Urol 1991; 14:4–7.

844 Vesico-ureteric reﬂux 52. Miyakita H, Puri P. Particles found in lung and brain following subureteral injection of polytetraﬂuoroethylene paste are not teﬂon particles. J Urol 1994; 152(2 Pt 2):636–8. 53. Miyakita H, O’Briain DS, Puri P. Absence of brain parenchymal damage following intravascular injection of polytetraﬂuoroethylene paste. Eur Urol 1998; 34(3):233–5.

54. Caldamone AA, Diamond DA. Long-term results of the endoscopic correction of vesicoureteral reﬂux in children using autologous chondrocytes. J Urol 2001; 165:2224–6. 55. Puri P, Chertin B, Velayudham M et al. Treatment of vesicoureteral reﬂux by endoscopic injection of Dextranomer/Hyaluronic acid Copopolymer (Deﬂux): Preliminary results. J Urol (In press).

90 Ureteroceles in the newborn PETER FREY, MARIO MENDOZA-SAGAON AND BLAISE J. MEYRAT

INTRODUCTION Ureteroceles are congenital cystic balloonings of the terminal intravesical portion of the ureter. The ureteral oriﬁce, often extremely difﬁcult to visualize, may be partially or totally obstructed. Ureteroceles vary in size and position. They can occupy the whole bladder, occasionally projecting into the bladder neck or posterior urethra.

PATHOGENESIS Although the oriﬁce of the ureterocele-bearing ureter looks anatomically obstructive, there is often no evidence of clinical obstruction. The theory of embryological obstruction therefore seems to be only of limited relevance, especially as the ureteral dilatation remains strictly localized. The fact that acquired obstruction leads to hydroureter and hydronephrosis only and not to ureterocele formation does not support the obstruction theory either. It may, however, explain the formation of intravesical single-system ureteroceles. Chwalla1 and Ericsson2 attributed the ureterocele formation to the persistence of Chwalla’s membrane, an epithelial sheet separating the lumen of the distal portion of the Wolfﬁan duct and the urogenital sinus, which normally disappears spontaneously, approximately 2 months after conception. Stephens,3 however, postulates that the terminal ureter is caught in the expansion stimulus to the bladder growth and therefore undergoes extensive enlargement resulting in the formation of the ureterocele. Tanagho4 suggests that the ureterocele forms secondarily to local dilatation of the ureteral bud, well before its migration from the Wolfﬁan duct. Tokunaka and colleagues5 could demonstrate poor muscle development in the dome of the ureterocele compared to the distal ureter, and suggest that ureterocele formation is based on a segmental embryonic arrest of the development of the most distal portion of the ureter. The above

theories regarding the pathogenesis of the ureteroceles are still only speculations.

Pathological anatomy and associated pathology Ureteroceles can be attached to the terminal ureter draining the upper moiety of a duplex collecting system or to the ureter of a single system. According to Caldamone6 and Frey,7 duplex system ureteroceles occur in approximately 85% of diagnosed cases, and can vary in size and position. Occasionally, they are small and well demarcated from the bladder wall. In the extreme, they present as huge, undemarcated subtrigonal masses. The swelling may also protrude towards the contralateral ureteral oriﬁce obstructing the latter or, even more important, may induce complete bladder outlet obstruction. However, more often the ipsilateral oriﬁce of the ureter draining the lower pole is pulled upwards by the distended ectopic ureterocele, and therefore the suburothelial tunnel becomes shortened, and reﬂux and subsequent megaureter and hydronephrosis can develop. On the contralateral side, reﬂux and secondary hydronephrosis can occasionally be seen. This is probably due to the disruption of the trigonal symmetry. If the ectopic oriﬁce is distal to the urethral sphincter mechanism, continuous incontinence is present. However, sporadic intermittent incontinence can also be observed, probably as a consequence of the interaction with the trigonum too. The function of the upper renal moiety – being nearly always dysplastic – is absent in over 80% of cases or, if present, is drastically reduced.6,7 Ureteroceles are attached to single collecting systems in approximately 15% of cases.6,7 Often, the cystic swelling is asymmetrical and the ureteral oriﬁce is placed on its slopes in an eccentric position. The wall of the ureterocele consists of a ﬁbrous, muscular middle part lined with ureteral and bladder urothelium on either side, respectively. They are usually smaller in size than ectopic ureteroceles. In the single-system group, the size might be in relation to the degree of obstruction caused by the pinpoint oriﬁce.8

846 Ureteroceles in the newborn

These ureteroceles rarely prolapse causing bladder neck obstruction. Reﬂux is extremely uncommon. An over-full bladder can induce eversion of the ureterocele, mimicking bladder diverticulum formation. Although the ureter and pelvicalyceal structures are distended to different degrees, function of the renal unit is often within clinically acceptable limits for the kidney to be preserved.

CLASSIFICATION Ericsson,2 in 1954, classiﬁed ureteroceles into orthotopic or simple and ectopic: orthotopic if the ureter forming the ureterocele ends in a normal or next to the normal site in the bladder; ectopic if the ureterocele extends and opens into the bladder neck or posterior urethra. Regarding duplex systems, Stephens3 classiﬁed ureteroceles of the upper renal pole ureter as stenotic if the oriﬁce lies within the bladder being the site of obstruction, sphincteric if the oriﬁce is in the urethra distal to the sphincter, sphincterostenotic if both characteristics are present. In very rare instances when the ureterocele protrudes as a long tongue-like structure into the urethra, Stephens applied the term ‘coeco-ureterocele’. These traditional classiﬁcations, either based on the location of the ureteral oriﬁces or on the anatomical description, can be confusing. The best classiﬁcation to date is based on the report of the Committee on Terminology, Nomenclature and Classiﬁcation of the Urology Section of the American Academy of Pediatrics.9 It subdivides ureteroceles based on: • the number of ureters that drain the kidney ipsilateral to the ureterocele • the location and extent of the ureterocele • the additional anatomic distortions of the ureterocele resulting from eversion, prolapse, or secondary incompetence or obstruction of the other ureteral oriﬁce or the bladder neck. Thus, a duplex-system ureterocele is when the ureterocele is attached to the upper pole ureter of a completely duplicated collecting system, and a single-system ureterocele is when the ureterocele is attached to a single ureter draining the kidney. Regarding the location and extension, if the ureterocele and its oriﬁce are located entirely within the bladder, the term intravesical is used. If the ureterocele and its oriﬁce extends beyond the trigone to the bladder neck or outside of the bladder to involve the urethra the term ectopic is applied. Intravesical ureteroceles are usually associated with single systems, but may also be associated with the upper moiety ureter of a duplex system (Fig. 90.1). Similarly, ectopic ureteroceles are usually associated with the upper pole ureter of a duplex-system but also could be present in a single system.10

Figure 90.1 Ectopic ureterocele in relation to the upper moiety of a duplex collecting system

‘Simple’ or ‘adult-type’ single-system intravesical ureteroceles are extremely rare in children. The oriﬁce of this type of ureterocele is not intrinsically obstructed and therefore may not be associated with hydronephrosis or renal dysplasia.10

INCIDENCE According to Malek and Utz,11 the incidence is one in 5000–12 000 pediatric admissions. Genton and Markwalder12 reported an incidence of one in 1500 admissions, being probable closer to the true incidence which seems to be commonly understated. Campbell13 reported one in 4000 autopsies. Moreover, he observed ureteroceles in 3.5% of all children presenting with persistent pyuria. Duplex-system ectopic ureteroceles are four to seven times more common in females than in males, but the condition is more complex in boys.14 Conversely, single-system intravesical ureteroceles appears to have a slightly male predilection.10 Both kidneys are equally affected. Unlike intravesical ureteroceles, 80–95% of ectopic ureteroceles are associated with an upper renal pole ureter of a duplex system.15 Bilateral ureteroceles are found in approximately 10% of cases.8

Clinical presentation 847

CLINICAL PRESENTATION The most common clinical presentation of ureteroceles in infants and children – if not diagnosed prenatally – is the urinary tract infection in 39–73.5% of the cases7,16–18 Sepsis, hematuria, urinary incontinence, and/or ﬂank pain can be present. Non-speciﬁc symptoms such as failure to thrive, irritability or recurrent vomiting – typical of post-renal failure due to obstruction – should instigate further investigation of the urinary tract. In cases of severe obstruction and consequent gross megaureter and hydronephrosis, a palpable mass may be present in the loin or in the pelvis. In baby girls, the ureterocele may prolapse through the urethra and can be seen as a temporarily vaginal or vulvar mass (Fig. 90.2). The extremely rare paraurethral cyst and the hydrocolpos have to be considered in the differential diagnosis. Prolapsing botryoid sarcoma has to be excluded. Figure 90.3 Antenatal ultrasonography. Ureterocele in the fetal bladder as seen in the 30th gestational week

Figure 90.2 Prolapsing ureterocele in a female newborn

DIAGNOSIS Ureteroceles can either be diagnosed in the antenatal or in the immediate postnatal period. After the 30th week of pregnancy the ureterocele may occasionally be demonstrated in the fetal bladder (Fig. 90.3). More often, however, the antenatal ultrasonogram performed after the 16th gestational week shows a cystic swelling of the fetal kidney and the deﬁnite diagnosis of hydronephrosis and its causative pathology can only be established by immediate postnatal investigations (Fig. 90.4). These investigations consist of ultrasonography, intravenous

Figure 90.4 Antenatal ultrasonography. Fetal kidney with cystic, pelvic dilatations (hydronephrosis)

pyelography, micturition cystourethrography and cystoscopy. In addition, DMSA, DTPA or MAG3 renal scintigraphy should be used to detect renal scarring, to evaluate renal function and degree of ureteral obstruction (Fig. 90.5). Occasionally, the ureterocele can even be demonstrated on the renogram.

848 Ureteroceles in the newborn

Figure 90.5 Isotope scan (DMSA) demonstrating the ureterocele (uptake defect in the bladder) and the non-function of the upper renal moiety

Ultrasonographic ﬁndings are of a cystic mass within the bladder (Fig. 90.6). Dilatation of the associated ureter and pelvicalyceal structures can be demonstrated. Intravenous urography (IVU) shows a ﬁlling defect within the bladder varying in size and position. It is of importance to know that on late radiographs, at a state when the bladder is completely ﬁlled with contrast medium, the ﬁlling defect representing the ureterocele can be masked. The ectopic ureterocele is seen as a ﬁlling defect placed eccentrically along the bladder wall extending into the bladder neck or into the posterior urethra (Fig. 90.7). The intravesical ureterocele, however, is surrounded by contrast medium demonstrating most of its circumference. In the presence of a single-system ureterocele and very rarely of a duplex system ureterocele, delayed excretion of contrast medium and hydronephrosis of different degrees are seen (Fig. 90.8a,b). If the ureterocele is attached to a duplex system, the upper renal pole – generally hydronephrotic due to the ureterocele obstruction – pulls downwards the lower renal portion of the collecting system which could be also hydronephrotic due to obstruction and/or reﬂux, and shows the typical radiological ‘drooping lily’ sign (Fig. 90.7). The total amount of visible calyces is reduced. Depending on the renal function, the contrast excretion of the upper moiety can be absent (the upper moiety is then often dysplastic), or is delayed, showing a grossly dilated pelvis and ureter. With the micturition cystogram, possible reﬂux into the different renal units

Figure 90.6 Postnatal ultrasonography. Ureterocele within the bladder

Figure 90.7 Intravenous urography. Eccentric ﬁlling defect in the bladder representing an ectopic ureterocele. The radiological sign of the ‘drooping lily’ suggests the presence of a duplex system kidney with a non-functioning upper moiety, which is in relation to the ureterocele. Note the reduced amount of calyces

Surgical treatment 849

particular cases where conventional imaging failed to be conclusive. Cystoscopy often leads to the diagnosis of small ureteroceles that are not detected by ultrasound or by IVU. The bladder should always be inspected carefully in different ﬁlling states in order not to miss ureteroceles which are compressed or even everted – mimicking a paraureteral diverticulum – by high intravesical ﬁlling pressures.

SURGICAL TREATMENT

(a)

Ureteroceles are, in the majority of cases, complex anomalies often associated with induced secondary pathology. Although considerable controversy still exists regarding their best treatment, the ﬁnal aims of the surgical treatment are to relieve obstruction and preserve renal function. Four major pathological entities have to be taken into account in the planning of the correct surgical treatment:20 • the degree of renal dysplasia and its resulting loss of renal function • the presence of reﬂux into the ureterocele-bearing ureter, the ipsilateral ureter and/or the contralateral ureter • the altered trigonal anatomy as well as the weakness of the detrusor muscle backing the ureterocele • the degree of obstruction caused by the prolapsing or ballooning ureterocele. A standardized approach is probably impossible and it seems reasonable to individualize the management according to the aspect of each particular case.

Intravesical ureteroceles

(b) Figure 90.8 Intravenous urography. (a) Intravesical ureterocele attached to a single collecting system ureter. Note the radiological sign of the ‘cobra head’. (b) Intravesical ureterocele attached to the ureter of the upper moiety of a duplex collecting system. Note the presence of function in the upper renal moiety

can be assessed, bearing in mind that reﬂux into the contralateral ureter can be present. Recent studies have estimated that, in children with a ureterocele, 50% will have reﬂux into the ipsilateral lower pole, 25% into the contralateral ureter, and 10% into the ureterocelebearing ureter.19 In addition, magnetic resonance imaging may help to delineate detailed anatomy in

Generally, intravesical ureteroceles in neonates can easily be treated only by endoscopic puncture or incision, which is the least invasive approach and is associated with minimal morbidity.21–23 This procedure can be performed with the patient under general or regional anesthesia, on a same-day surgery or outpatient basis.22 Satisfactory postoperative urinary tract decompression has been reported between 85 and 100%.22–24 Moreover, recovery of renal function following endoscopic puncture or incision has been reported.22,23 Although endoscopic puncture or incision may be considered as the only treatment, sometimes a second surgery may become necessary in 17–18% of cases.19,25 Postoperative VUR has been reported between 6 and 40% and almost half of them require a second lower urinary tract surgery.21–24,26 If renal function is severely compromised, a ureteronephrectomy may be indicated. Due to the high association of postoperative VUR, ureterocele unrooﬁng is now rarely performed.

850 Ureteroceles in the newborn

Ectopic ureteroceles For the treatment of duplex system ureteroceles, three surgical options are available: • Heminephrectomy with partial or total ureterectomy, allowing the ureterocele to collapse. • Total correction, which consists of ureterocele enucleation – including detrusor muscle reconstruction – ureteral reimplantation of the lower pole ureter and upper heminephroureterectomy. • Incision or unrooﬁng of the ureterocele either as an endoscopic procedure or by open surgery. Duplex-system ectopic ureteroceles could be treated by an upper pole heminephro-ureterectomy alone – if preoperative VUR is not present – or associated with enucleation of the ureterocele, ureteral reimplantation, and/or reconstruction of the urethra, bladder neck and trigone as a second-stage treatment (primary total correction).17,27,28 Heminephro-ureterectomy alone seems to be indicated also for smaller size ureteroceles if the risk of secondary diverticula formation and obstruction due to prolapse of the remaining mucosal folds is minimal. Moreover, one can postulate that heminephroureterectomy could be performed as a primary treatment in all cases awaiting the outcome, which then will dictate any necessary secondary treatment. If required, a ureteropyelostomy or uretero-uretero anastomosis – if an acceptable upper renal pole function exists – can be performed as secondary procedures. A temporary ureterostomy is only very rarely indicated in severely infected cases. In accordance with Hendren and Mitchell,29 we generally favor the technically demanding primary total correction treatment, fulﬁlling the aim of early establishment of normal anatomy and function as close as possible. There is no doubt that transurethral endoscopic incision or unrooﬁng of the ureterocele serves as standard emergency treatment of severely infected cases such as pyonephrosis. This treatment is also indicated in obstructing ureteroceles, so as to release the acute high pressure in the upper renal tract. Controversy still exists regarding the advantages of the endoscopic puncture or incision of ectopic ureteroceles as a ‘ﬁrst-stage’ treatment, principally due to the high association of postoperative reﬂux and secondary operations.19,26,30,31 Surgeons in favor of the endoscopic puncture or incision ‘ﬁrst-stage’ treatment in neonates with ectopic ureteroceles, suggest that: 1 Approximately one-third of these patients will be deﬁnitively treated by this technique 2 Early renal and ureteral decompression will allow improvement or stabilization of renal function, as well as a decreased risk of pyelonephritis 3 It allows a delay for a deﬁnitive surgical correction, if necessary, with a technical easier operation after the

neonatal period due to bladder growth, as well as a decreased distention of the affected ureter 4 Upper pole heminephrectomy will be associates to a secondary open procedure at the bladder level in 10–50% of cases and these percentages could be increased if vesico-ureteral reﬂux is presented preoperatively 5 Elective total reconstruction will require two open procedures, while primary endoscopic treatment will require only an associated open procedure (usually at the lower urinary tract) in 50–80% of cases 6 Upper pole heminephrectomy increases the risk of lower pole renal atrophy due to vascular compromise.19,26,27,30,32–34 However, additional long-term results and follow-up studies are mandatory to support these proposals. Three series of long-term follow-up endoscopic incision of ectopic ureteroceles have reported a postoperative nephroureteral decompression in 80–100% of cases, postoperative VUR into the ureterocele and upper pole segment in 32–48% of cases and a second operation rate (lower urinary tract surgery in the majority of cases due to recurrent infection and vesico-ureteral reﬂux) of 64–83.3%.19,27,32

Preoperative preparation It is important to correct any ﬂuid or electrolyte imbalances of the neonate preoperatively. Good vascular access and all modern monitoring of pediatric anesthesia is mandatory. Although blood transfusion rarely becomes necessary if applying an adequate operative technique, blood should always be cross-matched. If a non-endoscopic technique will be performed, the bladder is catheterized and instilled preoperatively to facilitate its opening. The skin areas surrounding the planned incisions are prepared twice with concentrated Betadine solution and covered with an Opsite® drape.

Endoscopic puncture or incision With improvements in urologic endoscopic technology, a more conservative approach in ureterocele management is feasible. Several authors have demonstrated the advantages of the endoscopic incision of ureteroceles in the preservation of renal tissue.33,35,36 Several techniques of endoscopic puncture or incision of ureteroceles exist. Tank’s technique37 promotes a high, lateral incision placed far away from the bladder neck using the loop or Collins knife through a pediatric resectoscope. Scholtmeijer38 advocates the use of a diathermic hook, which is inserted in the existing obstructed ureteral oriﬁce and subsequently pulled vertically to create an incision. To date, the most common utilized techniques are those described by Monfort33 and

Surgical treatment 851

Rich.21 Monfort’s technique33 consists of a 2–3 mm low horizontal incision just above the bladder neck using a sharp electrode and a Charriere # 9, 0° cystoscope. Rich’s technique,21 consists of a same length incision using a Bugbee electrode through a 10 Fr Storz pediatric resectoscope, but just above the distal junction of the ureterocele with the bladder to avoid leaving a ﬂap of ureterocele that might obstruct the bladder outlet and to preserve a ﬂap valve of the collapsed ureterocele. A thin and sharp electrode can also be ‘constructed’ out of a ureteral catheter of which the very tip has been cut off and into which the guide wire, acting as an electrode, has been reinserted. All these techniques bear the risk of interfering with the structures of the lower pole oriﬁce, but Monfort’s and Rich’s techniques seems to be the safest due to less dissection of the uretero-vesical junction. Prior to any operation of duplex-system ureteroceles, the lower pole oriﬁce has to be visualized to prevent such damage. A post-incisional micturition cystogram is mandatory to detect reﬂux into the incised ureterocele, the contralateral ureter, and/or into the lower pole ureter in the case of a duplex system. If reﬂux develops – rarely seen in neonates and infants with single-system intravesical ureteroceles – and the renal function is acceptable we prefer to correct it endoscopically with a subureteral injection procedure.39

Ureterocele enucleation The patient is positioned ﬂat on the back and the buttocks are equally supported with a sandbag. This position brings the bladder forward and ‘out’ of the abdominal cavity, providing better access to the intravesical structures. Using a modiﬁed Pfannenstiel incision, the skin and the anterior rectus sheath are opened transversally. The recti are bluntly separated in the midline and the bladder is well mobilized laterally. Over the bladder dome the peritoneal covering has to be carefully stripped off, avoiding its rupture. The previously ﬁlled, catheterized bladder is incised longitudinally, taking care not to interfere with the bladder neck. The lower end of the incision is secured with a 5-0 resorbable monoﬁlament suture to prevent tearing into the bladder neck or urethral sphincter. The edges of the incised bladder are suspended and held open with 5-0 holding sutures over the Denis Browne ring retractor. The cranial blade, covered with a swab, is positioned inside the bladder dome, pulling it upwards and forwards, exposing the trigonal area. The ureterocele, the oriﬁce of the lower renal pole ureter – often hidden behind its wall – and the contralateral ureter are visualized (Fig. 90.9). Each ureter is catheterized with an infant feeding tube or a ureteral catheter. The dome of the ureterocele is held with a Babcock or Aliss clamp and the urothelium is incised in an elliptical fashion (Fig. 90.10a,b). A dissection plane between the wall of the

Figure 90.9 Operative treatment: intraoperative ﬁndings of a duplex system ectopic ureterocele

ureterocele from the urothelium and the detrusor muscle is performed (Fig. 90.10c). Once the ureterocele is freed completely, the remaining intramural ureter is mobilized (Fig. 90.10d). If the ureterocele is thin-walled or reaches well into the bladder neck or the posterior urethra, this procedure can be extremely difﬁcult to perform. Care has to be taken not to damage the urethral sphincter or its nerve supply. Once the ureterocele is resected, its backing detrusor muscle must be carefully reconstructed using 5-0 resorbable monoﬁlament sutures (Fig. 90.10e). This is to minimize diverticula formation and/or to prevent incontinence.40 In girls, damage of the underlying vagina has to be avoided during this procedure. At this stage the lower renal pole ureter is routinely reimplanted according to Cohen’s technique,41 creating a transverse submucosal tunnel (Fig. 90.10f). At this stage, the bladder is closed, applying a continuous resorbable monoﬁlament 5-0 suture to the mucosa and a running 4-0 suture to the muscular layer. The bladder is drained with a transurethral or a suprapubic Silastic balloon catheter. The reimplanted ureter is splinted and drained with a feeding tube or ureteral catheter for 6 days. A paravesical Redivac® or Mano-Vac® drain remains for 48 hours. The urethral or suprapubic catheter is removed 8–10 days postoperatively. Prophylactic antibiotics (e.g. amoxycilin) are administered perioperatively and are continued until absence of reﬂux is conﬁrmed with micturition cystography 6 months postoperatively. The ureterocele-bearing ureter, according to the function of the upper renal moiety, can be resected in the course of a subsequent heminephro-ureterectomy or brought out through a separate small groin incision to form a terminal ureterostomy. The latter procedure is advisable if recovery of the renal function, justifying the salvage of the upper renal pole, can be expected. However, if the upper moiety already shows adequate function, uretero-uretero anastomosis or primary reimplantation en bloc of the upper and lower pole ureters

852 Ureteroceles in the newborn

(a)

(b)

(c)

(d)

(e)

(f)

Figure 90.10 Operative treatment – ureterocele enucleation. (a) Planned elliptical incision on the dome of the ureterocele. (b) The ureterocele is held with a Babcock clamp and the elliptical incision is performed. (c) A plane between the wall of the ureterocele and the urothelium or the detrusor muscle, respectively, is dissected. (d) The intramural ureter of the upper moiety is mobilized, taking care not to damage the lower moiety ureter. (e) Reconstruction of the detrusor muscle backing the ureterocele and the urothelial defect. (f) The lower moiety ureter is reimplanted according to Cohen’s technique, creating a transverse suburothelial tunnel

can be performed. In the case of single-system ureterocele, renal function is normally preserved and, after enucleation of the ureterocele, straightforward ureteral reimplantation can be performed.

Heminephro-ureterectomy Surgical approach is through a transverse anterior ﬂank incision just below the palpable edge of the lowest rib.

The incision is started 1–2 cm lateral to the abdominal midline and extended laterally well over the ﬂank. After transection of the subcutaneous fat, the muscular layers are bluntly dissected in their anatomical direction, avoiding the blood loss often caused by sharp dissection. In neonates this exposure guarantees the same view as the commonly applied transmuscular cutting dissection used in older children. The peritoneum is then pushed gently towards the midline, avoiding its rupture. The wound is held open with a Denis Browne ring retractor. Gerota’s

References 853

(a)

(b)

Figure 90.11 Operative treatment – heminephrectomy. (a) Transverse resection of the affected upper renal moiety of a duplex system. (b) After haemostasis the renal parenchyma and the renal capsule are closed

fascia is exposed and opened posteriorly. The pararenal fat is dissected to expose the entire kidney, allowing the upper and lower renal pole blood supply as well as the origin of the two ureters to be visualized. The upper dilated ureter can easily be found and the upper renal moiety is usually anatomically demarcated from the lower segment by an obvious groove. Different color and consistency of the often dysplastic upper renal pole can be of additional help in the anatomical deﬁnition of the two segments. Sutures (3-0) are looped around the upper pole vessels and are held taut or, alternatively, the circulation of the upper pole is interrupted, applying small vascular clamps (bulldog clamps). If the resulting ischemic areas correspond to the anatomically suspected upper renal pole, the line of resection is deﬁned. In case the ischemic area remains smaller than the anatomical upper pole, one has to look for additional upper renal pole vessels often branching off the lower renal pole vessels within the hilar area. The upper renal pole vessels are tied and transﬁxed using 4-0 sutures (e.g. Maxon® or PDS®) and then cut. The renal capsule is incised transversally and peeled off towards both poles, a procedure not always easy to perform in scarred kidneys. The affected moiety is resected transversally – rather than by wedge incision – using the ‘hot knife’ or the diathermy needle (Fig. 90.11a). Bleeding vessels are diathermed or ligated by transﬁxion using absorbable 5-0 sutures. It is important to remove the entire pelvicalyceal structures of the upper renal pole and to carefully inspect the remaining kidney for opened lower pole calyces, which need to be closed meticulously with absorbable 5-0 sutures.

Once hemostasis is achieved, the renal capsule is approximated and sutured with a 4-0 absorbable running suture (Fig. 90.11b). If these sutures tear out, deep 3-0 catgut sutures are placed parallel to the resection line, acting as suspension for the closing sutures. This maneuver is to prevent further tearing out of the renal tissue and eases closure. Hemostatic agents or ﬁbrin sealing (Tissucol®) can occasionally be of additional help to control hemostasis. Heminephrectomy is now accomplished without having interrupted the circulation to the lower moiety. Following this procedure, the upper renal pole ureter is dissected towards its distal portion. The dissection line is kept close to the diseased ureter in order not to disturb the lower pole ureter blood supply. In neonates it is often technically possible to reach as far down as the uretero-vesical junction, where the ureter can be resected and transﬁxed with a 4-0 resorbable monoﬁlament suture. If this cannot be achieved through the original incision, a small transverse inguinal incision is performed, allowing the ureterovesical junction to be exposed. Once the heminephro-ureterectomy is completed, the renal fascia is closed after insertion of a pararenal drain and the muscular layers are approximated using continuous 4-0 or 5-0 resorbable monoﬁlament sutures. The subcutaneous tissues are adapted and the skin closed with an intradermal running absorbable or nonabsorbable monoﬁlament suture.

Open unrooﬁng Open unrooﬁng is only indicated in severely infected cases where endoscopic incision is impossible due to the miscorrelation of the anatomical size of the urethra and/or the non-availability of cystoscopy.

REFERENCES 1. Chwalla R. The process of formation of cystic dilatations of vesical end of ureter and of diverticula at ureteral ostium. Urol Cutan Rev 1927; 31:499. 2. Ericsson NO. Ectopic ureterocele in infants and children: a clinical study. Acta Chir Scand 1954; 197 (Suppl.):1. 3. Stephens FD. Caecoureterocele and concepts on embryology and aetiology of ureteroceles. Aust NZ J Surg 1971; 40:239–48. 4. Tanagho EA. Anatomy and management of ureteroceles. J Urol 1972; 107:729–36. 5. Tokunaka S, Gotoh T, Koyanagi T et al. Morphological study of the ureterocele: a possible clue to its embryogenesis as evidence by a locally arrested myogenesis. J Urol 1981; 126:726–9.

854 Ureteroceles in the newborn 6. Caldamone AA. Duplication anomalies of the upper tract in infants and children. Urol Clin N Am 1985; 12:75–91. 7. Frey P, Cohen SJ. Ureteroceles in infancy childhood: in search of the correct surgical approach. Experience in 61 cases. Pediatr Surg Int 1989; 4:175. 8. Innes Williams D. Ureteric duplications and ectopia. In: Innes Williams D, Johnston JH, editors. Paediatric Urology. 2nd edn. London: Butterworths, 1982:167–87. 9. Glassberg KI, Braren V, Duckett JW et al. Suggested terminology for duplex systems, ectopic ureters and ureteroceles. Report of the Committee on Terminology, Nomenclature and Classiﬁcation, American Academy of Pediatrics. J Urol 1984; 132:1153–4. 10. Zerin JM, Baker DR, Casale JA. Single-system ureteroceles in infants and children: imaging features. Pediatr Radiol 2000; 30:139–46. 11. Malek RS, Utz DC. Crossed, fused, renal ectopia with an ectopic ureterocele. J Urol 1970; 104:665–7. 12. Genton N, Markwalder F. Ureterozele. In: Bettex M, Genton N, Stockmann M, editors. Kinderchirurgie, 2nd edn. Stuttgart: Thieme, 1982: 8.98–8.104. 13. Campbell M. Ureterocele. A study of 94 instances in 80 infants and children. Surg Gynecol Obstet 1951; 93:705. 14. Eklöf O, Löhr G, Ringertz H et al. Ectopic ureterocele in the male infant. Acta Radiol (diagn.) (Stockh.) 1978; 19:145–53. 15. Brock WA, Kaplan WG. Ectopic ureteroceles in children. J Urol 1978; 119:800–3. 16. Shekarriz B, Upadhyay J, Fleming P et al. Long-term outcome based in the initial surgical approach to ureterocele. J Urol 1999; 162:1072–6. 17. De Jong TPVM, Dik P, Klijn AJ et al. Ectopic ureterocele: results of open surgical therapy in 40 patients. J Urol 2000; 164:2040–3. 18. Besson R, Tran Ngoc B, Laboure S et al. Incidence of urinary tract infection in neonates with antenatally diagnosed ureteroceles. Eur J Pediatr Surg 2000; 10:111–13. 19. Cooper CS, Passerini-Glazel G, Hutcheson JC et al. Longterm follow-up of endoscopic incision of ureteroceles: intravesical versus extravesical. J Urol 2000; 164:1097–9. 20. Kelalis PP. Renal pelvic and ureter. In: Kelalis PP, King LR, Belman AB, editors. Clinical Pediatric Urology. 2nd edn. Philadelphia: WB Saunders, 1985:672–725. 21. Rich MA, Keating MA, Snyder HM et al. Low transurethral incision of single system intravesical ureteroceles in children. J Urol 1990; 144:120–1. 22. Di Benedetto V, Morrison-Lacombe G, Begnara V et al. Transurethral puncture of ureterocele associated with single collecting system in neonates. J Pediatr Surg 1997; 32:1325–7. 23. Pﬁster C, Ravasse P, Barret E et al. The value of endoscopic treatment for ureteroceles during the neonatal period. J Urol 1998: 159:1006–9.

24. Jelloul L, Berger D, Frey P. Endoscopic management of ureteroceles in children. Eur Urol 1997; 32:321–6. 25. Pesce C, Musi L, Campobasso P et al. Endoscopic and minimal open surgical incision of ureteroceles. Pediatr Surg Int 1998; 13:277–80. 26. Blyth B, Passerini-Glazel G, Camuffo C et al. Endoscopic incision of ureteroceles: intravesical versus ectopic. J Urol 1993; 149:556–9. 27. Jayanthi VR, Koff SA. Long-term outcome of transurethral puncture of ectopic ureteroceles. Initial success and late problems. J Urol 1999; 162:1077–80. 28. Coplen DE, Spencer-Barthold J. Controversies in the management of ectopic ureteroceles. Urology 2000; 56:665–8. 29. Hendren WH, Mitchell ME. Surgical correction of ureteroceles. J Urol 1979; 121:590–7. 30. Smith C, Gosalbez R, Parrott TS et al. Transurethral puncture of ectopic ureteroceles in neonates and infants. J Urol 1994; 152:2110–12. 31. Spencer Barthold J. Editorial: Individualized approach to the prenatally diagnosed ureterocele. J Urol 1998; 159:1011–12. 32. Di Benedetto V, Monfort G. How prenatal ultrasound can change the treatment of ectopic ureterocele in neonates? Eur J Pediatr Surg 1997; 7:338–40. 33. Monfort G, Morrisson-Lacombe G, Coquet M. Endoscopic treatment of ureteroceles revisited. J Urol 1985; 133:1031–3. 34. Gotoh T, Koyanagi T, Matsuno T. Surgical management of ureteroceles in children: strategy based on the classiﬁcation of ureteral hiatus and the eversion of ureteroceles. J Pediatr Surg 1988; 23:159–65. 35. Di Benedetto V, Meyrat BJ, Sorrentino G, Monfort G. Management of ureteroceles detected by prenatal ultrasound. Pediatr Surg Int 1995; 10:485. 36. Patil U, Mathews R. Minimal surgery with renal preservation in anomalous complete duplicated systems. J Urol 1995; 154:727–8. 37. Tank ES. Experience with endoscopic incision and open unrooﬁng of ureteroceles. J Urol 1986; 136:241–2. 38. Scholtmeijer RJ. Surgical treatment of ureteroceles in childhood – a reappraisal. Z Kinderchir 1987; 42:103–8. 39. Frey P, Berger D, Jenny P et al. Subureteral collagen injection for the endoscopic treatment of vesicoureteral reﬂux in children. Follow-up study of 97 treated ureters and histological analysis of collagen implants. J Urol 1992; 148:718–23. 40. Gomez F, Stephens GD. Cecoureterocele: morphology and clinical correlations. J Urol 1983; 129:1017–19. 41. Cohen SJ. The Cohen technique of ureteroneocystostomy. In: Eckstein HB, Hohenfellner R, Williams DI, editors. Surgical Pediatric Urology. Stuttgart: Thieme, 1977: 269–74.

91 Congenital posterior urethral obstruction REISUKE IMAJI, DANIEL MOON AND PADDY A. DEWAN

INTRODUCTION

INCIDENCE

Posterior urethra obstruction continues to be a signiﬁcant cause of morbidity, mortality, and ongoing disability in the pediatric age group. Boys with obstructive uropathy and dysplasia represent the single largest group of children undergoing renal dialysis and transplantation under 5 years of age. End-stage renal disease develops in a signiﬁcant proportion (30–42%).1–4 Even with this clinical signiﬁcance, and the fact that the condition has been recognized for well over 150 years, our understanding of the embryology, developmental anatomy, and treatment remains limited.

The true incidence of congenital posterior urethral obstruction is difﬁcult to ascertain. Most authors believe that only those with typical appearance on micturating cystourethrograms should be counted. However, some authors have reported the lesion is more common than previously thought.20–22 The often-quoted incidence of posterior urethral obstruction is one in 5000 to one in 8000 infant males, and multicenter review in the British Isles between 1970 and 1980 estimated the incidence to be approximately one in 25 000 live births.23

EMBRYOLOGY HISTORICAL PERSPECTIVE In 1717, the earliest description of posterior urethral obstruction was by Morgagni,5 followed by Langenbeck’s description in 1802 in his monograph on stone disease.6 The ﬁrst use of the term valves was by Velpeau, in 1832,7 and subsequently many reports of posterior urethral obstruction can be found in the literature. The most important contribution to the subject was made by Hugh Hampton Young in 19198 and 1929.9 Young was the ﬁrst to describe the endoscopic diagnoses of posterior urethral obstruction and classiﬁed them into three types. This description included a three-part classiﬁcation based on his initial 12 patients as well as a review of the literature.8 Most of these patients were diagnosed by digital palpation of the lesion through the bladder neck, passage of urethral sounds, and/or postmortem examination; not all lesions were visualized. A recent in-depth analysis of Young’s original work has revealed a number of problems with his conclusions and the way in which they were reached.10–17 Post-mortem studies utilizing a slightly different technique of dissection have suggested that congenital obstruction of the posterior urethra is due to a membrane with a posterior defect and paramedian reinforcements.18–20

Posterior urethral obstruction is congenital, but there is no agreement as regards the true embryogenesis. There is no genetic basis and no pattern of inheritance. The urethrovaginal folds, appearing at 11 weeks’ gestation, from the plicae colliculi diverging from the distal end of the verumontanum. Field and Stephens believed these to be vestiges of the receding Wolfﬁan ducts, which migrated posterolaterally to converge on the posterior wall of the urethra, creating the inferior urethral crests.25 Misplacement of the duct oriﬁces leads to abnormal migration and failure of the incorporation of the ducts into the urethral wall, leading to a persisting obstructive lesion. Fusion of these folds anteriorly would explain the formation of a membranous obstruction with a posterior deﬁcit.

CLASSIFICATION Young and colleagues in 1919 classiﬁed posterior urethral valves into types I, II and III, based primarily on autopsy ﬁndings8 (Fig. 91.1). According to Young, type I valves are sails or exaggerated plicae colliculi, which extend distally from either side of the verumontanum to

856 Congenital posterior urethral obstruction

Type III valves are rare and are widely considered to be a severe form of Young’s type I urethral valves.17 In our experience, and in a review of cysto-endoscopies of boys with urethral obstruction, a ﬁbrous membrane without attachment to the verumontanum has a central rather than posterior defect and is below the verumontanum in the bulbar, rather than posterior urethra.25–28 These lesions are known as a Cobb’s collar,30 Moormann’s ring,31 or congenital stricture, and represent the misnamed 1929-Type IIIa posterior urethral valve. COPUM was not an entity included in Young’s classiﬁcation, although it is most closely represented by the folds in Type Ia and Ib, and the endoscopic representation of Type IIIb. Type Ia and Ib lesions are most likely a disrupted, or instrumented COPUM, and Type Ic lesions probably do not exist. With lack of substantiation of Type II and Type III (above the verumontanum), we are then left with two distinct causes of congenital urethral obstruction: a membrane in the posterior urethra distal to the verumontanum but with connecting folds and a posterior defect (COPUM), and a ﬁbrous membrane in the bulbar urethra with a central defect (Cobb’s collar).

PATHOLOGY Figure 91.1 HH Young’s classiﬁcation is a six part classiﬁcation devised from 12 patients. Note that one form of Type III is above the verumontanum.8

attach to the anterolateral walls of the urethra; type II valves are folds that arise from the verumontanum and pass proximally towards the bladder neck where they divide into ﬁn-like membranes; type III valves are diaphragms with a central perforation located distal or proximal to the verumontanum, but not attached to it. Most authors agree that Young’s classiﬁcation is incorrect, in particular, many authors have questioned the existence of Type II valves,11–16 concluding that they are normal mucosal folds mistaken for valves. A diagnosis of Type I valves is the most common. The clinical description of a valve as two separate leaﬂets is derived from autopsy specimens in which the urethra is laid open by cutting through the anterior wall. However, when viewed endoscopically it is seen to be a single structure originating from the inferior margin of the verumontanum, the lateral folds fusing anteriorly to form a slit-like aperture. Plicae colliculi or fraenula passing anteriorly from the verumontanum must fuse across the anterior or dorsal urethra to qualify as a true obstructing urethral valve. Recent endoscopic studies appear to demonstrate that the usual posterior urethral lesion is a membrane with a posterior defect, distal to the verumontanum but connected to it by mucosal folds, termed a congenital obstructive posterior urethral membrane (COPUM).25–29

The pathological manifestations of posterior urethral obstruction can be divided into primary pathology and secondary pathology.

Primary pathology The macroscopic appearance of an obstructing membrane is described in the preceding section on classiﬁcation. The posterior urethral obstruction represents a mechanical obstruction in the urethral conduit leading to sequential secondary pathological changes, the severity of which will depend on the degree and timing of the primary obstruction. Proximal to the COPUM, back-pressure changes are nearly always present. There is now evidence that a COPUM represents a spectrum of lesions of varying severity, ranging from small folds without obstruction to unyielding membranes with a small deﬁcit and high degree of outlet obstruction.29,32 As with so many developmental anomalies, variable morphological expression of the same embryological pathology results in a range of phenotypes, all of which represent a single aberrance, rather than separate entities.

Secondary pathology The secondary pathological changes affect the posterior urethra – which dilates and elongates – the bladder, the ureter, and the kidneys.

Clinical features 857

BLADDER PATHOLOGY Congenital infravesical obstruction as seen in posterior urethral obstruction has a signiﬁcant longstanding or even permanent deleterious effect on the bladder. Symptomatic voiding dysfunction occurs in 15–33%33–35 of all boys after treatment for posterior urethral obstruction. Obstruction in the posterior urethra causes high vesical pressures, progressive muscle thickening, trabeculation, sacculation and, in severe cases, diverticulum formation. A large vesical diverticulum affords a degree of protection to the upper renal tracts and is associated with good prognosis.36 Investigators have often shown four types of detrusor problems persisting after valve ablation of the obstruction – small capacity, uninhibited detrusor contractions, highpressure voiding, and myogenic failure. Histologic studies of trabeculated bladders have shown normal histology in cases with mild to moderate trabeculation, whereas increased collagen and connective tissue elements are seen in severely trabeculated bladders. Fetal bladders with posterior urethral obstruction have increased muscle thickness and slightly increased connective tissue elements.

URETERIC PATHOLOGY Ureteric dilatation in posterior urethral obstruction may be due to vesico-ureteric reﬂux (VUR), vesico-ureteric junction (VUJ) obstruction, inefﬁcient ureteric drainage secondary to high vesical pressures or due to dysplastic ureters.

VESICO-URETERIC REFLUX VUR has been reported in 19–78%1,35,37–40 of children with posterior urethral obstruction and is thought to be due to dilatation of ureteric oriﬁces and high-pressure voiding. Once the urethral obstruction has been resolved a signiﬁcant proportion of patients will have complete resolution of their reﬂux.38 But some observers believe that VUR and renal dysplasia in posterior urethral obstruction is a primary event and is due to abnormal location of the ureteric bud arising from the Wolfﬁan duct. The incidence of bilateral and unilateral reﬂux is almost equal; however, bilateral reﬂux and posterior urethral obstruction denotes severe disease with a mortality rate of 57% in Johnson’s series; unilateral reﬂux denotes less severe disease. In fact, in such cases the contralateral side is protected by the ‘pop off ’ mechanism which keeps bladder pressures low.36 The kidney on the side affected with reﬂux is usually nonfunctioning as a result of dysplasia.

RENAL PATHOLOGY Renal damage occurs in posterior urethral obstruction due to a variety of reasons: (i) primary renal dysplasia; (ii) renal dysplasia induced by early intrauterine bladder

outlet obstruction, VUR or VUJ obstruction; (iii) postnatal urinary tract infection; (iv) persistent bladder dysfunction. The argument as to whether renal dysplasia is a primary event, or is secondary to urinary obstruction has not been settled. Renal dysplasia is associated with abnormal histology and is not reversible. Hydronephrosis and stasis secondary to obstructive uropathy has normal renal histology and is reversible with treatment. Using a fetal lamb model, Beck has given experimental evidence that early obstruction of the developing kidney results in dysplastic changes, while obstruction in the later half of embryogenesis results in hydronephrosis.41 On the other hand, Hoover described that frequent association of posterior urethral obstruction, reﬂux, and renal dysplasia suggests a common embryological error.42 Henneberry and Stephens proposed that renal dysplasia associated with posterior urethral obstruction is not secondary to reﬂux or high pressures, but a primary embryologic malformation that is the result of an abnormal position of the primitive urethral bud,43 suggesting that this may be the reason why the long-term outcome does not depend on management.1,2,4 Posterior urethral obstruction can also produce an impaired tubular function. Dinneen et al. suggested that defective urine concentration occurs in as many as 60% of boys with posterior urethral obstruction, and is severe in 15%.44 The resultant concentrating defects cause high urinary output and sodium loss, and severe polyuria carries a risk of dehydration and electrolyte imbalance. Furthermore, high urine output and a severe bladder dysfunction can cause incontinence and further renal damage.

PULMONARY HYPOPLASIA Oligohydramnios secondary to decreased fetal urine output produces an abnormally small uterine cavity. This compresses the fetus and interferes with the normal growth and expansion of the fetal thorax, resulting in pulmonary hypoplasia. Recently published data suggest that the kidneys themselves have an important role in early lung growth, while the presence of amniotic ﬂuid contributes to growth later in gestation.

CLINICAL FEATURES Advances in antenatal diagnosis have resulted in an increase in the number of babies with urinary tract obstruction being diagnosed either in utero or within the ﬁrst few days of life, some of whom have posterior urethral obstruction. In the neonatal period, the baby may present with septicemia, urinary tract infection, uremia, and metabolic acidosis. Urinary symptoms may include a poor urinary stream, which can be an unreliable sign as

858 Congenital posterior urethral obstruction

some infants with severe obstruction have fully developed detrusor hypertrophy, enabling them to have a good stream. Quite often the bladder and/or kidneys are palpable in infants with bladder outlet obstruction. Apart from these acute forms they can present with chronic urinary stasis and upper tract changes, vomiting, failure to thrive, and loss of weight. Rarely, they may present with abdominal distension due to urinary ascites or perirenal urine collection. Urinary ascites is usually a result of perforation of the kidney and in many instances the site of actual leak is not obvious radiologically.

INVESTIGATIONS The order of investigations in posterior urethral obstruction will be dictated by the age of the patient and mode of presentation. In the unstable neonate, an ultrasound scan is all that is necessary. Once the infection has been brought under control the diagnosis can be conﬁrmed by a micturating cystourethrogram (MCU). An intravenous urogram (IVU) is of little immediate value and is contraindicated if there is acute renal failure.

Figure 91.3 Urethral obstruction in a newborn. Ultrasound clearly showing thick-walled bladder

Ultrasound The kidneys are ﬁrst scanned to determine the severity of hydronephrosis and to identify any perineal collections of urine. The dilated ureters can be traced down to the bladder (Fig. 91.2). In an uncatheterized patient, a dilated posterior urethra can be demonstrated by a perineal sagittal scan. The bladder is thick-walled (Fig. 91.3).

Micturating cystourethrogram MCU is the gold standard for the diagnosis of posterior urethral obstruction. The examination should be performed in such a way as to record the micturition in the lateral or steep oblique position. The following features can usually be demonstrated: • dilatation and elongation of the posterior urethra (Fig. 91.4). • circumferential ﬁlling defect at the level of the pelvic ﬂoor (Fig. 91.5). • prominence of the bladder neck, particularly the posterior lip (Fig. 91.6). • vesico-ureteric reﬂux in many infants (Fig. 91.7). All these features may not be seen at the same time on a single radiograph. Posterior urethral obstruction may not be seen in all cases with voiding cystogram. Therefore a high index of suspicion is necessary to diagnose and treat the posterior urethral obstruction.21,45

Intravenous urogram

Figure 91.2 Urethral obstruction in an 8-day-old male infant. Ultrasound shows hydronephrosis and hydro-ureter

In infants, the IVU has largely been superseded by ultrasound and radionuclide studies, but nevertheless provides a useful baseline for subsequent examination, or as an anatomical study of ureters for boys requiring bladder enlargement.

Investigations 859

Figure 91.4 Micturating cystourethrogram in a 12-day-old male infant demonstrates elongated and dilated posterior urethra secondary to posterior urethral obstruction

Figure 91.6 Posterior urethral obstruction in a 21-day-old male infant. Micturating cystourethrogram showing a thin stream beyond the bulging valve. Note gross bilateral vesicoureteric reﬂux

Figure 91.5 Micturating cystourethrogram in a newborn demonstrating posterior urethral obstruction and vesicoureteric reﬂux. Note obstruction at the level of the pelvic ﬂoor

Figure 91.7 Urethral obstruction in an 18-day-old male infant demonstrate elongation and dilatation of posterior urethra and small capacity bladder. Note right intrarenal reﬂux

860 Congenital posterior urethral obstruction

Radionuclide studies Radionuclide studies are inaccurate in the presence of infection and vesico-ureteric reﬂux. In infants in whom a postoperative ultrasound scan shows no improvement, a MAG3 scan may help to distinguish between persistent obstruction and cystic dysplasia. The uptake is negligible in dysplasia. Postoperatively, a renogram should be performed to assess the differential glomerular ﬁltration rate, which will also give useful information with regard to obstruction at the VUJ.

Whitaker test This test is useful in cases of suspected ureteric obstruction in older children, but it is invasive and of little value in neonates.

PRENATAL DIAGNOSIS AND TREATMENT Infants born with posterior urethral obstruction have upper tract dilatation and renal damage that varies with the severity and duration of obstruction in utero. The recent developments in the ﬁeld of antenatal ultrasonography have resulted in the in utero diagnosis of posterior urethral obstruction, which has enabled evaluation and treatment to begin before the onset of infection, electrolyte abnormalities, and azotemia. The advantage of prenatal diagnosis is considerable. The maternal and fetal management can be planned early, which usually results in maternal transport to a regional center where the newborn can receive optimal treatment immediately after birth. The antenatal sonographic appearance of the fetus with urethral obstruction varies. The cardinal signs of urethral obstruction include dilatation of the fetal urinary bladder and proximal urethra with thickening of the bladder wall. Even in the absence of these signs one can make a conﬁdent antenatal diagnosis of urethral obstruction, especially in the presence of a constellation of ﬁndings including oligohydramnios and evidence of spontaneous urinary tract decompression (ascites, perirenal urinoma, peritoneal calciﬁcation). Urethral obstruction in utero produces a wide variety of clinically signiﬁcant effects in addition to obvious obstructive uropathy. Fetal urine is produced by the 13th gestational week, a decrease production of which results in an abnormally small uterine cavity. This compresses the fetus and interferes with normal growth and expansion of the fetal thorax, resulting in pulmonary hypoplasia. Bladder distension and urinary ascites expands the fetal abdomen and compromise the

development of abdominal wall muscle, resulting in the prune belly appearance. Pulmonary and renal consequences vary in severity with the degree of urethral obstruction in utero; where high-grade oligohydramnios and pulmonary hypoplasia develops and leads to postnatal respiratory insufﬁciency and death. In less severe cases, enough urine passes to give a sufﬁcient amniotic ﬂuid volume to allow adequate pulmonary growth. Intrauterine intervention is now possible, and has developed from the pioneering research of Harrison and co-workers.46–48 The most difﬁcult problem has been the selection of fetus with obstructive uropathy who might beneﬁt from in utero treatment. Studies of the natural history of untreated congenital hydronephrosis have shown that the fetus with mild bilateral hydronephrosis and normal amniotic ﬂuid volume requires no in utero intervention. Also, the fetus who presents with severe oligohydramnios and severely dysplastic kidneys sonographically is unlikely to beneﬁt from antenatal intervention. Between the two groups are cases with obstructive uropathy where potentially fatal renal and pulmonary damage may be averted by intervention. Prognostic criteria have been developed (urinary Na < 100 mmol/L, Cl < 90 mmol/L, osmolarity < 210 mosmol/L and normal fetal kidney on ultrasound) that predict neonatal and long-term outcome. Hutton et al. recently examined the relationship between gestational age at prenatal detection of posterior urethral obstruction and outcome.49 They found that prenatal detection of posterior urethral obstruction at or before 24 weeks of gestation predicted a poor outcome. Respiratory distress at birth also predicted a poor outcome. The insertion of a vesico-amniotic shunt passed either percutaneously using ultrasound or via a fetoscope will allow the bladder to decompress into the amniotic cavity. The international fetal surgery register of 1985 reported 73 cases of fetal obstructive uropathy treated by in utero placement of a vesico-amniotic shunt. The shunts are not satisfactory for long-term fetal urinary tract decompression due to the high incidence of catheter clogging, displacement, and risk of chorioamnionitis.50 Open decompression for fetal obstructive uropathy is still in the experimental stage, awaiting further control trials to establish its efﬁcacy.

POSTNATAL MANAGEMENT OF NEONATES WITH POSTERIOR URETHRAL OBSTRUCTION Most neonates with posterior urethral obstruction when ﬁrst seen are acutely ill with electrolyte abnormalities, metabolic acidosis, uremia, and septicemia. They may have respiratory insufﬁciency, the severity of which will

Postnatal management of neonates with posterior urethral obstruction 861

depend on the degree of associated pulmonary hypoplasia, improved management of these ill neonates has resulted in a better outcome for the treatment of posterior urethral obstruction. The treatment strategy in neonates with posterior urethral obstruction can be divided into three stages: • initial treatment and conﬁrmation of diagnosis • surgical treatment of the obstructing membrane • follow-up and treatment of associated pathology and complications.

Initial treatment and conﬁrmation of diagnosis The initial resuscitation of the sick neonate and conﬁrmation of clinical impression by radiology should proceed hand in hand. Almost all neonates presenting with posterior urethral obstruction will need intravenous rehydration and electrolyte replacement. At the same time, blood samples can be obtained for: • Full blood count, including platelet count that may be low in septicemic babies. • Urea, creatinine, and electrolytes which should be estimated as baseline values. • Blood and urine should be sent for culture and sensitivity tests prior to commencing antibiotic therapy. • Arterial blood samples will determine the degree of acidosis, helping to determine if sodium bicarbonate should be administered. Temporary vesical drainage can be achieved by passing a ﬁne feeding tube (size 5 or 6 Fr gauge) transurethrally. Balloon catheters are not suitable for vesical drainage in posterior urethral obstruction, as they may accentuate bladder spasms. A suprapubic catheter can facilitate the urethra being visualized prior to instrumentation. A sample of urine obtained on catheterization should be sent for microscopy and culture. Once urine and blood samples are obtained for culture and sensitivity tests, the baby should be commenced on an antibiotic. An aminoglycoside or cephalosporin is suitable initially and changes can be made once the urine and blood culture results are available. Respiratory insufﬁciency should be considered, and information of the respiratory states sought by means of a chest X-ray and blood gas estimation, and treated aggressively as and when necessary. The conﬁrmation of diagnosis usually involves a MCU. This should wait until the general condition of the patient is improved and the infection is brought under control. However, an ultrasound scan can be done even in a sick neonate, and a sagittal perineal scan in a sick patient can be diagnostic, particularly if the penile urethra is occluded during micturition.

Surgical treatment of posterior urethral obstruction There is no consensus as regards the optimum method of treatment of posterior urethral obstruction. The range of opinion varies from primary ablation alone to upper renal tract drainage, followed by delayed ablation. Ideally, the treatment option should be individualized, depending on the condition of the baby, the state of the upper renal tracts, and the size of the baby’s genitalia. The surgical options available are: 1 Primary ablation alone a. Retrograde, transurethral iii. endoscopic iii. Fogarty balloon catheter iii. Whitaker–Sherwood diathermy hook b. Antegrade iii. percutaneous antegrade ablation iii. antegrade laser ablation 2 Primary ablation followed by delayed upper tract reconstruction 3 Primary ablation with immediate upper tract reconstruction 4 Initial vesicostomy followed by transurethral ablation at the time of closure 5 Upper tract diversion followed by transurethral ablation 6 Temporary nephrostomy diversion on insertion of DJ stents.

PRIMARY ABLATION ALONE – RETROGRADE TRANSURETHRAL Most agree that urethral fulguration should be avoided in patients who do not void urethrally. Endoscopic Transurethral ablation under direct vision is the treatment of choice for posterior urethral obstruction. Other methods for ablation of the obstructing membrane must be compared to this standard technique as regards their efﬁcacy and complications rate. Opinions are divided between early urinary diversion and immediate ablation followed by expectant observation or early ureteral reconstruction, with most pediatric urologists agreeing that primary fulguration is the best initial treatment.1,37,38,51 Fulguration can be undertaken once the infant’s overall condition and renal function have stabilized. The development of smaller endoscopic equipment, as well as improved ﬁberoptics, has permitted transurethral endoscopic incision or fulguration of posterior urethral obstruction in virtually all but the most premature patients. In most cases, primary ablation is sufﬁcient to decompress the bladder and upper renal tracts. If the genitalia in a premature infant are too small, alter access suprapubically or a vesicostomy are performed.

862 Congenital posterior urethral obstruction

Bugbee electrodes, available for use with the 8 Fr fulgurating cystoscope, can be used for fulguration of obstructing membrane. Unfortunately, the electrode is relatively large and it is difﬁcult to get pinpoint accuracy during fulguration. One satisfactory alternative is to use a 3 Fr ureteric catheter with a metal stylet that can be used to coagulate. This can be passed through the side channel of an 8 Fr cystoscope. The obstructing membrane are incised at the 5, 7 and 12 o’clock positions (Fig. 91.8a–b). Fogarty balloon catheter The baby is anesthetized and a 6 Fr urethral catheter is passed transurethrally. The bladder is ﬁlled with contrast material until the posterior urethra is ﬁlled and an obstructing membrane identiﬁed. The catheter is then removed and, under ﬂuoroscopic control, a no. 4 Fogarty balloon catheter is placed into the bladder and inﬂated approximately with 0.75 ml of saline. With gentle withdrawal, the operator visualizes engagement at the level by the balloon. Sharp withdrawal of the catheter ruptures the COPUM without injuring the sphincter (Fig. 91.8). Immediately, the balloon passes the obstructing site and the disruption is palpated by the operator, withdrawal stops, and the balloon is deﬂated before completing withdrawal of the catheter. Gentle compression of the bladder demonstrates the urethra and conﬁrms ablation. Postoperative catheter drainage is recommended. Alternatively, a 7 Fr scope can be used to visualize the balloon passing the level of the obstruction. The advantages of the technique are (a) its suitability in small neonates and (b) it can be performed in areas of the world where pediatric endoscopic equipment is not

easily available. However, a signiﬁcant number of children have shown periurethral extravasation of contrast in a post-ablation cystourethrogram. Whitaker–Sherwood diathermy hook Innes Williams successfully used a diathermy hook to ablate posterior urethral obstruction. Whitaker and Sherwood have modiﬁed the hook to its present form, which is fully insulated, except for the inside of the hook itself where the metal is bare for application of the diathermy. The advantages are its small caliber, 6–7 Fr, and applicability without the need for a general anesthetic. Whitaker has published good results using this technique in neonates, a view substantiated from other centers. However, the proximal end of external stricture is above the obstruction, putting the sphincter at risk. The sterile lubricated hook is passed up the urethra, pointing to the 12 o’clock position, with the bladder full of contrast medium. The COPUM is immediately engaged by rotating it to either side and often will not disengage until the diathermy is applied. The obstructing membrane is destroyed with the smallest effective diathermy current at the 3 and 9 o’clock positions, and elsewhere if it can be re-engaged. With advances in cystoscopes, this relatively blinded technique is less favored.

PRIMARY ABLATION ALONE – ANTEGRADE Percutaneous antegrade ablation Zaontz combined the techniques of antegrade of urethral obstruction ablation and percutaneous endoscopy to

Figure 91.8 An endoscopic view of a COPUM showing the non-instrumented urethral obstruction with the typical defect in the posterior aspect of the membrane. When the anterior lip of the defect is held forward the oriﬁce is enlarged, similar to what happens with the passage of the cystoscope or a catheter in most cases

Postnatal management of neonates with posterior urethral obstruction 863

develop this innovative approach. The disadvantages of urethral instrumentation are avoided and the technique is applicable even in small premature infants. Six patients were successfully treated with minimum complications.52 Antegrade laser ablation The advantages of laser are thermal coagulation of tissue with minimal vaporization and immediate tissue survival. After secondary tissue slough, re-epithelialization occurs without scarring or ﬁbrosis. Biewald and Schier reported 13 neonates whose obstructing membrane were resected using the neodymium-YAG laser. There were no strictures or other complications.53 Bhatnagar et al. reported 23 boys with posterior urethral obstruction who underwent endoscopic Nd:YAG laser surgery. All patients had a good stream and there were no complications.54

PRIMARY ABLATION FOLLOWED BY DELAYED UPPER TRACT RECONSTRUCTION In most cases, upper tract changes will improve over a period of time after ablation. Persistence of dilated upper renal tracts is usually due to vesico-ureteric obstruction secondary to high intravesical pressure; VUR may also be the cause. Results of reimplanting reﬂuxing ureters are poor usually because an abnormal bladder is the cause of the reﬂux in some cases, while other workers advocate early reconstruction.

drained by a vesicostomy, as can also occur after transurethral ablation. The Blocksom technique of vesicostomy is the technique of choice in the infant. Those who advocate vesicostomy claims that there are no adverse effects on bladder capacity following temporary vesicostomy and that bladder capacity returns to normal once vesicostomy is closed. The bladder should be closed at the time of the subsequent diathermy of the urethral obstruction. Delayed ablation of a COPUM can be performed as early as 4–6 months using retrograde or antegrade techniques. For the formation of the vesicostomy the Blocksom procedure is the technique of choice in the infant (Fig. 91.9).

UPPER TRACT DIVERSION FOLLOWED BY TRANSURETHRAL ABLATION Upper tract diversion in posterior urethral obstruction is practiced less and less except in some developing countries. Primary ablation or temporary vesicostomy

PRIMARY ABLATION WITH IMMEDIATE UPPER TRACT RECONSTRUCTION Hendren suggested this approach for treating most severe types of urethral obstruction of the obstruction. Most others believe that this approach is too aggressive, the beneﬁts are doubtful, and it probably has no place in the management of a neonate with posterior urethral obstruction. Relatively early bladder augmentation of the bladder with ureter may, however, have a place in some cases.

(a)

(b)

INITIAL VESICOSTOMY FOLLOWED BY TRANSURETHRAL ABLATION Those who advocate diversion contend that primary ablation does carry a signiﬁcant risk of urethral trauma. There is general agreement that there are some indications for temporary diversion in neonates, including prematurity, small body size and/or small urethral caliber with massive VUR. In 1974, Duckett described the use of cutaneous vesicostomy as an alternative to primary ablation in a neonate. By creating a vesicostomy, urethral instrumentation is avoided, high voiding pressures causing persistent high-grade reﬂux are managed, and hydroureteronephrosis due to poor ureterovesical drainage is relieved. However, others contradict at least some of these arguments – sometimes vesico-ureteric junction obstruction is seen when a hypertrophied bladder is

(c)

(d)

(e)

Figure 91.9 Blocksom technique of cutaneous vesicostomy: (a) type of incision; (b) rectal fascia is exposed; (c) a triangular ﬂap of rectus sheath and muscle is excised; (d) incision is made in the dome of the bladder; (e) the bladder wall is sutured to the fascia with interrupted sutures. The edges of the bladder are sutured to the skin with interrupted Vicryl

864 Congenital posterior urethral obstruction

will be enough for hydroureteronephrosis to resolve in most cases. But for late presentation cases, and if signiﬁcant dilatation of upper tract persists, in spite of lower tract drainage and ablation, most authors would agree that some form of non-intubated upper tract drainage may be beneﬁcial. However, one has to bear in mind that dilatation does not mean obstruction and that temporary nephrostomy diversion on the use of DJ catheters may ameliorate the hydronephrosis. Krueger and associates, in a provocative article, state that in their series infants treated with high-loop cutaneous ureterostomy ultimately fared better with regard to renal function and growth than did another group managed by primary transurethral ablation of the COPUM.55 Reinberg et al. demonstrated in 79% of patients who treated initially with high diversion mild to severe renal failure developed versus 47% with primary ablation.2 Others, however, have found no advantage in upper tract diversion in the short or long term,1,4,38 and no controlled study has been conducted.

TEMPORARY NEPHROSTOMY DIVERSION ON INSERTION OF DJ STENTS If upper tract is needed in spite of a successful ablation, temporary nephrostomy with an insertion of DJ stents may be useful in patients with vesico-ureteric junction obstruction. The insertion of DJ stents prevent dry bladder and keep bladder cycle, which is needed for the normal bladder development.

Follow-up and treatment of associated pathology and complications URETHRAL STRICTURE One signiﬁcant complication of the transurethral approach is the development of urethral strictures, which can occur in up to 50% of cases and is due to urethral trauma of instrumentation. As the availability of miniature endoscopes, the incidence of urethral stricture has been markedly decreased. Urethral strictures after transurethral fulguration were reported in three of 36 patients by Crooks,21 four of 30 patients by Bruce et al.56 and three of 82 by Lal et al. However, Hendren20 reported no strictures in his series.

Incontinence Another suggested complication of the above approach is urinary incontinence, which is probably usually due to the secondary bladder abnormality rather than injury to the external sphincter. The incidence of voiding dysfunction in posterior urethral obstruction has been reported to occur in 13–38% of all patients treated, of which incontinence is the most common problem. If there is sphincteric incompetence this can be treated

with alpha-adrenergic drugs, bladder neck repair or by an artiﬁcial urinary sphincter. Bladder anomalies causing incontinence are detrusor hyper-reﬂexia, reduced compliance and myogenic failure. Detrusor hyper-reﬂexia and reduced compliance are treatable with anticholinergic pharmacotherapy, but bladder augmentation will be necessary in many cases. Myogenic failure may be most effectively treated with clean intermittent catheterization.

VESICO-URETERIC REFLUX If persisting long after successful treatment of urethral obstruction, vesico-ureteric reﬂux can be successfully treated along the usual guidelines for the treatment of reﬂux. Persistence of a dysfunctional, high-pressure bladder must always be borne in mind.

VESICO-URETERIC OBSTRUCTION Ureteral dilatation persisting after treatment of an obstructing membrane is either due to vesico-ureteric junction obstruction or ureteral atony. Diuretic renograms may be helpful in the differentiation between the two conditions although temporary drainage of the upper tract may be necessary to make the diagnosis.

RENAL DYSPLASIA Unilateral renal dysplasia with a nonfunctioning kidney should be treated by nephroureterectomy. Bilateral renal dysplasia will go on to develop end-stage renal disease and will require dialysis and renal transplantation.

PROGNOSIS AND PROTECTIVE FACTORS It is generally agreed that in patients presenting with posterior urethral obstruction, the younger the presentation, the worse the prognosis in the past.3,57 Imaji et al. demonstrated that boys presented earlier tend to have severe obstructing membrane in the posterior urethra.32 With the widespread use of prenatal ultrasound, most patients are now found prenatally. However, earlier diagnosis and treatment of children with posterior urethral obstruction may not improve the clinical prognosis,57 as indicated by detection at or before 24 weeks of gestation predicting a poor renal outcome.58 Hutton et al. also reported that the prognosis is closely associated with qualitative aspect of second trimester ﬁndings.49 Parkhouse and Woodhouse identiﬁed four factors indicating poor prognosis in a study of 98 boys followed up for 15 years: • • • •

presentation before the ﬁrst year of age presence of bilateral vesico-ureteric reﬂux proteinuria daytime incontinence at 5 years of age.3

References 865

Initial serum creatinine or radiological appearance of the upper tracts may not accurately reﬂect eventual functional outcome, but creatinine values during the ﬁrst years of life correlate signiﬁcantly with the longterm renal function.39 Connor and Burbige also reported from the study of 50 patients that long-term renal functional impairment was related to the serum creatinine at age one year.35 Corticomedullary differentiation on initial ultrasound seems to correlate with good subsequent renal function. In a study of 28 infants less than 6 months old, 17 infants had corticomedullary junction evident in at least one kidney and all of them had normal creatinine values on long-term follow-up.59 Rittenberg and colleagues identiﬁed three anatomical associations with posterior urethral obstruction that provides a pressure ‘pop-off ’ mechanism, resulting in preservation of better renal function:36 • syndrome of posterior urethral obstruction, unilateral vesico-ureteric reﬂux and renal dysplasia • large congenital-type bladder diverticula • urinary extravasation with or without ascites.

REFERENCES 1. Tietjen DN, Gloor JM, Husmann DA. Proximal urinary diversion in the management of posterior urethral valves: is it necessary? J Urol 1997; 158:1008. 2. Reinberg Y, de Castano I, Gonzalez R. Inﬂuence of initial therapy on progression of renal failure and body growth in children with posterior urethral valves. J Urol 1992; 148:532. 3. Parkhouse HF, Barratt TM, Dillon MJ et al. Long-term outcome of boys with posterior urethral valves. Br J Urol 1988; 62:59. 4. Walker RD, Padron M. The management of posterior urethral valves by initial vesicostomy and delayed valve ablation. J Urol 1990; 144:1212. 5. Morgagni JB. Seats and Causes of Diseases Investigated by Anatomy; in Five Books, Containing a Great Variety of Dissections with Remarks to Which are Added Very Accurate and Copious Indexes of the Principal Things and Names Therein Contained. In: Millar A, Cadell T, editors. 3rd edition. Johnson and Payne, London 1769; 3:540–56. 6. Langenbeck JM. Eine einfache und sichere methode des steinschnittes. 1802. 7. Velpeau AALM. Urètre et Prostate. Traite Complet d’anatomie Chirurgicale 1832; 2:247. 8. Young HH, Frontz WA, Baldwin JC. Congenital obstruction of the posterior urethra. J Urol 1919; 3:289. 9. Young HH, McKay RW. Congenital valvular obstruction of the posterior urethra. Surg Gynecol Obstet 1929; 48:509. 10. Kaplan GW. Posterior urethra. In: Kelatis PP, King LR, Belman AB, editors. Clinical Pediatric Urology. WB Saunders, Philadelphia, 1976: pp 301–26.

11. Parkkulainen KV. Posterior urethral obstruction: valvular or diaphragmatic? Endoscopic diagnosis and treatment. In: Bergsoma D, Duckett JW, editors. Birth defects: Urinary malformations in children. Alan L Liss Inc, New York. 1977; 63. 12. Williams DI, Eckstein HB. Obstructive valves in the posterior urethra. J Urol 1965; 93:236. 13. Waterhouse K, Hamm FC. The importance of urethral valves as a cause of vesical neck obstruction in children. J Urol 1962; 87:404. 14. Duckett JW, Snow BW. Disorders of the urethra and penis 1986; 5:2000. 15. Gonzales ET. Posterior urethral valves and bladder neck obstruction. Urol Clin North Am 1978; 5:57. 16. Glassberg KI. Current issues regarding posterior urethral valves. Urol Clin North Am 1985; 12:175. 17. Kendall AR, Karaﬁn L. Obstructive posterior urethral valves: the light at the end of the tunnel. J Urol 1975; 113:266. 18. Presman D. Congenital valves of the posterior urethra. J Urol 1961; 86:602. 19. Robertson WB, Hayes JA. Congenital diaphragmatic obstruction of the male urethra. Br J Urol 1969; 41:592. 20. Hendren WH. Posterior urethral valves in boys. A broad clinical spectrum. J Urol 1971; 106:298. 21. Crooks KK. The protean aspects of posterior urethral valves. J Urol 1996; 126:763. 22. Pieretti RV. The mild end of the clinical spectrum of posterior urethral valves. J Pediatr Surg 1993; 28:701. 23. Atwell JD. Posterior urethral valves in the British Isles: A multicenter B.A.P.S. review. J Pediatr Surg 1983; 18:70. 24. Field PL, Stephens FD. Congenital urethral membranes causing urethral obstruction. J Urol 1974; 111:250. 25. Dewan PA. Congenital obstructing posterior urethral membrane (COPUM): further evidence for a common morphological diagnosis. Pediatr Surg Int 1993; 8:45. 26. Dewan PA, Zappala SM, Ransley PG, Duffy PG. Endoscopic reappraisal of the morphology of congenital obstruction of the posterior urethra. Br J Urol 1992; 70:439. 27. Dewan PA, Pillay S, Kaye K. Correlation of the endoscopic and radiological anatomy of congenital urethral obstruction and the external urethral sphincter. Br J Urol 1997; 79:790. 28. Dewan PA, Keenan RJ, Lequesne GW, Morris LL. Cobb’s collar or prolapsed congenital obstructive posterior urethral membrane (COPUM). Br J Urol 1994; 73:91. 29. Dewan PA, Goh DG. Variable expression of the congenital obstructive posterior urethral membranes. Urology 1995; 45:507. 30. Cobb BG, Wolf JA, Ansell JS. Congenital stricture of the proximal urethral bulb. J Urol 1968; 99:629. 31. Moormann JG. Congenital bulbar urethral stenosis as a cause of disease of the urogenital junction. Urologe 1972; 11:157. 32. Imaji R, Moon D, Dewan PA. Congenital posterior urethral obstruction: variable morphological expression. J Urol 2001; 165:1240.

866 Congenital posterior urethral obstruction 33. Whitaker RH, Keeton JE, Williams DI. Posterior urethral valves: a study of urinary control after operation. J Urol 1972; 108:167. 34. Cass AS, Stephens FD. Posterior urethral valves: diagnosis and management. J Urol 1974; 112:519. 35. Connor JP, Burbige KA. Long-term urinary continence and renal function in neonates with posterior urethral valves. J Urol 1990; 144:1209. 36. Rittenberg MH, Hulbert WC, Snyder HM, Duckett JW. Protective factors in posterior urethral valves. J Urol 1988; 140:993. 37. Smith GHH, Canning DA, Schulman SL, Snyder HM, Duckett JW. The long-term outcome of posterior urethral valves treated with primary valve ablation and observation. J Urol 1996; 155:1730. 38. Close CE, Carr MC, Burns MW, Mitchell ME. Lower urinary tract changes after early valve ablation in neonates and infants: is early diversion warranted? [see comments]. J Urol 1997; 157:984. 39. Warshaw BL, Hymes LC, Trulock TS, Woodard JR. Prognostic features in infants with obstructive uropathy due to posterior urethral valves. J Urol 1985; 133:240. 40. Belloli G, Battaglino F, Mercurella A, Musi L, D’Agostino S. Evolution of upper urinary tract and renal function in patients with posterior urethral valves. Pediatr Surg Int 1996; 11:339. 41. Beck AD. The effect of intra-uterine urinary obstruction upon the development of the fetal kidney. J Urol 1971; 105:784. 42. Hoover DL, Duckett JW. Posterior urethral valves, unilateral reﬂux and renal dysplasia: a syndrome. J Urol 1982; 128:994. 43. Henneberry MO, Stephens FD. Renal hypoplasia and dysplasia in infants with posterior urethral valves. J Urol 1980; 123:912. 44. Dinneen MD, Duffy PG, Barratt TM, Ransley PG. Persistent polyuria after posterior urethral valves. Br J Urol 1995; 75:236. 45. Imaji R, Dewan PA. The clinical and radiological ﬁndings in boys with endoscopically severe congenital posterior urethral obstruction. Br J Urol 2001; 88:263. 46. Harrison MR, Ross N, Noall R, de Lorimier AA. Correction of congenital hydronephrosis in utero I. The model: fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J Pediatr Surg 1983; 18:247.

47. Harrison MR, Nakayama DK, Noall R, de Lorimier AA. Correction of congenital hydronephrosis in utero II. Decompression reverses the effects of obstruction on the fetal lung and urinary tract. J Pediatr Surg 1982; 17:965. 48. Harrison MR, Anderson J, Rosen MA, Ross NA, Hendricks AG. Fetal surgery in the primate I. Anesthetic, surgical, and tocolytic management to maximize fetal–neonatal survival. J Pediatr Surg 1982; 17:115. 49. Hutton KAR, Thomas DFM, Davies BW. Prenatally detected posterior urethral valves: qualitative assessment of second trimester scans and prediction of outcome. J Urol 1997; 158:1022. 50. Elder JS, Duckett JW, Snyder HM. Intervention for fetal obstructive uropathy: has it been effective. Lancet 1987; 2(8566):1007. 51. Burbige KA, Hensle TW. Posterior urethral valves in the newborn: treatment and functional results. J Pediatr Surg 1987; 22:165. 52. Zaontz MR, Firlit CF. Percutaneous antegrade ablation of posterior urethral valves in infants with small caliber urethras: an alternative to urinary diversion. J Urol 1986; 136:247. 53. Biewald W, Schier F. Laser treatment of posterior urethral valves in neonates. Br J Urol 1992; 69:425. 54. Bhatnagar V, Agarwala S, Lal R, Mitra DK. Fulguration of posterior urethral valves using the Nd:YAG laser. Pediatr Surg Int 2000; 16:69. 55. Krueger RP, Hardy BE, Churchill BM. Growth in boys with posterior urethral valves. Primary valve resection vs. upper tract diversion. Urol Clin North Am 1980; 7:265. 56. Bruce J, Stannard V, Small PG, Mayell MJ, Kapila L. The operative management of posterior urethral valves. J Pediatr Surg 1987; 22:1081. 57. Reinberg Y, De Castano I, Gonzalez R. Prognosis for patients with prenatally diagnosed posterior urethral valves. J Urol 1992; 148:125. 58. Hutton KAR, Thomas DFM, Arthur RJ, Irving HC, Smith SEW. Prenatally detected posterior urethral valves: is gestational age at detection a predictor of outcome? J Urol 1994; 152:698. 59. Hulbert WC, Rosenberg HK, Cartwright PC, Duckett JW, Snyder HM. The predictive value of ultrasonography in evaluation of infants with posterior urethral valves. J Urol 1992; 148:122.

92 Neuropathic bladder PATRICK A. DEWAN, PAUL D. ANDERSON AND GUNNAR AKSNES

INTRODUCTION A neuropathic bladder in the newborn is usually associated with anomalies of other systems, and is often congenital, but occasionally acquired (Box 92.1). With the advent of prenatal ultrasound, congenital causes of a neuropathic bladder are now frequently identiﬁed prior to birth. The ﬁndings before birth can range from simple non-emptying of a large bladder, to marked trabeculation with secondary upper tract changes. The nature of the bladder changes and the subsequent response of the kidneys, and the response to treatment, determine the ultimate outcome for the child. The primary aim of Box 92.1 Anomalies associated with a neuropathic bladder in the newborn Congenital

• Apparent Meningomyelocele Sacral agenesis

• Occult Diastatomyelia Intradural lipoma Lipoemningocele Tight ﬁlum terminale Dermoid cyst or sinus Anterior sacral meningocele Sacrocoxygeal teratoma Acquired Trauma Ischaemic injury Cerebral palsy Post obstructive: Prolapsed ureterocele Posterior urethral obstruction Anterior urethral diverticulum Neuroblastoma with spinal extension

therapy is to preserve renal function, while attaining continence, with the least risk of subsequent iatrogenic problems.

ANATOMY AND INNERVATION The bladder in the newborn is an intra-abdominal, extraperitoneal organ lined by the urothelium that is characterized by its almost complete impermeability to both ion and water transport. This epithelium is derived from the endoderm of the urogenital sinus. The muscle of the bladder, the detrusor, consists of interwoven smooth muscle ﬁbers that tend to coalesce with the bladder neck and proximal urethra, forming the internal sphincter complex. The three layers (outer longitudinal, middle circular, and inner longitudinal) work with the muscle of the proximal urethra and bladder neck to facilitate continence and bladder emptying. The superﬁcial layer is derived from the mesoderm, the deeper from endoderm, the former being identiﬁed to have an extension to the verumontanum in the male.1 This smooth muscle extension may play a part in the initiation of micturition by producing the funneling of the bladder neck seen at the commencement of voiding.2 More distally is the external sphincter, which is formed from the striated muscle of the pelvic ﬂoor. The autonomic and somatic nervous systems are involved in the innervation of the bladder and sphincter; the parasympathetic component of the autonomic innervation is derived from the sacral segments of the spinal cord. These ﬁbers emerge as preganglionic ﬁbers within the pelvic nerve, which then joins the hypogastric nerve to form the vesical plexus. The postganglionic ﬁbers emerge from synapses close to the bladder and urethra, where they have the overall effect of producing sustained bladder contraction. Acetylcholine is the neurotransmitter for both the preganglionic and postganglionic ﬁbers, although there is certainly more than one principal neurotransmitter. Within the bladder, the parasympathetic cholinergic receptors are largely

868 Neuropathic bladder

muscarinic (M2). Other neurotransmitters documented to be present in the bladder include: vasoactive intestinal peptide, neuropeptide Y, substance P, somatostatin, calcitonin gene-related peptide, cholecystokinin, dopamine, serotonin, histamine, and tyrosine hydroxylase. The exact roles of these neurotransmitters, as well as their complex interactions, remain unclear. The sympathetic component of the autonomic innervation arises from spinal cord segments T11–L2 with preganglionic ﬁbers traveling to the hypogastric and inferior mesenteric ganglia where they synapse with the noradrenergic, postganglionic ﬁbers, which in turn travel to the bladder and urethra via the hypogastric nerve. Sympathetic input is mediated by both α and β adrenoreceptors. The α adrenoreceptors are more densely represented at the bladder base and produce contraction, while the β adrenoreceptors, which are more common in the bladder body, produce relaxation. Thus α activity promotes outlet resistance, while β activity promotes urine storage and opposes cholinergic tone. Somatic motor innervation arises from the S2–S4 segments and passes via the pudendal nerve to the striated muscle of the external sphincter. While the external sphincter is voluntary muscle, in infancy external sphincter tone is mediated via spinal cord reﬂex. It is only as the child matures that cortical inhibitory inﬂuences develop that allow voluntary relaxation and contraction, which contribute to the development of continence. Normal bladder sensation is relayed via pelvic and hypogastric nerves, with parasympathetic visceral afferent ﬁbers transmitting information from pain, temperature, and stretch receptors. In the newborn and infant, voiding occurs, as a result of a spinal reﬂex secondary to bladder distension, which stimulates the efferent limb of the reﬂex arc, resulting in spontaneous detrusor contraction. Initially, as the bladder ﬁlls, the periurethral striated muscles make the external urinary sphincter contract to prevent urine loss. The act of micturition occurs with subsequent relaxation of the external sphincter, resulting in the bladder emptying at low pressure. During the ﬁrst year of life the number of voiding episodes per day remain constant at about 20, occurring during both sleep and while awake; with increased age there is a reduction in the voiding frequency that relates to the relative increase in bladder volume and decreasing proportion of the caloric intake associated with ﬂuid.3

FETAL BLADDER FUNCTION The rudimentary bladder becomes separated from the hindgut at 8 weeks’ gestation, at the time when it ﬁrst receives urine from the metanephros.4 Muscle cells,

deriving from surrounding mesenchyme, are ﬁrst seen in the bladder at 7 weeks’ gestation and sphincter function is able to be at 8 weeks. By the 12th week, the characteristic muscle ﬁber bundles of the detrusor can be identiﬁed. The closure of the urachus occurs at 16 weeks and bladder cycling commences, this process is probably important in the modulation and differentiation of the detrusor muscle from mesodermal cells. Fetal bladder activity also has an effect on the expression of connective tissue proteins, which in turn determine compliance. Obstructed fetal bladders demonstrate increased bladder wall thickness with an increased elastin and decreased collagen content, similar to that seen in a bladder with neuropathic dysfunction. Receptors for neurotransmitters can also be detected at 16 weeks’ gestation when it is presumed that innervation begins. The bladder can reliably be identiﬁed at 16–18 weeks’ gestation on prenatal ultrasound, revealing both structural and functional information. Filling and emptying cycles can be observed, occurring at 10 to 15minute intervals and emptying the bladder to completion. At 40 weeks’ gestation mean urine production is 28 ml/h with cycles lasting 50–155 minutes.5 A variety of abnormalities can be detected at this stage: inability to identify the bladder may indicate poor renal function or bladder exstrophy; massive dilatation of the bladder may signify posterior urethral obstruction, as may a thickened bladder wall, trabeculation, and vesico ureteric reﬂux.6 Poor emptying is suggestive of an atonic bladder.

CLASSIFICATION OF NEUROPATHIC BLADDER A number of classiﬁcation systems have been devised for neuropathic bladder dysfunction, none of which are of great assistance in the clinical management of patients. When one considers the practical circumstance of the patient, the important functional parameters of the bladder should be considered ﬁrst, while incontinence and renal injury are the secondary effects of signiﬁcance.7 The fundamental functions of the bladder in the newborn are to store urine, and then empty the urine at low pressure. Both of these functions must occur at appropriate pressures that ensure renal function is not adversely affected. For this to occur, not only must the detrusor and sphincteric muscles function adequately, but their function must also be coordinated. During the storage phase, the bladder must remain compliant and the sphincters competent, and during emptying, bladder contraction must occur in concert with sphincter relaxation. When considering the truly neuropathic bladder the following terms need to be deﬁned: • noncompliant bladder – a bladder that has limited increase in volume for a given increase in pressure. Thus, reduced compliance implies a small capacity

Evaluation 869

or high storage pressure. Poor compliance is deﬁned as a storage pressure of 30 cm water or more at a volume of 75% of expected capacity for age by Kaefer et al.8,13 • bladder hypertonicity – high pressure during bladder ﬁlling due to increased detrusor tone • hyper-reﬂexic bladder – spontaneous contractions which generate a transient pressure increase of greater than 15 cmH2O during the ﬁlling phase • atonic bladder – contracts poorly and usually empties inefﬁciently. Bladder outlet obstruction, as in urethral obstruction, leads to poor emptying. In addition there may be detrusor hypertrophy and a resulting small volume noncompliant bladder, which has neuropathic characteristics. Subsequent high storage pressures may result in upper tract dilatation. Suprasacral lesions where spinal reﬂex arcs remain intact are more likely to result in a hyperreﬂexic bladder. Compliance may be increased and urine storage occurs at low pressures, but incontinence will predominate because of the high pressure contractions. Sacral lesions that interrupt the spinal reﬂex arc are a more likely cause than atonic bladder. Detrusor–sphincter dyssynergy is characterized by both hyper-reﬂexic detrusor contraction and simultaneous sphincter closure. This results in both poor emptying and high intravesical pressures.

EVALUATION Clinical History and examination are the most important tools to use in the evaluation of the dysfunctional bladder. Of particular importance is a detailed voiding history, including strength and character of the stream, frequency and volumes of voiding episodes, and noting the presence of wetting between voids. This information may be elicited both from history and from direct observation of the child. Other historical features of speciﬁc interest include prenatal and birth history, incidence of urinary tract infection and pattern of bowel function, as well as a general medical history. Once the features related to the etiology have been effectively identiﬁed, the speciﬁcs of bladder function in the newborn need to be assessed, which should also include evaluation of the sensory and motor levels of any neurological deﬁcit, deep tendon reﬂexes, anal sphincter tone, and bulbocavernosal reﬂexes. Speciﬁc examination of the buttocks, sacrum, and perineum may reveal tuffs of hair, sacral deﬁciency or occult spinal dysraphism. The genitalia should also be examined for foreskin, meatal, and labial anomalies. The skin may be abnormal if it has been wet constantly, the bladder may easily

empty on palpation of the abdomen, or the kidneys and bladder may be easily palpable in an infant in retention. In addition, to evaluate the clinical features, the patient should undergo urinalysis and culture.

Radiological Radiological studies are useful in both deﬁning the cause as well as evaluating the severity of a neuropathic bladder. Frequently, in cases with occult spinal dysraphism, bladder dysfunction is the only demonstrable neurological deﬁcit. Thus, radiological examination of the spine is indicated when the cause of the neuropathic bladder is not immediately evident. X-ray of the lumbar and sacral spine may demonstrate a subtle or clinically evident laminal deﬁcit. Magnetic resonance imaging or spinal ultrasound in the ﬁrst 6 months of life may reveal a lipomyelomeningocele, thickened ﬁlum terminalae, or a tethered cord. Ultrasound examination of the urinary tract provides both structural and real-time functional information. It has the advantages of being non-invasive, does not involve radiation exposure and is able to be performed without sedation, even on the very young. These advantages make ultrasound the ideal modality for repeated follow-up investigation. The initial scan should be performed in the ﬁrst week of life to evaluate renal size and parenchymal thickness, and the presence and degree of hydronephrosis. The bladder volume, wall thickness, presence of trabeculation, and residual volume can also be demonstrated. Repeat scanning at 1 month, then 3monthly for the ﬁrst year assesses the state of the upper tracts and is a guide to the success of treatment. Micturating cystourethrography (MCU) enables the evaluation of reﬂux (present in 30% of newborns with myelodysplasia9), determines the presence of urethral obstruction, as well as assessing the structure of the bladder itself. This is a more invasive test, but is well tolerated by infants. Radionuclide scanning provides functional information including differential renal function or obstruction. A patient with a clinically low-pressure system would be appropriately investigated with an ultrasound, MCU and DMSA scan at 1 month and then followed with ultrasound if the patient remains well.

Urodynamics Urodynamic evaluation provides the most accurate method of quantifying and classifying the neuropathic bladder. It is, however, moderately invasive and should be applied selectively. Urodynamic studies are indicated when the diagnosis is in doubt, to assess the need for speciﬁc interventions such as surgery or anticholinergic drugs, or to follow-up these interventions.

870 Neuropathic bladder

Cystometry measures intravesical pressure and volume as the bladder is ﬁlled at a measured rate. Pressure and volume data can be plotted against each other to produce a cystometrogram, which can detect dynamic abnormalities such as hyper-reﬂexic contractions or detrusor–sphincter dyssynergy. From these measurements, compliance can be derived, which reﬂects the bladder’s ability to store urine at a safe pressure. A poorly compliant bladder is more likely to result in hydronephrosis. Additional data points that can be measured include post void residual volume and leakpoint pressure. Leak-point pressure is a useful concept that reﬂects the outlet resistance. A leak-point pressure greater than 40 cm H2O is more likely to develop upper tract changes,10,11 therefore one aims to keep intravesical pressure beneath this level. In the normal neonate, intravesical pressure remains low and rises slowly as the bladder ﬁlls. When the bladder volume approaches capacity the increased pressure initiates bladder contraction and sphincter relaxation occurs. Bladder capacity is an important determinant of continence by reﬂecting the period of time between voids. Normal bladder capacity can be estimated by either the formula bladder capacity (in ml) = [age (in years) + 2] × 30 in older children,12 or the formula bladder capacity (in ml) = [7.0 × weight (in kg) −1.2 ml] in infants.

MANAGEMENT Clinical The management of a patient with a neuropathic bladder depends on a number of factors, including age, physical disability, family circumstances, incontinence, urine infections, and renal status. A patient with normal kidneys, and no adverse changes on the MCU, is unlikely to have a high-pressure bladder. Such an infant may be managed with gentle intermittent suprapubic bladder pressure to induce voiding, while continuing to monitor the kidneys with 3-monthly ultrasounds. If the upper tracts do not become distended, and the child remains free of urinary tract infections, the infant may not require any other therapy until continence becomes an issue. If bladder emptying is inadequate, clear intermittent catheterization (CIC) is the treatment of choice. If CIC is not feasible a vesicostomy may be indicated for either physical or social reasons. This aggressive approach is supported by Kaefer et al., who showed that CIC and anticholinergic medication reduces the need for subsequent bladder augmentation from 41% to 17%,13 possibly because of the effect of oxybutinin on inhibition of smooth muscle growth.14 Anticholinergic medication, therefore, may improve the ﬁnal outcome for the bladder

particularly if it tends to store urine at high pressure. However, even if low outlet resistance is the prevailing problem, indicated by constant leaking with no demonstrable residual volume on ultrasound, then anticholinergic medication may still assist in lowering the average pressure in the bladder, and thus improving the prospect of continence. Urinary tract infection in patients with a neuropathic bladder is often managed with antibiotics where, in fact, a better approach is to consider other treatment modalities. The commencement of a high ﬂuid intake, with extra water if the infant is milk-fed, and encouraging a frequent voiding pattern (if not on CIC) is the preferred management program. If the bladder is emptied via CIC, and infections persist, the catheter technique should be reviewed. Catheterizations may need to be done more frequently, the catheter changed more often or the foreskin may need to be removed in male patients. In girls, or in boys where the catheterization is difﬁcult, it may be necessary to construct a continent urinary stoma (Mitrofanoff procedure) for bladder emptying. Prophylaxis would seem to be reasonable but is rarely indicated, particularly as it often leads to the development of resistant organisms.15 The anticholinergic medication used can be either oxybutinin 0.2 mg/kg/dose, 2–4 times/day, propantheline 1.5 mg/kg/dose, 3–4 times/day. Alternatively some will use the tricyclic antidepressant imiprimine in a dose of 0.7 mg/kg, 2–3 times/day. Currently, oxybutinin is the preferred option for most pediatric urologists.

CLEAN INTERMITTENT CATHETERIZATION Lapides ﬁrst described CIC for patients with a neuropathic bladder in 1970, initially in a 30-year-old woman. He subsequently published the outcome for over 200 patients over a 5-year period, including its use in young children and infants.16,17,18 Today, the effectiveness of CIC for achieving continence and preserving kidney function in children with a neuropathic bladder is well documented.19 Size of catheter The size of the catheter used for CIC naturally depends on the age of the patient; in small infants 6 Fr will usually be suitable and as the child gets older the size of the catheter can be increased to 10 Fr or even 12 Fr. If the urethra is pathologically narrowed, such as with a stricture, one might need to use a smaller size than usual for the child’s age. In children who have bladder augmentation lined with intestinal epithelium it is often desirable to use a larger size catheter to be able to empty mucus from the bladder. Sometimes special catheters, such as Tiemann catheters with a bend close to the tip, are easier or necessary to use for CIC. Urotherapy nurses have an important role in the education and follow-up of children on CIC and their carers, and are often of great help in solving other practicalities such as ﬁnding

Management 871

an optimal catheter. If there are persistent problems with catheterization, a cystourethroscopy is indicated to identify urethral strictures, folds, recesses or false passages that make catheterization difﬁcult, as well as treating these problems where possible. Frequency of catheterization The required frequency of catheterization depends on several factors, including bladder capacity and storage pressures, residual urine volume, leak-point pressure, outﬂow resistance, the presence of incontinence, infections, and the ability to spontaneously void. Usually it will be sufﬁcient to perform CIC between four and six times daily to preserve renal function, avoid infections, and attain continence. If not, one should consider additional treatment with anticholinergic medication and bladder augmentation to increase storage volume and decrease storage pressure, and/or bladder neck surgery to increase outﬂow resistance. A continent diversion with a catheterizable abdominal stoma is the alternative if the primary aims of the therapy are still not accomplished. Such aggressive actions are rarely appropriate in infants. Child doing their own catheterization The age at which a child is able to do CIC varies considerably. Relevant factors include the age at which CIC was started, physical handicaps, developmental progress, and psychosocial situation. However, at school age many of these children are able to perform self-catheterization independently.

Surgical The principle aims of treatment are to maintain adequate renal function and ensure social continence, although ‘social’ continence in a baby is very different to that of an adult. For most patients with a neuropathic bladder, conservative measures are sufﬁcient to achieve both these aims. The least imposition on the patient’s lifestyle and the avoidance of urinary tract infections is also desirable. However, for a proportion of the child patients with a neuropathic bladder, surgical treatment is necessary to achieve the best outcome.

SURGICAL TREATMENT OF INFRAVESICAL OBSTRUCTION Infravesical obstruction should always be treated. Thus, COPUM, urethral strictures, obstructing phimosis, and meatal stenosis should have the appropriate surgical treatment in children with a neuropathic bladder.

VESICOSTOMY Vesicostomy is an effective drainage procedure and an acceptable temporary solution to preserve renal function in a baby or small child with the combination of a neuro-

pathic bladder and deteriorating renal tracts, particularly when CIC is not feasible for either physical or social reasons.20 A vesicostomy is readily reversible if and when a different permanent solution is desirable. The procedure is performed by ﬁrst ﬁlling the bladder. A transverse skin incision about halfway between the umbilicus and pubis is employed. The dome of the bladder at or just posterior to the urachus is brought out. The bladder is opened, the serosa sewn to the fascia, and the mucosa sewn to the skin. The vesicostomy is stented with a Malecot catheter for about 3–7 days. The most common complications of vesicostomy are stomal prolapse or stenosis. Stoma stenosis may result in residual urine and be a cause of recurrent infections. The continuous drainage resulting from a vesicostomy may also cause a reduction in bladder capacity and skin infection and ulceration. However, vesicostomy is often a good solution to high-pressure neuropathic bladder which empties poorly.

URETERIC REIMPLANTS Vesico-ureteric reﬂux (VUR) has been reported to be present in 15% up to 78% of children with neuropathic bladders of different etiologies,21,22 and the rate of spontaneous resolution is low in these patients. In low-grade reﬂux, CIC and anticholinergic medication often lead to resolution of VUR, but high-grade reﬂux most often requires surgical treatment to prevent renal damage.23 Ureteric reimplantation yields good results in a neuropathic bladder with both acceptable compliance and absence of hyper-reﬂexia.24 Reported rates of resolution of VUR are between 82 and 100% with different techniques. Subureteric injection treatment (STING) can be used instead of ureteric reimplantation, especially in lower grade reﬂux, with reported resolution of VUR in neuropathic bladders between 60 and 90%.25 Ureteric reimplantation of a primary obstruction of the lower ureter is uncommon and, if considered as a diagnosis, it should be remembered that the high intravesical pressures are more likely to cause the appearance of obstruction, rather than the obstruction being due to a primary anatomical anomaly of the vesico-ureteric junction. Also, if VUR is present and the ureteric tunnels adequate, the treatment required is to augmentation of the bladder rather than ureteric reimplantation.

NEPHRECTOMY Patients with a neuropathic bladder are at risk for progressive renal failure, even today.26 However, a kidney with poor function can prevent or delay end-stage renal failure and the need for dialysis and renal transplant, therefore one should preserve renal parenchyma whenever possible. Nephrectomy is considered when one kidney has less then 10–15% of total renal function, and there are persisting urinary tract or systemic problems arising from that kidney, such as recurrent urinary tract

872 Neuropathic bladder

infections, pain or hypertension. Nephrectomy can be performed either through a lateral or lumbotomy approach. In this group of patients, particular consideration should be given to the possible use of the ureter either as a cutaneous ureterostomy for catheterization of the bladder, or for bladder augmentation.

CONTINENT DIVERSION A continent diversion is one that allows the urine to be drained via the insertion of a catheter into an abdominal stoma, which consists of a continent epithelial-lined conduit. The initial report by Mitrofanoff in 1980 discussed the use of both the appendix and the ureter;27 since then a number of alternatives have been suggested, including ileum, colon tube, bladder mucosal ﬂap,28 buried bladder tube, stomach, fallopian tube, vas, and skin-lined tubes. The availability of the ureter has increased with a number of inventive suggestions to make tissue available, including the use of the ureter following nephrectomy (which can be performed extraperitoneally), after reimplantation of the ureter, combined with transureteroureterostomy,29 or with the use of part of a duplex system.30 The latest addition to the armamentarium is the use of the detubularized, reconﬁgured ileal segment, as described by Monti in 1997.31 The stoma position is determined by the body habitus of the patient and can include either iliac fossa or the umbilicus.

BLADDER NECK SURGERY Continence in the newborn period is not a priority, and preservation of the upper tracts and the prevention of infection are more important, therefore the techniques aimed at bladder neck tightening are not important. If, later in life, the bladder capacity is adequate and the outlet resistance is low, techniques such as the Young/Dees bladder neck reconstruction,32,33 the Kropp procedure of tubularizing part of the back wall of the bladder in continuity with the urethra,34 or the use of the anterior bladder ﬂap procedure of Pippi Salle35 can be considered. The fascial wrap procedure and its modiﬁcation are becoming more popular, particularly the use of the rectal fascia, attached to the pyrimidalis muscle.36 Any of these techniques has the disadvantage of potentially interfering with the emptying of the bladder, thus they usually need to be combined with CIC.

BLADDER AUGMENTATION Bladder enlargement has little role in the newborn period in any form, particularly if one considers traditional methods of surgically increasing the size of the bladder. However, the use of concepts that result in a urothelial-lined bladder may shift the focus, with bladder enlargement being able to be considered in special circumstances that include upper tract deteriora-

tion, high-grade VUR and an obviously adverse, highpressure, small volume bladder. Bladder enlargement in older patients, who are being managed for a combination of incontinence and upper tract deterioration, has usually involved the incorporation of small bowel, large bowel or stomach segments, but only after failed management with CIC and anticholinergic medication. The complications of infection, mucous and stone formation or bladder perforation has led to the development of alternatives, which enable the neo-bladder to have a urothelial lining and thus are more applicable to younger patients. Autoaugmentation, which is removing the detrusor from the urothilium,37 and diverticulocystoplasty, in which bladder diverticula are reconﬁgured to become part of the main cavity of the bladder, have limited if any application to the ﬁrst year of life.38 The more extensive operations that include autoaugmentation with the addition of a demucosalized segment of the intestinal tract of autoaugmentation colocystoplasty,39 and autoaugmentation gastrocystoplasty40 have no role in the ﬁrst years of life, but should be considered if bladder enlargement is needed later in life. Ureterocystoplasty, on the other hand, can be considered in special circumstances, as it not only produces excellent results for bladder augmentation but overcomes the upper tract deterioration associated with infection and high bladder pressures: infections are reduced by improving the upper tract drainage and the pressures are reduced by the clam ureterocystoplasty. Eckstein and Martin41 were the ﬁrst to describe the technique which is now able to be applied to the ﬁrst years of life with an extraperitoneal approach, while preserving both kidneys.30,42–44

CONCLUSION The neuropathic bladder in the newborn is an uncommon condition that can be associated with a number of causes. Because incontinence is not an issue, the treatment should be primarily aimed at preserving renal function and leaving options open for subsequent management, while ensuring that the parents are educated about the possible future management. However, there are occasionally more extreme examples of bladder dysfunction that adversely affect the renal parenchyma, therefore CIC, anticholinergic medication, vesicostomy and bladder augmentation should be kept in mind in the ﬁrst year of life.

REFERENCES 1. Woodburne RT. Anatomy of the bladder and bladder outlet. J Urol 1968; 100(4):474–87.

References 873 2. Bradley WE, Timm GW, Scott FB. Innervation of the detrusor muscle and urethra. Urol Clin North Am 1974; 1(1):3–27. 3. Goellner MH, Ziegler EE, Fomon SJ. Urination during the ﬁrst three years of life. Neph 1981; 28(4):174–8. 4. Peters CA. Bladder. In: Oldham KT, Colombani PM, Foglia RP, eds, Surgery of Infants and Children. Chapt 92.2. Philadelphia: Lippincott-Raven, 1997:1515–42. 5. Campbell S, Wladimiroff JW, Dewhurst CJ. The antenatal measurement of fetal urine production. J Obs Gyn Br Com 1973; 80:680–6. 6. Dewan PA. Urethral valves or COPUM? Changing the nomenclature. Comtemporary Urology 1999; September:15–29. 7. Bankhead RW, Kropp BP, Cheng EY. Evaluation and treatment of children with neurogenic bladders. J Child Neurol 2000; 15(3):141–9. 8. Kaefer M, Zurakowski D, Bauer SB, Retik AB, Peters CA, Atala A et al. Estimating normal bladder capacity in children. J Urol 1997; 158(6):2261–4. 9. Kaplan WE, Firlit CF. Management of reﬂux in the myelodysplastic child. J Urol 1983; 129:1195–7. 10. Bauer SB, Hallett M, Khoshbin S, Lebowitz RL, Winston KR, Gibson S et al. Predictive value of urodynamic evaluation in newborns with myelodysplasia. JAMA 1984; 252(5):650–2. 11. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126(2):205–9. 12. Koff SA. Estimating bladder capacity in children. Urol 1983; 21:248. 13. Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomentingocele. J Urol 1999; 162(3 Pt 2):1068–71. 14. Park JM, Bauer SB, Freeman MR, Peters CA. Oxybutynin chloride inhibits proliferation and suppresses gene expression in bladder smooth muscle cells. J Urol 1999; 162(3 Pt 2):1110–14. 15. Bakke A, Digranes A, Hoisaeter PA. Physical predictors of infection in patients treated with clean intermittent catheterization: a prospective 7-year study. Br J Urol 1997; 79(1):85–90. 16. Lapides J, Diokno AC, Lowe BS, Kalish MD. Followup on unsterile intermittent self-catheterisation. J Urol 1974; 111:184–7. 17. Lapides J, Diokno AC, Silber SJ, Lowe BS. Clean, intermittent self-catheterization in the treatment of urinary tract disease. J Urol 1972; 107:458–61. 18. Lapides J, Diokno AC, Gould FR, Lowe BS. Further observations on self-catheterization. J Urol 1976; 116:169–71. 19. Lie HR, Lagergren J, Rasmussen F, Lagerkvist B, Hagelsteen J, Borjeson MC et al. Bowel and bladder control of children with myelomeningocele: a Nordic study. Dev Med Child Neurol 1991; 33(12):1053–61.

20. Lluna GJ, Dominguez HC, Estornell MF, Martinez VM, Garcia IF. [Vesicostomy in children]. Arch Esp Urol 1995; 48(10):1023–6. 21. Diamond T, Boston VE. The natural history of vesicoureteric reﬂux in children with neuropathic bladder and open neural tube defects. Z Kinderchir 1987; 42 Supp I:15–16. 22. Jeffs RD, Jonas P, Schillinger JF. Surgical correction of vesicoureteral reﬂux in children with neurogenic bladder. J Urol 1976; 115(4):449–51. 23. Granata C, Buffa P, Di Rovasenda E, Mattioli G, Scarsi PL, Podesta E et al. Treatment of vesico-ureteric reﬂux in children with neuropathic bladder: a comparison of surgical and endoscopic correction. J Pediatr Surg 1999; 34(12):1836–8. 24. Merlini E, Beseghi U, De Castro R, Perlasca E, Podesta E, Riccipetitoni G. Treatment of vesicoureteric reﬂux in the neurogenic bladder. Br J Urol 1993; 72(6):969–71. 25. Misra D, Potts SR, Brown S, Boston VE. Endoscopic treatment of vesico-ureteric reﬂux in neurogenic bladder – 8 years’ experience. J Pediatr Surg 1996; 31:1262–4. 26. Brown S, Marshall D, Patterson D, Cunningham AM. Chronic pyelonephritis in association with neuropathic bladder. Eur J Pediatr Surg 1999; 9 Suppl 1:29–30. 27. Mitrofanoff P. Cystotomie continente transappendicularie dans le traitement des vessies neurologiques. Chir Pédiatr 1980; 21:297–305. 28. Gardiner RA. The invaginated sleeve technique for a continent cystostomy – ﬁve years’ clinical experience. Br J Urol 1994; 73:35–9. 29. Noble IG, Lee KT, Mundy AR. Transuretero-ureterostomy: a review of 253 cases. Br J Urol 1997; 79(1):20–3. 30. Moon D, Dewan PA, Anderson PD. Ureterocystoplasty: New Options. Aust N Z J Surg 2001; 71:189–92. 31. Monti PR, Lara RC, Dutra MA, de Carvalho JR. Catheterizable stoma form a short length of small bowel. Urol 1997; 49:112–19. 32. Young HH. An operation for the cure of incontinance associated with epispadias. J Urol 1922; 7:1–32. 33. Dees JE. Congenital epispadias with incontinence. J Urol 1949; 62:513–22. 34. Kropp KA, Angwafo FF. Urethral lengthening and reimplantation for neurogenic incontinence in children. J Urol 1986; 135(3):533–6. 35. Salle JL, de Fraga JC, Amarante A, Silveira ML, Lambertz M, Schmidt M et al. Urethral lengthening with anterior bladder wall ﬂap for urinary incontinence: a new approach. J Urol 1994; 152(2 Pt 2):803–6. 36. Decter RM. Use of the fascial sling for neurogenic incontinence: lessons learned. J Urol 1993; 150(2 Pt 2):683–6. 37. Cartwright PC, Snow BW. Bladder autoaugmentation: partial detrusor excision to augment the bladder without use of bowel. J Urol 1989; 142:1050–3. 38. Dewan PA, Lorenz C. Bladder incorporation of large paraureteric diverticula: diverticulocystoplasty. Aust N Z J Surg 1994; 64:731–4.

874 Neuropathic bladder 39. Dewan PA, Stefanek W. Autoaugmentation colocystoplasty: a case report. Pediatr Surg Int 1994; 9:526–8. 40. Lorenz C, Dewan PA. The evolution of autoaugmentation gastrocystoplasty. Pediatr Surg Int 1993; 8:491–5. 41. Eckstein HB, Martin MRR. Uretero-cystoplastik. Act Urol 1973; 4:255–7.

42. Dewan PA. Ureterocystoplasty with renal preservation in young infants. Pediatr Surg Int 1996; 11:146–9. 43. Dewan PA, Nicholls EA, Goh DW. Ureterocystoplasty: an extraperitoneal, urothelial bladder augmentation technique. Eur Urol 1994; 26:85–9. 44. Dewan PA, Condron SK. Extraperitoneal ureterocystoplasty with transureteroureterostomy. Urol 1999; 53(3):634–6.

93 Hydrometrocolpos DEVENDRA GUPTA

INTRODUCTION Hydrometrocolpos is a pathological distension of uterus and vagina with an excessive amount of ﬂuid in the presence of distal vaginal outﬂow obstruction.1–3 The incidence of hydrometrocolpos is 1 in 30 000 live births and is being increasingly diagnosed prenatally.3–6 The rarity of this anomaly is probably due to difﬁculty in diagnosis and high mortality resulting from infectious and associated anomalies.6 For the development of hydrometrocolpos there should be both an accumulation of excessive ﬂuid in the female genital tract as well as vaginal obstruction. The commonest type of ﬂuid that collects is mucus, and less often urine, and accordingly hydrometrocolpos is called the secretory and urinary type, respectively.2 In the secretory type, mucoid material is secreted mainly by the cervical part of uterine glands in response to maternal estrogenic hormones, operating prenatally and to some extent postnatally. The ﬂuid is viscid, pearly gray in color and may accumulate as much as 1 L. In urinary hydrometrocolpos, urine collects in the vagina as a backwash during micturation, although there is no distal vaginal mechanical obstruction (Fig. 93.1a–c). The other kinds of ﬂuid are blood or pus, resulting in hematometrocolpos and pyometrocolpos, respectively. The common causes of distal vaginal obstruction in secretory hydrometrocolpos are imperforate hymen, transverse vaginal septum, and vaginal atresia with or without persistence of a urogenital sinus (UGS) of cloaca. These anomalies may result from either a local error of development or as an inherited disorder, e.g. McKusick– Kaufman syndrome.7,8 Based on the type and level of obstruction, hydrometrocolpos has been classiﬁed into ﬁve types: I, low hymenal obstruction; II, mid-plane transverse membrane or septum; IIIa, high obstruction with distal vaginal atresia; IIIb, high obstruction with distal vaginal atresia and gluteal swelling; IV, vaginal atresia with persistence of the UGS; V, vaginal atresia with cloacal anomaly (Fig. 93.2).8 In the inherited type of hydrometrocolpos, obstruction is mainly due to

Figure 93.1 Urinary hydrometrocolpos in (a) persistent urogenital sinus, (b) female hypospadias, and (c) cloacal anomaly

876 Hydrometrocolpos

Figure 93.2 Classiﬁcation of secretory hydrometrocolpos (see text for details)

transverse vaginal septum or vaginal atresia. Rarely, fused labia may produce hydrometrocolpos. A rare variant is ipsilateral hydrometrocolpos in patients with double vagina and uterus, where vaginal septum causes obstruction of hemivagina, often associated with renal agenesis.9 Clinically, the neonate usually presents as a surgical emergency with lower midline mass with or without protrusion of hymen, often associated with signs and symptoms of compression of adjacent organs such as respiratory distress, vomiting and/or constipation, obstructive uropathies, e.g. dribbling or retention of urine, edema of lower limbs, and urinary and limb anomalies. Rarely, abdominal mass may be associated with gluteal swelling8 or acute abdomen with paralytic ileus.10 Also, acute fetal distress and immediate respiratory distress in a neonate has been reported.11 In the McKusick–Kaufman syndrome, hydrometrocolpos is always associated with postaxial polydactyly and less often congenital heart disease, and urinary and gastrointestinal anomalies.12 Rarely, these patients may present with anomalies seen in the Mullerian dysgenesis syndrome,8 staphyloma of the left eye13 and severe hydrops.14 In recent years, prenatal diagnosis has been made possible by routine antenatal ultrasound scan.3,15–17 In acutely distended patients, planned delivery by cesarian section may be considered.

The clinical examination should include not only abdominal examination, but also thorough perineal and rectal examination. The perineal examination should be done in the frog-leg or lithotomy position, under good light, in order to identify bulging membrane at the introitus, the diagnosis of type I anomaly is simple (Fig. 93.3a). However, when there is obstruction at a higher level, identiﬁcation and probing of perineal oriﬁces, endoscopy and radiological17 studies are essential. When three perineal oriﬁces are present, it is type II anomaly; with two oriﬁces it is type III or IV (Fig. 93.3b); and with one oriﬁce it is type V. Type IIIb will have cystic gluteal bulge. In type II anomaly there is mild depression at the vaginal site with a small oriﬁce, which can be dilated. Types III and IV can be differentiated by endoscopy and radiological studies. In patients with a cloacal anomaly (type V), it is often difﬁcult to assess the surgical anatomy preoperatively and one must be prepared to deal with this in the operating room.

PREOPERATIVE INVESTIGATIONS In addition to routine investigations of Hb%, urine bacteriology, blood grouping and cross-matching of blood, special preoperative investigations are necessary

Surgical management 877

5 Skeletal survey to rule out vertebral and digital anomalies. 6 Electrocardiogram to rule out cardiac anomalies. Rarely, chromosomal studies may be necessary to identify sex and chromosomal aberration in the presence of ambiguous-looking genitalia and absence of vagina. Recently, an important role of magnetic resonance imaging (MRI) has been shown in investigation of patients with hydrocolpos and associated congenital malformations.19 (a)

INDICATIONS FOR OPERATION Early operation is indicated when grossly distended hyprometrocolpos presents with bulging hymen or is associated with complications as discussed earlier. Laparotomy is indicated only for high vaginal obstruction and for treatment of abdominal obstruction and for treatment of abdominal complications or associated anomalies. (b) Figure 93.3 Hydrometrocolpos with (a) imperforate bulging hymen, and (b) vaginal atresia

not only to differentiate hydrometrocolpos from other neonatal pelvic masses, e.g. presacral or ovarian teratoma and rectosigmoid duplication, but also to conﬁrm the type of hydrometrocolpos and plan surgery.18 The investigations advocated are: 1 Straight X-ray of the abdomen – anteroposterior view and lateral view during micturating cystourethrogram to identify location of mass (Fig. 93.4a). 2 Abdominal ultrasonography (Fig. 93.4b) and computerized tomographic scan to identify dilated vagina and upper urinary tract anomalies, especially ipsilateral renal agenesis. Transperineal ultrasonography can help to measure a caudallyplaced obstructive septum in vaginal atresia and thereby help in planning reconstructive surgery.17 3 Retrograde genitourethrogram (RGU) to identify the UGS and its communication with the vagina (Fig. 93.4c). This may be combined with a hysterovaginogram to delineate the site of vaginal obstruction. 4 Endoscopic catheterization of vaginal and urethral oriﬁces in UGS, and vaginal, urethral and rectal oriﬁces in cloacal anomaly, in order to establish the internal anatomy by contrast studies. An invertogram may be of help to identify a rectovaginal ﬁstula in cloacal anomaly.16 A cutback may be helpful for better endoscopic visualization and studies.

Preoperative preparation Patients presenting with complications should be given incubator care with head-end elevated, parenteral antibiotics, and intravenous ﬂuid. In the case of respiratory distress, prompt decompression of gastrointestinal tract by nasogastric aspiration and administration of oxygen and humidity is indicated. If vomiting is present with or without constipation, in addition to nasogastric decompression, ﬂuid and electrolytes imbalance should be assessed and corrected. When dribbling or retention of urine is present, a no. 6 or 8 Foley catheter should be inserted into the bladder for better drainage of urine. When huge distended abdominal mass is present in the acutely ill neonate, a preliminary drainage by puncturing the vagina under ultrasonographic guidance may be done for 24–28 hours prior to corrective surgery. Where experience is available, vaginal septum (type II anomaly) can be incised safely under ultrasonic guidance and X-ray imaging in two places.2 In cloacal anomaly, cutback followed by intermittent catheterization may help to relive back pressure in vagina and bladder.20

SURGICAL MANAGEMENT The management of neonatal hydrometrocolpos has seen many disastrous procedures in the past.21–23 The present treatment of this disease, however, has a deﬁnitive protocol and awareness and appropriate investigations before surgery can avoid disasters. The aim of the treatment is distal vaginal drainage. In the

878 Hydrometrocolpos

(a)

(b)

(c)

(d)

Figure 93.4 Radiological investigations. (a) Straight X-ray of abdomen: anteroposterior view showing rounded soft-tissue mass arising from the pelvis and displacing intestines, bladder and rectum; lateral ﬁlm during cystourethrogram with radio-opaque catheter in the rectum showing mass arising from the pelvis. (b) Ultrasound scan of pelvis showing dilated vagina with sediment. (c) Retrograde genitourethrogram: demonstrating the UGS and its communication with the vaginal obstruction: simultaneous RGU and hysterogram per tube vaginostomy, suggestive of vaginal septum. (d) Hysterovaginogram demonstrating dilated vagina and uterus

presence of fused labia or adhesion, a cutback or separation of adhesion followed by vaginal drainage is adequate. In others it is a temporizing procedure and can be achieved by drainage into the perineum.22 In the neonate there are four basic deﬁnitive corrective surgical procedures for different types of hydrometrocolpos: • • • •

hymenectomy abdominoperineal repair abdominoperineal vaginal pull-through24 abdominoperineal vaginal pull-through and rectal pull-through.25

Hymenectomy (Fig. 93.5) INDICATIONS Type I hydrometrocolpos with bulging hymen.

TECHNIQUE Under general anesthesia, the patient is placed in the lithotomy position and the entire perineum, thighs, buttock and lower abdomen are prepared and draped, leaving the external genitalia exposed (Fig. 93.5a). In this position the bulging hymen becomes visible as a grayish membrane. If necessary the abdomen may be compressed to make the hymen more prominent. A no. 8 Foley catheter is inserted into the bladder to decompress it as well as for the identiﬁcation of the urethra during surgery. A 5-0 silk stay suture is placed at the center of the hymen and, with a no. 18 needle, an amount of ﬂuid is aspirated and sent for microscopic examination and culture (Fig. 93.5b). A circular hymenal segment is excised using a no. 11 blade (Fig. 93.5c). The cut margin is oversewn with vertical mattress sutures of 5-0 chromic catgut of 6-0

Surgical management 879

(a)

Bulging hymen

Stay suture

(a)

Transverse vaginal septum

(b)

Vaginal orifice

Figure 93.6 Type II hydrometrocolpos. (a) Transverse vaginal septum; (b) minute vaginal oriﬁce Circular incision (b)

(c) Vagina

(d)

(e)

Figure 93.5 Hymenectomy: (a) lithotomy position showing bulging hymen; (b) aspiration of vaginal ﬂuid; (c) circular hymenal incision; (d) cut margin retracted by vertical mattress sutures; (e) mattress sutures tied exposing the vaginal cavity

Vicryl (Fig. 93.5d) a soft silastic catheter is inserted into the vagina and an X-ray is taken while injecting Hypaque, in order to delineate the internal anatomy. The catheter is left in the vagina as a stent as well as for drainage (Fig. 93.5e). In the postoperative period, the vagina is irrigated three times a day for a week with normal saline. Suitable parenteral antibiotics may be given for 1 week to 10 days.

Abdominoperineal repair INDICATION Type II hydrometrocolpos. Patients with mid-transverse septum or atresia have a minute opening at the site of the vaginal oriﬁce (Fig. 93.6a,b). Close examination will reveal a pinpoint opening just proximal to the hymenal ring. If the septum is 1 cm thick, it is wiser to drain the vagina from above by laparotomy and then incise the septum under direct vision after deﬁning the anatomy, in order to prevent injury to the urethra and rectum during dissection. When a low transverse, vaginal septum is present as a bulging membrane, excision and drainage may be done by the perineal route.

TECHNIQUE The patient is placed in the semi-lithotomy position at the end of the operating table (Fig. 93.7a). The entire abdomen, perineum, genitalia, thighs, and buttocks are prepared with Betadine and the perineum and abdomen are draped. A size 6 or 8 Foley catheter is inserted into the bladder and the rectum is packed with Vaseline gauze. A transverse lower abdominal incision is made. The recti are transected and umbilical arteries and urachus are divided between ligatures after transﬁxing and ligating. On opening the peritoneum in the line of the skin incision, the top of the dilated uterus and abdominal part of distended vagina are visualized. In general, the mass occupies almost the whole of the abdominal cavity. The plastic adhesions, due to spillage from the Fallopian tube, are gently separated and the abdomen is explored. The cystic uterovaginal mass is delivered into the wound (Fig. 93.7b). The bladder is retracted forward by a Deaver’s retractor. In the case of hydrometrocolpos, the bladder is retracted forward until the lower cervical part of the uterus is exposed. A stab incision is made through the center of the pursestring suture and mucoid material is aspirated by a soft rubber catheter (Fig. 93.7c). A transverse hysterotomy is done at this level and a long curved Kelly’s clamp is inserted through this into the dilated proximal vagina (Fig. 93.7d). In the case of hydrocolpos, the bladder is reﬂected off the distended vagina and the latter is opened by a vertical incision and drained before inserting the Kelly’s clamp. Attention is diverted to the perineum and the minute vaginal oriﬁce is progressively dilated up to the size 8 Hegar. A nasal speculum is inserted into the vagina and under direct vision the septum is divided with the scalpel at the site of the bulge produced by the tip of a Kelly’s forcep. The Kelly’s forcep is pushed downwards through the incision into the distal vagina (Fig. 93.7f). It is ﬁxed at the perineum either by a silk stay suture or adhesive plaster. The hysterotomy is closed in two layers with a 3-0

880 Hydrometrocolpos

(b)

(a)

Vicryl suture and the abdomen is closed without drainage. In the postoperative period the vagina is irrigated three times a day under parenteral antibiotic coverage for a week. The Foley catheter is removed after 48 hours. Vaginal dilatation should be continued for 6 months.

Abdominoperineal vaginal pull-through INDICATION (b)

( )

(c) Kelly's forcep

Nasal speculum

(d)

Vaseline gauze Silastic catheter

Types III and IV hydrometrocolpos. In type III hydrometrocolpos (Fig. 93.8a) there is high obstruction with completed distal vaginal atresia, whereas in type IV anomaly there is vaginal atresia with persistence of a UGS. In the latter group of patients, when the urethra opens high on the anterior wall of the UGS just below the obstructing septum (Fig. 93.8b), a simple incision of septum converts the UGS into a common chamber from where infected urine and mucus reﬂux into the vagina, resulting in pyometrocolpos. The infected entrapped urine in the vagina may ﬂow retrogradely into the peritoneum through the Fallopian tubes and produce ﬁbrinous plastic adhesion between loops of bowel. Hence, it is important in this type of anomaly to separate the genital from the urinary tract. In this technique, the vagina is exteriorized on to the perineum by an abdominoperineal vaginal pull-through operation and the UGS is left intact to function as the urethra. In both types III and IV anomalies there is absence of opening in the perineum at the size of the vagina due to vaginal atresia (Fig. 93.8c).

TECHNIQUE (e)

(f)

Figure 93.7 Abdominoperineal repair of type II hydrometrocolpos: (a) Low transverse abdominal incision; (b) hydrometrocolpos delivered from abdominal wound; (c) pursestring suture on vaginal wall; (d) Kelly’s forcep introduced through the hysterotomy and tip advanced to the most dependent part of the dilated vagina; (e) vaginal septum is being incised while the vaginal oriﬁce is spread open by the nasal speculum and the septum is pushed downwards by Kelly’s forcep – the septum is incised and the Kelly’s forcep pushed down and out, grasping the tip of the Silastic catheter; (f) vagina being drained by an indwelling perineal catheter

The patient is placed in the semi-lithotomy position. The entire abdomen and perineum are prepared with Betadine and draped as in the pervious operation. The rectum is packed with Vaseline gauze and a size 6 or 8 Foley catheter is inserted into the bladder. The abdomen is opened by a transverse lower abdominal incision. The hydrometrocolpos is delivered into the wound after separating the ﬁbrinous adhesions. Packs are placed and the vaginal content is aspirated through a no. 18 needle on a syringe and sent for microscopic examination and culture and sensivity. The vaginal content is drained by a soft rubber catheter. The assistant introduces the index ﬁnger through a vertical incision in the anterior wall of the vagina (Fig. 93.8d). The tip of the index ﬁnger is advanced to the most dependent part of the vagina behind the UGS, keeping the urethral catheter as a guide. With the assistant’s ﬁnger in situ, the surgeon makes a second incision behind the UGS in the perineal skin. An inverted U-shaped ﬂap from the perineal skin is elevated (Fig. 93.8e). The incision is deepened to meet the

Surgical management 881

(a)

(b)

(c) UGS

Vaginal atresia

(d)

(e)

(f)

(g)

Figure 93.8 (a) Type III hydrometrocolpos; (b) type IV hydrometrocolpos; (c) perineum with no vaginal oriﬁce; (d) incision on the perineum while assistants’s ﬁnger pushes down the posterior vaginal wall; (e) inverted U-shaped incision in the perineum; (f) skin ﬂap elevated and vaginal wall incised and sutured to perineal skin ﬂap; (g) sutures tied, exteriorizing the vaginal cavity

posterior wall of the vagina which is being pushed down by the assistant’s ﬁnger. Care should be taken to avoid injury to the rectum; if necessary, a metal Hegar dilator may be introduced into the rectum for its identiﬁcation during dissection. When the posterior wall of the vagina is adequately mobilized, it is opened and its wall is sutured to the perineal skin ﬂap and vestibular mucosa, behind the UGS, by vertical mattress sutures of 5-0 Vicryl (Fig. 93.8f,g). The rectal Vaseline pack is removed. An indwelling soft size 16 silastic catheter is left in the vagina for 6 weeks. In the postoperative period, vaginal irrigation and parenteral antibiotics are continued for 10 days. Foley’s catheter is removed on the third day and the vaginal catheter after 6 weeks. Subsequently, the vagina is dilated for 3–6 months. If necessary, secondary surgery may be performed at puberty. In the case of a persistent UGS with back-wash urinary hydrometrocolpos, the junction of the vagina with the UGS is isolated by perineal dissection and diverted under direct vision. The posterior wall of the

distended vagina is exteriorized on the perineum by the abdominoperineal vaginal pull-through technique described above.26 Abdominoperineal vaginal and rectal pull-through operation for type V hydrometrocolpos and urinary hydrometrocolpos with cloaca In a cloacal anomaly there may be either secretory or urinary hydrometrocolpos. In addition, there may be other variants like unilateral hydrometrocolpos due to persistence of unilateral vaginal septum in patients having uterus didelphy and double vagina. Persistence of vaginal septum is very frequent. When vaginal atresia with cloacal anomaly (type V) 16 is present, the uterus is hugely distended and it is important to drain it. If the neonate is healthy and vigorous, the abdominoperineal vaginal and rectal pull-through or the abdominoperineal vaginal pull-through and colostomy can be done after separating the rectum and vagina from the UGS in urinary hydrometrocolpos. However, if the neonate is septic and premature with multiple associated anomalies,

882 Hydrometrocolpos

the vagina, colon and bladder should be decompressed by either an indwelling catheter or vesicotomy. Dilatation of the UGS or cloacal cutback, followed by intermittent catheterization, may help. The pull-through in this latter group of patients may be done at 6–12 months of age by the posterior sagittal approach advocated by Pena.27

13.

14.

REFERENCES 1. Gupta I, Barson AJ. Hydrocolpos with peritonitis in the newborn. J Clin Pathol 1980; 33:679–83. 2. Hahn-Pederson J, Kvist N, Nielsen OH. Hydrometrocolpos: current views on pathogenesis and management. J Urol 1984; 132:537–40. 3. Geipel A, Berg C, Germer U et al. Diagnostic and therapeutic problems in a case of prenatally detected fetal hydrocolpos. Ultrasound Obstet Gynecol 2001; 18(2):169–72. 4. Goecke TY, Dopfer R, Huenges R et al. Hydrometrocolpos, postaxial polydactyly, congenital heart disease and anomalies of the gastointestinal and genitourinary tracts: a rare autosomal recessive syndrome. Eur J Pediatr 1981; 136:297–305. 5. Manzella A, Filho PB. Hydrocolpos, uterus didelphys and septate vagina in association with ascites: antenatal sonographic detection. J Ultrasound Med 1998; 17:465–8. 6. Rohatgi M, Luthra M, Gupta DK et al. An unusual presentation of neonatal hydrometrocolpos with review of pathogenesis and management. Pediatr Surg Int 1987; 2:372–6. 7. David A, Bitoun P, Lacombe D et al. Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick–Kaufman syndromes. J Med Genet 1999; 36:599–603. 8. Rohatgi M, Gupta DK, Luthra M. Neonatal hydrometrocolpos associated with McKusick–Kaufman syndrome. Ind Pediatr 1989; 56:440–3. 9. Radhakrishnan J, Reyes HM. Unilateral renal agenesis with hematometrocolpos: report of two cases. J Pediatr Surg 1982; 17:749–50. 10. Franke B, Misbach D, Romer KH. McKusick–Kaufman syndrome as a cause of acute abdomen in the neonatal period. Zentralbl Chir 1988; 113:254–8. 11. Robin M, Clouzeau J, Lamba P et al. Neonatal hydrometrocolpos. A cause of immediate respiratory distress. Arch Fr Pediatr 1987; 44:185–7. 12. Chirayat D, Hahm SY, Marioin RW et al. Further delineation of the McKusick–Kaufman Hydrometro-

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

25. 26.

27.

colpospolydactyly syndrome. Am J Dis Child 1987; 141:1133–6. Cantani A, Santillo C, Cozzi F. McKusick–Kaufman syndrome: report of the 66th case complicated by a staphyloma of the left eye. Pediatr Pathol 1992; 26:193–6. Rosen RS, Bocian ME. Hydros fetalis in the McKusick–Kaufman syndrome: a case report. Am J Obstet Gynecol 1991; 165:102–3. Davis GH, Wapner RJ, Kurtz AB et al. Antenatal diagnosis of hydrometrocolpos by ultrasound examination. J Ultrasound Med 1984; 3:371–4. Petit P, Thomas D, Moeerman P et al. Abdominal distension as the ﬁrst echographic sign of hydrometrocolpos in a female fetus. Eur J Obstet Gynecol Reprod Biol 1991; 39:99–101. Scanlan KA, Pozniak MA, Fagerholm M et al. Value of transperineal sonography in the assessment of vaginal atresia. Am J Roentgenol 1990; 154:545–8. Rohatgi M, Kashyap RK. Management of abdominal mass in infants under one year of age. Ind Pediatr 1973; 9:717–20. Liu WF, Borrego O, Weiss M et al. Lethal pulmonary hypoplasia and hydrocolpos with transverse vaginal septum in a newborn: a case report and review of the literature. J Perinatol 1999; 19:454–9. Hendren WH. Further experience in reconstructive surgery for cloacal anomalies. J Pediatr Surg 1982; 17:695–717. Cook GT, Marshall VF. Hydrocolpos causing urinary obstruction. J Urol 1964; 92:127–32. Bhatnagar V, Agarwala S, Mitra DK. Tubed Vaginostomy: a new technique for preliminary drainage of neonatal hydrometrocolpos. Pediatr Surg Inter 1998; 13:613–14. Gupta DK, Lall A. Hydrometrocolplos in the Newborn. In: Gupta DK, editor. Newborn Surgery. New Delhi: Modern Publishers, 2000:518–20. Ramenofsky M, Raffensperger JG. An abdominoperealvaginal-pull-through for deﬁnitive treatment of hydrometrocolpos. J Pediatr Surg 1971; 6:381–7. Raffensperger JG, Ramenofsky ML. The management of cloaca. J Pediatr Surg 1973; 8:647–57. Gravier L, McKay DL, Katz A. Hydrocolpos, vaginal atresia and urethrovaginal ﬁstula in a neonate: abdominoperineal-vaginal pull-through. J Pediatr Surg 1977; 12:605–7. Pena A, DeVries PA. Posterior sagittal anorecetoplasty: important technical considerations and new applications. J Pediatr Surg 1982; 17:796–811.

94 Intersex RONALD J. SHARP

INTRODUCTION ‘Sex is what you see, gender is what you feel; comfort with each is necessary for happiness’.1 This brief but profound statement by Harry Benjamin is what proper management of children with intersex disorders is all about. Up until very recently sex assignment in neonates with ambiguous genitalia was based on the surgeon’s ability to reconstruct the genitalia.2,3 This resulted in many XY children with ambiguous genitalia, a small phallus or an absent phallus secondary to trauma being assigned female gender, believing that nurture alone would be sufﬁcient to establish a gender identity congruent to the sex of assignment. There is a mounting body of evidence indicating that this traditional paradigm is seriously ﬂawed.4–6 The ensuing sections will attempt to present some of the data supporting this idea and a new paradigm for management of intersex patients.

often bore the head, bust and genitalia of a god. Their purpose was to impart fertility to the crops. The columns were referred to as Hermes. Later, the head and busts of female goddesses were placed on the columns, hence the word hermaphrodite.7 Oriental and Greek civilizations thought of hermaphrodites as superhuman, and included them in much of their art (Figs 94.1 & 94.2).

HISTORY

Figure 94.1 Hermaphrodites. (From Epstein J. Altered Conditions: Disease, Medicine, and Storytelling. New York: Routledge, 1995)

Hermaphroditism has been described since antiquity. Rabbinical commentaries on Adam and Eve describe Adam as androgenous. The creation of Eve signiﬁes the separation of the two sexes. Mosaic Law recounted detailed descriptions of behavioral norms, which were a mixture of male and female privileges and restrictions for the hermaphroditic individual. The origin of the word hermaphrodite is uncertain. In ancient Greece, Hermaphrodito was a minor deity whose parents were Hermes and Aphrodite.7 The Roman poet Ovid created a myth surrounding the nymph Salmacis many years later. Salmacis’ advances were rebuffed by Hermaphrodito. She pleaded with the gods to unite her with him in one body. The gods complied, and from that time on Hermaphrodito had the sex organs of both. Another theory on the origins of the word comes from ancient Greece. Stone columns served as property markers. They

Figure 94.2 Hermaphrodites. (From Epstein J. Altered Conditions: Disease, Medicine, and Storytelling. New York: Routledge, 1995)

884 Intersex

Plato, Aristotle, Galen, and Hippocrates were among many early physicians and philosophers whose hypotheses on the origin of the intersex child were based on natural phenomena. This is in marked contrast to the Romans, who saw the birth of such children as an evil omen, and promptly destroyed these children by drowning or abandoning them in an open ﬁeld to die of exposure.7,8 This fear and loathing of the intersex child persisted throughout the Dark Ages. Antide Colles of Dole (1599) was accused of having intercourse with the devil, as ‘evidenced’ by her ambiguous genitalia. She was tortured until she confessed to the act, and then burned at the stake for her ‘sin’. Ambrose Pare published a paper entitled ‘Monsters and Marvels’ in 1573, which was the beginning of the naturalization and medicalization of intersex and other congenital disorders.9–13

EPIDEMIOLOGY In the USA and in most western European countries, female pseudohermaphroditism secondary to congenital adrenal hyperplasia is the most common intersex disorder. In South Africa, however, true hermaphroditism is the most common disorder;14 this may be explained by the fact that children with adrenogenital syndrome may die from adrenal insufﬁciency before they can be evaluated. The karyotypes vary tremendously in true hermaphrodites in various parts of the world. In South Africa, most true hermaphrodites are 46XX. In Europe, over 50% of true hermaphrodites are mosaics. In Japan, virtually all true hermaphrodites are XY. In the USA, roughly 80% of true hermaphrodites have an XX karyotype, with the remainder being mosaics and XYs.14–19 There have been 449 cases of true hermaphroditism recorded in the world literature since 1899; of these, 25% were diagnosed after the subject reached the age of 20.20,21 True hermaphroditism has been reported in siblings.22 Hypospadias occurs in 0.6–0.8% of male newborns. Extreme hypospadias is reported in anything from 6–33% of these reported cases. A study of 30 boys with extreme hypospadias demonstrated male pseudohermaphroditism in 28.23 Another study of 79 patients with hypospadias and cryptorchidism found an increased incidence of intersex problems as the meatal opening moved proximally (66%).24 It is estimated that four to six out of every 10 000 births have some type of genital ambiguity.25 Of females with inguinal hernias, 1–2% have been shown to have testicular feminization syndrome. This syndrome occurs in one in 20 000 to one in 64 000 male births.26 One type of male pseudohermaphroditism, 5αreductase deﬁciency, is an autosomal recessive trait. It has been discovered in very diverse cultures, ranging from New Guinea, Turkey and the Dominican Republic to the USA.27–31

EMBRYOLOGY In man, female sex differentiation is the innate tendency of the gonadal and genital primordia, against which maleness must be actively imposed.17 The fetus is completely dimorphic during the ﬁrst 4–6 weeks of life. Unless direction to the contrary is received from the germ cells, embryological development will proceed along female lines and any vestige of male internal ducts will atrophy and disappear. This sequence of events will unfold even in the absence of an ovary. Male development will ensue only if the primitive bipotential germ cells, which originate in the yolk sac and migrate to the urogenital ridge, receive instruction from testes-determining factor (TDF) to develop into a testis. Failure of germ cell migration, teratogenic destruction of an early testis, repressor gene action on the TDF locus, abnormal TDF or absence of receptors may result in normal female differentiation in an XY individual.32–34 TDF does not appear to be the same protein as the HY antigen.35,36 It is thought to be located on the short arm of the Y near the centromere. Some authors suggest that the HY antigen is not directly responsible for testicular development, but may be involved in spermatogenesis.35,37 It is at the point of testicular differentiation (6–8 weeks’ gestation) that male and female development take different courses. Male development is orchestrated by the testis and its attendant hormones, whereas the female development is directed by structural genes with no apparent input from the ovary. Once stimulated by TDF, the germ cells become surrounded by seminephrous tubules, which contain the Sertoli cells. These cells have two primary functions, i.e. to serve as attendants to the germ cells and to produce two hormones. The hormones are a Müllerian inhibiting factor (MIF) and an androgen-binding protein. MIF is the key to inhibiting development of the Müllerian internal ducts. In the absence of MIF, a uterus, vagina and fallopian tube will develop.17,18,32,36,38–40 The critical opportunity for the action of MIF is between the 7th and 8th week of gestation. Its chemical make-up, receptor and timing are critical. The other factor produced by the Sertoli cells is androgen-binding protein, which appears to ipsilaterally amplify the effect of testosterone on the developing Wolfﬁan structures. The Leydig cells are the next to arrive on the scene and line up outside the Sertoli cells. It is unclear to what degree the gonadotrophic hormones inﬂuence the development of these cells and their subsequent secretion of testosterone.32,18 There is a recent report of male pseudohermaphroditism in a patient with PAN-hypopituitarism.41 It is known, however, that human chorionic gonadotrophin (hCG), which is produced by the placenta, does stimulate the Leydig cells and peaks at the 9th week of gestation.32,33 Testosterone, produced by the Leydig cells, has two important functions. Aided by androgen-binding protein, testosterone locally and ipsilaterally orchestrates

Pathophysiology 885

the development of the Wolfﬁan structures, which are the prostate, seminal vesicle and vas deferens.32 The action of testosterone is felt to be by local diffusion, as evidenced by the lateral true hermaphrodite, where a testis on one side will be accompanied by ipsilateral Wolfﬁan structures and the ovarian side by Müllerian structures. In the absence of testosterone the Wolfﬁan structures will disappear. There does not appear to be a Wolfﬁan inhibiting factor. Testosterone is converted by 5α-reductase to dihydrotestosterone. This hormone is responsible for development of male external genitalia.32 Dihydrotestosterone must bind to cytoplasmic and nuclear receptors in order to direct the bipotential genital tubercle and folds to form a urethralized penis and scrotum. Androgen receptors are found in the somatic and genital cells of both sexes. The genital cells have a pH optimum of 5.5 and the somatic cells 7–9.32 A qualitative or quantitative defect of testosterone, 5αreductase, or the cellular receptors may result in external genital ambiguity. Female sexual differentiation of the internal genital ducts and external genitalia requires no gonadal input. Ovarian development begins at about the 7th–8th gestational week, with cortical production of oocytes by myosis, which achieves its maximum complement of oocytes by the 20th week. At the 10–11th gestational week, either genes on the X chromosome or autosomal genes prompt the development of granulosa cells, which surround the primary follicles. The granulosa cells appear to be attendants of the germ cells, which may serve to nurture and assure their prolonged existence. The granulosa and Sertoli cells are thought to serve a similar function for their respective germ cells. It has been suggested that an absence or abnormality of the granulosa cells may result in a streak ovary.32,33,42 Figures 94.1 and 94.2 summarize the timetable of normal female and male development, respectively.

CLASSIFICATION The classiﬁcation system currently used to describe the various intersex disorders has its origins in the Greek mythologic word hermaphrodite. In 1876,43 the preﬁxes ‘true’ and ‘false’ (pseudo) were added to hermaphrodite to clarify the anatomic differences within the overall spectrum of possibilities. This distinction was based on the gonadal morphology. Thus, a male pseudohermaphrodite is one with the external appearance of a female but the gonads of a male, whereas a female pseudohermaphrodite demonstrates male external genitalia and female internal genitalia. The true hermaphrodite is one that conforms to the original description of having the characteristics and gonads of both sexes. This classiﬁcation system requires that the gonads can be reasonably classiﬁed. Those with

dysgenetic or streak gonads do not ﬁt well into this gonadal-based classiﬁcation; therefore, a fourth category, mixed gonadal dysgenesis, was added. Another classiﬁcation system based on chromosomal morphology is more precise and avoids the emotionally charged words used to describe the various disorders (see Table 94.1).33 Because the original system is so entrenched, it is used in this chapter to avoid confusion.

PATHOPHYSIOLOGY Normal male sexual differentiation can be roughly broken down into three phases. The ﬁrst is the establishment of chromosomal sex, which directs the second phase, gonadal sex. In the third phase, the testes are responsible for the hormones that orchestrate male phenotypic development.29 Normal female differentiation occurs, even in the absence of a gonad.44 TDF is produced by genes on the short arm of the Y chromosome. Much evidence points to the SRY gene in this region as the most likely candidate.45 Mutations in this gene result in a wide range of abnormalities, from dysgenesis to cryptorchidism to XY females.32–34,46 Mutations affecting normal testicular development range from point mutations of a single amino acid to large deletions. Polymerase chain reaction (PCR) analysis allows researchers to pinpoint abnormalities in this and many other genes responsible for normal sexual development.47 The appearance of the Sertoli cells heralds the onset of testicular differentiation. MIS produced by the Sertoli cells is one of the ﬁrst products of the developing testes. MIS is produced in postnatal girls by the granulosa cells. The chromosome for MIS is located on gene 19, and its receptor, on gene 12. Expression of MIS seems to be affected only by mutations of the MIS gene and not by gonadal dysgenesis. It functions to block the differentiation of the Müllerian ducts in the fetus, inhibits aromatase in granulosa cells of the ovary in preadolescent girls, and possibly inhibits steroidogenesis in the prepubertal boy. This is supported by the fact that MIS levels remain elevated in boys until puberty and are suppressed in girls until puberty, at which point the opposite occurs. MIS levels are useful in the evaluation of intersex states and cryptorchidism. Normal levels vary widely, necessitating testosterone level and possibly hCG stimulation tests to make a ﬁnal determination in some cases48–52 (see Table 94.2). Testosterone, the next hormone to be produced, acts locally and systemically. It is converted to dihydrotestosterone by 5α-reductase peripherally, which potentiates its action on certain tissues, particularly the genital ridge area, where the bipotential genital premordia differentiate into normal male genitalia. The action of testosterone, both locally and peripherally, is dependent on its molecular conﬁguration and the androgen receptor. Complete absence of the

886 Intersex

androgen receptor, which has been discovered, deﬁnes the null phenotype. Individuals with this condition are anatomically perfect females who lack body hair. PCR analysis has demonstrated a huge range of abnormalities of the AR gene. In some cases, a point mutation with a single amino acid substitution has been shown to result in complete testicular feminization. Phenotypic aberrations range from cryptorchidism and hypospadias to complete testicular feminization. The degree of aberration does not seem to correlate with the location or the extent of abnormality of the AR gene. With continued PCR analysis of individuals with androgen insensitivity, a predictable pattern may emerge.35, 53–59 Androgen receptors have been demonstrated in every tissue, with the exception of the spleen.60 There is convincing evidence that the external genitalia and the internal sexual ducts are not the only areas masculinized by the effects of androgenic hormones. The brain may very well be ‘masculinized’ by the effects of androgen in the fetus and possibly in the very early neonatal period. Brain masculinization is suggested by animal studies, natural experiments, androgen receptor deﬁciency, congenital adrenal hyperplasia and neonatal circumcision mishaps. Studies have been done in sheep, in

which the female fetuses were treated with male hormone after phenotypic development was complete. These ewes demonstrated male social behavior after birth; this was manifested by their mounting other ewes and exhibiting aggressive behavior towards rams. These same experiments and results have been veriﬁed in other species.61 The natural experiments are several. The most striking is that of a Dominican kindred of 34 subjects with 5α-reductase deﬁciency. Of these children, 19 were raised unambiguously as females, and only one of the original 19 has maintained a female sex assignment beyond puberty. The same result was found in an isolated tribe in New Guinea, especially remarkable in this culture where strict gender segregation is practiced. XY females who lack the androgen receptor develop into perfect females phenotypically. Their gender identity is female in spite of the fact that they are exposed to high levels of testosterone. There are several case reports of undiagnosed genotypic female children with congenital adrenal hyperplasia (CAH) raised as males (Fig. 94.3). Most are married and lead normal lives in that role.10,12,13 In CAH children diagnosed early, there is a 50% incidence of homosexual orientation.62 A study in CAH patients showed a direct correlation between salt wasting

Table 94.1 Classiﬁcation of sexual differentiation Original classiﬁcation

Male pseudohermaphroditism

True hermaphroditism

Female pseudohermaphroditism

New classiﬁcation III. Depletion syndromes without Y cell lines III. Depletion syndromes with Y cell lines (45X/46XY) III. 46XY A. Gonadal dysgenesis (Swyer’s syndrome) B. Empty pelvis, *agonadia C. Enzyme deﬁciencies *1. 17-ketoreductase deﬁciency *2. 17α-hydroxylase deﬁciency *3. 5α-reductase deﬁciency D. Testicular feminization *1. Complete *2. Incomplete *E. Non-endocrine/non-sex chromosomal defects *F. 46XY True hermaphrodite IV. 46XX/46XY True hermaphrodite IV. 46XX *A. 46XX True hermaphrodite B. 46X Sex-reversed male C. Congenital adrenal hyperplasia *1. 21-hydroxylase deﬁciency forms *2. 11β-hydroxylase deﬁciency *3. 3β-OL dehydrogenase deﬁciency D. Maternal androgen *1. Drug *2. Tumors of pregnancy E. Non-endocrine/non-sex chromosomal defects VI. 47XXY

From Reindollar et al.33 by permission. * Syndromes presenting with sexual ambiguity.

Female pseudohermaphroditism 887

Figure 94.3 Timetable of normal male sexual differentiation. (From Reindollar et al.33 by permission)

(severity) and percentage of homosexual preference. The examples of ‘surgical accident’ are case reports and by themselves prove nothing but seem to support this thesis. The most remarkable is the story of Joan/John, who was born a normal male twin (originally named John) and suffered a penile amputation during a newborn circumcision gone awry. John was renamed Joan, and a genitoplasty was carried out in infancy. The family did everything to raise Joan as a girl, and maintained very close contact and follow-up with the institution that was managing her care. ‘Joan’, when interviewed as an adult, now says he felt from an early age that he was male and that the efforts of his physicians and parents to make him female left him confused. When his father ﬁnally told him the true story of his infancy, he was relieved and changed his role to that of a male. He underwent genital reconstruction and is now happily married.63 There is a remarkably similar story of a Laotian child with mixed gonadal dysgenesis who was raised unambiguously from infancy as female. He changed gender role during his teenage years. These are just two of many such stories.64,65 The story of John is especially important, as it appears that his case contributed to the reasoning for arbitrary neonatal sex assignment. Sex assignment is currently based on the surgeon’s ability to construct adequate genitalia rather

than the potential hormonal imprinting of the brain that likely occurs before birth. Cultural and social inﬂuences alone may not be sufﬁcient to deﬁne gender role.29,66–76

FEMALE PSEUDOHERMAPHRODITISM In the USA and Europe, female pseudohermaphroditism is the most common abnormality of sexual differentiation and commonly results from an enzymatic deﬁciency in the corticosteroid biosynthetic pathway, i.e. CAH.37 Maternal drug ingestion and tumors of pregnancy are less common causes.33 The incidence of CAH is between one in 5000 and one in 15 000 live births. Its greatest incidence has been found in Alaskan Yupak Eskimos, where it occurs once in every 684 births. One in every 13 Yupaks is heterozygous for this condition.33,37 Congenital adrenal hyperplasia occurs in both males and females. The 21-hydroxylase deﬁciency is the most common enzymatic deﬁciency in this disorder. Of those with 21-hydroxylase deﬁciency, 75% are salt losers and therefore, may become critically ill in the newborn period.37,77 The two genes that code for 21-hydroxylase are located on chromosome 6. Table 94.2 summarizes the various enzymatic deﬁciencies and their attendant clinical features.

888 Intersex

Table 94.2 Clinical and laboratory features of various disorders of adrenal steroidogenesis Genital ambiguity Female

Male

Clinical features Salt wasting Hypertension

+

0

0

0

+

++

0

+

0

+

+ +

0 +

0 +

+ 0

+ +

From New and Josso,17 by permission. n1 = normal. * The values presented apply to the infant and the very young child. † ↓ or normal in male; ↓ or normal in female.

Circulating hormones Postnatal virilization

Enzyme deﬁciency

Aldo

17-OHP

DHEA

Testosterone

Renin

21-hydroxylase: simple virilizing 21-hydroxylase: salt-wasting 11 β-hydroxylase 3β-HSD*

n1

↑↑

↑↑

↑

n1 or ↑

↑↑

n1 or ↑ (DHEA/Δ4) n1 or ↑

↓

↑↑

↑

↑↑

↓ ↓

↑ n1 or ↑

↑↑ n1 or ↑

↑ ↑↑↑

↑ †

↓↓ ↑

Male pseudohermaphroditism 889

XX females with congenital adrenal hyperplasia lend support to the theory that the brain can be masculinized by androgen exposure in the prenatal or immediate postnatal period. In 1985, Money reported 30 young women with a history of early treated congenital adrenal hyperplasia.78 He found that 37% had bisexual imagery or practice, as compared with only a 7% incidence in control patients. Five of the 11 had rated themselves as bisexual and considered themselves to be predominantly or exclusively lesbian. These ﬁndings lend support to the theory of brain dimorphism and early masculinization or feminization of the brain. There is a nonclassic form of 21-hydroxylase deﬁciency in which no ambiguity or electrolyte problems occur. It is manifested by subfertility, precocious puberty, hirsutism, slight clitoromegaly and sometimes short stature in males. It has been suggested that the nonclassic form is one of the most common recessive disorders in man.33,37

MALE PSEUDOHERMAPHRODITISM Male pseudohermaphroditism can be deﬁned as incomplete masculinization or complete feminization of an individual with an XY karyotype. Examination of male embryological development reveals numerous points at which either an abnormal effector, receptor or its timing could result in male pseudohermaphroditism. Table 94.3 lists many of the various etiological possibilities in male pseudohermaphroditism. An XY female could be explained by translocation of the TDF region of the Y chromosome to the X chromosome. It is known that the pseudoautosomal regions of the short arms of the X and Y chromosomes recombine during male meiosis. Since the testes determining factor (TDF) region is very close to this area, translocation of this segment could occur.37 This may account for the fact that one in 20 000 phenotypic males are 46XX and that there are also a lesser number of XY females.79 There is the possibility that the TDF protein or its receptor could be abnormal as well. Testicular dysgenesis in male pseudohermaphroditism is distinguished from mixed gonadal dysgenesis by the fact that in the male pseudohermaphrodite two testes are present and both are dysgenetic. In the case of mixed gonadal dysgenesis, one gonad is classically a streak ovary and the other is a dysgenetic testis. The timing of testicular dysgenesis is critical. If it occurs prior to 8 weeks’ gestation, the child may have a normal female phenotype. If it occurs after 20 weeks, the child will have a normal male phenotype, since the differentiation of the external genitalia is completed by this time. If dysgenesis occurs between 8 and 20 weeks, a spectrum of genital ambiguity may result. An abnormality of Leydig cell function or blunted response to hCG could result in low levels of testosterone production. Leydig cell hypoplasia

Table 94.3 Etiological possibilities in male pseudohermaphroditism Chromosomal level XY female (TDF locus translocated to X chromosome) Abnormal testes determining factor (TDF) Gonadal level Abnormal TDF receptor Testicular dysgenesis Leydig cell abnormality Qualitative or quantitative abnormality of testosterone Sertoli cell abnormality Qualitative or quantitative defect MIF Gonadotropin deﬁciency Hormonal level Enzymatic deﬁciency testosterone biosynthetic pathway 20,22-desmolase 20α-hydroxylase 3β-hydroxysteroid dehydrogenase 17α-hydroxylase 17,20-desmolase 17β-ketosteroid reductase Dihydrotestosterone deﬁciency 5α-reductase abnormality Androgen response Receptor abnormality – quantitative or qualitative Congenital anomalies involving the GI and genitourinary system

and agenesis have been reported.80,81 Sertoli cell abnormalities or absence may result in decreased levels or absence of MIF. The absence of the Sertoli cells, which are necessary for nurturing and preservation of the germ cells, may also result in infertility. The various enzyme deﬁciencies that result in decreased or defective testosterone production are autosomal recessive traits (Table 94.4).77 Hypogonadotrophic hypogonadism must also be considered.41,77,82 Failure of conversion of testosterone to dihydrotestosterone results from a 5α-reductase deﬁciency, which is an autosomal recessive trait. Children with a 5αreductase deﬁciency may virilize markedly at puberty if the gonads are intact.82 Receptor abnormalities are Xlinked recessive traits.83 In male pseudohermaphroditism there is a tremendous spectrum of phenotypes, ranging from simple hypoTable 94.4 Diminished androgen production – enzymatic deﬁciencies (all autosomal recessive) 20,22-desmolase 20α-hydroxylase 3β-hydroxysteroid dehydrogenase 17α-hydroxylase 17,20-desmolase 17β-ketosteroid reductase

890 Intersex

spadias to complete testicular feminization. Recent work with PCR analysis has demonstrated a wide variety of abnormalities at the chromosomal level, ranging from single amino acid substitutions to large deletions. The fact that normal levels of cytoplasmic receptor are found should not be confounding, as the receptor may not bind to the DNA molecule or, if bound, cannot transcribe. The extent of chromosomal abnormality does not seem to correlate with the degree of ambiguity. This may account for the proliferation of syndromes described (e.g. Reifenstein’s, Gilbert-Dreyfuss, Lubbs). In time, as more androgen-resistant children are examined by PCR analysis, some predictive patterns may arise that can be useful for sex assignment and treatment.84

TRUE HERMAPHRODITISM True hermaphroditism exists when both testicular and ovarian tissue are present. A lateral true hermaphrodite has a testis on one side and an ovary on the opposite side. In this setting, the internal ducts are congruent with the ipsilateral gonad. A majority of true hermaphrodites, however, have an ovotestis.37

Various hypotheses have been advanced to account for true hermaphroditism. The 46XX/46XYs are considered to be chimeras and may result from fusion of two fertilized ova. The 46XX/46XY individuals usually have a unilateral ovary and contralateral testes as opposed to an ovotestes combination. The 46XY true hermaphrodites may be chimeras with an undetected 46XX cell line. Many 46XX hermaphrodites are HY antigen positive or have Y-speciﬁc DNA sequences which indicate a translocation of the Y segment.33 Gonadal histology demonstrates fairly normal ovarian tissue with numerous follicles.14,33,37 Pregnancy and live births have been reported at least 14 times in true hermaphrodites.33,85 The testicular component of either a unilateral testis or ovotestes is often dysgenetic. This histological ﬁnding may explain the infertility and poor virilization seen at puberty in many of these children.39,40,86 There have, however, been two reports of male true hermaphrodites who have fathered children.21 At puberty, the gonad with the most hormonal predominance will affect the secondary sex characteristics of the individual, resulting in discordant feminization or masculinization.40,86–88 A series of true hermaphrodites reported by Aaronson demonstrated suboptimal testosterone levels and a

Figure 94.4 Timetable of normal female sexual differentiation. (From Reindollar et al.33 by permission)

Signs and symptoms 891

blunted hCG stimulation response at puberty. In all cases, the testicular tissue or the testicular portion of an ovotestis was preserved and the ovarian tissue removed. This may indicate a need for male hormonal support at puberty.14

MIXED GONADAL DYSGENESIS Children with mixed gonadal dysgenesis do not ﬁt well into the gonad-based intersex classiﬁcation. They classically have a testis on one side, a streak ovary on the opposite, and sex chromosomal mosaicism.89,90 Variations include unilateral gonadal agenesis and tumor, bilateral streak gonads or a gonad on one side and a tumor on the opposite. One suggested classiﬁcation system is based on the belief that these disorders are variations of Turner syndrome, with mosaicism for several different cell lines, the most common of which is 46X46XY. The absence of the second chromosome is thought to lead to an incomplete formation of the follicular mantle around the oocyte, which may lead to degeneration of the oocytes and formation of a streak ovary. Meiotic nondisjunction is a likely etiology in the majority of these single cell line depletion syndromes.33 Included in this classiﬁcation are some pure XY patients with gonadal dysgenesis (Swyer syndrome), sometimes associated with the absence of gonads or, more commonly, with bilateral streak gonads. This may occur because of failure of germ cell migration, teratogenic destruction of early testis, repressor gene action on the testicular determinant locus, or abnormal gonadal receptors for these gene products.33 These children are especially prone to developing tumors. In children with gonadal dysgenesis, the presence of a Y chromosome or even indirect evidence of a Y chromosome is associated with increased risk of tumor formation. This classiﬁcation, however, does not explain the ﬁve patients in one series who were 46XY but had testes and contralateral streak gonads and, in one case, dysgerminoma. The authors of this study were not able to prove the presence of mosaicism. A postzygotic mutation of the primordial gonad could account for this ﬁnding.

CLINICAL PRESENTATION Sex assignment is usually made in the ﬁrst seconds of life by the obstetrician or midwife. This assignment is based solely on the appearance of the external genitalia. When there is uncertainty, a chain of events of great import to the child and his or her family is initiated. How these events are handled by medical practitioners will determine in great part the future happiness of this child and the family. Many cases of intersex, however, go undiag-

nosed until puberty or later.16 In a report of 17 patients who presented at age 11 years or older, 41% presented with sexual dysfunction, 6% with infertility, 24% with amenorrhea, 6% with gynecomastia, 6% with cryptorchidism, and 12% with abdominal pain.16,20,21 In a study of 20 patients with severe hypospadias and undescended testes, all 20 were proven to have an intersex disorder. Ten were male pseudohermaphrodites, four had mixed gonadal dysgenesis, one was a true hermaphrodite, one was a XX male, and one had Klinefelter syndrome.91 Other reports indicate a 24–50% incidence of intersex when hypospadias and cryptorchidism are found.23,90–93 Of true hermaphrodites, 25% present at 20 years or older. Gynecomastia and periodic hematuria are the most common presenting complaints.94 Drash syndrome is characterized by ambiguous genitalia and nephropathy, which rapidly progresses to renal failure. Those with this syndrome are at very high risk of developing Wilms and gonadal tumors. It is recommended that they undergo prophylactic nephrectomy and gonadectomy early in their course.95 CAH, the most common intersex disorder in the USA, may ﬁrst present with lifethreatening adrenal crisis. This may occur anywhere from the 4th day of life to the 4th year. The prelude consists of poor feeding, vomiting, diarrhea, and signiﬁcant weight loss over a very short period. Untreated, this complication is rapidly fatal in both female and male patients with CAH.96

HISTORY A history of maternal drug ingestion should be sought. It has been shown that the placenta has the ability to aromatize many androgens to estrogens. This ability of the placenta can be exceeded however by high levels, exposure during a critical period at the end of the ﬁrst trimester, or by alterations in the type of androgen that is presented.33,97 Exogenous androgens which may not be broken down by the placenta are: ethisterone, norethindrone and danocrine.32,33 Evidence of maternal virilization should be sought and, if found, a luteoma, ovarian neoplasm or adrenal tumor in the mother should be suspected. Maternal blood should be drawn at delivery for testosterone and DHEA-S to rule out this possibility.33 An inquiry into the family history should also be made to see if other siblings or relatives have died in infancy, indicating the possibility of CAH.

SIGNS AND SYMPTOMS There is a report of a child who was diagnosed as a true hermaphrodite who presented with monthly bleeding into his left hemiscrotum. These bleeding episodes began at the age of 13, following an orchidopexy. The diagnosis

892 Intersex

was established 4 years later, when it was discovered that the tissue which had been ﬁxated into the hemiscrotum included a uterus and ovary.98 There have been other reports of true hermaphrodites presenting with abdominal pain, torsion and gonadal tumors.20

EXAMINATION Vital signs should always be taken. Hypertension may indicate CAH with an 11β-hydroxylase deﬁciency. The child with severe salt wasting may be hypotensive. A general physical examination should be carried out to look for associated anomalies, as major congenital anomalies and/or chromosomal disorders are often found. Subtle ﬁndings suggestive of an intersex disorder are heterochronia of the iris or mottling of the skin, which can be indicative of the chimerism of true hermaphroditism.33 The genital examination should look for evidence of aeolar/scrotal hyperpigmentation, as can be seen in CAH. The phallus should be carefully examined to see if there is a midline frenulum, which is more often seen in normal males, whereas a hypertrophied clitoris will often have only lateral folds. Careful evaluation should be made of the degree of hypospadias and the location of the opening of the urethra/urogenital sinus. Next, the labial scrotal folds should be examined for the presence of gonads. The presence of a gonad that is palpable within a labial scrotal fold is a good indication that CAH is not the condition being dealt with.77,99 The absence of a gonad, however, should be an alert to the possibility of a saltlosing crisis. The examination of the inguinal area and labial scrotal folds can be facilitated by applying some lotion or liquid soap to the area and then carefully palpating from a lateral to a medial direction. A gonad can often be missed if the examination is done on a fussy infant with dry skin and the examiner’s hand is dry. The presence of Müllerian structures should be sought, by performing a bimanual examination with one ﬁnger in the rectum and the other hand reaching over the symphysis.77

LABORATORY AND X-RAY EVALUATION Figure 94.5 outlines a diagnostic sequence that can be used to help differentiate the various types of intersex disorders. Blood should be drawn at the outset for karyotyping. This result can be obtained within 24 hours if bone marrow is used. Fibroblast cultures take as long as 6 weeks. A bucchal smear is no longer recommended.77 At the same time that blood for the karyotype is drawn, serum 17-hydroxyprogesterone, diahydroepiandrosterone (DHEA), cortisone and electrolytes should

Figure 94.5 Genetic female with adrenogenital syndrome presented as a teenager for his ureteroplasty

be determined. If CAH is suspected, serum electrolytes should be closely monitored thereafter to detect the development of adrenal insufﬁciency. 17-hydroxyprogesterone will be elevated in the cord blood of all infants, but will drop precipitously in the ﬁrst 24 hours to levels as low as 5 ng/ml. Children with CAH will have persistent elevation of their 17-hydroxyprogesterone and/or DHEA. Serum MIS levels may be obtained. Absent or very low levels indicate the absence of testes, the presence of ovaries, severe testicular dysgenesis, or a defect in the MIS gene.49,100–104 A plasma renin level may also be helpful, as mineralocorticoid deﬁciency may result in high renin levels.32 While awaiting the results of the serum studies, a genitogram is performed to determine the anatomy of the internal ducts. It is often helpful to inﬂate the balloon of an 8 Fr. foley and insert the tip into the urogenital sinus with the balloon against the perineum and gently inject contrast into the catheter. By this means, it is possible to ﬁll the urethra and bladder, and demonstrate the presence of Müllerian structures if present (Fig. 94.6). The anatomic information obtained from the genitogram serves to conﬁrm or refute other study results. Magnetic resonance imaging (MRI) is quite precise in evaluating the internal ducts compared to ultrasound or computed tomography (CT). MRI has excellent soft-tissue contrast resolution and is even sensitive enough to distinguish estrogen effect.105 Laparoscopy gives a much more detailed view of the pelvis.56 Gonadal biopsy could then be done through a much smaller incision. Cysto-vaginoscopy during this procedure is useful to further deﬁne the internal anatomy.106 A gonadal biopsy is necessary to determine the gonadal sex of the child. This biopsy should be pole-topole if an ovotestis is suspected.16 This is necessary in all children, with the exception of those with CAH, whose diagnosis can be established by karyotyping and serum steroid precursor assay. The results of the gonadal biopsy and karyotyping serve to classify children into the other

Sex assignment 893

Figure 94.6 Recommended diagnostic sequence for intersex disorder

three major categories, i.e. male pseudohermaphroditism, true hermaphroditism and mixed gonadal dysgenesis (see Figure 94.5). Male pseudohermaphrodites will require further study to deﬁne the etiology of their ambiguity and their subsequent treatment.82 A biopsy of the genital skin for culture should be obtained. The biopsy is used to assay for 5α-reductase and also to determine androgen receptor binding. Serum levels of testosterone, dihydrotestosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), DHEA, and androstenedione should be drawn. An hCG stimulation test is next done to help distinguish between hypogonadism and endorgan unresponsiveness. It also allows for the evaluation of the pituitary gonadal axis. A total of 5000 IU/m2 of hCG is given subcutaneously. Testosterone, FSH, LH and β-hCG levels are drawn at 48 and 120 hours. An elevated β-hCG level indicates that the drug was given. Depressed levels of FSH and LH indicate that the pituitary is normally responsive. If the 48-hour testosterone level is twice basal or greater, it can be assumed that a normally responsive testis is present. If no rise in testosterone is noted, the child is anorchic or has dysgenetic testes. If the 120-hour testosterone level is less than twice basal, then it must be assumed that an enzyme deﬁciency is present, causing a decrease in testosterone production.29 PCR analysis should be carried out for androgen receptor, 5α-reductase, and 21-hydroxylase.

Figure 94.7 Genitogram

SEX ASSIGNMENT Once the diagnostic evaluation has been completed, determination of sex assignment must be considered. Factors considered in sex assignment traditionally included:

894 Intersex

• • • • • • • •

Anatomy Diagnosis Age at diagnosis Potential fertility Gonadal sex Parental desires Socio-ethnic background Genetic sex.

The standard teaching is that anatomy10,12,52,64,67 except in CAH patients, dictates sex assignment in the newborn. That arbitrary sex assignment based on genital anatomy made in the newborn period is undoubtedly best for the patient is refuted by the high transition rates from female to male assignment in long-term studies and several key case reports.16,62,78,107 The idea that anatomy was key in making early decisions was based on the fact that it is easier to make a functional vagina than a functional penis. This is no longer the case. There are several centers around the world that report excellent results with penile construction. A recent report of 11 boys, seven of whom were prepubertal, described a one-stage penile construction (Figs 94.8 and 94.9). The surgery included urethral reconstruction, coaptation of erogenous nerves, and esthetic reﬁnements. All of the postpubertal patients report erogenous sensibility in the reconstructed phallus.108 This same group reported eight patients who had a prosthesis placed, six of which remain functional.109 Penile construction is now a viable option. It should be limited, however, to centers where surgeons have the requisite skills.108–119 Diagnosis usually indicates female assignment in XX neonates with CAH. These patients are potentially fertile and have normal internal anatomy. XX CAH patients who have been raised as male should be supported in

Figure 94.9 Constructed phallus. (Courtesy of David A. Gilbert, MD, Norfolk, Virginia)

that assignment if they are happy with that gender role. Diagnosis, age at diagnosis, potential fertility, gonadal sex, parental desires, and socio-ethnic background are factors that must be taken into consideration in those cases where proper assignment is not clear. Genetic sex is important in the sense that it may raise the question of prenatal androgen imprinting of the brain in those children who have functioning androgen receptors. It is very possible that pre- and postnatal androgen imprinting of the brain may be the most critical factor in sex assignment.5

FEMALE PSEUDOHERMAPHRODITISM

Figure 94.8 Modern phallic construction techniques aim to produce a phallus that will: allow the patient to void while standing, return tactile and erogenous sensibility, contain enough bulk to retain a penile stiffener, be esthetically acceptable to the patient, grow through childhood, and have a low incidence of donor site morbidity. (From Gilbert DA, Winslow BH. Penis construction. Semin Urol 1987;5:262–9)

All CAH children diagnosed in the neonatal period should be given a female sex assignment. Medical management can be very difﬁcult but must be instituted very soon after diagnosis. Cortisol therapy to overcome the deleterious effects of the enzymatic block that has produced the genital ambiguity must be carefully monitored, because both overtreatment and undertreatment with cortisol result in growth retardation, whereas undertreatment leads to further virilization. The fact that excess androgen is converted to estrogen, limiting bone growth, was discovered by an experiment of nature. A 28-year-old man who was 203 cm tall and still growing was found to totally lack estrogen receptors.120 A new medical treatment for CAH has been suggested based on this observation. The treatment protocol includes ﬂutamide (an antiandrogen) and testolactone, which inhibits the conversion of androgen to estrogen.120 Adrenalectomy for treatment of CAH has been proposed but is certainly not universally advocated.121

Feminizing genitoplasty 895

Maternal treatment with prenatal dexamethasone is currently being studied. This would theoretically prevent the genital masculinization in an XX fetus with CAH, but it may be harmful to an XY fetus who does not have this metabolic disorder.122

TRUE HERMAPHRODITISM Tradition suggests that if a true hermaphrodite presents in the neonatal period, the child should be assigned female sex.123–126 Questionable fertility potential as a male and the risk of testicular tumor are the stated reasons. There have been some reports of paternity in true hermaphrodites, and the risk of tumor is real but small.123 If the external genitalia are masculinized, there is a good possibility that androgen imprinting of the brain has occurred. In this circumstance male assignment may be strongly considered. Hypospadias repair and a testicular prosthesis would afford a good cosmetic and functional result in this setting. Socio-ethnic background and parental desires should play a prominent role in sex determination in the case of true hermaphrodites. If true hermaphroditism is discovered later, the child’s gender preference should be supported. If a male assignment is made, the child should be monitored for development of a testicular tumor. Male children should probably undergo an hCG stimulation test just prior to puberty to assess the functional capability of the native testicular tissue; if it is inadequate, they may require steroid supplementation during puberty.14

MIXED GONADAL DYSGENESIS The dysgenetic gonads in these children are very tumor prone. Tumors have been reported in the newborn period. Early bilateral gonadectomy and later appropriate hormonal replacement should be considered.14,127 Female sex assignment in the newborn has been the rule, but there is no compelling reason for this recommendation.64 If the external genitalia are sufﬁciently masculinized for hypospadias repair, male assignment should be considered.

MALE PSEUDOHERMAPHRODITISM Proper sex assignment in this group of patients is very challenging. All patients with testicular feminization syndrome (complete lack or nonfunction of the androgen receptor) should be given a female sex assignment, and all patients with 5α-reductase deﬁciency should be given a male assignment. Sex assignment of

the large number of patients outside of these two groups is problematic. If there is evidence of masculinization, then male assignment must be seriously considered and phallic reconstruction carried out later.

FEMINIZING GENITOPLASTY Feminizing genitoplasty has traditionally been carried out in the neonatal period. It was felt that this was somewhat of an urgent procedure to be done within the ﬁrst weeks of life, and that by so doing it would be further assured of concordance between sex assignment and gender identity. The current author is not certain that this is necessarily true. He recently cared for an 18year-old young woman who has CAH. She was referred to him at the age of 18 for a feminizing genitoplasty. She had been treated all of her life with steroids, and had been very compliant (see Fig. 94.15). The fact that she had a very hypertrophied clitoris in no way changed the behavior of her parents towards her, nor her feeling about herself and when she was 18 she made the decision on her own to have the genitoplasty and the vaginoplasty completed. She has a younger sister that is now 6 years of age and has exactly the same condition. Her sister is being raised as a little girl, feels comfortable in that role and will likely wait until she is 18 before she has her feminizing genitoplasty. There may be no role for early surgical correction, especially where anything that is done may be much more difﬁcult to reverse later if the child’s gender does not correspond to the sex of assignment.4,128 It may be that, even in cases of XX female pseudohermaphroditism, waiting until much later to carry out the genitoplasty will be best in the long-term interest of the child.129 Clitoroplasty is preferable to clitoridectomy, which often results in poor cosmetic appearance and decreased or absent sensation. Clitoral recession results in poor cosmetic results and painful erections in more than 50% of patients, but sensation is well preserved. The currently recommended technique of clitoral reduction with preservation of the neurovascular supply results in a good cosmetic result and normal sensation.43,129–134 Several techniques have been advocated (Figs 94.10–94.17). The technique I use is a modiﬁcation of that recommended by Mollard et al.135 I do not remove the wedge of skin. I make a single incision, which, when retracted, gives good access to the corpora. Anastomosis of the corpora recesses the glans. The prepuce folds over and makes a very adequate labia minora. At the same time, I do a cutback of the urogenital sinus, which helps deﬁne the labia majora. If the labia majora are redundant, I do not attempt to reduce them at this time, as they often shrink with time. If the labia majora remain redundant, a portion can be used for a subsequent vaginoplasty.

896 Intersex

Figure 94.10 Clitoroplasty

Figure 94.12 Patient A – preoperative view of adrenogenital syndrome

Figure 94.11 Clitoroplasty – mobilization of neurovascular bundle

Vaginoplasty in the newborn period has been advocated and made easier because there remains some neonatal estrogen effect on the vagina.107,123,136 Where there has been minimal masculinization, a simple cutback vaginoplasty is all that is necessary. It is important to ascertain the point at which the vagina arises from the urogenital sinus. If the vagina arises proximal to the external sphincter, a cutback vaginoplasty may injure the external sphincter and render the patient incontinent.15,123 Incontinence has not been a problem in patients who underwent repair with a posterior sagittal approach in one expert’s hands.137 In the author’s institution we have used a similar approach with some minor modiﬁcations in three postpubertal girls without any evidence of incontinence (see Figs 94.14 & 94.17). Early vaginoplasty is often associated with stenosis.138,139 If the vaginoplasty is delayed until puberty, the patient will

Figure 94.13 Patient A – postoperative view of clitoral reduction

usually be motivated to help with her dilatation to prevent introital stenosis. When a neovagina must be created, several techniques have been advocated. A technique using split-thickness skin grafts has been popular for many years.140,141 This operation should be reserved for the older patient, as it requires cooperation and motivation. The squamous epithelium most closely simulates the normal vaginal epithelium. The functional results have been excellent in long-term studies.142

Feminizing genitoplasty 897

Figure 94.14 Patient A – postvaginoplasty, age 12 years

Figure 94.16 Patient B – 1 month postclitoroplasty

Figure 94.17 Patient B – postvaginoplasty, posterior sagittal approach

Figure 94.15 Patient B – adrenogenital not referred for clitoroplasty until age 18

Colonic or ileal segments can be used for vaginal construction. These segments are less likely to stricture than split-thickness skin grafts. The downside is the appearance and excessive mucus production.143,144 Patients with a shortened vagina, as in those with testicular feminization, can be treated with progressive dilatation when they reach puberty.32 Hypospadias repair can be safely carried out at any age (Figs 94.18 & 94.19). I prefer to proceed when the child

reaches the age of about 6 months. Treatment with intramuscular testosterone prior to repair often doubles the size of the penis and often results in more redundant, better vascularized skin for the repair.30,145,146 If intersex children are managed with compassion and skill, they will be given the best chance for a happy and full life. This paradigm shift may be troubling for many who work in this ﬁeld. At the present time the current author does not believe the scientiﬁc information is available to enable fully informed decisions to be made and that it is obvious from the past that decisions have been ﬂawed in great part. Perhaps a paradigm shift is warranted, followed by careful long-term studies to see if the past can be improved upon. ‘Sex is what you see, gender is what you feel: Comfort with each is necessary for happiness.’1

898 Intersex

Figure 94.18 Patient with hypospadias

Figure 94.19 Postoperative hypospadias repair

REFERENCES 1. Benjamin H. Sex is what you see, gender is what you feel; comfort with each is necessary for happiness. International Gender symposium, Norfolk, Virginia, 1972. 2. Meyer-Bahlburg HF. Gender assignment and reassignment in 46,XY pseudohermaphroditism and related conditions. J Clin Endocrinol Metab 1999; 84:3455–8. 3. Krsti c´ Z, Perovic S, Radmanovi c´ S et al. Surgical treatment of intersex disorders. J Ped Surg 1955; 30:1273–81.

4. Diamond M. Pediatric management of ambiguous and traumatized genitalia. J Urol 1999; 162:1021–8. 5. Reiner WG. Assignment of sex in neonates with ambiguous genitalia. Curr Opin Pediatr 1999; 11:363–5. 6. Warne G. Advances and challenges with intersex disorders. Reprod Fertil Dev 1998; 10:79–85. 7. Kiefer J. The hermaphrodite as depicted in art and medical illustration. Transaction of American Association of Genito-Urinary Surgeons 1966; 58:121–72. 8. Bartsocas C, Bartsocas CS. Goiters, dwarfs, giants and hermaphrodites. Prog Clin Biol Res 1985; 200:1–18. 9. Epstein J. Altered Conditions: Disease, Medicine and Storytelling. New York: Routledge, 1995. 10. New MI, Kitzinger ES. President’s address: Pope Joan: A recognizable syndrome. J Clin Endocrinol Metab 1993; 76:3–13. 11. Bakan R. Queen Elizabeth I: A case of testicular feminization? Med Hypotheses 1985; 17:277–84. 12. Capizzi PJ, Horton CE. A case of colonial gender conﬂict: Thomas (Thomasine) Hall. Ann Plastic Surg 1989; 23:320–2. 13. Jones HW Jr. A long look at the adrenogenital syndrome*. Johns Hopkins Medical Journal 1979; 145:143–9. 14. Aaronson A. True hermaphroditism. A review of 41 cases with observations on testicular histology and function. Br J Urol 1985; 57:775–9. 15. Donahoe PK, Hendren WH. Perineal reconstruction in ambiguous genitalia: infants raised as females. Ann Surg 1984; 200:363–71. 16. Roslyn JJ, Fonkalsrud EW, Lippe B. Intersex disorders in adolescents and adults. Am J Surg 1983; 146:138–44. 17. Jost A, Vigier B, Perchellet JP. Studies on sex differentiation in mammals. Rec Progr Horm Res 1973; 29:1–6. 18. Hanna MK. Vaginal construction. Urology 1987; 29:272–5. 19. Guerra G Jr, Palandi de Mello M, Assumpcao JG et al. True hermaphrodites in the southeastern region of Brazil: a different cytogenetic and gonadal proﬁle. J Pediatr Endocrinol Metab 1998; 11:519–24. 20. Nichter LS, Freislag JA. Emergency operation in the true hermaphrodite. Surg Gynecol Obstet 1983; 156:493–6. 21. Raspa RW, Subramaniam AP, Romas NA. Intermittent hematuria and groin pain. Urology 1986; 28:133–6. 22. Milner WA, Garlick WB, Fink AJ et al. True hermaphrodite siblings. J Urol 1958; 79:1003–9. 23. Iyengar JK, Rohatgi M, Menon PSN et al. Clinical, cytogenetic and hormonal proﬁle in extreme hypospadias with bilaterally descended testes. Ind J Med Res 1986; 83:604–9. 24. Kaefer M, Diamond D, Hendren WH, Vemulapalli S, Bauer SB, Peters CA, Atala A, Retik AB. The incidence of intersexuality in children with cryptorchidism and hypospadias: stratiﬁcation based on gonadal palpability and meatal position. J Urol 1999; 162:1003–7. 25. Ladee-Levy JV. Ambiguous genitalia as a psychosocial emergency. Z Kinderchir 1984; 39:178–81.

References 899 26. Hussain AP, Hussain M. Testicular feminisation syndrome. J Ind Med Assoc 1984; 82:334–5. 27. Muram D, Dewhurst J. Inheritance of intersex disorders. Can Med Assoc J 1984; 130:121–5. 28. Kasik JW, Woods R, Nelson RM. Antenatal prediction of sex. Acta Obstet Gynecol Scand 1986; 65:659–60. 29. Wilson, JD, Grifﬁn JE, Russell DW. Steroid 5α-reductase 2 deﬁciency*. Endocr Rev 1993; 14:577–93. 30. Rajendran R, Hariharan S. Proﬁle of intersex children in South India. Ind Pediatr 1995; 32:666–71. 31. Gad YZ, Nasr H, Mazen I, Salah N, El-Ridi R. 5α-reductase deﬁciency in patients with micropenis. J Inher Metab Dis 1997; 20:95–101. 32. Rosenﬁeld RL, Lucky AW, Allen TD. The Diagnosis and Management of Intersex. Chicago: Year Book, 1980:1–156. 33. Reindollar RH, Tho SPT, McDonough PG. Abnormalities of sexual differentiation: evaluation and management. Clin Obstet Gynecol 1987; 30:697–713. 34. Scully RE. Gonadoblastoma. Cancer 1970; 25:1340–56. 35. Brown TR, Migeon CJ. Androgen receptors in normal and abnormal sexual differentiation. Adv Exp Med Biol 1986; 196:227–55. 36. Simpson A, Saenger P. Abnormal sexual differentiation. Male pseudohermaphroditism and abnormal steroid synthesis metabolism and action. Progr Clin Biol Res 1985; 171:175–206. 37. New MI, Josso N. Disorders of gonadal differentiation and congenital adrenal hyperplasia. Endocrinol Metab N Am 1988; 17:339–66. 38. Hammar B, Michowitz M, Solowiejczyk M. Testicular feminization syndrome. Am Surg 1980; August: 457–60. 39. Grace HJ. Intersexuality: deﬁnitions, diagnosis and dilemmas. Arch Androl 1986; 17:129–31. 40. McDaniel EC, Nadel M, Woolverton WC. True hermaphrodite with bilaterally descended ovotestes. J Urol 1968; 100:77–81. 41. Burgner DP, Kinmond S, Wallace AM, Young DG, Forest MG, Donaldson MDC. Male pseudohermaphroditism secondary to panhypopituitarism. Arch Dis Child 1996; 75:153–5. 42. Ismail AAA, Astley P, Wood MCA et al. Testosterone assays: guidelines for the provision of a clinical biochemistry service. Ann Clin Biochem 1986; 23:135–45. 43. Klebs E. Handbuch der pathologischen Anatomie. In: Herschwald A, editor. Berlin: Zweit Abtheilung, 1876. 44. Jost A. Recherches sur la differenciation sexuelle de l’embryon de lapin. III Role des gonades foetales dans la differentiation sexuelle somatique. Arch Anat Micr Morphol Exp 1947; 36:271–315. 45. Aleck KA, Argueso L, Stone J, Hackel JG, Erickson RP. True hermaphroditism with partial duplication of chromosome 22 and without SRY. Am J Med Genet 1999; 85:2–4. 46. Ferguson-Smith MA, Goodfellow PN. SRY and primary sexreversal syndromes. In: Scriver CR et al. Metabolic and Molecular Bases of Inherited Disease. 7th edn. Ch. 17. McGraw Hill, New York. 1995.

47. Braun A, Kammerer S, Cleve H et al. True hermaphroditism in a 46, XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological ﬁndings in a sporadic case. Am J Hum Genet 1993; 52:578–85. 48. Forest MG. Serum mullerian inhibiting substance assay – a new diagnostic test for disorders of gonadal development. N Engl J Med 1997; 336:1480–6. 49. Lee MM, Donahoe PK, Silverman BL et al. Measurements of serum müllerian inhibiting substance in the evaluation of children with nonpalpable gonads. N Engl J Med 1997; 336:1480–6. 50. Lee MM, Donahoe PK, Hasegawa T. Mullerian inhibiting substance in humans: Normal levels from infancy to adulthood. J Clin Endocrinol Metab 1996; 81:571–6. 51. Cass DT, Hutson J. Association of Hirschsprung’s disease and Müllerian inhibiting substance deﬁciency. J Pediatr Surg 1992; 27:1596–9. 52. Rey R, Al-Attar L, Louis F et al. Testicular dysgenesis does not affect expression of anti-Müllerian hormone by sertoli cells in premeiotic seminiferous tubules. Am J Pathol 1996; 148:1689–98. 53. La Spada AR, Wilson EM, Lubahn DB et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77–9. 54. Quigley CA, Friedman KJ, Johnson A et al. Complete deletion of the androgen receptor gene: Deﬁnition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status. J Clin Endocrinol Metab 1992; 74:927–33. 55. Edelstein RA, Carr MC, Caesar R et al. Detection of human androgen receptor mRNA expression abnormalities by competitive PCR. DNA Cell Biol 1994; 13:265–73. 56. McDougall EM, Clayman RV, Anderson K. Laparoscopic gonadectomy in a case of testicular feminization. Urology 1993; 42:201–4. 57. Quigley CA, Evans BAJ, Simental JA et al. Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc ﬁnger of the androgen receptor in vivo. Mol Endocrinol 1992; 6:1103–12. 58. Eil C, Austin RM, Sesterhenn I et al. Leydig cell hypoplasia causing male pseudohermaphroditism: Diagnosis 13 years after prepubertal castration. J Clin Endocrinol Metab 1984; 58:441–8. 59. Saito S, Kumamoto Y. The number of spermatogonia in various congenital testicular disorders. J Urol 1989; 141:1166–8. 60. Takeda H, Chodak G, Mutchnik S et al. Immunohistochemical localization of androgen receptors with mono- and polyclonal antibodies to androgen receptor. J Endocrinol 1990; 126:17–25. 61. Chalmers C, Book B, Foxcroft GR, Hunter RHF. Luteinizing hormone response to an oestradiol challenge in 5 intersex pigs possessing ovotestes. J Reprod Fert 1989; 87:455–61.

900 Intersex 62. Money J. The concept of gender identity disorder in childhood and adolescence after 39 years. J Sex Marital Ther 1994; 20:163–77. 63. Diamond M, Sigmundson HK. Sex reassignment at birth. Long-term review and clinical implications. Arch Pediatr Adolesc Med 1997; 151:298–304. 64. Reiner WG. Case study: sex reassignment in a teenage girl. J Am Acad Child Adolesc Psychiatr 1996; 35:799–803. 65. Dittmann RW. Ambiguous genitalia, gender-identity problems, and sex reassignment. J Sex Marital Ther 1998; 24:255–71. 66. Stoller RJ. The ‘bedrock’ of masculinity and femininity: bisexuality. Arch Gen Psychiat 1972; 26:207–12. 67. Imperato-McGinley J, Gautier T, Pichardo M, Shackleton C. The diagnosis of 5α-reductase deﬁciency in infancy. J Clin Endocrin Metabol 1986; 63:1313–18. 68. Canty TG. The child with ambiguous genitalia. A neonatal surgical emergency. Ann Surg 1977; 186:272–81. 69. Imperato-McGinley J, Miller M, Wilson JD et al. A cluster of male pseudohermaphrodites with 5α-reductase deﬁciency in Papua New Guinea. Clin Endocrinol 1991; 34:293–8. 70. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Male pseudohermaphroditism secondary to 5αReductase deﬁciency – a model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity. J Steroid Biochem 1979; 11:637–45. 71. Herdt GH, Davidson J. The Sambia ‘Turnim-Man’: sociocultural and clinical aspects of gender formation in male pseudohermaphrodites with 5-alpha-reductase deﬁciency in Papua New Guinea. Arch Sex Behav 1988; 17:33–56. 72. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5α-reductase deﬁciency. N Engl J Med 1979; 300:1233–7. 73. Dittmann RW, Kappes ME, Kappes MH. Sexual behavior in adolescent and adult females with congenital adrenal hyperplasia. Psychoneuroendocrinology 1992; 17:153–70. 74. Dorner G. Sex-speciﬁc gonadotropin secretion, sexual orientation and gender role behaviour. Exp Clin Endocrinol 1985; 86:1–6. 75. Dorner G, Docke F, Gotz F et al. Sexual differentiation of gonadotrophin secretion, sexual orientation and gender role behaviour. J Steroid Biochem 1987; 27:1081–7. 76. Gladue BA, Green R, Hellman RE. Neuroendocrine response to estrogen and sexual orientation. Science 1984; 225:1496–9. 77. Pagnon RA. Diagnostic approach to the newborn with ambiguous genitalia. Pediatr Adolesc Endocrinol 1987; 34:1019–31. 78. Money J. Pediatric sexology and hermaphroditism. J Sex Marital Ther 1985; 11:139–56. 79. Hodgkin J. Everything you always wanted to know about sex. Nature 1988; 331:300–1. 80. Lee PA, Rock JA, Brown TR et al. Leydig cell hypofunction

resulting in male pseudohermaphroditism. Fertil Steril 1982; 37:675. 81. Schwartz M, Imperato-McGinley J, Peterson RE et al. Male pseudohermaphroditism secondary to an abnormality in Leydig cell differentiation. J Clin Endocrinol Metab 1981; 53:123. 82. Berkovitz GD, Lee PA, Brown TR et al. Etiologic evaluation of male pseudohermaphroditism in infancy and childhood. Am J Dis Child 1984; 138:755–9. 83. Ferraz LFC, Baptista MTM, Maciel-Guerra AT, Guerra G Jr, Hackel C. New frameshift mutation in the 5α-reductase type 2 gene in a Brazilian patient with 5α-Reductase deﬁciency. Am J Med Genet 1999; 87:221–5. 84. Holterhus PM, Sinnecker GHG, Wollmann HA, Struve D, Homburg N, Kruse K, Hiort O. Expression of two functionally different androgen receptors in a patient with androgen insensitivity. Eur J Pediatr 1999; 158:702–6. 85. Gooren LJG. Reversal of the LH response to oestrogen administration after orchidectomy in a male subject with the androgen insensitivity syndrome. Horm Metabol Res 1987; 19:138. 86. Van Niekerk WA. True hermaphroditism: an analytic review with a report of 3 new cases. Am J Obstet Gynecol 1976; 126:890–907. 87. Olsson CA, Tessier PA, Brown ML et al. True hermaphroditism. J Urol 1971; 105:586–90. 88. Salvatierra O, Skaist LB, Morrow JW. True hermaphroditism discovered 10 years after hypospadias repair: report of 2 cases. J Urol 1967; 98:111–15. 89. McGillivray BC. Genetic aspects of ambiguous genitalia. Pediatr Clin North Am 1992; 39:307–17. 90. Salle B, Hedinger C. Gonadal histology in children with male pseudohermaphroditism and mixed gonadal dysgenesis. Acta Endocrinol 1970; 64:211–27. 91. Rohatgi M, Menon PSN, Verma IC, Iyengar JK. The presence of intersexuality in patients with advanced hypospadias and undescended gonads. J Urol 1987; 137:263–7. 92. Ritchey ML, Benson RC Jr, Kramer SA, Kelalis PP. Management of Müllerian duct remnants in the male patient. J Urol 1988; 140:795–9. 93. O’Brien WM, Gibbons MD. Hypospadias. Am Fam Physician 1989; 39:183–91. 94. Kropp BP, Keating MA, Moshang T, Duckett JW. True hermaphroditism and normal male genitalia: an unusual presentation. Urology 1995; 46:736–9. 95. Jensen JC, Ehrlich RM, Hanna MK et al. A report of 4 patients with the Drash syndrome and a review of the literature. J Urol 1989; 141:1174–6. 96. Donohoue PA, Parker K, Migeon CJ. Congenital adrenal hyperplasia. In: Scriver CR et al., editors. Metabolic and Molecular Bases of Inherited Disease. 7th edn. Ch. 94. McGraw Hill, New York. 1995. 97. Francois I, van Helvoirt M, de Zegher F. Male pseudohermaphroditism related to complications at conception, in early pregnancy or in prenatal growth. Horm Res 1999; 51:91–5.

References 901 98. Kuhn JM, Cleret JM, Lavoinne A et al. True hermaphroditism: from female to male endocrine status. J Clin Endocrinol Metabol 1985; 61:196–9. 99. Dewhurst J, Grant DB. Intersex problems. Arch Dis Child 1984; 59:1191–4. 100. Gustafson ML, Lee MM, Asmundson L et al. Müllerian inhibiting substance in the diagnosis and management of intersex and gonadal abnormalities. J Pediatr Surg 1993; 28:439–44. 101. Young J, Rey R, Couzinet B, Chanson P, Josso N, Schaison G. Antimüllerian hormone in patients with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1999; 84:2696–9. 102. Rey RA, Belville C, Nihoul-Fékété C, Michel-Calemard L, Forest MG et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement. J Clin Endocrinol Metab 1998; 84:627–31. 103. Josso N. Paediatric applications of anti-müllerian hormone research. Horm Res 1995; 43:243–8. 104. Lee MM, Donahoe BL, Silverman T et al. Measurements of serum müllerian inhibiting substance in the evaluation of children with nonpalpable gonads. J Urology 1997; 158:1637. 105. Hricak H, Chang YCF, Thurnher S. Evaluation with MR imaging. Radiology 1988; 169:69–74. 106. Martin TV, Anderson KR, Weiss RM. Laparoscopic evaluation and management of a child with ambiguous genitalia, ectopic spleen, and Meckel’s diverticulum. Tech Urol 1997; 3:49–50. 107. De Jong TPVM, Boemers TML. Neonatal management of female intersex by clitoro-vaginoplasty. J Urol 1995; 154:830–2. 108. Gilbert DA, Jordan GH, Devine CJ Jr et al. Phallic construction in prepubertal and adolescent boys. J Urol 1993; 149:1521–6. 109. Jordan GH, Alter GJ, Gilbert DA et al. Penile prosthesis implantation in total phalloplasty. J Urol 1994; 152:410–14. 110. Gilbert DA, Horton CE, Terzis JK et al. New concepts in phallic reconstruction. Ann Plast Surg 1987; 18:128–36. 111. Vorstman B, Horton CE, Winslow BH. Repair of secondary genital deformities of epispadias/exstrophy. Clin Plast Surg 1988; 15:381–91. 112. Perovic S. Phalloplasty in children and adolescents using the extended pedicle island groin ﬂap. J Urol 1995; 154:848–53. 113. Husmann DA, McLorie GA, Churchill BM. Phallic reconstruction in cloacal exstrophy. J Urol 1989; 142:563–4. 114. Sadove RC, Sengezer M, McRoberts JW, Wells MD. Onestage total penile reconstruction with a free sensate osteocutaneous ﬁbula ﬂap. Plast Reconstr Surg 1993; 92:1314–25. 115. Gilbert DA, Jordan GH, Devine CJ Jr, Winslow BH. Microsurgical forearm ‘cricket bat-transformer’ phalloplasty. Plast Reconstr Surg 1992; 90:711–16.

116. Gilbert DA, Williams MW, Horton CE et al. Phallic reinnervation via the pudendal nerve. J Urol 1988; 140:295–9. 117. Kai-Xiang C, Ru-Hong Z, Su Z. Cheng’s method for reconstruction of a functionally sensitive penis. Plast Reconstr Surg 1997; 99:87–92. 118. Gilbert DA, Winslow BH. Penis construction. Semin Urol 1987; 5:262–9. 119. Stolar CJH, Wiener ES, Hensle TW et al. Reconstruction of penile agenesis by a posterior sagittal approach. J Pediatr Surg 1987; 22:1076–80. 120. Merke DP, Cutler GB Jr. New approaches to the treatment of congenital adrenal hyperplasia. JAMA 1997; 277:1073–6. 121. Van Wyk JJ, Gunther DF, Ritzen EM et al. The use of adrenalectomy as a treatment for congenital adrenal hyperplasia. J Clin Endocrinol Metab 1996; 81:3180–90. 122. Mercado AB, Wilson RC, Cheng KC et al. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deﬁciency. J Clin Endocrinol Metab 1995; 80:2014–20. 123. Donahoe PK, Powell DM, Lee MM. Clinical management of intersex abnormalities. Curr Probl Surg 1991; 28:513–79. 124. Simpson JL. Diagnosis and management of genital ambiguity. Am J Obstet Gynecol 1977; 128:137–45. 125. Luks FI, Hansbrough F, Klotz DH Jr et al. Early gender assignment in true hermaphroditism. J Pediatr Surg 1988; 23:1122–6. 126. Montero M, Mendez R, Valverde D, Fernandez JL, Gomez M, Ruiz C. True hermaphroditism and normal male external genitalia: a rare presentation. Acta Paediatr 1999; 88:909–14. 127. Petersen L, Kock K, Jacobsen BB. Germ cell neoplasms in three intersex patients with 46,XY karyotype. Int Urol Nephrol 1992; 24:633–9. 128. Chase C. Letter to the Editor. Arch Sex Behav 1999; 28:103–5. 129. Schober JM. Long-term outcomes and changing attitudes to intersexuality. BJU Int 1999; 83:39–50. 130. Allen LE, Hardy BF, Churchill BM. The surgical management of the enlarged clitoris. J Urol 1982; 128:351–4. 131. Caufriez A. Male pseudohermaphroditism due to 17ketoreductase deﬁciency: report of a case without gynecomastia and without vaginal pouch. Am J Obstet Gynecol 1986; 154:148–9. 132. Barrett TM, Gonzales ET. Reconstruction of the female external genitalia. Urol Clin N Am 1980; 7:455–63. 133. Randolph JG, Hung W. Reduction clitoroplasty in females with hypertrophied clitoris. J Pediatr Surg 1970; 5:224–31. 134. Spence HM, Allen TD. Genital reconstruction in the female with the adrenogenital syndrome. Br J Urol 1973; 45:126–30. 135. Mollard P, Juskiewenski S, Sarkissian J. Clitoroplasty in intersex: a new technique. Br J Urol 1981; 53:363–71.

902 Intersex 136. Gonzalez R, Fernandes ET. Single-stage feminization genitoplasty. J Urol 1990; 143:776–8. 137. Pena A, Filmer B, Bonilla E et al. Transanorectal approach for the treatment of urogenital sinus: preliminary report. J Pediatr Surg 1992; 27:681–5. 138. Jones HW, Verkauf BS. Surgical treatment in congenital adrenal hyperplasia: age at operation and other prognostic factors. Obstet Gynecol 1970; 36:1–10. 139. Lobe TE, Woodall DL, Richards GE et al. The complications of surgery for intersex: changing patterns over two decades. J Pediatr Surg 1987; 22:651–2. 140. McIndoe AH et al. An operation for the cure of congenital absence of the vagina. J Obstet Gynecol 1938; 45:490–4.

141. Wiser WL, Bates GW. Management of agenesis of the vagina. Surg Gynecol Obstet 1984; 159:108–12. 142. Masters WH, Johnson VE. Human Sexual Inadequacy. Boston: Little, Brown, 1970. 143. Goligher JC. The use of pedicled transplants of sigmoid or other parts of the intestinal tract for vaginal construction. Ann R Coll Surg Engl 1983; 65:353–5. 144. Laub DR, Laub DR II, Biber S. Vaginoplasty for gender conﬁrmation. Clin Plast Surg 1988; 15:463–70. 145. Gearhart JP, Jeffs RD. The use of parenteral testosterone therapy in genital reconstructive surgery. J Urol 1987; 138:1077–8. 146. Lee PA. Micropenis. Pediatr Adolesc Endocrinol 1989; 19:149–54.

95 Male genital anomalies JOHN M. HUTSON

INTRODUCTION Development of the external genitalia is a complex process in the male, which predisposes to many congenital anomalies. Understanding the anomalies requires a detailed knowledge of the embryology, and particularly the central roles of androgens (in coordinating the masculinization of the anatomy) and the processus vaginalis (which allows descent of the intraabdominal fetal testis into the scrotum).

EMBRYOLOGY Masculinization of the external genitalia occurs in normal human embryos between 8 and 12 weeks of gestation. The inner genital folds fuse to create the male anterior urethra, while the outer genital folds fuse to make the scrotum. The genital tubercle enlarges to form the phallus. All these processes are mediated by release of testosterone from the embryonic testis. An enzyme in the target tissues, 5 alpha-reductase, converts the small amount of circulating testosterone into dihydrotestosterone, which binds 5–10 times more tightly to the androgen receptor than testosterone itself. Although the genitalia appear ‘male’ by 12 weeks of gestation, the phallus is still tiny, but it continues to grow throughout pregnancy to reach its newborn size (3–4 cm stretched length). The normal process of testicular descent is multistaged. The ﬁrst phase involves enlargement of the genito-inguinal ligament (or ‘gubernaculum’) and regression of the cranial suspensory ligament. The swollen distal gubernaculum anchors the embryonic testis near the groin during enlargement of the abdominal cavity. The hormonal regulation of this enlargement is unresolved, with Mullerian-inhibiting substance (MIS) appearing to have a role, but recent evidence suggests that Leydig insulin-like hormone (insulin-3 or Insl3 or relaxin-like factor) may be the active molecule.1,2

The second phase involves development of a peritoneal diverticulum (processus vaginalis) inside the gubernaculum. Migration of the gubernaculum (with elongation of the processus) to the scrotum is controlled by the genitofemoral nerve releasing calcitonin generelated peptide (CGRP), under stimulation of androgen.3 During migration the gubernaculum is not anchored in the groin, which could predispose to extravaginal torsion in the perinatal period. Following testicular descent, the processus vaginalis obliterates between the internal inguinal ring and the top of the scrotum, leaving the testis within the tunica vaginalis. Failure of closure leads to inguinal hernia, hydrocele or encysted hydrocele of the cord.

PENIS The penis of neonatal males is a focus of considerable parental anxiety and attention. The normal foreskin in a premature infant may appear relatively deﬁcient, but by term it protrudes beyond the glans. The inner prepuce is attached to the glans and the distal opening is narrow, sometimes making catheterization difﬁcult. Anomalies of the foreskin, such as phimosis or balanitis, are rare in the neonatal period, although phimosis can occur secondary to cystoscopy in boys with urethral valves.

Circumcision Neonatal circumcision is one of the commonest operations in the USA and Israel, although in other western countries the frequency is much lower.4,5 The procedure was known in the ancient societies of the Middle East, and may have arisen as a way of preventing balanitis and phimosis in an arid, sandy region. Circumcision is part of the ritual for such religions as Judaism, Christianity and Islam, which all arose in the same geographic area.

904 Male genital anomalies

In our own time there is controversy over the advantages versus the risks of routine neonatal circumcision.6–8 The American Academy of Pediatrics (AAP) ﬁrst issued guidelines about neonatal circumcision in 1971, concluding that there was no absolute medical indication for routine circumcision.9 By 1989, new evidence showed a potential beneﬁt of circumcision in preventing neonatal urinary tract infection and sexually transmitted diseases, including AIDS; this led to a revision of the guidelines to balance the risks against the advantages. The current position of the AAP is to provide parents with an informed choice with accurate and unbiased information. Where circumcision is requested the AAP now recommend procedural analgesia be provided.9 Circumcision should prevent phimosis, paraphimosis and balanitis, although good clinical studies proving this at a population level are hard to ﬁnd. Learman4 concluded that the evidence supporting circumcision was too weak to recommend routine operation. Urinary tract infection in neonatal males can be reduced by circumcision from 7/1000 to 1.9/1000,10 but whether improved penile hygiene would have the same effect is unknown. Sexually transmitted disease (STD) rates in circumcised men are 10% lower than without circumcision, when comparing men presenting to an STD clinic in a western country.11 In sub-saharan Africa, the beneﬁts of circumcision in reducing HIV risk may be much greater,12 although meta-analysis has not conﬁrmed a beneﬁt.13 Circumcision is linked with a threefold reduction in penile cancer, although the low frequency of the condition does not justify routine neonatal operation. Learman4 estimated that over 300 000 circumcisions were required to prevent one penile cancer/year. In Denmark, the incidence of penile cancer is falling, despite no increase in the number of circumcisions, suggesting that other factors, such as hygiene, are important.14 The complications of circumcision may be extreme, including amputation or diathermy necrosis,15 although most complications are minor (e.g. minor bleeding or infection) and uncommon (<1%)9 (Fig. 95.1). The plastibell device or the Gomco clamp both have a low (0.2%) complication rate in neonates, and are equally safe techniques.4 Neonatal circumcision should only be performed with adequate analgesia, using a ring penile block, local anesthetic cream, or a dorsal penile nerve block. If a Plastibell device is used it is important to select the right size to avoid the ring slipping down the shaft and causing a form of paraphimosis.16 The key to circumcision in the neonate is complete mobilization of the foreskin by separation from the glans with a lacrimal probe, and then inspection of the glans and urethral meatus to exclude hypospadias or other anomalies. Marking the level of the coronal groove through the base of the foreskin ensures that the skin of the shaft is not pulled up into the device.

Figure 95.1 Postoperative penile hemorrhage after circumcision

Hypospadias Failure of fusion of the urethral or inner genital folds leads to hypospadias (Greek for ‘hole underneath’). Secondary anomalies include deﬁciency of the ventral prepuce (leading to a ‘dorsal hood’), and relative deﬁciency in growth of the periurethral tissues compared with dorsal structures such as the corpora cavernosa. The latter causes ‘chordee’, or relative curvature of the penis, particularly on erection.17 Depending on diagnostic criteria, the incidence of hypospadias is 1/100 to 1/300.18 Siblings or the father are affected in about 10% of patients, suggesting polygenic inheritance. Hypospadias is an anomaly with a wide variation in severity, from a minor degree of meatal ectopia on the ventral glans to a severe abnormality with a perineal opening. ‘Hypospadias’ can be confused with more serious genital anomalies, and the most important initial aim is to exclude ambiguous genitalia (Fig. 95.2). Because hypospadias is an anatomical anomaly of anterior urethral development, the rest of the external (and internal) genitalia should be normal. By contrast, patients with ambiguous genitalia have extensive genital abnormalities secondary to failure of all aspects of androgen-dependent development. Genital anomaly can be excluded if the scrotum is completely fused and both testes are descended. Babies with possible ambiguity need immediate referral, while those with hypospadias alone can be managed after the neonatal period. Surgical treatment can be offered at 3–6 months of age, often as day surgery or overnight stay. Admission may be needed for urinary diversion, depending on severity of the anomaly and the surgeon’s preference. A wide range of techniques are available,19–21 which are not the main subject of this volume. Readers should consult the references for speciﬁc details. Epispadias is a more severe and distantly related condition, which is more related to exstrophy of the bladder, and is included in chapter 66.

Penis 905

Figure 95.2 Apparent ‘hypospadias and biﬁd scrotum’, in a child with a severe genital anomaly. This child needs urgent investigation for intersex anomalies

Figure 95.3 Urethral duplication in an infant

Micropenis/buried penis A small penis may be caused by inadequate hormonal stimulation during pregnancy (hypothalamic, pituitary or placental deﬁciency), although in some cases there is an anatomical deﬁciency. The buried penis occurs where the erectile tissue is adequate but the shaft skin is deﬁcient. Micropenis can be treated by androgen treatment, although whether postnatal hormone therapy is beneﬁcial is controversial.22,23 A number of operations have been proposed for buried penis, most of which use the foreskin.24 Penoscrotal web is a variant of buried penis where there is inadequate ventral shaft skin. This can be repaired later in infancy by Z-plasty.

Rare penile anomalies Rare anomalies of the penis may be obvious at birth, including urethral duplication (Fig. 95.3) and megalourethra, which may be associated with prune belly syndrome.17,25 Partial duplication of the caudal embryo may lead to duplication of the penis, while penile ‘agenesis’ is usually a form of posterior ectopia, with the erectile tissue and urethra buried in the perineal body and the meatus on the anterior lip of the anal canal.26,27 The latter anatomy is similar to the normal situation in marsupials, where the scrotum is inguinal in position and the phallus is in the perineum. Minor variants of penoscrotal transposition are common in intersex patients.28,29

Undescended testis Any anomaly in the anatomical structures involved in testicular descent, or their hormonal regulation, will lead to congenital maldescent. Failure of the transabdominal phase causes intra-abdominal testes that are truly ‘cryptorchid’ or hidden. Impalpable testes within the abdomen or canal are relatively uncommon (<5–10% of patients, depending on different authors30). Intra-abdominal testes are associated with hypoplasia or the ipsilateral scrotum and often with absence of the external inguinal ring. The latter is a useful clinical feature to conﬁrm absence of an inguinoscrotal migration. When the testis is inside the canal, the external ring may be open, consistent with intermittent emergence of the canalicular gonad. The common site for undescended testes is just outside the external ring. Denis Browne described this as the ‘superﬁcial pouch’, which is the name given to the tunica vaginalis when it is located in the groin, superﬁcial to the abdominal wall and deep to the superﬁcial abdominal wall fascia (Scarpa).31 Undescent is likely to have multiple causes, the commonest being failure of gubernacular migration for various mechanical reasons.30,32 Transient deﬁciency of gonadal androgens related to hypothalamic or pituitary anomalies or defects in placental function also may be important.33 A number of less common and rare causes for cryptorchidism have been proposed (Box 95.1 and Fig. 95.4).

906 Male genital anomalies Box 95.1 Proposed causes of cryptorchidism in rare cases 1. Aberrant location of genitofemoral nerve (perineal testis) 2. Persistent mullerian duct syndrome (transverse ectopia with uterus) 3. Prune belly syndrome (massive bladder enlargement precluding entrance into inguinal canal) 4. Posterior urethral valves (same proposed mechanism as 3) 5. Anterior abdominal wall defects (ruptured gubernaculum) 6. Connective tissue disorders (deﬁcient gubernacular migration) 7. Neural tube defects (genitofemoral nerve anomalies)

Figure 95.4 Ectopic undescended testis. In this case of perineal testis, it has been suggested that the cause is aberrant migration of the gubernaculum secondary to abnormal location of the genitofemoral nerve

In premature infants as well as many term babies, cryptorchidism may be transitory, with further descent into the scrotum in the ﬁrst 12 weeks postnatally.34 These so-called ‘late descenders’ are at a high risk of developing secondary cryptorchidism later in childhood.35 The etiology of the latter is unknown, but has been proposed to be failure of the processus vaginalis to obliterate fully postnatally, preventing the normal elongation of the spermatic cord with growth.36,37

DIAGNOSIS The aim of the physical examination is to locate the testis and determine its lowest position without undue tension. The latter corresponds with the caudal limit of

the undescended tunica vaginalis.38 In neonates the examination may be hampered by vigorous leg movements, small size of all structures (including the testis, which is only 1–2 ml in volume), and mobility of the testis within the tunica vaginalis. The scrotum is hypoplastic if the testis has never reached it, and the inguinal canal is shut in intra-abdominal testes. Palpation of a muscle defect at the pubic tubercle suggests the testis is inside the canal. Compensatory hypertrophy of the contralateral testis (2–3 ml) suggests atrophy of the ipsilateral organ (‘the vanishing testis’).

TREATMENT The aim of surgical treatment of undescended testis is to relocate the gonad into the scrotum before secondary dysfunction and degeneration occur (from high temperature). It is based on a premise, currently not proven in humans, that early placement of the testis in the scrotum will allow normal postnatal maturation to proceed. Careful study of testicular biopsies now suggests that the germ cells undergo maturation, from gonocytes to type A spermatogonia, within 6–12 months after birth,39 and that this maturation is deﬁcient or arrested in cryptorchid testes. Animal models support the premise that early intervention can prevent germ cell loss,40 but this has not been conﬁrmed in humans yet because of the inordinate lag time between treatment and end result (adult fertility). The recommended age of orchidopexy has changed over the years, reﬂecting the accumulating knowledge about testicular function in infants. In our own department, orchidopexy is done after 3–6 months, as long as the anesthetic support is adequate. Because 4–5% of males have undescended testes at birth, but about half of these show postnatal descent by 12 weeks, the baby should be re-examined then to conﬁrm persisting cryptorchidism prior to referral for surgery. At this age the operation is best performed by a trained pediatric surgeon who is familiar with the handling of delicate tissues.

Rare anomalies of the testis Tumors of the testis are rare at birth, but teratomas have been reported (Fig. 95.5). In a review of 68 patients with testicular tumors over 30 years we found one baby with a genital anomaly and a gonadoblastoma.41 A neonatal teratoma may need to be distinguished from a hydrocele or testicular torsion. If the hydrocele is too tense to palpate a normal testis, an ultrasound examination would be useful. Most teratomas can be shelled out of the testis, thereby avoiding orchidectomy. Exstrophy of the testis has been reported, presumed to be secondary to pressure necrosis of the scrotal skin from the baby’s heel, and prolapse of the scrotal contents.42 A similar defect has been reported in the

References 907

absent bilaterally: this ﬁnding can be used to diagnose cystic ﬁbrosis in neonates with possible meconium ileus (personal observation; 48,49). Apart from intersex anomalies with separate labioscrotal folds or biﬁd scrotum, scrotal anomalies are rare. There are case reports of ectopic hemiscrotum and duplication, which are a local manifestation of partial twinning of the caudal embryo or compression of the perineum by the feet of the fetus.50

REFERENCES

Figure 95.5 Neonate with a teratoma of the left testis

proximal penile urethra from probable pressure atrophy, leading to a congenital urethral ﬁstula.43 Duplication of the gonadal primordium can cause polyorchidism. The presentation is of three scrotal masses, all of which feel like normal testis.44 The differential diagnosis includes complete inguinoscrotal hernia, encysted hydrocele of the cord, and transverse testicular ectopia, where both testes are on the same side. In the latter situation the contralateral hemiscrotum is empty. No treatment may be required, although one gonad can be removed if the vas deferens is deﬁcient. Transverse testicular ectopia is a rare anomaly, which may be associated with prenatal rupture of the ipsilateral gubernaculum, allowing the testis to prolapse into the contralateral processus vaginalis. In most cases the ectopic testis has no gubernacular attachments; the diagnosis can be conﬁrmed on scrotal ultrasound.45 Transverse ectopia of the testis is seen also in a rare form of intersex known as persistent Mullerian duct syndrome.46 Transverse ectopia is treated by trans-septal scrotal orchidopexy (i.e. both testes are brought through the same inguinal canal into the scrotum and the contralateral hemiscrotum). The vas deferens may be absent in the Rokitansky syndrome or in babies with cystic ﬁbrosis. In the Rokitansky anomaly the caudal growth of the Wolfﬁan duct is arrested, leading to subsequent absence of the ipsilateral vas deferens, seminal vesicle and ureteric bud (and hence ipsilateral renal agenesis).47 The etiology of absent vas deferens is different in cystic ﬁbrosis, where the Wolfﬁan ducts undergo involution/atresia in midgestation. At birth, only the head of the epididymis is palpable, and the epididymal tail and vas deferens are

1. Nef S, Parada LF. Cryptorchidism in mice mutant for Insl3. Nat Genet 1999; 22:295–9. 2. Zimmerman S, Stedig G, Emmen JMA et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13:681–91. 3. Hutson JM, Hasthorpe S, Heyns CF. Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr Rev 1996; 18:259–60. 4. Learman LA. Neonatal circumcision: a dispassionate analysis. Clin Obstet Gynecol 1999; 12:849–59. 5. Stang HJ, Snellman LW. Circumcision practice patterns in the United States. Pediatrics 1998; 101:1066. 6. Bloom DA, Koo HP. Editorial. The circumcision issue. Clin Pediatr 1999; 38:243–4. 7. Langer JC, Coplen DE. Circumcision and pediatric disorders of the penis. Pediatr Clin North Am 1998; 45:801–12. 8. Szabo R, Short RV. How does male circumcision protect against HIV infection? Br Med J 2000; 320:1592–4. 9. American Academy of Pediatrics. Circumcision policy statement. Pediatrics 1999; 103:686–93. 10. To T, Agha M, Dick PT, Feldman W. Cohort study on circumcision of newborn boys and subsequent risk of urinary tract infection. Lancet 1988; 352:1813–18. 11. Parker SW, Steward AJ, Wren MN, Gollow MM, Straton JA. Circumcision and sexually transmissable disease. Med J Aust 1983; 2:288–90. 12. Quinn TC, Wawer MJ, Sewankambo N et al. Viral load and heterosexual transmission of human immunodeﬁciency virus type 1. N Engl J Med 2000; 342:921–9. 13. Van Howe RS. Circumcision and HIV infection: review of the literature and meta-analysis. Int J STD AIDS 1999; 10:8–16. 14. Frisch M, Früs S, Kjear SK, Mellye M. Falling incidence of penis cancer in an uncircumcised population (Denmark 1943–90). Br Med J 1995; 311:1471. 15. Coskunﬁrat OK, Sayilkan S, Velidedeoglu H. Glans and penile skin amputation as a complication of circumcision. Ann Plast Surg 1999; 43:457. 16. Cilento BG, Holmes NM, Canning DA. Plastibell® complications revisited. Clin Pediatr 1999; 38:239–42. 17. Stephens FD, Smith ED, Hutson JM. Congenital Anomalies of the Urinary and Genital Tracts. Oxford: Isis Medical Media, 1996:80–90.

908 Male genital anomalies 18. Duckett JW, Baskin LS. Hypospadias. In: O’Neill JA, Grosfeld JL, Fonkalsrud EW, Coran AG, Rowe MI, editors. Pediatric Surgery, 5th edn. St Louis: Mosby, 1988:1761–81. 19. Asopa HS. Newer concepts in the management of hypospadias and its complications. Ann Roy Coll Surg Engl 1998; 80:161–8. 20. Borer JG, Retik AB. Current trends in hypospadias repair. Urol Clin North Am 1999; 26:15–37. 21. Snodgrass WT. Tubularized incised plate hypospadias repair: indications, technique and complications. Urology 1999; 54:6–11. 22. Husmann DA. Editorial: Microphallic hypospadias – the use of human chorionic gonadotropin and testosterone before surgical repair. J Urol 1999; 162:1440–1. 23. Koff SA, Jayanthi VR. Preoperative treatment with human chorionic gonadotropin in infancy decreases the severity of proximal hypospadias and chordee. J Urol 1999; 162:1435–9. 24. Donahoe PK, Keating MA. Preputial unfurling to correct the buried penis. J Pediatr Surg 1986; 21:1055–7. 25. Boissonnat P, Duhamel B. Congenital diverticula of the anterior urethra associated with aplasia of the abdominal wall in the male infant. Br J Urol 1962; 34:56. 26. Beasley SW, Hutson JM, Howat AJ, Kelly JH. Posterior ectopia of penis mimics marsupial anatomy: case reported in association with a primitive cloacal anomaly. Pediatr Surg Int 1987; 2:127–30. 27. Gilbert J, Clark RD, Koyle MA. Penile agenesis: a fatal variation of an uncommon lesion. J Urol 1990; 43:338–9. 28. Garcia RD, Danuelos A, Marin C, De Tomas E. Peno-scrotal transposition. Eur J Pediatr Surg 1995; 5:222–5. 29. Ozkardes H, Germiyanoglu C, Gurdal M, Altug U, Erol D. Transverse testicular ectopia with penoscrotal transposition. Pediatr Surg Int 1994; 9:532–3. 30. Hutson JM, Beasley SW. Descent of the Testis. New York: Edward Arnold, 1992:50–73. 31. Browne D. The diagnosis of undescended testicle. Br Med J 1938; ii:92–7. 32. Husmann DA, Levy JB. Current concepts in the pathophysiology of testicular descent. Urology 1995; 46:267–6. 33. Hadziselimovic F, Duckett JW, Snyder HM, Schnaufer L, Huff D. Omphalocele, cryptorchidism, and brain malformations. J Pediatr Surg 1987; 22:854–6. 34. John Radcliffe Hospital Cryptorchidism Study Group. Cryptorchidism: a prospective study of 7500 consecutive male births, 1984–88. Arch Dis Childhood 1992; 67:892–9.

35. John Radcliffe Hospital Cryptorchidism Study Group. Boys with late descending testes: the source of patients with ‘retractile’ testes undergoing orchidopexy? Br Med J 1986; 293:789–90. 36. Clarnette TD, Hutson JM. Is the ascending testis actually ‘stationary’? Normal elongation of the spermatic cord is prevented by a ﬁbrous remnant of the processus vaginalis. Pediatr Surg Int 1997; 12:155–7. 37. Clarnette TD, Rowe D, Hasthorpe S, Hutson JM. Incomplete disappearance of the processus vaginalis as a cause of ascending testis. J Urol 1997; 157:1889–91. 38. Beltran-Brown F, Villegas-Alvarez F. Clinical classiﬁcation for undescended testes: experience in 1010 orchidopexies. J Pediatr Surg 1988; 23:444–7. 39. Huff DS, Hadziselimovic F, Snyder HMcC, Blythe B, Duckett JW. Histologic maldevelopment of unilaterally cryptorchid testes and their descended partners. Eur J Pediatr 1993; 152:S10–S14. 40. Zhou B, Hutson JM, Hasthorpe S. Efﬁcacy of orchidopexy on spermatogenesis in the immature mutant ‘transscrotal’ rat as a cryptorchid model by quantitative cytological analysis. Br J Urol 1988; 81:290–4. 41. Sugita Y, Clarnette TD, Cooke-Yarborough C, Waters K, Hutson JM. Testicular and paratesticular tumours in children: 30 years’ experience. Aust NZ J Surg 1999; 69:505–8. 42. Heyns CF. Exstrophy of the testis. J Urol 1990; 144:724–5. 43. Sharma AK, Kotharti SK, Goel D, Chaturvedi V. Congenital urethral ﬁstula. Pediatr Surg Int 2000; 16:142–3. 44. Thum G. Polyorchidism: case report and review of literature. Urology 1991; 145:370–2. 45. Chen K-C, Chu C-C, Chou T-Y. Transverse testicular ectopia: preoperative diagnosis by ultrasonography. Pediatr Surg Int 2000; 16:77–9. 46. Hutson JM, Baker ML. An hypothesis to explain abnormal gonadal descent in persistent Mullerian duct syndrome. Pediatr Surg Int 1994; 9:542–3. 47. Schlegel PN, Shin D, Goldstein M. Urogenital anomalies in men with congenital absence of the vas deferens. J Urol 1996; 155:1644–8. 48. Gracey M, Campbell P, Noblett HR. Atretic vas deferens in cystic ﬁbrosis. N Engl J Med 1969; Jan 30:276. 49. van Wingerden JJ, Franz I. The presence of a caput epididymis in congenital absence of the vas deferens. J Urol 1984; 131:764–6. 50. Cook WA, Stephens FD. Pathoembryology of the urinary tract. In: King LR, editor. Urological Surgery in Neonates and Young Infants, Philadelphia: WB Saunders, 1988:1–22.

96 Neonatal testicular torsion DAVID M. BURGE

INTRODUCTION Torsion of the neonatal testis is a well-recognized clinical entity which accounts for about 10% of all cases of testicular torsion admitted to pediatric surgical centers.1 Torsion usually occurs extravaginally, i.e. in the spermatic cord above the insertion of the tunica vaginalis (Fig. 96.1), but both intravaginal and mesorchial torsion are reported.2,3 Either testis may be involved. Bilateral torsion occurs and may be synchronous or metachronous.4,5 Apparent primary infarction of the neonatal testis in the absence of torsion occurs less commonly,6 and while it has been postulated that this represents previous torsion that has untwisted, good evidence exists to suggest that the initial event in neonatal torsion is a vascular one and that torsion may occur secondarily.2 The neonatal testis may be prone to extravaginal torsion because of its extreme mobility within the scrotum.7

CLINICAL FEATURES Neonatal torsion appears to be a condition of large term babies2 and it rarely, if ever, affects the preterm infant. Previously, breech delivery was suspected as being a causative factor. Recent reports, however, fail to conﬁrm

Figure 96.1 Anatomy of extravaginal torsion

this.2 Affected babies are usually totally asymptomatic. The typical physical features are of a hard, edematous hemiscrotum with a noticeable blue or black discoloration. The testis feels ﬁrmly adherent to the scrotal wall and is apparently nontender. While there may be some enlargement of the hemiscrotum, this is not usually marked. These features are usually present from birth, supporting the contention that neonatal torsion is often an antenatal event. However, the clinical features are not always noted at delivery and in many cases are not detected until the second or third day of age. Occasionally, features consistent with acute torsion (sudden onset of swelling, erythema and pain) may develop some days or weeks after delivery, and it appears that in these cases the torsion is more likely to be intravaginal. Torsion of an undescended testis may present in this way.2 Diagnosis can usually be made on the clinical features alone. The differential diagnosis includes hydrocele, testicular tumor, trauma, adrenal hemorrhage, and meconium peritonitis with tracking down a patent processus. Distinction from a simple hydrocele is usually easy by transillumination. Testicular neoplasia can be excluded by the presence of bluish discoloration and scrotal edema. Torsion can only be differentiated from spontaneous infarction at surgery. Some bruising of the scrotum may occur after breech delivery,8 but this is usually in the presence of a testis that feels normal to palpation. Intraperitoneal injury from birth trauma may result in hematocele formation, but the ﬂuctuation of this lesion will usually distinguish it from torsion. Adrenal hemorrhage may present with features indistinguishable for torsion but adrenal ultrasound would be diagnostic.9 While color Doppler studies of testicular artery ﬂow and radionuclide scanning of the scrotum might support the diagnosis, they are not required. A clinical diagnosis of neonatal torsion is sufﬁcient indication for scrotal exploration. While it might seem mandatory that this be conducted urgently, reports of

910 Neonatal testicular torsion

successful testicular salvage are rare.3,10–12 The classical clinical features seem to be due to the presence of established testicular infarction and it can be argued that the only reason for surgery is to ﬁx the contralateral testis. Because delayed torsion of the contralateral testis does occur and may be at extravaginal, intravaginal or mesorchial level, early surgery to assess the affected testis, excise it if necessary and securely ﬁx the contralateral testis is recommended. No speciﬁc preoperative preparation is required.

OPERATIVE TECHNIQUE Under general anesthesia, the scrotum is incised in the midline and dissection continued into the affected hemiscrotum (Fig. 96.2). Both testes are easily approached through this single incision (Fig. 96.3). In most cases, established infarction will have resulted in

edema and ﬁxation of the testis to the subcutaneous tissues. It is usual, however, to ﬁnd a plane of cleavage outside the tunica vaginalis, resulting in a clear demonstration of the site of torsion. In some instances, necrosis is well established and the exact origin of the pathology cannot be identiﬁed. If, as is usually the case, the testis is clearly beyond salvage, it is wise to excise it, having transﬁxed the spermatic cord above the site of torsion. Retention of a necrotic testis is inadvisable as it invites sepsis which may put the contralateral testis at risk. While there is a theoretical possibility that retention of the infarcted testis may result in some hormonal production,7 in the majority of cases in which the affected testis is not removed involution occurs.2 Following excision of the affected testis, the contralateral testis is exposed through the same excision. The tunica vaginalis is opened to allow accurate inspection of the anatomy and permit effective ﬁxation. The tunica vaginalis is then sutured to the tunica albuginea of the testis at four points, using a ﬁne non-absorbable monoﬁlament material, thus preventing intravaginal torsion. It is wise to incorporate the scrotal septum in the two medial sutures, thus ﬁxing the tunica vaginalis to the scrotum and preventing extravaginal torsion (Fig. 96.4). Care should be taken to site these two sutures fairly deep in the wound or else the testis will lie too superﬁcially and skin closure made more difﬁcult. The scrotal incision is then closed with a ﬁne continuous catgut suture. No speciﬁc postoperative care is required.

Figure 96.2 Midline scrotal incision

Figure 96.4 Technique of testicular ﬁxation

REFERENCES Figure 96.2 Midline exploration showing extravaginal torsion of right testis and normal left testis prior to ﬁxation

1. Brereton RJ, Manley S. Acute scrotal pathology in boys. Z Kinderchir 1980; 29:343–57.

References 911 2. Burge DM. Neonatal testicular torsion and infarction. Br J Urol 1987; 59:70–3. 3. Guiney EJ, McGlinchey J. Torsion of the testis and spermatic cord in the newborn. Surg Gynecol Obstet 1981; 152:273–4. 4. Gerstmann DR, Marble RD. Bilaterally enlarged testicles: an atypical presentation of intrauterine spermatic cord torsion. Am J Dis Child 1980; 134:992–4. 5. Tripp BM, Homsy YL. Prenatal diagnosis of bilateral neonatal torsion: a case report. J Urol 1995; 153:1990–1. 6. Johnston JH. The testicles and scrotum. In: Williams DI, editor. Paediatric Urology. London: Butterworths, 1989:450–74.

7. Jerkins GR, Noe HN, Hollabaugh RS et al. Spermatic cord torsion in the neonate. J Urol 1983; 129:121–2. 8. Dunn PM. Testicular birth trauma. Arch Dis Child 1975; 50:745. 9. Liu KW, Ku KW, Cheung KL, Chan YL. Acute scrotal swelling: a sign of neonatal adrenal haemorrhage. J Paediatr Child Health 1994; 30:368–9. 10. LaQuaglia MP. Bilateral neonatal torsion. J Urol 1987; 138:1051–4. 11. Lonigo LA, Martin LW. Torsion of the spermatic cord in the newborn infant. N Engl J Med 1955; 178:702–5. 12. Stone KT, Kass EJ, Cacciarelli AA, Gibson DP. Management of suspected antenatal torsion: what is the best strategy? J Urol 1995; 153:782–4.

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11 Long-term outcomes in newborn surgery

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97 Long-term outcomes in newborn surgery MARK D. STRINGER

INTRODUCTION The development of neonatology in general and neonatal surgery in particular since the 1950s, has enabled the survival of an ever increasing number of newborn infants with severe congenital malformations. Traditionally, neonatal surgeons have rightly been concerned with early morbidity and mortality. During the last few decades, however, the care of these infants has progressively improved and although survival and early complications remain important outcome measures, long-term results and quality of life are becoming increasingly important to parents, clinicians, and health economists. This is particularly true in a population where long-term handicap is acknowledged to occur in a signiﬁcant proportion of survivors.

IMPORTANCE OF LONG-TERM OUTCOMES A knowledge of long-term outcomes is important for several reasons: • to inform parents (and patients) about future health expectations • to anticipate potential long-term complications that might be avoidable by careful monitoring and timely intervention, e.g. renal impairment secondary to neurogenic bladder in spinal dysraphism • to guide current clinical practice, e.g. umbilical excision used to be common practice in the surgical management of gastroschisis but the potentially damaging long-term psychological effects of this procedure have encouraged pediatric surgeons to preserve the umbilicus, which is now possible in most cases • to provide information on when not to operate. Understanding the natural history of conditions such as gastro-esophageal reﬂux and vesico-ureteric reﬂux is only possible as a result of carefully

conducted longitudinal follow-up studies. Only when the natural history has been deﬁned can we be conﬁdent about the need for intervention. Progress in neonatal anesthesia, surgery and perioperative care have enabled surgeons to perform increasingly complex operations on the newborn. This achieves early correction of the abnormality and, by exploiting the infant’s potential for adaptation, may improve the functional outcome. Only the fetus is capable of more plasticity. Thus, neonatal repair of anorectal malformations has been advocated as this may facilitate earlier development of neural pathways between the anorectum and the developing brain and improve subsequent bowel control.1 However, just because neonatal surgery is possible does not mean it is automatically better. We must await studies of long-term functional outcomes. Data on long-term outcomes are difﬁcult to obtain. Studies require meticulous data collection over many years and the co-operation of patients who have had more than enough exposure to medical facilities. Studies are hampered by poor continuity of care (which in turn is discouraged by overstretched health care systems), and a highly mobile patient population. Changes in practice make it difﬁcult to evaluate the impact of a previous intervention in a speciﬁc condition. Comparisons of outcomes between centers are hindered by different staging systems and outcome measures.

COMMON THEMES Common themes emerge repeatedly in discussions of long-term outcomes. In addition to disease-speciﬁc consequences and, in the case of newborns, gestation/ birth weight-speciﬁc consequences, the long-term issues that must be addressed include: growth and nutrition; psychological and cognitive development; potential for malignancy; effects on fertility and sexuality; genetic

916 Long-term outcomes in newborn surgery

considerations; and medicolegal aspects. The deﬁnition of long-term outcome is variable. Strictly, it means outcome at maturity, i.e. when the child reaches adulthood. In practice, the paucity of available data means that relatively short-term studies are used as surrogate measures of long-term outcome and in most instances we have to rely on follow-up studies that extend over several years. Also common to studies of long-term outcomes are potential methodological ﬂaws. For example, the lack of normal controls is especially signiﬁcant when trying to interpret data on continence, sexuality, and fertility. The potential for ascertainment bias must always be considered when deﬁning the cohort of individuals under investigation and their willingness to be included in follow-up studies.

Long-term consequences of prematurity/low birth weight In addition to the long-term consequences of congenital malformations and related surgical interventions, the neonatal surgeon must be mindful of the morbidity and mortality associated with prematurity and low birth weight (Fig. 97.1). Major neonatal morbidity increases with decreasing gestational age and birth weight. Many publications have highlighted the morbidity of neonates at different gestational ages and birth weights.2,3 The picture continues to change with advances in neonatal care but there is, nevertheless, a growing cohort of physically and mentally handicapped survivors. Prematurity is deﬁned by the World Health Organiza-

Figure 97.1 Outcome by gestational age (adapted from Rennie 1998) 3

tion as birth before 37 completed weeks of gestation, and low birth weight as less than 2500 g. Very low birth weight infants are born weighing less than 1500 g. Infants below the 10th or third centile for birth weight (deﬁnitions vary) are termed ‘small for gestational age’. Infants disadvantaged by prematurity, low birth weight or intrauterine growth retardation are at risk of longterm morbidity that may be compounded by surgery for a congenital malformation. Overall, about 25% of survivors born below 28 weeks are disabled and about 11% above 28 weeks. Low birth weight infants now comprise about 50% of all cases of cerebral palsy, the prevalence of which is increasing. Preterm infants, particularly those of very low birth weight, are at risk of cerebral palsy, visual impairment, sensorineural hearing loss, school failure, and impaired cognitive performance. This causes difﬁculties with behavior, continence, personal care, and problems with locomotion and communication. In a study of 10 surviving extremely low birth weight infants (< 1000 g) who underwent emergency abdominal surgery, Chacko et al.4 identiﬁed a worse short-term neurodevelopmental outcome than control infants matched for gestational age and birth weight. Whether this reﬂects severity of disease (which is likely) or surgery per se is uncertain. Families of such infants do need to be aware of such problems and the decision to operate is always best taken in collaboration with a neonatologist after considering the global condition of the infant.

Psychological consequences of newborn surgery Any discussion of long-term outcomes in neonatal surgery would not be complete without reference to psychological/cognitive development. Few studies have addressed this area and interpretation of ﬁndings is difﬁcult because of potential confounding variables such as socioeconomic status, domestic environment, parental IQ, intrauterine development, type of subsequent interventions, etc. Ludman et al.5,6 investigated the cognitive performance of 30 term infants born with surgically correctable life-threatening abnormalities who underwent emergency neonatal surgery and compared them with a matched group of healthy newborn babies. At 1 year of age the infants who underwent surgery were performing within the normal range, but signiﬁcantly less well than the controls in almost all areas of development. Of the various neonatal and perinatal factors studied, the length of hospital admission was the one most strongly associated with developmental progress at 1 year of age. At 3 years the cognitive functioning of children whose condition had been resolved in the early months of life was similar to the controls. Those children who required further medical or surgical treatment were

Common themes 917

functioning at lower levels than the controls, with language development being most affected. Poorer outcome at 3 years was most strongly correlated with the number of operations. Family factors were also positively correlated with language development.

Long-term outcome of newborn surgical conditions These can be characterized under four broad headings: those conditions with almost no long-term sequelae; those with deﬁnite but variable sequelae (the largest group); those conditions that may present for the ﬁrst time in adult life; and those with unknown consequences. Outcome may be related to the congenital anomaly itself, to the treatment or operative procedure, or to both. Examples of each of these will be considered, each illustrating different aspects of long-term outcome. Additional sources should be consulted for more detailed accounts of speciﬁc conditions.7

NEONATAL SURGICAL CONDITIONS/ INTERVENTIONS WITH ALMOST NO LONG-TERM SEQUELAE Hypertrophic pyloric stenosis frequently presents in the newborn period. Diagnosis and treatment are well established and Ramstedt’s pyloromyotomy is a highly successful procedure with few early complications. Gastric emptying has been investigated by several authors. Scintigraphic studies of gastric emptying in adults for both liquids and solids are normal.8 The incidence of peptic ulceration has been the subject of several studies but lack of appropriate controls renders most of these relatively meaningless. Ludtke et al.8 compared 18 adults who had received medical treatment for pyloric stenosis in infancy with 38 adults who had undergone pyloromyotomy and found no difference in the frequency of dyspeptic symptoms. Adhesive intestinal obstruction is extraordinarily uncommon after pyloromyotomy. Probably the most important long-term consideration is the inheritance risk. Carter and Evans9 concluded that the risk of developing hypertrophic pyloric stenosis was 5% for sons and 2.5% for daughters born to a male proband and 20% for sons and 7% for daughters born to a female proband. Whilst large capillary hemangiomas have the potential to cause serious complications in infancy, the vast majority of cutaneous strawberry lesions simply regress and cause no long-term functional or cosmetic physical disturbance. From autopsy studies in adults, it is known that most simple small parenchymal cysts in solid organs such as spleen or liver never cause symptoms. Now that prenatal sonography is routinely performed, these cysts are detected more frequently and the avoidance of overzealous investigation or treatment is just as important as identifying clinically important lesions.

NEONATAL SURGICAL CONDITIONS/ INTERVENTIONS WITH DEFINITE BUT VARIABLE LONG-TERM SEQUELAE Anorectal malformations The long-term outcome of anorectal anomalies is complicated by the diversity of these malformations. The meaningful comparison of long-term functional outcomes after repair of anorectal malformations has traditionally been bedevilled by lack of uniformity in the classiﬁcation of defects, variation in operative techniques, methods, age at assessment, and whether subjects were assessed with or without the use of continence aids. Many factors inﬂuence the functional outcome after repair of these malformations which are increasingly being undertaken in early infancy (Box 97.1). Similar considerations apply to the evaluation of children with Hirschsprung’s disease with the added dimension of the vast array of histologic abnormalities in this condition. With the widespread adoption of the posterior sagittal method of repair of anorectal malformations10 some consistency is beginning to emerge. The prognosis for each type of defect is gradually being deﬁned, although the ﬁnal outcome for an individual may not be apparent until adulthood. Clinical assessment, based mainly on the history and physical examination, has been the most common method of evaluating functional outcome.11 Various scoring systems have been developed ranging from the relatively simple Kelly score which relies on an assessment of continence, soiling, and puborectalis contraction12 to more sophisticated evaluations.13,14 These may be supplemented by anatomical imaging using endoanal sonography and/or magnetic resonance imaging and by manometric measures of anorectal physiology. It is clear that the type of anorectal malformation is a critical determinant of functional outcome. Children with a perineal ﬁstula are more likely to be continent but are often constipated. Some long-term studies have found that 10–17% of children with a treated low anomaly had soiling but it is not clear whether this Box 97.1 Factors inﬂuencing the functional long-term outcome after repair of an anorectal malformation

• Age and sex • Type of malformation (importance of a robust • • • • • • • •

classiﬁcation) Level of malformation Sacral and spinal defects Associated anomalies Type and timing of surgery Internal sphincter preservation Method, timing and independence of assessment Surgical complications Psychosocial and cognitive factors

918 Long-term outcomes in newborn surgery

problem is preventable if these children are subjected to careful follow-up and early treatment of constipation.15,16 Certainly, problems with fecal continence persist into adult life in a minority of patients with a low malformation. Most children with a high malformation are likely to suffer from fecal incontinence, although some show an improvement in fecal control as they get older.11 Early bowel management techniques are important in helping this group achieve social continence. Another major prognostic factor is the presence of a sacral defect.13,14 If more than two sacral vertebrae are missing, the pelvic and perineal musculature are often poorly developed and the perineum appears relatively ﬂat. The importance of occult myelodysplasia, which tends to be associated with higher lesions,17 the role of internal sphincter preservation, and the relative importance of primary and secondary colonic motility disorders are unclear. The surgical technique of anorectal reconstruction is likely to have a signiﬁcant effect on prognosis but this has not been convincingly demonstrated. Several authors consider that the posterior sagittal repair of anorectal malformations has not changed the prognosis of these children18–20 whilst others have reported improved results.21 Finally, the timing of surgery may be important. Neonatal repair may facilitate earlier development of neural pathways between the anorectum and the developing brain.1,22 However, the operation is technically more demanding in the neonate and the incidence of iatrogenic damage may be increased if this became standard practice. There is no evidence as yet to suggest that the results of neonatal repair are better than those achieved by surgery at 3 months of age. Urinary continence is usually normal after posterior sagittal repair except in children with a cloacal malformation and those with partial or complete sacral agenesis.13 There are few long-term reports of sexual function and fertility in patients with treated anorectal malformations. Low malformations are probably associated with normal fertility,11 although childbirth may pose risks to the perineum. Teenage girls with cloacal malformations are at risk of menstrual disorders. In Pena’s series of 22 girls aged 14 years or more, seven were menstruating normally, six had primary amenorrhea and nine had speciﬁc gynecological problems that required surgical intervention.23 Surgical complications also affect long-term outcome but most of these occur in early childhood. They include anal stenosis, either from ischemia or inadequate postoperative dilatations, and rectal mucosal prolapse; a revision anoplasty may be necessary in both situations. Vaginal stenosis and urethrovaginal ﬁstula are potential complications after cloacal repair. Rarely, a persistent or recurrent rectourethral ﬁstula may occur but a clinically signiﬁcant posterior urethral diverticulum almost never develops after posterior sagittal anorectoplasty. Some of the urological abnormalities previously attributed to surgical intervention are in fact congenital.24

In recent years, attention has been focused on the potential psychosocial sequelae of anorectal malformations and their treatment.25 Although behavioral problems are more common in these children, maladjustment is not directly related to poor functional outcome. Parental attitudes to the disability are a major factor in determining psychological outcome. The stress induced by a major anorectal malformation in affected patients and their families is considerable. Gastroschisis During the past four decades advances in neonatal care, parenteral nutrition, and surgical materials and technique have progressively improved the outlook for gastroschisis such that at least 90% of affected babies now survive. The abnormal character of the bowel at birth and the prolonged initial ileus might be expected to predispose to future bowel obstruction, malabsorption, abnormal bowel habit, or chronic abdominal pain. Outcome studies have often been limited by small numbers of patients,26–30 follow-up for mean periods of less than 10 years,31,32 or by analysis of data concentrating on survival and reoperation. Few studies have attempted to trace adult survivors and many have confused the issue by including patients with repaired exomphalos.33,34 In an attempt to examine some of these issues, Davies and Stringer35 reported an uncontrolled long-term study of all babies born in their unit with gastroschisis and surviving more than a year. Twenty-three subjects (70% of survivors) with a median age of 16 years (range 12–23 years) responded to a structured questionnaire. Twentytwo (96%) were in good health and, overall, growth was within normal limits. Neonates with gastroschisis are frequently growth-retarded but the survivors of uncomplicated gastroschisis appear to eventually achieve relatively normal growth. Whilst this observation has been disputed,34 detailed studies have demonstrated that catch-up growth occurs throughout childhood, mostly within the ﬁrst 5 years, leading to normal percentile ranks in older children.29,31,32 Children with gastroschisis complicated by intestinal atresia fare less well.32 Eight (35%) of the subjects reported in our series had undergone further surgery related to gastroschisis, including two for adhesive small bowel obstruction at 9 and 13 years of age, and three for unsightly scars.35 The severity of adhesion formation after gastroschisis repair appears to be very variable but mechanical bowel obstruction clearly represents a small but signiﬁcant long-term risk. Ventral hernia repair has been necessary in 10% or more of survivors in some longer-term studies28,32 but with the judicious use of staged silo repair and meticulous fascial closure this should now be a rare complication. Chronic recurrent abdominal pain was reported by a quarter of our subjects. Shorter-term follow-up studies have recorded a higher prevalence of this symptom29,31 which may indicate that either spontaneous improvement or adaptation occurs with age.

Common themes 919

Investigations in such patients have generally found no pathology but pathological acid gastro-esophageal reﬂux was present in four of 13 symptomatic patients in one study.31 Swartz et al.32 found that chronic abdominal complaints in general were conﬁned to those who had undergone intestinal resection in addition to gastroschisis repair. Acute appendicitis has rarely been described in patients with a previously repaired gastroschisis which is fortunate as the gastroschisis bowel is typically nonrotated and thus the appendix may well be abnormally sited. After gastroschisis repair, absence of an umbilicus may cause considerable distress, particularly in adolescents.29,35 Current surgical methods should aim to conserve the umbilicus whenever possible.36 Successful pregnancy is possible after gastroschisis repair but there is little information on fertility in these patients. Similarly, although gastroschisis is not considered to have a major genetic component, the inheritance risk for affected parents has not yet been determined. Ileal resection Analysis of the long-term consequences of a neonatal surgical procedure must be considered in the context of any underlying pathology. For example, ileal resection in the newborn may be necessary during the surgical management of a variety of conditions including intestinal atresia, midgut volvulus, intussusception, small bowel duplication cyst, meconium ileus, and necrotizing enterocolitis (NEC). The latter is the commonest reason and, as the remaining bowel usually recovers normal structure and function, this condition provides an opportunity to study the effects of ileal resection in the newborn. NEC has an estimated incidence 0.3 per 1000 live births in the UK37 and between 20 and 40% of affected infants require surgery. Long-term sequelae in survivors are dominantly those related to prematurity and, to a lesser extent, gut dysfunction. Jackman et al.38 reviewed 30 children at 2–7 years of age who had survived surgery for neonatal NEC. Five (17%) had severe developmental delay, two were visually handicapped, two had severe chronic lung disease, one had cerebral palsy, and two had short bowel syndrome. Only 50% of the surviving cohort were healthy. Tobiansky et al.39 compared the short-term neurodevelopmental outcome of 20 very low birth weight (VLBW) infants who developed NEC and required surgery with 40 control infants matched for gestation and 29 VLBW infants who developed NEC and did not require surgery. Although infants with NEC who require surgery tend to have more severe disease4 and are not a strictly comparable group, in this study they had a signiﬁcantly higher incidence of developmental morbidity. Short bowel syndrome has been relatively well researched40,41 and the long-term effects of extensive ileal resection are well known (Box 97.2).42–45 Until recently,

Box 97.2 Potential long-term consequences of ileal resection

• • • • • • •

Gallstones Vitamin B12 deﬁciency Renal calculi (oxalate) Calcium/vitamin D malabsorption Diarrhea Ileocolic perianastomotic ulceration Impaired growth

limited ileal resection in the newborn was not thought to be associated with signiﬁcant long-term sequelae. Davies et al.46 studied the long-term nutritional and metabolic effects of limited ileal resection (< 50 cm) for neonatal NEC. Subjects underwent a detailed evaluation which included clinical, anthropometric, hematological, and biochemical assessments, together with a biliary and renal ultrasound scan and measurement of bone mineral density. Seventeen children of median age 7 years (range 5.5 to 13.7) were compared with seven control subjects who had developed neonatal NEC but who had been managed non-operatively. Five had previously undergone an isolated ileal resection and 12 had also had variable lengths of colon removed. The length of resected ileum ranged from 3 to 44 cm, with a median of 10 cm. Median height, weight, and body mass index after ileal resection were between the 25th and 50th centiles; no child was stunted or wasted. These ﬁndings are in agreement with most other studies of growth after neonatal surgery for NEC.47,48 Hematological and biochemical parameters were normal. No renal calculi were detected and bone mineral density measurements were normal in all except one child. However, limited ileal resection was associated with asymptomatic vitamin B12 deﬁciency in one child and cholelithiasis in four (two after isolated ileal resection and two after ileocolic resection). The prevalence of cholelithiasis after limited ileal resection for NEC was 24% at a median age of 7.0 years. There are many potential factors relevant to the etiology of gallstones in infants with NEC including prematurity, parenteral nutrition/prolonged fasting, ileal resection, phototherapy, hemolytic disorders, and frusemide therapy.49,50 However, the absence of cholelithiasis in the small group of medically treated NEC controls suggests that ileal resection or surgery is a major predisposing factor. Valman and Roberts43 reported vitamin B12 malabsorption in seven of 10 infants who had over 45 cm of ileum resected. In their patients, the serum level of vitamin B12 did not fall below the normal range for several years, puberty being a particularly vulnerable time. Parashar et al.48 found only one child with vitamin B12 deﬁciency after a mean follow-up of 6 years in a series of 27 children who had undergone ileocolic resection for a variety of etiologies. The study by Davies et al.46 demonstrated that vitamin B12 deﬁciency may occur as a

920 Long-term outcomes in newborn surgery

late complication even after a relatively short ileal resection. Vitamin B12 malabsorption in these patients is not necessarily permanent and may subsequently improve spontaneously.51 Serial assessments of vitamin B12 status are required after ileal resection in both children with normal levels and in those with proven malabsorption. Iron deﬁciency anemia due to ileo/jejuno-colic perianastomotic ulceration has been reported as a late complication of intestinal resection in infancy by several authors.52–54 All reported cases have presented between 3 and 13 years after their original surgery with severe anemia from overt or occult lower gastrointestinal bleeding with or without abdominal pain and diarrhea (Table 97.1). The etiology of this condition is unknown but the pathology of the ulceration suggests a process of chronic inﬂammation and repair.

NEONATAL SURGICAL CONDITIONS PRESENTING IN ADULT LIFE An understanding of long-term outcomes of neonatal surgical conditions is important for adult as well as pediatric specialists. Some conditions that typically present in early infancy may be unfamiliar to the adult specialist but may nevertheless rarely present for the ﬁrst time in adult life when the diagnosis may be delayed or overlooked. Awareness of this possibility may avoid inappropriate management of affected patients. For example, intestinal malrotation may present for the ﬁrst time with intestinal obstruction in an adult.55 Presentation of Hirschsprung’s disease in adult life is uncommon but well recognized. Most such patients have short segment disease and must be distinguished from those with the more common condition of idiopathic megarectum or megacolon. Hirschsprung’s disease should be considered in any patient with a long history of constipation, particularly if the symptoms originated in early infancy or if there is a major reliance on suppositories or enemas. There is a male preponderance, and most patients are less than 30 years at diagnosis.56 Malignant change This is one of the central themes of long-term outcome. The risk of malignancy is usually greatest in adult life. This aspect of long-term outcome underlines the importance of links between pediatric and adult specialists. There are numerous examples of malignancy complicating congenital anomalies and a knowledge of these may inﬂuence surgical decisions in the infant. For example, malignancy may complicate the undescended testis,57 the multicystic dysplastic kidney,58 and mesenteric cysts.59 Alimentary tract duplication cysts, particularly those arising from the rectum or stomach, may also be complicated by malignancy in adult life. At least nine cases of adenocarcinoma arising in a rectal duplication cyst have been reported in adults (seven females, two males; aged 31–62 years).60 This complication may be unavoidable if

the duplication cyst is clinically silent but when dealing with a recognized rectal duplication cyst it is important for pediatric surgeons, whenever possible, to attempt complete excision rather than marsupialization. Malignant change is a well recognized complication of choledochal cysts, mostly affecting adults. However, teenagers are also at risk.61,62 The age-related cancer risk has been estimated at 0.7% in the ﬁrst decade, 7% in the second decade, and 14% after 20 years of age.63 Iwai et al.64 reported a girl of 12 years of age with a type IV choledochal cyst and extensive carcinomatous change in the extrahepatic biliary system. Pancreatobiliary ductal malunion is now an accepted predisposing factor to malignancy in choledochal cysts and in primary gallbladder cancer. Chronic inﬂammation, possibly as a result of secondary bile acids and/or reﬂuxed pancreatic enzymes, might be the mechanism promoting malignant change.65 Radical excision of the choledochal cyst is now regarded as the optimum management in order to minimize the risk of future malignancy and other complications. Even after cyst excision, however, malignancy may affect incompletely excised extrahepatic ducts or dilated intrahepatic ducts, indicating the need for lifelong surveillance. In particular, type IV cysts need careful observation.

NEONATAL SURGICAL CONDITIONS/ INTERVENTIONS WITH UNKNOWN LONG-TERM CONSEQUENCES There are many neonatal surgical conditions and interventions about which very little is known of the longterm consequences. Few genuinely long-term studies have been undertaken. In particular, the adult psychosocial sequelae of neonatal surgery have not been explored. Results from short-term studies indicate that some conditions/interventions are associated with a signiﬁcant risk of cognitive disturbances. For example, surviving infants with some congenital diaphragmatic hernia who had required treatment with extracorporeal membrane oxygenation had a 25% prevalence of suspected developmental delay and 17% had abnormal neurology at 1–4 years of age.66 The implications for pregnancy and childbirth from neonatal pelvic surgery are largely unknown. There are as yet undeﬁned malignancy risks associated with congenital anomalies or their treatment such as the potential for esophageal cancer in patients with repaired esophageal atresia.67 The longterm impact of relatively ubiquitous vascular access devices in the newborn is largely unknown although both arterial and venous complications are well described.68 Long-term cosmetic deformity and potential effects on limb growth need to be considered. The lifetime risk of adhesive intestinal obstruction after neonatal abdominal surgery is unknown although there are some useful data indicating that this is likely to be extremely small within a few years of the initial surgery.

Table 97.1 Reported cases of peri-anastomotic ileo/jejuno-colic ulceration53

Author Parashar et al.

Paterson et al.

Age (years) at presentation

Volvulus Intussusception

Jejuno-colic Ileo-colic

Silk –

Colonic atresia NEC Gastroschisis Gastroschisis Ileal atresia Gastroschisis NEC Gastroschisis Volvulus NEC

Ileo-colic Jejuno-colic Ileo-colic Ileo-colic Jejuno-colic Ileo-colic Ileo-colic Ileo-colic Ileo-colic Ileo-colic

Dexon Dexon – – – – Silk Silk CCG and silk CCG and silk

Sex

Primary condition

M M

1 month 4 months

M F M

2 days 6 weeks 4 months

Couper et al.

Hamilton et al.

Anastomosis

Suture material

Age at operation

M>F

Infancy

M M M F

9 weeks 2 days 3 years 2 days

Type and site of ulcer

Treatment

Outcome

4 13

Multiple, small, ileal and colic Multiple, small, ileal and colic

Well 18 months ‘Symptoms relieved’

12 11 3 8 10 5 7 5 10 8

Single, large, anastomotic Multiple, small, ileal and colic – Single, anastomotic Two small bowel Single, large, ileal Single, large, ileal Single, large, ileal Single, large, ileal Single, anastomotic

Resection Sulphasalazine and iron Resection – – Resection Resection – Resection Resection Resection Lactose-free diet Cholestyramine and iron

Well 18 months – – Recurrence 4 months Well 7 months – Recurrence 3 months Recurrence 8 years Well 7 months Well 3 years

Common themes 921

922 Long-term outcomes in newborn surgery

Of 649 neonates undergoing laparotomy in a 10-year period at the Hospital for Sick Children, London, 54 (8.3%) developed adhesive intestinal obstruction requiring surgery.69 Seventy-ﬁve percent of obstructions occurred within 6 months and 90% of obstructions developed within 1 year of surgery. Recurrent adhesive small bowel obstruction affected ﬁve patients. In a smaller study of 304 neonates from the Netherlands, adhesive intestinal obstruction was recorded in 3.3% of cases during a similar period.70

CONCLUSIONS

9. 10. 11.

12. 13.

The success of newborn surgery should encourage us to look beyond the horizon of mortality and early postoperative morbidity. Neonatal surgeons have a responsibility to study the long-term outcomes in their patients in order to adequately inform parents, anticipate future complications, and guide current surgical practice. In addition to speciﬁc consequences of the congenital anomaly and its treatment and the effects of prematurity, long-term studies must consider nutrition and growth, psychological and cognitive development, fertility and sexuality, future inheritance risks, and potential late complications such as malignancy. Neonatal records must be retained for reference and better methods of tracking patients need to be developed to facilitate future research in this area.

14.

15.

16.

17.

18. 19.

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46. Davies BW, Abel G, Puntis JWL, Arthur RJ, Truscott J, Oldroyd B, Stringer MD. Limited ileal resection in infancy; the long term consequences. J Pediatr Surg 1999; 34:583–7. 47. Abbasi S, Pereira GR, Johnson L et al. Long-term assessment of growth, nutritional status, and gastrointestinal function in survivors of necrotising enterocolitis. J Pediatr 1984; 104:550–4. 48. Parashar K, Booth IW, Corkery JJ, Gornall P, Buick RG. The long-term sequelae of ileocolic anastomosis in childhood: a retrospective survey. Br J Surg 1990; 77:645–6. 49. Whitington PF, Black DD. Cholelithiasis in premature infants treated with parenteral nutrition and furosemide. J Pediatr 1980; 97:647–9. 50. St-Vil D, Yazbeck S, Luks FI, Hancock BJ, Filiatrault D, Youssef S. Cholelithiasis in newborns and infants. J Pediatr Surg 1992; 27:1305–7. 51. Ooi BC, Barnes GL, Tauro GP. Normalization of vitamin B12 absorption after ileal resection in children. J Pediatr Child Health 1992; 28:168–71. 52. Parashar K, Kyawhla S, Booth IW et al. Ileocolic ulceration: a long-term complication following ileocolic anastomosis. J Pediatr Surg 1988; 23:226–8. 53. Ceylan H, Puntis JWL, Abbott C, Stringer MD. Recurrent peri-anastomotic ileo/jejuno-colic ulceration. J Ped Gastroenterol Nutr 2000; 30:450–2. 54. Hamilton AH, Beck JM, Wilson GM et al. Severe anaemia and ileocolic anastomotic ulceration. Arch Dis Child 1992; 67:1385–6. 55. Gilbert HW, Thompson MH, Armstrong CP. The presentation of malrotation of the intestine in adults. Ann Roy Coll Surg Engl 1990; 72:239–42. 56. Hawley PR, Ritchie JK. Hirschsprung’s disease in adults. In: Kamm MA, Lennard-Jones JE, editors. Constipation. Petersﬁeld: Wrightson Biomedical Publishing Ltd, 1994:199–203. 57. Hutson JM. Undescended testes. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER, editors. Pediatric Surgery and Urology: Long Term Outcomes. Philadelphia: WB Saunders, 1998:603–15. 58. Manzoni GM, Caldamone A. Multicystic kidney. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER, editors. Pediatric Surgery and Urology: Long Term Outcomes. Philadelphia: WB Saunders, 1998:623–41. 59. Kurtz RJ, Heimann TM, Beck AR, Holt J. Mesenteric and retroperitoneal cysts. Ann Surg 1986; 203:109–12. 60. Stringer MD. Adenocarcinoma within a rectal duplication. Ann Roy Coll Surg Eng 1999; 81:436. 61. Yamaguchi M. Congenital choledochal cyst. Analysis of 1,433 patients in the Japanese literature. Am J Surg 1980; 140:653–7. 62. Bismuth H, Krissat J. Choledochal cystic malignancies. Ann Oncol 1999; 10 Suppl 4:S94–S98. 63. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in choledochal cysts: age related incidence. Arch Surg 1983; 118:986–8.

924 Long-term outcomes in newborn surgery 64. Iwai N, Deguchi E, Yanagihara J et al. Cancer arising in a choledochal cyst in a 12-year-old girl. J Pediatr Surg 1990; 12:1261–3. 65. Reville RM, van Stiegmann ML, Everson GT. Increased secondary bile acids in a choledochal cyst. Possible role in biliary metaplasia and carcinoma. Gastroenterology 1990; 99:525–7. 66. Van Meurs KP, Robbins ST, Reed VL et al. Congenital diaphragmatic hernia: long term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatrics 1993; 122:893–9. 67. Adzick NS, Fisher JH, Winter HS, Sandler RH, Hendren WH.

Esophageal adenocarcinoma 20 years after esophageal atresia repair. J Pediatr Surg 1989; 24:741–4. 68. Barrett AM, Squire R. Vascular access. In: Stringer MD, Oldham KT, Mouriquand PDE, Howard ER (editors). Pediatric Surgery and Urology: Long Term Outcomes. Philadelphia: WB Saunders, 1998:779–86. 69. Wilkins BM, Spitz L. Incidence of postoperative adhesion obstruction following neonatal laparotomy. Br J Surg 1986; 73:762–4. 70. Festen CT. Postoperative small bowel obstruction in infants and children. Ann Surg 1982; 196:580–3.

Index

AAPSS classiﬁcation (American Academy of Pediatrics), sacrococcygeal teratomas, 17 abdomen approach, sacrococcygeal teratomas, 711 birth trauma, 33–35 mesenteric cysts, 489–496 neuroblastoma surgery, 726–729 pain after gastroschisis repair, 916 pressure laparoscopy, 185–186 wall defect repair, 608 ultrasound, 133 abdominal wall defects, 605–613 bladder exstrophy, 620 gastrostomy, 412 intra-operative colloid infusions, 67 prenatal diagnosis, 20–21, 607 primary closure risk, 98 umbilical artery transfer, 122–123 see also gastroschisis; omphalocele erythema, meconium ileus, 466 prune belly syndrome, 637–638 abdominoperineal approaches hydrometrocolpos, 879–882 sacrococcygeal teratomas, 711–712 abdominoplasty, prune belly syndrome, 640 aberrant micturition, 806 ablation posterior urethral valves, 861–864 see also diathermy ABO blood groups, hemolytic disease of newborn, 153 abscesses adrenal, 35 liver, 597, 598–600 accessory auricles, 227 acetazolamide, sacrococcygeal tumors, 656 acetylcholinesterase Hirschsprung’s disease, 516 histochemistry, 521 neural tube defects, amniocentesis, 764 acid–base balance, 95 on ionized calcium, 96 postoperative, 97 preoperative assessment, 50 acidosis hypokalemia, 95 respiratory distress, 49 acrocentric chromosomes, 170 acute renal failure, 98 acute tubular necrosis, extracorporeal membrane oxygenation, 322 adenomas, pancreas, 442–443 adhesive intestinal obstruction, 376 long-term outcomes, 918–920 after meconium peritonitis surgery, 475 adrenal gland birth trauma, 34–35 failure, 93 neuroblastoma surgery, 726–727, 728 (Fig.)

see also congenital adrenal hyperplasia adrenaline (epinephrine), 81 adrenergic nerve ﬁbers, Hirschsprung’s disease and, 516 adrenergic receptors, bladder, 868 adriamycin, foregut malformations, 4, 7, 339 age, mediastinal masses, 247–248 aircraft, transport of neonate, 40 air leaks, pulmonary, 277–282 detection at surgery, 305–306 air/water test, tracheo-esophageal ﬁstula, 348 airway clinical examination, 59–60 embryology, 295 immature, 219 internal stenting, 264 obstruction, 329–330 bronchogenic cysts, 249 cervical teratomas, 697 esophageal duplication cysts, 360 fetus, 17 lymphatic malformations, 688, 693 mediastinal masses, 247–248 vascular rings, 270 see also subglottic stenosis; tracheomalacia; upper airway obstruction albinism, oculocutaneous, 148 albumin, calcium binding, 96 alfafetoprotein cervical teratomas, 700 liver tumors, 739, 740, 741 (Fig.) maternal serum, abdominal wall defects, 607 neural tube defects, 763–764 sacrococcygeal teratomas, 712 alkalosis hypochloremic, 55, 95, 97, 393 hypokalemia, 94, 95 metabolic, 95 respiratory, persistent pulmonary hypertension of neonate, 75 respiratory distress, 49 alleles, 170 alloimmune hemolytic anemia, 153, 154 alloimmune thrombocytopenia, neonatal, 149 alphafetoprotein see alfafetoprotein Alport variants, 148 altitude, air transport of neonate, 40 Altman classiﬁcation, sacrococcygeal teratomas, 705, 704 (Fig.) alveolar ventilation, 74 amblyopia, orbital hemangiomas, 665–666 ambulances, transport of neonate, 40 ambulation, myelomeningocele, 768 amebic liver abscess, 600 amegakaryocytic thrombocytopenia, 149 American Academy of Pediatrics on circumcision, 904 classiﬁcations sacrococcygeal teratomas, 17 ureterocele, 846 amino acids, parenteral nutrition, 108–109, 110 extracorporeal membrane oxygenation, 321

926 Index amniocentesis, 16 neural tube defects, 764 amniotic band syndrome, fetal surgery, 195 amniotic ﬂuid on exteriorized intestine, 607 prevention maneuvers, 607 obstructive uropathy, 192 renal function, 794–795 ampliﬁcation (genetic) N-myc gene, 656, 658, 724, 725 tumors, 656, 658 amputation, soft-tissue sarcomas, 734 analgesia, postoperative, 78–79 inguinal hernia, 565 morphine, 64 anasarca, extracorporeal membrane oxygenation, 321–322 anastomosis duodenoduodenostomy, 428–429 esophageal atresia, 345 leak, 346 stricture, 347, 371 hepatoenterostomy, 593 jejuno-ileal atresia, 451–452 leaks, 454 lip–tongue, Pierre Robin sequence, 209 necrotizing enterocolitis resection, 507 rectorectal, 462 resection for meconium ileus, 468 ulceration, 919 (Table) Anderson-Hynes pyeloplasty, 820–821 laparoscopic, 822 androgen-binding protein, 884 androgen receptor absence, 885–886 gene abnormalities, 886 androgens, exogenous, 891 anemias, 153–154 iron deﬁciency, intestinal resection, 918 physiological, 153 prematurity, 67, 153–154 anencephaly, 762 anesthesia, 59–70 breathing circuits, 61 bronchoscopy, 330 fetal surgery, 190 inguinal hernia repair, 563 thoracoscopy, 183–184 for tracheostomy, 220 aneuploidy, 161, 170 Angelman’s syndrome, 165 angel-wing sign, pneumomediastinum, 278 AngioCath, cut-downs, 125 angiomas subglottic stenosis, 254 see also hemangiomas angiotensin II type 2 receptor gene (AT2 gene), 818 animal models congenital biliary dilatation, 589 congenital diaphragmatic hernia, 309 esophageal atresia and TEF, 339 aniridia, tumor syndromes, 657 anisometropia, orbital hemangiomas, 666 annular pancreas, 423, 425 (Table) anomalous pelvi-ureteric junction obstruction, 799 anoplasty, minimal, posterior sagittal, 543, 546 anorectal anomalies, 535–552 bladder exstrophy, 620 cloacal septation defects, 9–10 computed tomography, 135 female, 539–541 long-term outcomes, 913, 915–916 male, 535–538, 541–542, 542 radiology, 132, 537 interventional, 137–138 rectal atresia as, 461 anorectal manometry, Hirschsprung’s disease, 520–521

anorectoplasty, cloacal exstrophy, 634 antacids, gastro-esophageal reﬂux, 374 antegrade ablation, posterior urethral valves, 862–863 antenatal diagnosis see prenatal diagnosis anterior cricoid split, 256–257, 258 anterior mediastinum, masses, 248–249 anterior meningoceles, sacrococcygeal teratomas vs, 707 anteroposterior renal pelvis diameter, fetus, 818 antibiotics extracorporeal membrane oxygenation, 321 hepatic portoenterostomy, 586 hydronephrosis, 796 liver abscess, 599 midgut loop volvulus, 436 necrotizing enterocolitis, 502 posterior urethral valves, 861 TPN-related cholestasis, prevention, 113 vesico-ureteric reﬂux, 806 antibodies, 142–143 hemolytic disease of newborn, 153 see also maternal antibodies anticholinergic drugs neuropathic bladder, 870 preoperative, 60 anticipation (genetic), 165 anticoagulants, 152–153 extracorporeal membrane oxygenation, 321 see also heparin anti-codons, 170 antidiuretic hormone, renal response, 91–92 antiﬁbrinolytic agents, 668 antigen-presenting cells, 140 antiperistaltic segment colon, interposition, 573 small intestine, 572–573 antithrombin deﬁciency, 152 antral web, 386 anus bladder exstrophy, 620 duplications, 486 see also anorectal anomalies aorta, neuroblastoma surgery, 729 aortic arch, anomalies, 267–269, 270–274 esophageal atresia and TEF, 343–344 aortography, vascular rings, 271 aortopexy, 261–262, 348 results, 263–264 apnea choanal atresia, 201 gastro-esophageal reﬂux, 370, 372 inguinal hernia, 562 postoperative, 565 Pierre Robin sequence, 211 prematurity, 67–68 tracheomalacia, 260 apparent life-threatening episodes, 202 tracheomalacia, 260, 261 appendicectomy, malrotation, 438 appendicostomy, continent, 551 apple-peel jejuno-ileal atresia, 447–448 aqueduct of Sylvius Arnold–Chiari malformation, 775 stenosis, 775, 777 (Fig.) argon lasers, hemangiomas, 669–670 Arnold–Chiari malformation, 22, 23, 762, 775 see also Chiari II malformation arrhythmias see cardiac arrhythmias arteries blood sampling, blood gas monitoring, 71–72 cannulation, 52, 121–124 see also umbilical artery catheters chemotherapy via, intrahepatic, 741 ligation, hemangiomas, 669 see also blood supply arteriovenous ﬁstula, 665 artiﬁcial valves, intestinal, 573–574

Index 927 ascites, 497–500 chylous, 288–289, 498–499 cysts vs, 492 aseptic technique, ventriculoperitoneal shunts, 778, 780 asphyxia, choanal atresia, 201–202 asphyxiating thoracic dystrophy, 244–245 aspiration of gastric contents after esophageal atresia repair, 347 gastro-esophageal reﬂux, 370–371 pneumonitis, 370, 372, 373 asplenia, gastric volvulus, 401 associations (of anomalies), 168 asthma, after tracheo-esophageal ﬁstula repair, 348 atelectasis choanal atresia, 201 laparoscopy, 186 atlanto-axial instability, Pierre Robin sequence, 211 atonic bladder, 869 atracurium, 63 atropine with muscle relaxant reversal agents, 65 preoperative, 60 auditory deﬁcit, extracorporeal membrane oxygenation, 323–324 auscultation, anesthesia monitoring, 65–66 autoaugmentation, bladder, 872 autoimmune hemolytic anemia, 153 autoimmune thrombocytopenia, 149 autonomic nervous system, choanal atresia, 202 autonomy, ethics and, 174 autosomal dominant inheritance, 163, 164 (Table), 170 tumor syndromes, 654 autosomal dominant polycystic kidney disease, ultrasound, 787–788 autosomal recessive inheritance, 163–164, 170 tumor syndromes, 654–655 autosomal recessive polycystic kidney disease, 598, 787–788 autotransplantation, heart, conjoined twins, 646 awake intubation, 64, 65 axilla, lymphatic malformations, 692 axillary artery cannulation, 123 Ayre’s T-piece, 61 azygos vein catheterization, 127–128 esophageal atresia and TEF surgery, 342–343 bacterial infections liver abscesses, 598–599 meningitis, 776 necrotizing enterocolitis, 501 ventriculoperitoneal shunts, 781 prevention at surgery, 778, 780 Ballantine syndrome (‘mirror syndrome’), 18, 194 balloon dilatation esophagus, 137, 347, 354 necrotizing enterocolitis, 509 pelvi-ureteric junction, 822 posterior urethral obstruction, 862 subglottic stenosis, 255 balloon stenting, airway, 264 barium enema Hirschsprung’s disease, 519–520 intussusception reduction, 557, 558 malrotation, 436 necrotizing enterocolitis, 509 barium esophagogram, vascular rings, 271 barium esophagograms, congenital esophageal stenosis, 353–354, 355 barium meal gastric volvulus, 401, 402 (Fig.) hypertrophic pyloric stenosis, 393 malrotation, 435–436 Barrett’s esophagus, after atresia repair, 349 bases, nucleic acids, 157–158 Beckwith–Wiedemann syndrome, 606 hypoglycemia, 95 macroglossia, 215, 216 tumor genetics, 658

bedside treatment, abdominal wall defects, 608–609 benign neonatal hemangiomatosis, 667 Benjamin, H., quoted, 883 Bernard–Soulier syndrome, 147–148 best interests standard, 173–176 bethanechol, for gastro-esophageal reﬂux, 375 Bianchi, A., intestinal tapering and lengthening, 571 bicarbonate metabolic acidosis, 98 regulation, 95 respiratory acidosis, 95 therapy, 95 biﬁd (cleft) sternum, 239, 241–243 bile, electrolytes, 55 (Table), 97 (Table) bile ascites, 497–498 biliary atresia, 579–588 biliary dilatation, congenital (choledochal cyst), 589–596 malignant change, 918 biliary sludge, 112, 113 biliary tract atresia, long-term follow-up, 586–587 conjoined twins, 646 drainage, congenital biliary dilatation, 592 duodenal obstruction, 424 obstruction, 51 congenital biliary dilatation from, 589 see also common bile duct biochemical markers, 16 biopsy gonad, intersex, 892–893 Hirschsprung’s disease, 522–523 rectum, 521, 522 (Fig.) lung, thoracoscopy, 184 lymphomas, mediastinum, 250 male pseudohermaphroditism, 893 neuroblastomas, 724 soft-tissue sarcomas, 734 birth trauma, 28–36 birth weight extracorporeal membrane oxygenation, 317, 323 pneumothorax mortality, 280 bladder, 867–868 augmentation, 872 cloacal exstrophy, 633 management, 635 distension with hydronephrosis, 804–806 exstrophy, 619–627 primary closure, 623–627 transport of neonate, 42, 622 fetus, 868 aspiration, 192 incontinence, 864 instability, vesico-ureteric reﬂux, 837 posterior urethral valves, 857 prune belly syndrome, 638 ultrasound, 787 neuropathic, 869 prenatal, 794 see also neuropathic bladder bladder neck bladder exstrophy, repair, 622–623, 623–627 neuropathic bladder, surgery, 872 rectovesical ﬁstula, 537–538, 543–544, 545, 549–551 blind biﬁd ureteral duplication, 831 blockage clearance, parenteral nutrition, 111 Blocksom technique, vesicostomy, 863 blood gases, 49 postoperative monitoring, 71–72 blood groups, hemolytic disease of newborn, 153 blood loss anemia from, 153 intraoperative, 66 sacrococcygeal teratoma surgery, 707 blood pressure, monitoring, 66 blood supply interruption see vascular occlusion

928 Index blood supply – continued lung, 295–296 pulmonary sequestrations, 300, 301, 302 trachea, 296 blood transfusion anemia, 154 intraoperative, 66 neuroblastoma surgery, 726 Bloom syndrome, 654 blueberry mufﬁn baby, 721 blue nevi, 678 blue rubber bleb nevus syndrome, 667 B-lymphocytes, 139 responses, 142 body weight ﬂuid therapy and, 56 parenteral nutrition, 114 postnatal loss, 90 Boerhaave’s syndrome, 365, 366 bone radionuclide examinations, 135 see also skeletal anomalies bone marrow inherited failure syndromes, 149 neuroblastoma, 724 Borchardt, triad of, gastric volvulus, 401 bougienage congenital esophageal stenosis, 354 subglottic stenosis, 255 brachial plexus, birth trauma, 31–32 brain computed tomography, 135 feminization, 889 magnetic resonance imaging, 136 masculinization, 886, 889, 894 brain-derived neurotrophic factor, hypertrophic pyloric stenosis and, 391 branchial cysts (sinuses), 227–228 breast milk, protection against necrotizing enterocolitis, 501 breathing choanal atresia, 201–202 pressures, 259 pulmonary interstitial emphysema, 278 breathing circuits, anesthesia, 61 breech presentation scrotal bruising, 909 spinal cord trauma, 30 bronchi right main, resection and reanastomosis, 274 see also airway bronchitis, after tracheo-esophageal ﬁstula repair, 348 bronchogenic cysts, 249–250, 302–304 thoracoscopy, 184 bronchomalacia, treatment choice, 264 (Table) bronchopulmonary dysplasia extracorporeal membrane oxygenation and, 318, 323 fat in parenteral nutrition, 111 gastro-esophageal reﬂux, 371 tracheomalacia, continuous positive airway pressure, 263 bronchopulmonary sequestration, prenatal diagnosis, 18–19 bronchoscopy, 329–333 esophageal atresia and TEF, 341 instruments, 329 subglottic stenosis, 255 tracheomalacia, 260–261 tracheostomy, 220 vascular rings, 271 bucket-handle anorectal malformation, 535 Bugbee electrode, posterior urethral valve diathermy, 805, 862 bulbar ﬁstula, recto-urethral, 536–537 burden of suffering, 173 buried penis, 905 Burkitt’s lymphoma, genetics, 659 buttons, gastrostomy, 419 caesarean delivery

abdominal wall defects, 607 defects requiring, 15 myelomeningocele, 765 see also ex utero intrapartum treatment café au lait macules, 678 caffeine, surgery in premature babies, 68 calciﬁcation kidney, ultrasound, 788 meconium peritonitis, 473–474 mediastinal masses, 248 calcium homeostasis, 96 infusions, 96 treatment of hypocalcemia, 51 calcium resonium, hyperkalemia treatment, 93 calcium Sandoz, 96 caloric metabolism see energy metabolism Candida albicans, central venous catheters, 129 Cantrell pentalogy, 239, 240–241, 606 capillary blood sampling, blood gas monitoring, 71–72 capillary hemangiomas, 663 cavernous, 665 intradermal, 664 juvenile, 665 long-term outcomes, 915 caput succedaneum, 28 carbamazepine, neural tube defects, 763 carbohydrate parenteral nutrition, 106–107, 110 protein sparing, 108 reduction for cholestasis, 114 see also glucose carbon dioxide pneumoperitoneum, 185 tension cerebral blood ﬂow, 76 congenital diaphragmatic hernia, 313 monitoring, thoracoscopy, 183 transcutaneous monitoring, 72 ventilation and, 74 carbon dioxide lasers, hemangiomas, 669 carcinogens, 656 cardiac arrhythmias central venous catheters, 128 cisapride, 375 cardiac catheterization, ectopia cordis, 240 cardiac failure, hemangiomas, 667 cardiac output management, 79–82 pneumoperitoneum, 185 cardiac tamponade central venous catheters, 111 pneumopericardium, 280, 281 cardiopulmonary bypass, coagulopathy, 151 cardiovascular system anesthesia, monitoring, 66 conjoined twins, 646 homeostasis, 79–80 pneumoperitoneum, 185 preoperative assessment, 49–50 carina, 295 Caroli’s disease, 598 carotid artery extracorporeal membrane oxygenation, 319 reconstruction vs ligation, 324 left, anomalous origin, 268, 273 carriers, recessive disorders autosomal, 163 X-linked, 164 cartilage grafts, subglottic stenosis, 257–258 catecholamines, neuroblastomas, transplacental, 721 catheter introducers, 125, 126 (Fig.) catheterization clean intermittent, 870–871 cloacal exstrophy reconstructions, 635 posterior urethral valves, 804–805, 861

Index 929 catheters gastrostomy, 415 urinary, anorectal anomalies, 548–549 vascular, 121–129 extracorporeal membrane oxygenation, 319 see also central venous catheters see also umbilical artery catheters caudal cell mass, 762 cavernous hemangiomas, 663 CD1a-positive T-lymphocytes, 142 CD38 thymocyte-associated antigen, 141–142 CD45RA-positive and -negative T-lymphocytes, 142 CD antigens, 139, 140 (Table) lymphocytes, 141–142 cecum, embryology, 435 cell adhesion, neutrophils, 143 cell adhesion molecules embryogenesis, 5 Hirschsprung’s disease, 514 cell division, 160–161 cell-junctional molecules, 5 cell-mediated immune responses, 139–143 cell proliferation, embryogenesis and, 5–6 cellular blue nevus, 678 cellular variant cystic mesoblastic nephromas, 747–748 central nervous system extracorporeal membrane oxygenation complications, 322 neuroblastoma involvement, 722 see also brain; spinal cord central venous catheters, 52 complications, 52, 128–129 infections and, 52, 110, 128–129 maintenance, 128 percutaneous, 125 positions, 111 pressure monitoring, 66, 79 surgical introduction, 125–128 thoracoscopy and, 183 thrombosis, 128, 152 centromeres, 170 cephalhematomas, 28–29 cerebral blood ﬂow, carbon dioxide tension, 76 cerebral palsy extracorporeal membrane oxygenation, 324 incidence, 914 cerebrospinal ﬂuid ﬁstula, myelomeningocele closure, 768 hydrocephalus analysis, 777 drainage, 777–778 shunts see ventriculoperitoneal shunts cervical aortic arch, 269, 274 cervical esophagostomy, 345 cervical lymphangiomas, prenatal diagnosis, 17 cervical teratomas, 697–703 prenatal diagnosis, 17 CFTR gene and protein, 465 CHARGE association, 201, 340 Chediak–Higashi syndrome, 148 chemotherapy ﬁbrosarcoma, 736 liver tumors, 741, 742 (Table) neuroblastoma, 725–726 rhabdomyosarcoma, 735 sacrococcygeal teratoma, 712 chest congenital anomalies, 239–246 drainage, 279–280 congenital diaphragmatic hernia, 43, 312 esophageal atresia surgery, 343 esophageal perforation, 367 hemangiomas, 666 prenatal diagnosis, 18–20 X-rays congenital cystic adenomatoid malformations, 298–299 congenital diaphragmatic hernia, 310

congenital lobar emphysema, 296–297 vascular rings, 270–271 Chiari II malformation, fetal surgery, 195 child-centeredness, 173 chimerism, true hermaphroditism, 890 chin suture, minimal-access fetal surgery, 191 chlorhexidine, parenteral nutrition circuitry, 110 chloride balance, neonatal phases, 54 (Table) chlorothiazide, hyperinsulinism, 442 choanal atresia, 48 (Table), 201–205 Pierre Robin sequence with, 211 transport of neonate, 42 cholangiography see operative cholangiography cholangitis, hepatic portoenterostomy, 586 cholecystitis, parenteral nutrition, 113 cholecystokinin, TPN-related cholestasis, 113 cholecystostomy, for bile ascites, 498 choledochal cyst see congenital biliary dilatation choledochopancreatic duct junction, anomalies, 590 cholelithiasis after congenital biliary dilatation surgery, 594 necrotizing enterocolitis, 917 parenteral nutrition, 113 choleretics, TPN-related cholestasis, 113 cholestasis, parenteral nutrition, 112–114 necrotizing enterocolitis surgery, 508 cholinergic nerve ﬁbers, Hirschsprung’s disease and, 516 histochemistry, 521 chondrocytes, injection for vesico-ureteric reﬂux, 842 chordee, 904 chorionic villus sampling, 16 neural tube defects, 763 choristomas, lingual gastric, 231–232 choroid plexus, endoscopic coagulation, 781 chromatids, 160–161, 170 chromosomes, 160–163 anomalies colonic atresia with, 458 hepatoblastomas, 739 Hirschsprung’s disease, 515 male pseudohermaphroditism, 889 mixed gonadal dysgenesis, 891 true hermaphroditism, 884, 890 tumors, 653, 655 Chwalla’s membrane, 845 chyle, 284 chylopericardium, shunting, 289 chylothorax, 283–290 chylous ascites, 288–289, 498–499 chylous cysts, mesenteric, 489 cimetidine, 375 cine computed tomography see ultrafast computed tomography circumcision, 903–904 see also foreskin circumferential wrap, after cloacal exstrophy surgery, 634 cirsoid angioma, 665 cisapride, for gastro-esophageal reﬂux, 375 C-KIT deﬁciency, mast cells, gastric perforation, 406 C-KIT receptor, interstitial cells of Cajal, 517 Clark electrode, oxygen tension, transcutaneous monitoring, 72 classiﬁcations abdominal cysts, 489 atresias biliary, 579, 580 (Fig.) colonic, 457 duodenal, 423–424 esophageal, 338 jejuno-ileal, 445–448 rectal, 460–461 congenital biliary dilatation, 590 congenital cystic adenomatoid malformations, 298 (Table) conjoined twins, 644 hemangiomas, 664–665 hydrometrocolpos, 875, 876 (Fig.) intersex, 886 (Table) megaureter, 823

930 Index classiﬁcations – continued neuropathic bladder, 868–869 posterior urethral valves, 855–856 sacrococcygeal teratomas, 705, 706 (Fig.) tracheo-esophageal ﬁstula, 338 ureteral duplication anomalies, 831 ureterocele, 846 vascular rings, 267 clavicle, birth trauma, 36 clean intermittent catheterization, 870–871 cleft palate, Pierre Robin sequence, 207, 210–211 cleft sternum, 239, 241–243 clingﬁlm, bladder exstrophy, transport of neonate, 42 clip and drop back procedure, necrotizing enterocolitis, 507 clitoris, genitoplasty, 895, 896 (Fig.), 897 (Fig.) cloaca anomalies, 9–10, 540–541, 542 hydrometrocolpos, 875 (Fig.), 881–882 outcomes, 916 posterior sagittal approach, 550 vaginal ﬁstula vs, 540 exstrophy, 629–636 transport of neonate, 42 cloacal membrane, 619 Clostridium difﬁcile, Hirschsprung’s disease enterocolitis, 522 Clostridium perfringens, necrotizing enterocolitis, 507 coagulation abnormalities, 150–151 extracorporeal membrane oxygenation and, 317 neuroblastoma, 722 postoperative, 83–84 preoperative assessment, 51–52 see also thrombocytopenia coagulation proteins, 150–151 Cobb’s collar, 856 coccyx, sacrococcygeal teratomas, 707 codeine phosphate, 64 codons, 158, 170 cognitive function long-term outcomes, 914–915, 918 see also neurodevelopmental handicap Cohen’s method, reimplantation of ureter, 824–825, 826 (Fig.) collagens hemangiomas, 663 hypertrophic pyloric stenosis and, 391–392 injection for vesico-ureteric reﬂux, 841 type IV, enteric nervous system development, 514 ureterovesical junction obstruction, 823 colloid infusions intraoperative, 66 abdominal wall defects, 67 pre-renal renal failure, 82 shock, 98 colon atresia, 457–463 cloacal exstrophy, 633 duplications, 485 esophagoplasty, 345 ﬁstula, gastrostomy, 418 short small intestine, 569 stenosis surgery, 459 tumor genetics, 659 colonic interposition, 573 colostography, 538, 545 colostomy anorectal anomalies, 541–542, 544–546 Hirschsprung’s disease, 522–523 combustion, laser therapy, subglottic stenosis, 256 common bile duct cystic dilatation see congenital biliary dilatation iatrogenic injury, 444 common sheath ureteric reimplantation, 833 communicating hydrocephalus, 775 communities, ethics, 179 complement receptors, 143 compliance, bladder, 868–869 computed tomography, 135

choanal atresia, 202 congenital cystic adenomatoid malformations, 299 kidney, 792 liver abscess, 599 neurenteric cysts, 360 neuroblastomas, 723 see also ultrafast computed tomography condenser humidiﬁers, 73 congenital adrenal hyperplasia, 886–889, 891, 892 gender assignment, 894 treatment, 894–895 congenital anomalies chest, 239–246 embryology, 3–14 fetal surgery, 191–195 genetics, 167–169 hydrocephalus, 775–776 lung, 295–308 congenital biliary dilatation (choledochal cyst), 589–596 malignant change, 918 congenital cystic adenomatoid malformation, 48 (Table), 297–299 congenital diaphragmatic hernia vs, 47, 298–299 fetal surgery, 193 prenatal diagnosis, 18–19, 298 congenital diaphragmatic hernia, 47, 48 (Table), 309–315 anesthesia, 67 congenital cystic adenomatoid malformations vs, 47, 298–299 fetal surgery, 192–193, 312 prenatal diagnosis, 19–20, 192–193, 310 preoperative respiratory stabilization, 49, 310–311 repair, 311–312 thoracoscopy, 185 transport of neonate, 42–43 ventilation, 78, 310–311 see also under extracorporeal membrane oxygenation congenital esophageal stenosis, 353–357 congenital heart disease coagulopathy, 151 congenital diaphragmatic hernia, 78 detection, 50 duodenal obstruction incidence, 425 (Table) esophageal atresia and TEF, 339 omphalocele, 606 pectus carinatum and, 243 postoperative tracheostomy, 224 prune belly syndrome, 639 right aortic arch, 269 congenital hepatic ﬁbrosis, 598 congenital high airway obstruction syndrome (CHAOS), 193, 195 congenital obstructive posterior urethral membrane (COPUM), 856–857 congenital thrombocytopenia, 149–150 conjoined twins, 643–648 constant positive airway pressure see continuous positive airway pressure constipation after anorectal anomaly surgery, 551 Hirschsprung’s disease, 518 jejuno-ileal atresia, 448 rectal atresia, 462 consumption coagulopathy, 150 central venous catheter thrombosis, 128 see also disseminated intravascular coagulation continence conjoined twins, 647 see also fecal incontinence; urinary incontinence continent appendicostomy, 551 continent urinary diversion, 872 continuous positive airway pressure (CPAP), 75 tracheomalacia, bronchopulmonary dysplasia, 263 contralateral exploration, inguinal hernia repair, 565 contrast agents intravenous urography, 790 meconium ileus treatment, 137, 467–468 contrast studies, 132 congenital segmental dilatation of intestines, 554–555

Index 931 see also entries beginning barium . . .; operative cholangiography COPUM (congenital obstructive posterior urethral membrane), 856–857 cord blood T-lymphocytes, 141–142 Cornblath, M., hypoglycemia thresholds, 95 cornea, methylcellulose drops, 32 cor pulmonale, Pierre Robin sequence, 211 corticomedullary junction, posterior urethral valves, outcome assessment, 865 cough, seal-bark, tracheomalacia, 260 court intervention, 176 cow’s milk protein allergy, gastro-esophageal reﬂux, 374 crab-leg ribs, spondylothoracic dysplasia, 245 cranial sonography, 133 craniopagus conjoined twins, 644 (Table) craniorachischisis, 762 C-reactive protein, ventriculoperitoneal shunts, 780 creatinine, serum, 796 posterior urethral valves, 805, 864–865 cricoid split, 256–257, 258 cricopharyngeus, perforation, 365 critical illness, nutrition, 105–106 crural repair, gastric volvulus, 403 cryotherapy, hemangiomas, 670 cryptorchidism, 905–906 intersex, 891 meconium peritonitis, 473 prune belly syndrome, 639 Culp spiral ﬂap pyeloplasty, 821 culture, decision-making and, 176–178 curettage, nevi, 679–680 cutaneous ﬁstula, anorectal anomaly, 539, 542–543 cut-downs disadvantages, 121 infra-umbilical, 122 peripheral vein cannulation, 125 cyanide toxicity, sodium nitroprusside, 81 cyanotic attacks, gastro-esophageal reﬂux, 372 cyclic parenteral nutrition, 113, 114 cyst(s) biliary atresia, 582 liver, 597–598 meconium peritonitis, 472, 475 multicystic dysplastic kidney, aspiration, 813 neck, 227–228 parenchymal, long-term outcomes, 915 cystectomy choledochal, 592 pulmonary, 303–304 cysteine, parenteral nutrition, 108 cystic adenomatoid malformation see congenital cystic adenomatoid malformation cystic dilatation of common bile duct see congenital biliary dilatation cystic ﬁbrosis absent vas deferens, 907 genetics, 465–466 meconium ileus, 465 peritoneal calciﬁcation, 473 polymerase chain reaction, 166, 167 screening, 467 sweat electrolytes, 55 (Table) cystic hygroma, 230, 248 prenatal diagnosis, 17 see also lymphatic malformations cystic mesoblastic nephromas (cellular variant), 747–748 cystic peritonitis, giant, 466 cystography, radionuclide examinations, 839–840 cystometry, neuropathic bladder, 870 cystoscopy posterior urethral valves, 805, 861–862 ureterocele, 849 cytokines, 140, 141 (Table) cytoskeleton, embryogenesis and, 5 D7 (Schwann cell marker), hypertrophic pyloric stenosis and, 391

Dandy–Walker malformation, 775, 776 D-dimers, coagulation abnormalities, 84 deafness, extracorporeal membrane oxygenation, 323–324 decompression, nasogastric tubes vs gastrostomy, 411–412 Deﬂux, injection for vesico-ureteric reﬂux, 841–842 deformations, 168 dehydration, preoperative, 54 hypertrophic pyloric stenosis, 393 delayed-type hypersensitivity, 141 deletions, ﬂuorescence in situ hybridization, 162–163 Δ508 mutation, CFTR gene, 465–466 dendritic cells, 143 Denis Browne incision, esophageal duplication cysts, 362 Denys–Drash syndrome (Drash syndrome), 655, 891 de Pezzer catheter, gastrostomy, 415 depressed skull fracture, birth trauma, 29 dermabrasion, nevi, 679–680 dermoid cysts mouth, 231 nasal, 719–720 presacral, 705 dermoid sinuses, nasal, 719–720 descending aorta, right-sided, with left aortic arch, 268–269, 273 desﬂurane, 62 designated therapists, central venous catheters, 128 Desmopressin (DDAVP), 151 detrusor, 867 posterior urethral valves, 857 detrusor–sphincter dyssynergy, 869 developing countries, ethics and, 177–180 dexamethasone congenital diaphragmatic hernia, 312 prenatal, female pseudohermaphroditism, 895 dexranomer, injection for vesico-ureteric reﬂux, 841–842 dextrose ﬂuid therapy, 92 (Table) hyperkalemia treatment, 93 hypoglycemia treatment, 50, 83 diagnosis, congenital anomalies, 168–169 dialysis, peritoneal, 82 diamond-shaped duodenoduodenostomy, 429 results, 431 diaphragm defects, gastric volvulus, 401 embryology of malformations, 7–9 plication, 375 thoracoscopy, 185 see also congenital diaphragmatic hernia; phrenic nerve palsy diarrhea electrolytes, 55 (Table), 97 (Table) Hirschsprung’s disease, 518 neuroblastoma, 250–251, 722 diathermy posterior urethral valves, 805, 861, 862 recurrent tracheo-esophageal ﬁstula, 348 diathermy hook (Whitaker–Sherwood), posterior urethral valves, 862 diazoxide, hyperinsulinism, 442 diet, gastro-esophageal reﬂux therapy, 374 diffuse neonatal hemangiomatosis, 667 Di Georges sequence ﬂuorescence in situ hybridization, 163 hypocalcemia, 96 digital ﬂuoroscopy, 132 dihydrotestosterone, 885, 903 dilatation of intestines, congenital segmental, 553–556 dilatation therapy anorectal anomalies, 550–551 subglottic stenosis, 255 dimercaptosuccinic acid see DMSA radionuclide examinations dipeptides enteral nutrition, 115 see also glutamine diploidy, 170 dipyridamole, 77 dismembered pyeloplasty, 799, 820–821 laparoscopic, 822

932 Index disomy, maternal, 165 disruptions, 167–168 disseminated intravascular coagulation, 51 giant hemangioma syndrome, 150 postoperative, 84 purpura fulminans, 152 see also consumption coagulopathy distal saphenous vein cannulation, 124 distributive justice, ethics and, 174 diuresis, physiological, 92 diuretic renograms, 797–798 megaureter, 802 pelvi-ureteric junction obstruction, 819–820 diverticula colon, 485 embryonic, 479 diverticulocystoplasty, 872 DJ stents, nephrostomy, posterior urethral valves, 864 DMSA radionuclide examinations, 135, 790, 791 (Fig.) multicystic dysplastic kidney, 810 renal scarring, 837, 840 ureterocele, 801 vesico-ureteric reﬂux, 806 DNA, 157–160 dobutamine, 80 dominant inheritance autosomal, 163, 164 (Table), 170 tumor syndromes, 654 X-linked, 165 domperidone, for gastro-esophageal reﬂux, 375 dopamine, 80 shock, 98 Doppler ultrasound, 134 sacrococcygeal teratomas, 194, 707 twin-to-twin transfusion syndrome, 194 vascular rings, 271 dorsalis pedis artery cannulation, 123 dorsal lumbotomy nephrectomy, 812 pyeloplasty, 820 double aortic arch, 267–268 surgery, 272 double CD4/CD8-labelled T-lymphocytes, 141 double enterostomy, necrotizing enterocolitis, 505, 506 (Fig.) double-hit theory (two-hit theory), 654, 657 double uterus, 541 double vagina, 541 Down syndrome anorectal anomalies, 542 duodenal atresia, 424, 425 (Table) genetics, 161, 162 Hirschsprung’s disease, 515 right ductus arteriosus, 268 triple test, 16 tumors, 655 drainage hydrometrocolpos, 877–879 liver abscess, 599–600 see also chest, drainage Drash syndrome (Denys–Drash syndrome), 655, 891 dressings, after tracheostomy, 224–225 drooping lily sign, 833, 848 drugs maternal, intersex, 891 tumors from, 656 DTPA radionuclide examinations, 135, 790 ductus arteriosus aortic anomalies, 268, 269, 273–274 closure, 49 see also patent ductus arteriosus dumbbell cyst, 720 dumping syndrome, 115 duodenoduodenostomy, 428–429 duodenojejunal pouch, 574 duodenoplasty, megaduodenum, 430 duodenoscopy, for duodenal web, 429

duodenum atresia, 20, 423–424 ﬂuid and electrolytes, 55 (Table) radiography, 341 (Fig.) results of repair, 431 duplications, 483 embryology, 435 intestinal preservation maneuvers, 452 intubation, biliary atresia diagnosis, 581 obstruction, 423–433 gastrostomy, 412 jejunal obstruction vs, prenatal diagnosis, 45 perforation, 395 web, surgery for, 429, 430 (Fig.) duplication anomalies, 479–488 esophagus, 359–364 thoracoscopy, 184, 363 mouth, 231 rectum, 485–486 malignancy, 918 upper urinary tract, 831–836 imaging, 790 ureterocele, 845, 846, 848 urethra, 905 vs mesenteric cysts, 490–491 see also enterogenous cysts dura defect, nasal glioma surgery, 716 myelomeningocele, 767 (Fig.), 768 ‘dying spells’ see apparent life-threatening episodes dysplasias, 168 renal imaging, 788 (Fig.) posterior urethral valves, 857, 864 see also multicystic dysplastic kidney dyspnea, nasal obstruction, 201–202 echocardiography ECMO catheter placement, 319 esophageal atresia and TEF, 341 prenatal, ectopia cordis, 240 ECMO see extracorporeal membrane oxygenation ectopia cordis, 239–243 ectopic mucosa duplication cysts, 360, 480, 483 Meckel’s diverticulum, 617 ectopic ureter, 801, 802 (Fig.) prenatal ultrasound, 794 (Table) ectopic ureterocele, 832, 846 management, 801, 850 prenatal ultrasound, 794 (Table) edema, extracorporeal membrane oxygenation, 320 Edgerton classiﬁcation, hemangiomas, 664 edrophonium, 65 electrical impedance studies, gastro-esophageal reﬂux, 373 electrical stimulation, anorectal anomaly surgery, 548 electrolytes, preoperative, 52–53 Elliott, Carl, on culture and ethics, 178 embolization, central venous catheter fragments, 129 embolization (therapeutic), hemangiomas, 669 embryology abdominal wall defects, 606 alimentary tract duplications, 479–480 aortic arch, 267 (Fig.) cloacal exstrophy, 630 esophageal atresia and TEF, 339 exstrophy–epispadias complex, 619–620 kidney, 793–794 lung, 295 lymphatic system, 283–284, 687 malformations, 3–14 malrotation, 435 nasal tumors, 715 neural tube defects, 761–762 ovary, 751, 885 prune belly syndrome, 637

Index 933 renal pelvis, 831 sexual development, 884–885, 890 (Fig.), 903 ureter, 831 ureterocele, 845 embryoma, salivary, 233 emphysema see lobar emphysema empyema, 290 encephalocele, 715, 718–719, 762, 769–771 nasal glioma vs, 716 encephalopathy, colonic interposition, 573 endonasal perforation, 203 endopyelotomy, 821–822 endorectal pull-through operations Hirschsprung’s disease, 522, 526 laparoscopic, 187 endoscopic retrograde choledochopancreatography, congenital biliary dilatation, 591 endoscopy congenital esophageal stenosis, 354 gastro-esophageal reﬂux, 372–373 hydrocephalus, 781–782 intraoperative, pancreaticobiliary duct system, 594 subureteric Teﬂon injection, 834, 841, 842, 871 ureterocele unrooﬁng, 850–851 ureter repair, 827 uterus, 190 vascular rings, 271 see also bronchoscopy; endopyelotomy; laparoscopy; percutaneous procedures, endoscopic gastrostomy; thoracoscopy endothelin(s), congenital diaphragmatic hernia, 309–310 endothelin-3, Hirschsprung’s disease, 515–516 endothelin-B receptors (EDNRBs), Hirschsprung’s disease, 515–516 endothelin-converting enzyme-1 (ECE-1), aganglionic colon, 516 endothelium hemangiomas, 664 lymphatic system embryology, 284 endotracheal intubation anesthesia technique, 64–65 tubes, 61 cervical teratomas, 699 ex utero intrapartum treatment, 17 Pierre Robin sequence, 209 postoperative management, 72–73 subglottic stenosis from, 253–254 transport of neonate, 39 tracheo-esophageal ﬁstula, 42 endotracheal tubes Pierre Robin sequence, 208 at tracheostomy, 220 endoureterotomy, 827 end-tidal carbon dioxide monitoring, thoracoscopy and, 183 end-to-end rectorectal anastomosis, transanal, rectal atresia, 462 enemas after anorectal anomaly surgery, 551 intussusception reduction, 557–559 energy metabolism (caloric metabolism), 104–106 neonatal phases, 54 (Table), 103–104 energy requirements, 104 Pierre Robin sequence, 210 enﬂurane, 62 enhancers, 170 enteral nutrition, 114–115 after duodenal obstruction repair, 430 TPN-related cholestasis, 113–114 weaning from parenteral nutrition, 114 enteric glia see nerve-supporting cells enteric nervous system, hypertrophic pyloric stenosis, 390–391 enteritis necroticans, 501 enterocolitis ﬂuid losses, 55 Hirschsprung’s disease, 518, 522 radiography, 519 see also necrotizing enterocolitis enterocytoma, 231

enterogenous cysts, 251 neurenteric, 248, 251, 359, 360, 361–362 see also duplication anomalies enteroglucagon, intestinal growth, 569 enterostomy jejuno-ileal atresia surgery, 453 meconium ileus treatment, 468 necrotizing enterocolitis, 505, 506 (Fig.) early closure, 509 see also ileostomy enterotomy, meconium ileus, 468 enucleation mesenteric cysts, 493–494 ureterocele, 851–852 environment congenital malformations, 3, 4 neural tube defects, 762–763 thermal, 47 tumors, 656 epidermal growth factor embryogenesis and, 6 hypertrophic pyloric stenosis, 392 epidermolysis bullosa, with pyloric atresia, 383, 385 epignathus, 229–230 epinephrine, 81 epiphyseal separations, birth trauma, 36 epispadias, management, 622, 626–627 Epstein–Barr virus, tumors, 655 Epstein’s syndrome, 148 epulis, 230–231 Erb’s palsy, 31–32 erythromycin, gastro-esophageal reﬂux, 375 escharotic management, omphalocele, 610 esophagitis reﬂux, 371 spontaneous relaxation of lower esophageal sphincter, 369–370 esophagograms congenital esophageal stenosis, 353–354, 355 for perforation, 366 prone video, 346 esophagoplasty, 345 esophagoscopy congenital esophageal stenosis, 354 vascular rings, 271 esophagostomy, cervical, 345 esophagus atresia, 48 (Table), 337–352 anesthesia, 66–67 duodenal atresia, 424, 425 (Table) embryology, 6 gastrostomy, 344, 412 isolated, surgery, 344–346 perforation vs, 366 prenatal diagnosis, 20 sagittal computed tomography, 135 thoracoscopy, 184–185 tracheomalacia with, 259–260, 347–348 transport of neonate, 42 see also anastomosis, esophageal atresia congenital stenosis, 353–357 duplication cysts, 359–364 thoracoscopy, 184, 363 dysmotility, after esophageal atresia repair, 349 identiﬁcation at surgery, 343 intra-abdominal, 370 misplaced tracheostomy, 224 perforation, 365–368 iatrogenic injury, 356, 365–366, 367–368 pH monitoring, 373 strictures anastomotic, 347, 371 balloon dilatation, 137 vascular rings, 270 estrogens, tumors, 656 ethics, 173–181 conjoined twins, 643

934 Index ethics – continued myelomeningocele, 766 ethnicity, neural tube defects, 763 examination (clinical) congenital anomalies, 168–169 hydrometrocolpos, 876 hypertrophic pyloric stenosis, 392–393 neuropathic bladder, 869 preoperative, 59–60 exchange transfusion, for coagulation abnormalities, 84 excision nevi, 680–684 soft-tissue sarcomas, 734–735 exencephaly, 763 (Table) EXIT procedure see ex utero intrapartum treatment exomphalos see omphalocele exons, 158, 170 expiratory dyspnea, nasal obstruction, 202 expression (genetic), 170 inherited disorders, 163 exstrophy testis, 906 see also bladder, exstrophy exstrophy–epispadias complex, 619–627 exteriorization, ‘idiopathic’ intestinal perforation, 508 external inguinal ring, cryptorchidism, 905 external jugular vein cannulation, 124–125 central venous catheters, 126 external tracheal stenting, 262–263 extracellular matrix proteins Hirschsprung’s disease, 514 hypertrophic pyloric stenosis, 391–392 extracellular water, 53 extracorporeal membrane oxygenation (ECMO), 49, 317–327 complications, 321–322 congenital diaphragmatic hernia, 311, 322 feeding problems, 323 respiratory problems, 323 transport of neonate, 43 decreased usage, 78 hemorrhage from, 51–52 long-term outcomes, 918 management, 318–322 medical management, 321 selection criteria, 317–318 extralobar sequestration, 300, 301 extravasation, parenteral nutrition, 111 extrinsic pelvi-ureteric junction obstruction, 817 extubation, after anesthesia, 65 ex utero intrapartum treatment (EXIT), 17, 193, 312 cervical teratomas, 699 congenital high airway obstruction, 195 lymphatic malformations, 688 face, nevus surgery, 681 facial nerve, birth trauma, 32 failure of medical management, extracorporeal membrane oxygenation and, 318 failure to thrive gastro-esophageal reﬂux, 371 Pierre Robin sequence, 210 Fallot’s tetralogy, right aortic arch, 269 familial adenomatous polyposis, hepatoblastomas, 739 families ethics and, 174–180 tumors, 655 Fanconi anemia, 149, 654–655 thrombocytopenia with absent radii vs, 149 fasting, preoperative, 60 fat chyle, 284 parenteral nutrition, 107–108, 110 complications, 111 protein sparing, 108 reduction for cholestasis, 114 fat metabolism, parenteral nutrition, vs glucose intake, 106–107

fat overload syndrome, 111 Fc receptors, 143 fecal incontinence after anorectal anomaly surgery, 551, 915–916 sacrococcygeal teratomas, 712 Fechtner syndrome, 148 feeding duodenal obstruction repair, 430 extracorporeal membrane oxygenation, 323 gastro-esophageal reﬂux therapy, 374 gastrostomy, 411, 412 jejuno-ileal atresia repair, 453–454 necrotizing enterocolitis surgery, 509 Pierre Robin sequence, 210 pyloromyotomy, 395 sham, esophageal atresia, 345 feeding tubes, stenting for choanal atresia, 203–204 feminizing genitoplasty, 895–896 femoral artery cannulation, 124 femoral vein cannulation, 125 femur, birth trauma, 36 proximal epiphysis, 36 fentanyl, 64 fetal cells, maternal circulation, 16 fetal circulation, 49 fetal diagnosis see prenatal diagnosis fetal distress, trauma, 27 fetal lobectomy, 19, 193 fetal nucleated red blood cells, 16 fetal procedures congenital cystic adenomatoid malformations, 299 ovarian cyst puncture, 753 posterior urethral valves, 22, 860–861 fetal surgery, 189–198 congenital diaphragmatic hernia, 192–193, 312 diseases for, 15 (Table) myelomeningocele, 22–23, 194–195 sacrococcygeal teratomas, 194, 706 FETENDO see minimal-access fetal surgery fetus airway obstruction, 17 bladder, 868 aspiration, 192 blood loss, 153 chylothorax, 289–290 immune responses, 141 intussusception, 557 obstructive uropathy, 817–818 trauma, 27, 28 (Fig.) water distribution, 89 ﬁbrin glue, chylothorax treatment, 289 ﬁbro-adhesive meconium peritonitis, 472, 474 ﬁbromuscular stenosis, esophagus, 353, 354, 356 ﬁbronectin, enteric nervous system development, 514 ﬁbrosarcomas, 736–737 ﬁbrosis, ureterovesical junction obstruction, 823 ﬁlters, parenteral nutrition, 110 ﬁnger ﬂap, nasal glioma surgery, 717–718 ﬁre, laser therapy, subglottic stenosis, 256 ﬁrst branchial cleft anomaly, 227–228 ﬁstulae, ﬁrst branchial cleft anomaly, 227 5-prime (genetics), 170 ﬂat bottom, 536 (Fig.), 538, 541 ﬂexible bronchoscopy, 331–332 ﬂocculation, ovarian cyst torsion, 752 ﬂuid balance see water balance ﬂuid therapy, 92–95 abdominal wall defects, 608 amounts, 56 postoperative, 82, 97 preoperative, 52–53, 54 requirements for parenteral nutrition, 106 shock, 98 transport of neonate, 39 ﬂuorescence-activated cell sorting (FACS), 16 ﬂuorescent in situ hybridization, 162

Index 935 ﬂuoroscopy, 132 congenital esophageal stenosis, 355 esophageal atresia, 344, 345 (Fig.) gastro-esophageal reﬂux, 372 prone video esophagogram, 346 tracheomalacia, 260 ﬂutamide, 894 ﬂutter valve (Heimlick), 280 Fogarty balloon catheter, posterior urethral valves, 862 Foley Y pyeloplasty, 821 folic acid deﬁciency, neural tube defects, 762–763 follicle-stimulating hormone, ovarian cysts, 751 follicular carcinoma of thyroid, 232–233 fonticulus nasofrontalis, 715 foregut malformations duplications, 479 embryology, 6–7 foreskin urinary tract infections, 838 see also circumcision forms, transport of neonate, 41 formulae, enteral nutrition, 114 chemically-deﬁned, 115 fractures, birth trauma, 36 skull, 28, 29 fragile chromosome syndromes, tumors, 655 Frank–Starling curve, 80 free radicals, fat in parenteral nutrition, 111 frontal bones, embryology, 715 frusemide (furosemide), diuretic renography, 797–798, 819 fundoplication, 375–376 congenital esophageal stenosis and, 355 after esophageal atresia repair, 347 laparoscopic, 186–187 funnel chest, 243 furosemide, diuretic renography, 797–798, 819 gadolinium DTPA, magnetic resonance imaging, 136 gallbladder, parenteral nutrition, 112 gallium citrate, radionuclide examinations, 135 gallstones see cholelithiasis gametes, 170 ganglion cells, myenteric plexus absence, 513–516 hypertrophic pyloric stenosis, 390 gangrene, necrotizing enterocolitis, 502–505 gas bloat syndrome, 376 gas enemas, intussusception reduction, 557–559 gas exchange, Intralipid utilization test, 107 gastrectomy, for perforation, 408 gastric choristoma, lingual, 231–232 gastric ﬂuid, electrolytes, 55 (Table), 97 (Table) gastric mucosa see ectopic mucosa gastric outlet obstruction, electrolytes, 96–97 gastric volvulus, 399–404 gastrin hypertrophic pyloric stenosis, 389–390 intestinal growth, 569 gastro-colic ﬁstula, after gastrostomy, 418 gastrocutaneous ﬁstula, 419 gastro-esophageal junction, 369 gastro-esophageal reﬂux, 369–380 abdominal wall defects, 610 after esophageal atresia repair, 346–347, 349 tracheomalacia, 260 Gastrograﬁn enema, meconium ileus, 137, 467–468 gastrointestinal tract conjoined twins, 646–647 duplications see duplication anomalies glutamine, 109 hemangiomas, 666 prenatal diagnosis, 20–21 prune belly syndrome, 639 gastropexy, gastric volvulus, 403 gastroschisis, 605–613 anesthesia, 67

colonic atresia with, 457 ﬂuid and electrolytes, 55 (Table) gastrostomy, 412 hypothermia, 41, 47 jejuno-ileal atresia with, 453 long-term outcomes, 916–917 prenatal diagnosis, 21 primary closure risk, 98 transport of neonate, 41 umbilical artery transfer, 122–123 umbilicus excision at surgery, 913, 917 gastroscopy gastro-esophageal reﬂux, 372–373 see also percutaneous procedures, endoscopic gastrostomy gastrostomy, 411–421 esophageal atresia, 344, 412 gastric volvulus, 403 jejuno-ileal atresia, 452 laparoscopy fundoplication, 187 leakage, 419 Pierre Robin sequence, 210 reinsertion of catheter, 419 skin-level devices, 419–420 gavage feeding, Pierre Robin sequence, 210 Gaviscon, 374 G-banding, 161 gender assignment, 887, 891, 893–894 cloacal exstrophy, 630–631, 635 historical aspects, 883 male pseudohermaphroditism, 895 true hermaphroditism, 895 identiﬁcation, prenatal ultrasound, 794 urinary tract infections, 838 genes, 157–158 genetic aspects, 157–171 cystic ﬁbrosis, 465–466 esophageal atresia and TEF, 338 Hirschsprung’s disease, 515–516 hypertrophic pyloric stenosis and, 389 malformations, 4 neural tube defects, 762 neuroblastomas, 724 prune belly syndrome, 637 tumors, 653–656 ampliﬁcation, 656, 658 Beckwith–Wiedemann syndrome, 658 Burkitt’s lymphoma, 659 colon, 659 hepatoblastomas, 659 rhabdomyosarcomas, 658–659 Wilms’ tumor, 655–656 genetic imprinting, 165, 170 gene tracking analysis, 167 genioglossus, breathing, 201 genitalia birth trauma, 36 bladder exstrophy, 620–621 cloacal exstrophy, 630 management, 634, 635 intersex, 892 male, anomalies, 903–908 prune belly syndrome, 638–639 genitography, 892, 893 (Fig.) genito-inguinal ligament, 903 genitoplasty feminizing, 895–896 penis construction, 894 genitourethrogram, hydrometrocolpos, 877 genito-urinary rhabdomyosarcoma, 735 genomes, 158 gentamicin, 321 parenteral nutrition, 110 geography, neural tube defects, 763 germ cell tumors anterior mediastinum, 248–249

936 Index germ cell tumors – continued head and neck, 229 prune belly syndrome and, 639 giant cystic peritonitis, 466 giant hemangioma syndrome (Kasabach–Merritt syndrome), 150, 667 gingiva, granular cell tumor, 230–231 glabellar ﬂap, nasal glioma surgery, 717 glabellar island ﬂap, nasal glioma surgery, 718 glia, enteric see nerve-supporting cells glial-derived neurotrophic factor (GNDF) Hirschsprung’s disease, 514, 515 hypertrophic pyloric stenosis, 391 glial ﬁbrillar acidic protein (GFAP), hypertrophic pyloric stenosis, 391 glioma, nasal, 715–719 gliosis, aqueduct stenosis, 775 Gli transcription factors, Sonic hedgehog gene, VACTERL, 339 global aspects, ethics, 180 glomerular ﬁltration rate changes at birth, 89, 90, 91 fetus, 793–794 glossectomy, reduction, 216–217 glossopexy, Pierre Robin sequence, 209 glossoptosis, 208, 210 vacuum-glossoptosis-apnea, choanal atresia, 201 glucagon, treatment of hypoglycemia, 83 glucose hyperinsulinism requirements (diagnosis), 441 therapy, 442 infusion, 50 metabolism, 95–96 postoperative, 83 monitoring, transport of neonate, 39 parenteral nutrition, 106–107 see also dextrose glucose 6-phosphate dehydrogenase deﬁciency, 151 jaundice, 154 glutamine parenteral nutrition, 109 supplements, 569 glutathione, 109 glycopyrrolate, with muscle relaxant reversal agents, 65 goitre, congenital, 232–233 gonadal dysgenesis, mixed, 885, 889, 891, 895 ‘good-looking’ perineum, 536 (Fig.), 538 grafts cartilage, subglottic stenosis, 257–258 external tracheal stenting, 263 skin nasal glioma surgery, 717–718 nevus surgery, 681–684 see also transplantation granular cell tumor of gingiva, 230–231 granulation tissue gastrostomy, 419 subglottic stenosis, 254 trachea, tracheostomy, 224 granulomatous infections, mediastinum, 250 granulosa cells, 885 gray platelet syndrome, 148 greater saphenous vein see distal saphenous vein cannulation Grosfeld approach, lymphatic malformations, 693 growth extracorporeal membrane oxygenation patients, 323 after gastroschisis repair, 916 growth factors congenital diaphragmatic hernia, 309 hemangiomas, 663 hypertrophic pyloric stenosis, 392 pulmonary stretch, 312 see also speciﬁc growth factors growth hormone, intestinal adaptation, 569 grunting expiration, 202 gubernaculum, 903 half-times, MAG3 radionuclide imaging, 797

halothane, 62 hamartomas hemangiomas as, 663 mesenchymal, liver, 740 mesoblastic nephromas vs, 747 hand, Poland’s syndrome, 243 haploidy, 170 haplotypes, 170 head birth trauma, 28–30 circumference, 776 extracorporeal membrane oxygenation patients, 323 rhabdomyosarcoma, 736 ventral suspension, Pierre Robin sequence, 208, 209 (Fig.) head of pancreas, excision, 443 healed meconium peritonitis, 472 hearing loss, extracorporeal membrane oxygenation, 323–324 heart conjoined twins, 646 see also entries beginning cardiac . . . heart rate, 79 heating hyperthermia, neural tube defects, 763 operating theaters, 60 see also radiant heaters Heimlick ﬂutter valve, 280 Helicobacter pylori, after esophageal atresia repair, 349 helicopters, transport of neonate, 40 helix technique, intestinal tapering and lengthening, 571 hemangioendotheliomas, liver, 740 hemangiomas, 663–673 cleft sternum, 242 Kasabach–Merritt syndrome, 150, 667 liver, 666, 739 lymphatic malformations vs, 690 oral cavity, 230 parotid gland, 233 see also angiomas; capillary hemangiomas hematemesis gastro-esophageal reﬂux, 371–372 hypertrophic pyloric stenosis, 392 hematocele, vs torsion of testis, 909 hematology, 147–155 hematomas, liver cysts from, 597 subcapsular, 33, 507–508 hematuria, ureterovesical junction obstruction, 824 heminephro-ureterectomy, 850, 852–853 hemiscrotectomy, paratesticular rhabdomyosarcoma, 736 (Fig.) hemoﬁltration, veno-venous, 82–83 hemoglobin, preoperative, 60 hemoglobinopathies, 154 hemolytic disease of newborn, 153, 154 hemolytic jaundice, 51 hemophilias, 150 hemorrhage adrenal, 34–35 esophageal duplication cysts, 360 from extracorporeal membrane oxygenation, 51–52 gastrostomy, 418 intra-abdominal, birth trauma, 33, 35 neuroblastomas, 722 postoperative, 83–84 tracheostomy, 223 see also blood loss; intracranial hemorrhage; intraventricular hemorrhage hemorrhagic disease of newborn, 151 hemostasis hepatic portoenterostomy, 584, 585 liver tumor resection, 743 hemothorax, 290 Hendren’s technique (tapering of megaureter), 803 heparin, 153 arterial cannulation, 121 extracorporeal membrane oxygenation, 321 hepatic ﬁbrosis, congenital, 598

Index 937 hepaticoenterostomy see hepatoenterostomy hepatic portoenterostomy, 579, 582–587 hepatitis, alfafetoprotein, 740 hepatoblastomas, 739 alfafetoprotein, 740 chemotherapy, 741, 742 (Table) genetics, 659 surgery, 742–744 hepatocellular carcinoma, 740 hepatoenterostomy anastomosis, 593 congenital biliary dilatation, 591 herbicides, teratogenesis, 4 hereditary pelvi-ureteric junction obstruction, 818 hereditary spherocytosis, 154 Hermansky-Pudlak syndrome, 148 hermaphroditism historical aspects, 883 true, 890–892, 895 classiﬁcation, 886 (Table) incidence, 884 pseudohermaphroditism vs, 885 see also pseudohermaphroditism hiatus hernia, 370, 374 high-frequency jet ventilation (HFJV), 77 high-frequency oscillatory ventilation (HFOV), 49, 76 congenital diaphragmatic hernia, 78, 311 surgery for congenital diaphragmatic hernia, 67 hindgut duplications, 479, 485–486 Hirschsprung’s disease, 513–533 adult presentation, 918 colonic atresia with, 458 congenital segmental dilatation of intestines vs, 555 ﬂuid and electrolytes, 55 (Table) meconium ileus vs, 467 see also endorectal pull-through operations histamine H2 receptor antagonists, 374–375 histochemistry, Hirschsprung’s disease, 521 histones, 170 histopathology, neuroblastomas, 724 histoplasmosis, mediastinum, 250 historical aspects esophageal atresia and tracheo-esophageal ﬁstula, 337 intersex, 883–884 neural tube defects, 761 parenteral nutrition, 103 Pierre Robin sequence, 207 posterior urethral valves, 855 history-taking congenital anomalies, 168 neuropathic bladder, 869 Hodgkin’s disease, mediastinum, 250 home care, tracheostomy, 223 homeobox genes, esophageal atresia and TEF, 338 homosexuality, congenital adrenal hyperplasia, 886–887 homovanillic acid, neuroblastomas, 723 HOX11L1 homeobox gene, Hirschsprung’s disease, 516 H-type tracheo-esophageal ﬁstula, 346 human chorionic gonadotrophin, 884 ovarian cysts, 751 stimulation test, male pseudohermaphroditism, 893 humerus, birth trauma, 36 humidiﬁcation, 73 on water loss, 91 hyaluronic acid, enteric nervous system development, 514 HY antigen, 884 hybridization, chromosome analysis, 162–163 hydramnios see polyhydramnios hydration diuretic renography, 819 physical examination, 59 see also dehydration; water balance hydrocele, inguinal hernia vs, 562–563 hydrocephalus, 775–783 magnetic resonance imaging, 136 (Fig.) myelomeningocele association, 766, 768

hydrocolpos, 541 prenatal ultrasound, 794 (Table) see also hydrometrocolpos hydrolyzed casein formulae, 115 hydrometrocolpos, 875–882 see also hydrocolpos hydronephrosis fetal, 818, 838 fetal surgery, 191–192 imaging, 788–791 management, 793–808 multicystic dysplastic kidney vs, 809–810, 811 prenatal diagnosis, 21, 192, 793–795 upper urinary tract obstruction, 817–829 ureter enlargement with, 801–804 grading, 819 hydrops congenital cystic adenomatoid malformations, 19, 298 cystic hygroma, 17 fetal pleural effusion, 289 sacrococcygeal teratomas, 706 3β-hydroxylase deﬁciency, 888 (Table) 11β-hydroxylase deﬁciency, 888 (Table) 21-hydroxylase deﬁciencies, 887, 888 (Table), 889 17-hydroxyprogesterone, congenital adrenal hyperplasia, 892 hymenectomy, 878–879 hyoscine patches, esophageal anastomosis leak, 346 hyperbilirubinemia, preoperative assessment, 51 hypercapnia carbon dioxide pneumoperitoneum, 185 permissive, 76, 318 hyperglycemia, 95 parenteral nutrition, 110 hyperinsulinism, 50, 95, 441–444 hyperkalemia, 93, 94 (Fig.) shock, 98 hypernatremia, 93 hypertension mesoblastic nephromas, 748 multicystic dysplastic kidney, 811 neuroblastoma, 722 hyperthermia, neural tube defects, 763 hypertonic bladder, 869 hypertrophic pyloric stenosis, 389–398 from erythromycin, 375 gastric volvulus, 400, 401 long-term outcomes, 915 reﬂux esophagitis, 371 hyperventilation, 75 carbon dioxide pneumoperitoneum, 185 persistent pulmonary hypertension of neonate, 75–76 transport of neonate, congenital diaphragmatic hernia, 43 hypocalcemia, 96 postoperative, 83 preoperative assessment, 51 hypochloremic alkalosis, 55, 95, 393 gastric outlet obstruction, 97 hypogammaglobulinemia, physiological, 142–143 hypoglycemia, 95 hyperinsulinism, 441–444 parenteral nutrition, 111 postoperative, 83 preoperative assessment, 50 treatment, 50, 83 hypokalemia, 94–95 hypomagnesemia, 51, 96 hyponatremia, 93 shock, 98 hypopituitarism, pseudohermaphroditism, 884 hypospadias, 904 embryology, 10–11 female, 875 (Fig.) intersex, 884, 891, 904 repair, 897, 898 (Fig.) hypothermia, 47 transport of neonate, 39

938 Index hypothermia – continued gastroschisis, 41 very-low-birth-weight babies, 39 hypothetic double aortic arch, 267 hypothyroidism, macroglossia, 216 hypotonia, extracorporeal membrane oxygenation, 324 hypovolemia, extracorporeal membrane oxygenation, 321–322 hypoxia endotracheal suctioning, 72 isoﬂurane, 62 meconium peritonitis, 471–472 Pierre Robin sequence, 211 hypoxic respiratory failure, acute, 76–78 hysteroscopy, 190 iatrogenic injury anorectal surgery, 916 chylothorax, 284 common bile duct, 444 gastric volvulus, 401 perforated esophagus, 356, 365–366, 367–368 urethral stricture, 864 ‘idiopathic’ intestinal perforation, 508 ignition, laser therapy, subglottic stenosis, 256 ileocecal valve artiﬁcial, 573–574 jejuno-ileal atresia repair, 454 short bowel syndrome, 572 ileostomy electrolytes, 55 (Table), 97 (Table) necrotizing enterocolitis, 506 see also enterostomy ileum atresia ﬂuid and electrolytes, 55 (Table) after necrotizing enterocolitis, 509 see also jejuno-ileal atresia duplications, 483–485 patent omphalomesenteric duct, 615–616 resection Meckel’s diverticulum, 617 see also resections, intestines iminodiacetic acid derivatives, radionuclide examinations, 135 immune deﬁciency, chylothorax, 286 immune-mediated thrombocytopenia, 147, 149 immune system, 139–146 glutamine, 109 immune thrombocytopenic purpura, maternal, 149 immunoglobulins, 142–143 immunoreactive trypsin, cystic ﬁbrosis screening, 467 imperforate anus ethical considerations, 175 without ﬁstula, 538, 540 ﬂuid and electrolytes, 55 (Table) interventional radiology, 137–138 laparoscopic endorectal pull-through operations, 187 imprinting, genetic, 165, 170 inappropriate antidiuretic hormone secretion see syndrome of inappropriate antidiuretic hormone secretion incarcerated inguinal hernia, 562, 565–566 incisions esophageal atresia and TEF surgery, 341 esophageal duplication cysts, 362 hemiscrotectomy, 736 (Fig.) lung surgery, 304 myelomeningocele, 767 nephrectomy, 812 pyloric atresia, 384 pyloromyotomy, 394–395 tracheostomy, 220 ventriculoperitoneal shunts, 778, 779 incontinence see fecal incontinence; urinary incontinence incubators postoperative care, 83 radiography, 132 transport of neonate, 40–41

India, Tamilnadu, rectal atresia incidence, 460 indium-labelled leucocytes, radionuclide examinations, 135 induced delivery see preterm induced delivery induction, in embryogenesis, 4 induction of anesthesia, 64–65 infantile pyknocytosis, 153 infarction jejuno-ileal atresia etiology, 445 testis, 909 inguinal hernia, 562 infections arterial cannulation, 121 bacterial see bacterial infections central venous catheters, 52, 110, 128–129 extracorporeal membrane oxygenation, 321 gastrostomy, 418 granulomatous, mediastinum, 250 hydrocephalus from, 776 hydrometrocolpos, 880 parenteral nutrition, 110 Malassezia furfur, 125 post-splenectomy, prevention, 33 subglottic stenosis, 253–254 tracheostomy, 222 ureterocele, 847 urinary tract see urinary tract, infections ventriculoperitoneal shunts, 781 prevention at surgery, 778, 780 viral, intrauterine, thrombocytopenia, 149–150 inferior epigastric vein, central venous catheters, 127 inferior mesenteric artery, neuroblastoma surgery, 729 inferior vena cava cannulation, 126–127 neuroblastoma surgery, 727 pneumoperitoneum, 185 infra-umbilical cut-downs, 122 infusion/sensory apparatus, arterial cannulation, 121 inguinal canal, testis descent, 905 inguinal hernia, 561–568 recurrence, 566 testicular feminization syndrome, 884 inhalational anesthetic agents, 62–63 inhaled nitric oxide (iNO), 77 chylothorax, 286 congenital diaphragmatic hernia, 311 intraventricular hemorrhage, 52 persistent pulmonary hypertension of neonate, 49, 77 inheritance patterns, 163–166 inheritance risk, hypertrophic pyloric stenosis, 915 inherited thrombocytopenias, 147–149 innominate artery aberrant left, 269 anomalous origin, 268 surgery, 273 reimplantation, 273 innominate osteotomy, transverse, 623 inotropes, 80–81 shock, 98 insensible water loss, 53, 90–91, 106 inspiratory dyspnea, nasal obstruction, 201, 202 insulin-like growth factor-I hypertrophic pyloric stenosis, 392 intestinal adaptation, 569 pulmonary stretch, 312 integrins, embryogenesis, 5 intensive care, ﬂexible bronchoscopy, 332 intercellular adhesion molecule-1 (ICAM-1), Hirschsprung’s disease, 515 interferons, 141 (Table) for hemangiomas, 668–669 interleukins, 141 (Table) internal airway stenting, 264 internal jugular vein cannulation, 125 central venous catheters, 126 extracorporeal membrane oxygenation, 319 international staging system for neuroblastoma, 722

Index 939 intersex, 883–898 interstitial cells of Cajal (ICC) Hirschsprung’s disease, 517 hypertrophic pyloric stenosis and, 391 interventional radiology, 137–138 intestines abdominal wall defects dilatation, 607 exteriorized, 607 adaptation, 569–570 antiperistaltic segment, 573 artiﬁcial valves, 573–574 atresia, 20 conjoined twins, 646 gastroschisis, 606 see also under speciﬁc parts congenital segmental dilatation, 553–556 duplications, 483, 484, 485 idiopathic perforation, 508 lengthening, 571–572 obstruction anesthesia, 67 ﬂuid and electrolytes, 97 ﬂuid losses, 55 peritoneal ﬂuid, 437 transport of neonate, 43 see also adhesive intestinal obstruction; volvulus peri-anastomotic ulceration, 919 (Table) preservation maneuvers, 452–453, 570 resections see resections, intestines transplantation short bowel syndrome, 570, 574 TPN-related cholestasis, 113 intracellular water, 53 fetus, 89 intracerebral hemorrhage, birth trauma, 30 intracranial hemangiomas, 666 intracranial hemorrhage birth trauma, 29–30 extracorporeal membrane oxygenation monitoring for, 322 pre-existing, 317–318 risk, 317 hyperglycemia, 95 intradermal capillary hemangiomas, 664 intrahepatic arterial chemotherapy, 741 intrahepatic bile duct dilatation, 593–594 intralesional steroids, hemangiomas, 669 Intralipid extracorporeal membrane oxygenation, 321 utilization test, 107 intralobar sequestration, 300–302 intramural duplication cysts, esophagus, 359, 362, 363 (Fig.) intraoperative endoscopy, pancreaticobiliary duct system, 594 intraoperative management ﬂuid and electrolytes, 97 see also blood loss; operative trauma intrasymphyseal band, bladder exstrophy, 620 intratracheal pulmonary ventilation congenital diaphragmatic hernia, 311 see also trachea, gas insufﬂation intrauterine viral infections, thrombocytopenia, 149–150 intravenous access, 124–129 extracorporeal membrane oxygenation, 319 preoperative, 52 intravenous anesthetic agents, 63 intravenous infusions parenteral nutrition, complications, 111 see also ﬂuid therapy intravenous urography, 790–791 adrenal hemorrhage, 35 duplication anomalies, 833 multicystic dysplastic kidney, 810 pelvi-ureteric junction obstruction, 820 ureterocele, 848, 849 (Fig.) ureterovesical junction obstruction, 824

intraventricular hemorrhage extracorporeal membrane oxygenation, 318 inhaled nitric oxide, 52 pneumothorax and, 280 posthemorrhagic hydrocephalus, 775 ultrasound, 133 intravesical ureterocele, 846, 849 intrinsic pelvi-ureteric junction obstruction, 817 introns, 170 intussusception, 557–560 induced, 573 reduction, 137 invagination, embryogenesis, 4–5 inversion plication, intestinal, 452, 453 (Fig.) inversions, chromosomal, 161 inverted Y ureteral duplication, 831 invertograms, 537, 538 involution, hemangiomas, 668 iodine-131 metaiodobenzylguanidine (MIBG), neuroblastoma, radionuclide examinations, 135, 722 ipsilateral hydrometrocolpos, 876 iron deﬁciency anemia, intestinal resection, 918 irrigation enterotomy, meconium ileus, 468 minimal-access fetal surgery, 190–191 ischemia necrotizing enterocolitis, 501 peripheral, from arterial cannulation, 121 ischiopagus conjoined twins, 644 (Table) isochromosomes, 170 isoﬂurane, 62 isolated ventricle, 781 iso-osmolar contrast agents, 132 isosorbide, hydrocephalus, 777 Jarcho–Levin syndrome, 245 jaundice diagnosis, 580 hemolytic, 51 hypertrophic pyloric stenosis, 392 inherited anemias, 154 physiological, 51 preoperative assessment, 51 radionuclide examinations, 135 ultrasound, 133 see also cholestasis jaw index, Pierre Robin sequence, 207 jejunal interposition, esophageal atresia, 346 jejunal interposition hepatoduodenostomy, 593 jejuno-ileal atresia, 445–456 see also ileum, atresia jejuno-ileal stenosis, 446 jejunum feeding via, 411, 412 hepatic portoenterostomy, 582–586 obstruction, prenatal diagnosis, 45 see also duodenojejunal pouch Jeune’s disease, 244–245 junctional epidermolysis bullosa, with pyloric atresia, 383, 385 justice, ethics and, 174 juvenile capillary hemangioma, 665 Kalikinski plication, ureterovesical junction obstruction, 825 karyotyping, 161–163 chorionic villus sampling, 16 intersex, 892, 893 (Fig.) Kasabach–Merritt syndrome (giant hemangioma syndrome), 150, 667 Kasai procedure (hepatic portoenterostomy), 579, 582–587 Kelly’s forcep, repair of hydrometrocolpos, 879–880 keratinization, 91 kernicterus, 51 ketamine, 63 kidney birth trauma, 35 embryology, 793–794 function assessment, preoperative, 53–54

940 Index kidney – continued polycystic disease see polycystic kidney disease posterior urethral valves, 857 postoperative management, 82–83 prenatal diagnosis, 21 prune belly syndrome, 638 radiology, 787 see also speciﬁc investigations radionuclide examinations, 135, 790, 791 (Fig.), 797–798, 802, 809–810, 819–820 see also DMSA radionuclide examinations scarring, vesico-ureteric reﬂux, 837, 840 ultrasound, 133, 134 (Fig.), 787–789, 792, 796–797, 818–819 multicystic dysplastic kidney, 809 prenatal, 795, 817–818 see also headings beginning renal . . .; hydronephrosis; mesoblastic nephromas; polycystic kidney disease Kimura, K., intestinal tapering and lengthening, 572 KIT ligand, on interstitial cells of Cajal, 517 Klumpke’s paralysis, 31 Knudson theory (two-hit theory), 654, 657 laboratory investigations hyperinsulinism, 441 intersex, 892–893 jaundice, 580 mediastinal masses, 248 neuroblastomas, 723–724 parenteral nutrition monitoring, 114 posterior urethral valves, 861 preoperative, 52, 60 Ladd procedure duodenal obstruction, 429 malrotation, 437–438 laminin, enteric nervous system development, 514 language development, neonatal surgery on, 915 laparoscopy, 185–187 anorectal anomaly repair, 543–544 congenital segmental dilatation of intestines, 554 (Fig.), 555 gastrostomy, 417 intersex, 892 nephrectomy, 814–815 ovarian tumors, 756 pyeloplasty, 822 pyloromyotomy, 186, 395 video-assisted choledochal cyst excision, 594 laparotomy ‘idiopathic’ intestinal perforation, 508 necrotizing enterocolitis, 505 posterior sagittal anorectoplasty with, 549–551 large congenital melanocytic nevi, 676–678 laryngeal mask airways, 61 Pierre Robin sequence, 209 laryngomalacia, 219 laryngoscopes, 61 bronchoscopy, 329, 330 (Fig.) technique, 64–65 laryngo-tracheo-esophageal clefts, 7 larynx bronchoscopy, 331 hemangiomas, 666 laser therapy antegrade ablation of posterior urethral valves, 862–863 granulation tissue removal subglottic stenosis, 254–256 tracheostomy, 224 hemangiomas, 669–670 nevi, 678, 680 lateral cervical cyst, 228 lateral decubitus views, radiography, 132 lateral true hermaphroditism, 885, 890 leak-point pressure, cystometry, 870 Leber’s hereditary ophthalmopathy, 165 LEC-CAMs, 5 lectin domains, LEC-CAMs, 5 left aortic arch, anomalies, 268–269

surgery, 273 left carotid artery, anomalous origin, 268, 273 Lehbein two-stage operation, meconium peritonitis, 474–475 lengthening, intestines, 571–572 lens culinaris hemagglutinin test (LCH), 739, 740, 741 (Fig.) leptomeningeal cysts, 29 leptomeningeal melanosis, 676–677 levator ani, anorectal anomaly surgery, 548 Leydig cells, 884 LHR (right lung to head circumference ratio), 20, 310, 313 life support, withdrawal, 175–176 life-threatening episodes see apparent life-threatening episodes Li-Fraumeni syndrome, radiation, 656 Ligasure coagulator, thoracoscopic lung biopsy, 184 lignocaine, bronchoscopy, 330 limbs anomalies, Pierre Robin sequence, 211 conjoined twins, 647 lymphatic malformations, 693 nevus surgery, 683 rhabdomyosarcoma, 735–736 limited ileal resection, long-term outcomes, 917 Lindholm–Benjamin laryngoscope, bronchoscopy, 329, 330 (Fig.) lingual dermoids, 231 lingual gastric choristoma, 231–232 lingual thyroid, 232 linkage analysis, 167, 170 lipogenesis, 106 lipomas, lymphatic malformations vs, 690 liposarcoma, 737 lip–tongue anastomosis, Pierre Robin sequence, 209 Livaditis myotomy, esophageal atresia, 345 liver abscesses, 597, 598–600 birth trauma, 33 coagulopathies, 151 congenital diaphragmatic hernia, 193, 312, 313 conjoined twins, 646 cysts, 597–598 diagnosis, 580 glutamine, 109 hemangiomas, 666, 739 hilum, dissection, 582–583 omphalocele, 606 parenteral nutrition, complications, 112–114 subcapsular hematomas, 33, 507–508 transplantation, biliary atresia, 579–580, 587 tumors, 739–745 see also hepatoblastomas see also hepatoenterostomy liver cell adhesion molecule (L-CAM), 5 lobar emphysema, 48 (Table) anesthesia, 67 congenital, 296–297 lobectomy, 304–306 congenital lobar emphysema, 297 fetal, 19, 193 long-chain triglycerides, parenteral nutrition, 107, 108 long common channel theory, congenital biliary dilatation, 589 long-gap esophageal atresia, 338, 343, 345 longitudinal segmental pyloric atresia, 384 long saphenous vein, cannulation, 124 long-term outcomes, 913–922 loop colostomy, anorectal anomalies and, 544 low birth weight, 46, 47 extracorporeal membrane oxygenation and, 317, 323 ﬂuid requirements, 92 insensible water loss, 106 long-term effects, 914 lower esophageal sphincter, 369–370 lower midline syndrome, 606 lower urinary tract obstruction prenatal diagnosis, 22 see also neuropathic bladder; posterior urethral valves lung agenesis, 304

Index 941 air leaks, 277–282 detection at surgery, 305–306 anatomy, 295–306 aplasia, 304 biopsy, thoracoscopy, 184 care on extracorporeal membrane oxygenation, 321 choanal atresia, 201–202 congenital anomalies, 295–308 cysts parenchymal, 302–303, 304 see also bronchogenic cysts dysplasia see bronchopulmonary dysplasia hypoplasia, 304 diaphragmatic hernia, 9, 309, 310, 313 posterior urethral valves, 857–858 prune belly syndrome, 639 interstitial emphysema, 277–278 high-frequency jet ventilation, 77 sequestration, prenatal diagnosis, 18–19 surgery, 304–306 vascular rings, 271 ventilator-induced injury, 75–76 see also pulmonary hypertension lung to head circumference ratio (LHR), 20, 310, 313 lung-to-head ratio, congenital diaphragmatic hernia, 192–193 lymphadenitis, inguinal hernia vs, 563 lymphangiectasis, pulmonary, 303 lymphangiomas cervical, prenatal diagnosis, 17 macroglossia, 215–216, 230 mesenteric, 489–490 parotid gland, 233 see also lymphatic malformations lymphatic malformations, 687–695 see also cystic hygroma; lymphangiomas lymphatic system, 283–284 communication with biliary system, 581, 582 (Fig.) lymph nodes inguinal hernia vs, 563 neuroblastoma, 727 soft-tissue sarcomas, sampling, 734 lymphocytes, development, 139 lymphoma, mediastinum, 249, 250 macrocephaly, extracorporeal membrane oxygenation, 323 macroglossia, 215–218 lymphangiomas, 215–216, 230 lymphatic malformations, 693 macrophages, 143 MAG3 radionuclide examinations, 790, 791 (Fig.), 797–798 multicystic dysplastic kidney, 810 pelvi-ureteric junction obstruction, 819 magnesium sulphate, for hypomagnesemia, 51 magnetic resonance choledochopancreatography, congenital biliary dilatation, 591 magnetic resonance imaging, 136–137 cervical teratomas, 698–699 congenital cystic adenomatoid malformation, 19 congenital diaphragmatic hernia, 20 intersex, 892 mediastinal masses, 248 nasal glioma, 716 neuroblastomas, 723 neurocutaneous melanosis, 676 prenatal diagnosis, 16, 136 sacrococcygeal teratomas, 18, 136 (Fig.), 706, 707–708 urinary tract, 792 vascular rings, 271 magnetic resonance spectroscopy, 136–137 major histocompatibility complex class II antigens, Hirschsprung’s disease, 514–515 malabsorption enteral nutrition, 115 jejuno-ileal atresia repair, 454 Malassezia furfur, infections, parenteral nutrition, 125 malformations

deﬁnition, 168 see also congenital anomalies malignancy, 918 congenital cystic adenomatoid malformations, 297 multicystic dysplastic kidney, 811 sebaceous nevi, 679 teratomas, 697, 705, 707 Malone procedure (continent appendicostomy), 551 malrotation, 435–439 adult presentation, 918 duodenal obstruction, 427 incidence, 425 (Table) ﬂuid and electrolytes, 55 (Table) gastric volvulus, 401 jejuno-ileal atresia with, 449 laparoscopic surgery, 187 mandatory intermittent ventilation, vs synchronized ventilation, 75 mandible, Pierre Robin sequence, 207, 211 manometry anorectal, Hirschsprung’s disease, 520–521 congenital esophageal stenosis, 354 gastro-esophageal reﬂux, 373 manual reduction of intussusception, 559 Marfan’s syndrome, chest wall anomalies, 243 markers biochemical, 16 molecular genetics, 167 marsupialization, mesenteric cysts, 495 masks, anesthesia, 61 mast cells, C-KIT deﬁciency, gastric perforation, 406 maternal antibodies alloimmune hemolytic anemia, 153 thrombocytopenia, 149 maternal autoimmune thrombocytopenia, 149 maternal circulation, fetal cells, 16 maternal disomy, 165 maternal–fetal risks, fetal surgery, 189 maternal interests (Sara Ruddick), 178 maternal ‘mirror syndrome’, sacrococcygeal teratomas, 18, 194 maternal monitoring, fetal surgery, 190 maternal risk factors indications for ultrasound, 15–16 intersex, 891 maternal serum alfafetoprotein, abdominal wall defects, 607 maternal trauma, 27, 28 (Fig.) maximal oxidative capacity, glucose, 107 May–Hegglin anomaly, 148 McKusick–Kaufman syndrome, 876 mean airway pressure, alveolar ventilation, 74 Meckel’s band, 616 Meckel’s diverticulum, 617 meconium jejuno-ileal atresia, 448 passage, anorectal anomalies, 535, 538, 540, 544 meconium ileus, 465–470 Gastrograﬁn enema, 137, 467–468 meconium peritonitis, 471–477 jejuno-ileal atresia, 449 meconium plug syndrome, cystic ﬁbrosis, 467 mediastinum lymphatic malformations, 692–693 masses, 247–251 thoracoscopy, 184 ultrasound, 133, 134 (Fig.) medical records, transport of neonate, 39–40 medium-chain triglycerides chylothorax, 286 enteral nutrition, 115 parenteral nutrition, 108 megacolon, Hirschsprung’s disease, 518 megacystis-megaureter syndrome, 806 megaduodenum, duodenoplasty, 430 megaureter, 823 non-reﬂuxing, 801–804 primary obstructive, prenatal ultrasound, 794 (Table) meiosis, 161, 170

942 Index melanocytic nevi, congenital, 675–678 melanoma, congenital melanocytic nevi, 676 membrane oxygenators, 320 membranous pyloric atresia, 384 meninges, rhabdomyosarcoma, 736 meningitis hydrocephalus, 776 incidence, 139 meningocele, 762, 763 (Table) anterior, sacrococcygeal teratomas vs, 707 frontonasal, 718–719 meningomyelocele see myelomeningocele menstrual disorders, cloacal malformations, 916 mental retardation extracorporeal membrane oxygenation, 324 myelomeningocele, 768 Pierre Robin sequence, 211 mercapto acetyl triglycine see MAG3 radionuclide examinations mesenchymal hamartomas, liver, 740 mesenteric cysts, 489–496 mesenteroaxial gastric volvulus, 399 mesentery, intestinal preservation maneuvers, 452–453 mesoblastic nephromas, 747–750 computed tomography, 792 magnetic resonance imaging, 136 mesothelial cysts, abdomen, 490 messenger RNA, 158 metabolic acidosis, 95 bicarbonate, 98 hyperkalemia, 93 postoperative, 97 metabolic alkalosis, 95 metabolism complications of parenteral nutrition, 110–111 neonatal phases, 54 metaiodobenzylguanidine (MIBG), neuroblastomas, radionuclide examinations, 135, 722 metastases incidence, 652 neuroblastomas, 721 methylcellulose drops, cornea, 32 methylene blue, tracheo-esophageal ﬁstula, 348 metoclopramide, for gastro-esophageal reﬂux, 375 metronidazole, TPN-related cholestasis, 113 microbipolar dissection, lymphatic malformations, 691 microchelitis, lymphangiomas, 230 microcolon, 449, 466, 467 (Fig.) microﬁlaments, embryogenesis and, 5 micrognathia, 207, 210 micropenis, 905 microsatellite markers, 170 microscopic meconium peritonitis, 472–473 micturating cystourethrography, 788 (Fig.), 789, 796 multicystic dysplastic kidney, 810 neuropathic bladder, 869 posterior urethral valves, 804, 858–859 ureterocele, 801, 848–849 post-incisional, 851 vesico-ureteric reﬂux, 839–840 duplication anomalies, 834 (Fig.) micturition, 868 aberrant, 806 middle mediastinum, 249–250 middle sacral artery, sacrococcygeal teratomas, 707, 709, 711 midgut duplications, 479 embryology, 435 loop volvulus, 427, 435, 436, 437 see also malrotation midline cervical clefts, 228 midline raphe subepithelial ﬁstula, 535, 536 (Fig.), 541 migration gastrostomy catheters, 419 Teﬂon particles, 841 Mikulicz enterostomy, 505, 506 (Fig.) miliary atelectasis, choanal atresia, 201

milrinone, 82 minimal-access fetal surgery, 190–191 ovarian tumors, 756 sacrococcygeal teratomas, 194 see also under endoscopy; laparoscopy minimal anoplasty, posterior sagittal, 543, 546 minimally invasive surgery, 183–188 minimal metabolic rate, non-protein energy reserve vs, 103–104 minisatellite markers, 170 ‘mirror syndrome’, maternal, sacrococcygeal teratomas, 18, 194 mitochondrial inheritance, 165 mitogen responses, T-lymphocytes, 141 mitosis, 160–161, 170 mivacurium, 64 mixed gonadal dysgenesis, 885, 889, 891, 895 modular diets, malabsorption, 115 molecular genetics, single-gene disorders, 166–167 Monfort’s operation, prune belly syndrome, 640 Monfort’s technique, ureterocele unrooﬁng, 851 Mongolian spots, 678 monitoring anesthesia, 65–66 central venous catheters, 79 esophageal pH, 373 extracorporeal membrane oxygenation, 322 fetal surgery maternal, 190 radiotelemetry, 189 parenteral nutrition, 114 postoperative, 71–72 prematurity, 68 thoracoscopy and, 183 transport of neonate, 39, 40 ventilation, anesthesia, 66 monoclonal antibody UJ13A, neuroblastoma localization, 722 monocytes, 143 Montreal platelet syndrome, 148 Morgagni hernia, gastric volvulus, 401 morphine, 64 mortality congenital diaphragmatic hernia, 312–313 extracorporeal membrane oxygenation, 322–323 malformations, 3 Pierre Robin sequence, 211 pneumothorax, 280 prenatal, 15 sacrococcygeal teratomas, 706 vascular rings, 274 mosaicism, mixed gonadal dysgenesis, 891 mouth, lesions, 229–232 mouth-breathing, inability of neonate, 201 mucosa transplantation, 570 mucosectomy, congenital biliary dilatation, 592 Müllerian duct persistent, 907 ureteric anomalies, 831 Müllerian inhibiting factor, 884, 885 estimation, 892 Mulliken and Glowacki classiﬁcation, hemangioma, 664 multicystic dysplastic kidney, 800–801, 809–816 prenatal ultrasound, 794 (Table) multinodular hemangiomatosis of liver, 666 muscle, prune belly syndrome, 638 muscle relaxants see neuromuscular blocking agents musculocutaneous ﬂaps, conjoined twins, 647 mushroom catheter, gastrostomy, 415 mutations, tumors, 653 myelodysplasia, cloacal exstrophy, 630 myelography, neurenteric cysts, 360, 361 (Fig.) myelomeningocele, 762, 764–769 anesthesia, 67 closure, 766–768 fetal surgery, 22–23, 194–195 magnetic resonance imaging, 136 (Fig.) prenatal diagnosis, 22–23 prevention, 769

Index 943 transport of neonate, 42 see also neural tube defects myenteric plexus ganglion cell absence, 513–516 Hirschsprung’s disease, 513, 518 hypertrophic pyloric stenosis, 390, 392 MYOD gene, rhabdomyosarcoma, 659 myotomy, esophageal atresia, 345 myotonic dystrophy, congenital, 165 NADPH diaphorase Hirschsprung’s disease, 517 histochemistry, 521 see also nitric oxide synthase narcotic analgesics, 64 nasal obstruction, 201–202 ﬂexible bronchoscopy and, 332 nasal tumors, 715–720 nasogastric tubes enteral nutrition, 114 esophageal atresia diagnosis, 340 gastric volvulus, 401 gastrostomy vs, 411–412 transport of neonate, 39 intestinal obstruction, 43 unusual course, 366 nasopharyngeal airways, Pierre Robin sequence, 208–209 nasotracheal intubation, 65, 72 cervical teratomas, 699 Nd: YAG lasers antegrade ablation, posterior urethral valves, 863 hemangioma, 670 H-type tracheo-esophageal ﬁstula, 346 for subglottic stenosis, 256 neck ectopia cordis, 239 lesions, 227–228 lymphatic malformations, 692 masses prenatal diagnosis, 17 ultrasound, 133 rhabdomyosarcoma, 229, 736 see also cervical teratomas necrotizing enterocolitis, 501–512 abdominal wall defects, 610 enteral nutrition, 115 extensive, 507 ﬂuid and electrolytes, 55 (Table) preservation maneuvers, 570 surgery outcomes, 917 transport of neonate, 43 needle aspiration, pneumothorax, 280 neodymium see Nd: YAG lasers neonatal alloimmune thrombocytopenia, 149 neonatal intensive care units, necrotizing enterocolitis surgery in, 508 neonatal staining (hemangioma), 664 neostigmine, 65 nephrectomy mesoblastic nephromas, 748–750 multicystic dysplastic kidney, 800, 810–815 neuroblastoma, 727 neuropathic bladder, 871–872 pelvi-ureteric junction obstruction, 822 see also heminephro-ureterectomy nephritis, ventriculoperitoneal shunts, 781 nephroblastomatosis, 655, 657 nephrocalcinosis, ultrasound, 788 nephrostomy, 138 posterior urethral valves, 805, 864 nephro-ureterectomy heminephro-ureterectomy, 850, 852–853 polar, 833–834 nerve ﬁbers bladder, 867–868 Hirschsprung’s disease and, 516, 521

ureterovesical junction obstruction, 823 see also peptidergic nerve ﬁbers nerve growth factor Hirschsprung’s disease, 514 hypertrophic pyloric stenosis and, 391 nerve injuries, birth trauma, 31–33 nerve-supporting cells Hirschsprung’s disease, 517 hypertrophic pyloric stenosis and, 391 Neuhauser’s sign, 466 neural cell adhesion molecule (NCAM), 5 Hirschsprung’s disease, 514 hypertrophic pyloric stenosis and, 390–391 neural crest cells choanal atresia, 201 migration, Hirschsprung’s disease, 513 tumor syndromes, 655 neural nevus, 677 neural tube defects, 761–773 neurenteric canal, defects, 479–480 neurenteric cysts, enterogenous, 248, 251, 359, 360, 361–362 neuroblastomas, 652, 657–658, 721–731 iodine-131 metaiodobenzylguanidine, radionuclide examinations, 135, 722 mediastinum, 250–251 stage IVS, 724–725 neurocrine drugs, for gastro-esophageal reﬂux, 375 neurocutaneous melanosis, 676 neurodevelopmental handicap extracorporeal membrane oxygenation, 323–324 necrotizing enterocolitis, 509–510 see also cognitive function neuroﬁbromatosis penetrance, 163 tumors, 655 neuroﬁbrosarcoma, 737 neurogenic bladder see neuropathic bladder neuromuscular blocking agents, 63–64 reversal, 65 for ventilation, 75 neuron-speciﬁc enolase, neuroblastomas, 724 neuropathic bladder, 867–874 myelomeningocele, 766, 768 sacrococcygeal teratomas, 712 neuropeptide Y, absence in hypertrophic pyloric stenosis, 390 neuropores, 762 neurotransmitters, bladder, 867–868 neurotrophic factor-3, Hirschsprung’s disease, 514 neurotrophin receptors, neuroblastomas, 724 neurotrophins Hirschsprung’s disease, 514 hypertrophic pyloric stenosis, 391 neurulation, embryology, 761–762 neutrophils, 143 nevi, congenital, 675–685 nevus of Ito, 678 nevus of Ota, 678 nevus spilus, 678 nifedipine, hyperinsulinism, 442 Nissen’s fundoplication, 376 congenital esophageal stenosis and, 355 nitric oxide see inhaled nitric oxide (iNO) nitric oxide synthase Hirschsprung’s disease, 517 hypertrophic pyloric stenosis and, 390 nitrofen, 4 diaphragmatic hernia model, 8–9, 309 nitrogen balance, 54 neonatal phases, 54 nitrous oxide, 63 N-myc gene, ampliﬁcation, 656, 658, 724, 725 non-communicating hydrocephalus, 775 non-compliant bladder, 868–869 non-depolarizing muscle relaxants, 63–64 non-disjunction, 161, 170 non-Hodgkin’s lymphomas, mediastinum, 250

944 Index non-invasive ventilation, 78 non-ionic contrast agents, 132 non-protein energy intake, parenteral nutrition, 108, 110 non-protein energy reserve, minimal metabolic rate vs, 103–104 norepinephrine, 81 notochord embryology, 761–762 esophageal atresia and TEF, 339 split, 479–480, 762 NTV (third ventriculostomy), endoscopic, 781–782 nuchal cord thickening, 16 nuchal translucency measurement, 16 nuclear medicine see radionuclide examinations nucleated red blood cells, 16 nucleosomes, 160, 170 nursing position, Pierre Robin sequence, 208 nutrients, malformations and, 4 nutrition, 103–119 chylothorax, 285–286 enteral see enteral nutrition ethics, 179 jejuno-ileal atresia repair, 454 neural tube defects, 762–763 parenteral see parenteral nutrition Pierre Robin sequence, 210

oral cavity, lesions, 229–232 orbital hemangiomas, 665–666 orbital rhabdomyosarcoma, 736 orchidopexy, 906 prune belly syndrome, 640 true hermaphroditism case, 891–892 organizers, in embryogenesis, 4 organoaxial gastric volvulus, 399 oscillotonometry, blood pressure monitoring, 66 osteotomies, pelvis, bladder exstrophy, 623 ovarian cysts, 751–757 cloacal exstrophy, 630 laparoscopic surgery, 187 prenatal ultrasound, 794 (Table) ovary embryology, 751, 885 incarcerated inguinal hernia and, 562 tumors, 751–757 overhead heaters see radiant heaters overwhelming post-splenectomy infection (OPSI), prevention, 33 oxygenators, extracorporeal membrane oxygenation, 320 oxygen tension transcutaneous monitoring, 72 ventilation and, 74 oxygen therapy, 74

obliterated omphalomesenteric duct, 616 obstructive uropathy fetal surgery, 191–192 ﬂuid and electrolytes, 56 imaging, 789–791 oligohydramnios, 795 persistent cloaca, 541 prenatal diagnosis, 21–22, 795 prune belly syndrome theory, 637 upper urinary tract, 817–829 urinary ascites, 497 occipital encephalocele, 769, 770 occipito-atlanto-axial instability, Pierre Robin sequence, 211 oculocutaneous albinism, 148 oesophagus see esophagus OK432 (Group A Streptococcus pyogenes), cystic hygromas, 230 oligohydramnios, 794–795 pelvi-ureteric junction obstruction, 191–192 posterior urethral valves, 857–858 oligonucleotide primers, 170 omental cysts, 489–496 omeprazol, 375 omphalocele, 605–613 anesthesia, 67 cloacal exstrophy, 629, 630 conjoined twins, 646 ectopia cordis with, 240 Cantrell pentalogy, 240–241 ﬂuid and electrolytes, 55 (Table) Meckel’s diverticulum, 617 prenatal diagnosis, 20–21, 45 (Fig.) primary closure risk, 98 transport of neonate, 41 umbilical artery transfer, 122–123 omphalomesenteric duct patent, 615–616 remnants, 615–617 omphalopagus conjoined twins, 644 (Table) oophorectomy, 756 open fetal surgery, 190 ‘open lung’ approach, high-frequency oscillatory ventilation, 76 operative cholangiography, 581, 582 (Fig.) congenital biliary dilatation, 591, 592 (Fig.) operative trauma, energy requirements, 104–105 opioids analgesics, 64 endogenous, on metabolic stress, 104–105 opsonization, 143 oral airways, 61, 209 (Fig.) choanal atresia, 202

p53 gene and protein family, 657 rhabdomyosarcoma, 658–659 pacemaker cells, intestinal see interstitial cells of Cajal (ICC) pain, abdomen, after gastroschisis repair, 916 Palmaz stent, airway, 264 pancreas adenomas, 442–443 annular, 423, 425 (Table) duplications, 481 excisions, 442–443 radiology, 441–442 pancreatic duct disorders, 594 junction with bile duct, anomalies, 590 pancreatic juice, electrolytes, 55 (Table), 97 (Table) pancreaticobiliary malunion, 589, 590 malignant change, 918 pancuronium, 64 paracentesis, necrotizing enterocolitis, 503–505 paracentric inversions, 170 chromosomal, 161 paralysis Erb’s palsy, 31–32 Klumpke’s, 31 myelomeningocele, 765 postoperative, abdominal wall defects, 606 spastic diplegia, interferon-α, 669 see also phrenic nerve palsy parameningeal rhabdomyosarcoma, 736 parasympathetic nervous system, bladder, 867–868 paratesticular rhabdomyosarcoma, 735, 736 (Fig.) parenchymal lung cysts, 302–303, 304 parenteral nutrition, 106–114 abdominal wall defects, 606, 610 central venous catheterization, 125–126 chylothorax, 285–286 chylous ascites, 499 complications, 110–114 energy requirements, 104 ethics, 177, 178–180 extracorporeal membrane oxygenation, 321 historical aspects, 103 infections, 110 Malassezia furfur, 125 after jejuno-ileal atresia repair, 454 necrotizing enterocolitis surgery, 508 postoperative, 97 prescription, 109–110 parents, ethics and, 174–180 Paris–Trousseau syndrome, 148

Index 945 parotid gland tumors, 233 hemangiomas, 665 partial liquid ventilation, 311 partial twinning, gastrointestinal tract duplications, 479 particle migration, Teﬂon injection, 841 ‘patch, drain and wait’, necrotizing enterocolitis, 507 ‘Patched’ cell surface protein, esophageal atresia and TEF, 339 patching, serosal, 570 patent ductus arteriosus ﬂuid therapy and, 92 thoracoscopic closure, 184 PAX genes, rhabdomyosarcomas, 658 peak inspiratory pressure (PIP), 73, 74 peanut agglutinin-positive/CD8-positive T-lymphocytes, 142 pectus carinatum, 243 pectus excavatum, 243 pedal artery cannulation, 123 pediatric urethral sounds, choanal atresia surgery, 203 Pellegrino, Edmund, on culture and ethics, 178 pelvis bladder exstrophy, 620 osteotomies, 623 neuroblastoma surgery, 729 pelvi-ureteric junction obstruction, 798–800, 817–823 bilateral, 822–823 duplication anomalies, 835 fetal surgery, 191–192 prenatal diagnosis, 21, 817–818 prenatal ultrasound, 794 (Table) penetrance, 170 inherited disorders, 163 penetrating trauma, fetus, 27 penis, 903–905 bladder exstrophy, 620–621, 626 construction, 894 hypospadias, 11 prune belly syndrome, 638–639 rare anomalies, 905 penoscrotal web, 905 pentagastrin, hypertrophic pyloric stenosis, 389–390 pepsin, reﬂux esophagitis, 371 peptidergic nerve ﬁbers Hirschsprung’s disease and, 516–517 hypertrophic pyloric stenosis, 390 pelvi-ureteric junction obstruction, 817 percutaneous central venous catheters, 125 percutaneous procedures antegrade ablation, posterior urethral valves, 862 endopyelotomy, 822 endoscopic gastrostomy, 413, 416–417 complications, 418 nephrostomy see nephrostomy proctography, 137 (Fig.), 138 transhepatic cholangio-drainage (PTCD), after hepatic portoenterostomy, 586 transhepatic venous sampling, pancreas, 441–442 umbilical blood sampling (PUBS), 16 venous cannulation, 124–125 perforation biliary tract, 497–498 duodenum, 395 endonasal, 203 esophagus, 365–368 iatrogenic injury, 356, 365–366, 367–368 Hirschsprung’s disease, 519 intestinal fetus, 471, 472 ‘idiopathic’, 508 meconium ileus, 468 necrotizing enterocolitis, 502 peritonitis, ﬂuid and electrolytes, 55 (Table) stomach, 405–409 after gastrostomy, 418 urinary tract, 497 peri-anastomotic ulceration, intestines, 919 (Table) pericentric inversions, 170

chromosomal, 161 pericytes, capillary hemangiomas, 663 perineum bladder exstrophy, 620 cutaneous ﬁstula, anorectal anomaly, 539, 542–543 ‘good-looking’, 536 (Fig.), 538 hemangiomas, 666 hypospadias, 11 peripheral ischemia, from arterial cannulation, 121 peripheral nerve injuries, birth trauma, 31–33 peripheral vein cannulation, 124 cut-downs, 125 peristalsis hypertrophic pyloric stenosis, 393 short bowel syndrome and, 571–572 peritoneal dialysis, 82 peritoneum calciﬁcation, cystic ﬁbrosis, 473 drainage ‘idiopathic’ intestinal perforation, 508 necrotizing enterocolitis, 505–506 ﬂuid, intestinal obstruction, 437 jejuno-ileal atresia, 450 meconium peritonitis, 472–473 peritonitis ﬂuid and electrolytes, 55 (Table) giant cystic, 466 see also meconium peritonitis permissive hypercapnia, 76, 318 Per-Q-Cath (central venous catheter system), 125 persistent pulmonary hypertension of neonate (PPHN) hyperventilation, 75–76 inhaled nitric oxide, 49, 77 sensorineural handicap, 323 pH esophagus monitoring, 373 reﬂux, 371 genital vs somatic cells, 885 phagocytosis, 143 pharynx hypotonia, 332 tumors, 229–232 phenobarbital, radionuclide examinations, jaundice, 135 phenytoin, tumors, 656 Philadelphia chromosome, 653 phimosis, 903 phosphodiesterase inhibitors, 77, 81–82 phototherapy, ﬂuid requirements, 92 phrenic nerve palsy, birth trauma, 32, 33 (Fig.) exclusion, 31 physiological hydronephrosis, fetal, 818 physiological jaundice, 51 Pierre Robin sequence, 168, 207–213 transport of neonate, 42 pigeon chest, 243 placenta abruption, 27 hemangiomas, 666 neuroblastomas, 721 placode formation, 5 plasma, for strangulated volvulus, 436 Plastibell device, 904 platelet-derived growth factor BB, hypertrophic pyloric stenosis, 392 platelets, 147–150 Kasabach–Merritt syndrome, 667 neuroblastoma, deﬁciency, 722 postoperative dysfunction, 83–84 preoperative assessment, 52 transfusions extracorporeal membrane oxygenation, 321 thrombocytopenia with absent radii, 149 pleura effusions, 283–293 esophageal perforation, 366 fetus, 289–290

946 Index pleura – continued esophageal atresia and TEF surgery, 342 pleuroamniotic shunting, fetal pleural effusion, 289–290 pleurodesis, chylothorax, 289 pleuroperitoneal canal, 295 congenital diaphragmatic hernia, 309 pleuroperitoneal membrane, malformations, 7–9 pleuroperitoneal shunts, for chylothorax, 286–289 plication diaphragm, 375 thoracoscopy, 185 megaureter, 803 ureterovesical junction obstruction, 825 see also inversion plication pneumatosis intestinalis, 501 necrotizing enterocolitis, 502 (Fig.), 503 pneumomediastinum, 278–279 pneumonia, after extracorporeal membrane oxygenation, 323 pneumopericardium, 280–281 pneumoperitoneum artiﬁcial, laparoscopy, 185 colonic atresia, 458 gastric perforation, 406 necrotizing enterocolitis, 501, 503 pneumoscrotum, gastric perforation, 406 pneumothorax, 48 (Table), 279–280 artiﬁcial, thoracoscopy, 184 congenital diaphragmatic hernia, transport of neonate, 43 esophageal perforation, 366 see also tension pneumothorax Poland’s syndrome, 243–244 polar nephro-ureterectomy, 833–834 Politano–Leadbetter technique, reimplantation of ureter, 826–827 polyalveolar morphology, 296 polycystic kidney disease, 598 multicystic dysplastic kidney vs, 800 prenatal ultrasound, 794 (Table) ultrasound, 787–788 polycystic liver disease, 598 polycythemia, spurious coagulopathy, 151 polydimethylsiloxane, injection for vesico-ureteric reﬂux, 841–842 polygenic inheritance, 164–165 polyhydramnios cervical teratomas, 697 chest masses, 19 congenital cystic adenomatoid malformations, 297, 298 duodenal obstruction, 424 esophageal atresia, 20 polymerase chain reaction, 166 polymorphic DNA markers, 167 polyorchidism, 907 polyp, umbilicus, 616–617 Polytef paste (polytetraﬂuoroethylene), subureteric injection, 834, 841, 842, 871 pop-off valve syndromes, posterior urethral valves, 805, 865 ‘portable’ radiography, 132 porta hepatis, dissection, 582–583 portal hypertension, 598 parenteral nutrition, 112 portal vein gas, necrotizing enterocolitis, 501, 502 (Fig.) preduodenal, 427 portoenterostomy, hepatic, 579, 582–587 port-valves, gastrostomy, 419–420 port wine stains, 664, 665 (Fig.) carbon dioxide laser, 669 position nephrectomy, 812 for nursing, Pierre Robin sequence, 208 sacrococcygeal teratoma resection, 708 positive airway pressure see continuous positive airway pressure positive end-expiratory pressure (PEEP), 74 posterior lumbotomy see dorsal lumbotomy posterior mediastinum, 250–251 posterior sagittal anorectoplasty indications, 542

laparotomy with, 549–551 limited, 547–548 outcomes, 915, 916 rectal atresia, 462 technique, 548–549 posterior sagittal minimal anoplasty, 543, 546 posterior tibial artery cannulation, 123 posterior urethral valves, 804–806, 855–866 prenatal diagnosis, 22, 796, 860–861 prenatal ultrasound, 794 (Table) radionuclide examinations, 790, 859–860 posthemorrhagic hydrocephalus, 775 post-hepatic mesenchymal plate (PHMP), defects, 8–9 postoperative management, 71–88 abdominal wall defects, 610 analgesia, 78–79 inguinal hernia, 565 morphine, 64 fetal surgery, 191 ﬂuid and electrolytes, 97 parenteral nutrition, 97 tracheostomy, 222–223 vascular rings, 274 postoperative paralysis, abdominal wall defects, 606 postoperative resting energy expenditure (REE), 105 postoperative vesico-ureteric reﬂux, ureteroceles, 849 posture gastro-esophageal reﬂux therapy, 374 for nursing, Pierre Robin sequence, 208 see also position potassium gastric outlet obstruction, 97 requirements, 93 (Table) potassium balance, 93–95 neonatal phases, 54 Potter’s sequence, 168 pouch, duodenojejunal, 574 pouch of Douglas, bladder exstrophy, 621 pouter pigeon deformity, 243 Prader-Willi syndrome, 165 preauricular sinuses (pits), 227 prednisolone, hemangiomas, 668 preduodenal portal vein, 427 prematurity, 46 anemia of, 67, 153–154 anesthesia, 67–68 chylothorax, 285 duodenoduodenostomy, 428 esophageal perforation, 366 extracorporeal membrane oxygenation, 317 ﬂuid therapy, amounts, 56 ﬂuid volumes, 53 glomerular ﬁltration rate, 90 inguinal hernia, 561 intussusception, 557 long-term effects, 914 renal function, 82 sodium regulation, 91 sodium requirements, 93 sweating, 90 temperature regulation, 83 transepidermal water loss, 91 premedication, 60 prenatal diagnosis, 15–26, 45, 46 abdominal wall defects, 20–21, 607 bladder exstrophy, 621–622 cloacal exstrophy, 631 congenital cystic adenomatoid malformations, 18–19, 298 congenital diaphragmatic hernia, 19–20, 192–193, 310 duodenal obstruction, 424–426 epignathus, 229 esophageal atresia and TEF, 340 hydronephrosis, 21, 192, 793–795 junctional epidermolysis bullosa, 383 lymphatic malformations, 687–688 magnetic resonance imaging, 16, 136

Index 947 sacrococcygeal teratomas, 706 meconium peritonitis, 474 neural tube defects, 763–764 obstructive uropathy, 21–22, 795 pelvi-ureteric junction obstruction, 21, 817–818 pleural effusion, 289 posterior urethral valves, 22, 796, 860–861 sacrococcygeal teratomas, 17–18, 705–706 tumors, 652 ovarian, 751–752 ultrasound, 15–16, 45, 133 ureterovesical junction obstruction, 823 urinary tract duplications, 832 vascular rings, 271 vesico-ureteric reﬂux, 837 prenatal echocardiography, ectopia cordis, 240 prenatal intussusception, 557 prenatal steroids on sodium regulation, 91 on transepidermal water loss, 91 prenatal transport of surgical fetus, 39 preoperative assessment, 45–58 for anesthesia, 59–60 coagulation abnormalities, 51–52 ﬂuid and electrolytes, 96–97 tracheostomy, 219–220 preoperative respiratory stabilization, congenital diaphragmatic hernia, 49, 310–311 prepuce urinary tract infections, 838 see also circumcision prepyloric antral diaphragm, 386 presacral tumors, 707 pressure bandages, hemangiomas, 670 pressure-ﬂow studies pelvi-ureteric junction obstruction, 820 posterior urethral valves, 860 pressure-limited ventilators, 73–74 pressure support ventilation, 75 preterm induced delivery abdominal wall defects, 607 defects requiring, 15 preterm labor, fetal surgery, 191 primary excision, soft-tissue sarcomas, 734 priming, extracorporeal membrane oxygenation circuit, 320 processus vaginalis, 561, 903 procollagen type I, hypertrophic pyloric stenosis and, 391–392 proctography, percutaneous, 137 (Fig.), 138 professional integrity, ethics and, 174 prokinetic agents abdominal wall defects, 610 for gastro-esophageal reﬂux, 375 promoters, 158, 170 prone video esophagogram, 346 propofol, 63 prostaglandin E2, intestinal adaptation, 569–570 prostatic ﬁstula, recto-urethral, 536–537 protein(s) enteral nutrition, 114 metabolism, surgery, 105 parenteral nutrition, 108–109 synthesis, 158–159, 160 (Fig.) protein C/S deﬁciency acquired, 152 inherited, 152 proton pump inhibitors, 375 prune belly syndrome, 630, 637–642, 806 prenatal ultrasound, 794 (Table), 796 pseudocholinesterase, 63 pseudocysts, abdomen, 490 pseudohermaphroditism classiﬁcation, 886 (Table) female, 887–889, 894–895 incidence, 884 male, 889–890, 895 investigations, 893

true hermaphroditism vs, 885 pseudomacroglossia, 215 pseudo-von Willebrand’s disease, 148 psycho-social aspects after esophageal atresia repair, 349 long-term, 914–915, 918 myelomeningocele, 769 pubic bones, bladder exstrophy, 620 pull-through operations cloacal exstrophy, 635 Hirschsprung’s disease, 522, 523–527 hydrometrocolpos, 880–882 for rectal atresia, 461, 462 see also endorectal pull-through operations; posterior sagittal anorectoplasty pulmonary air leaks see air leaks pulmonary arteries embryology, 295 left, after vascular ring surgery, 274 pulmonary arterioles, constriction, 50 pulmonary hypertension congenital diaphragmatic hernia, 309–310 extracorporeal membrane oxygenation for, 49 Pierre Robin sequence, 211 see also persistent pulmonary hypertension of neonate pulmonary interstitial emphysema, 277–278 high-frequency jet ventilation, 77 pulmonary lymphangiectasis, 303 pulmonary sequestration, 300–302 pulmonary sling, 269–270 surgery, 274 pulmonary veins, embryology, 295 pulsed dye lasers, hemangiomas, 670 pulse oximetry, 72 pumping extracorporeal membrane oxygenation, 320 pleuroperitoneal shunts for chylothorax, 288 puncture ovarian cyst, 754 fetal, 753 ureterocele, 835 purpura fulminans, 152 pursestring sutures, gastrostomy, 415 pyeloplasty dismembered, 799, 820–821 laparoscopic, 822 pelvi-ureteric junction obstruction, 820–821 pyelostomy, posterior urethral valves, 805 pygopagus conjoined twins, 644 (Table) pyknocytosis, infantile, 153 pyloromyotomy laparoscopic, 186, 395 Ramstedt procedure, 394–395 pyloroplasty for gas bloat syndrome, 376 pyloric atresia, 384, 385 pylorus aplasia, 384 atresia, 383–385 ﬂuid and electrolytes, 55 (Table) duplications, 482–483 stenosis ﬂuid and electrolytes, 55 (Table) see also hypertrophic pyloric stenosis pyruvate kinase deﬁciency, 154 Q-switched lasers, nevus of Ito/nevus of Ota, 678 quality of life esophageal atresia repair, 349 myelomeningocele, 768 radial artery, catheters, 52, 123 radially expanding trocars, laparoscopy, 186 radiant heaters, 47, 83 ﬂuid requirements and, 92 radiation, tumors from, 656

948 Index radiography, 131–132 choanal atresia, 202 duodenal atresia, 341 (Fig.) duodenal obstruction, 426, 427 (Fig.) enterocolitis, Hirschsprung’s disease, 519 esophageal atresia, 340, 341, 344 gastric volvulus, 401, 402 (Fig.) jejuno-ileal atresia, 448–449 pneumothorax, 279 pyloric atresia, 383 pyloric duplications, 482–483 respiratory distress, 47 radiology, 131–138 anorectal anomalies, 132, 537 interventional, 137–138 colonic atresia, 458 Hirschsprung’s disease, 519 hydrometrocolpos, 877 kidney, 787 see also speciﬁc investigations liver abscess, 599 meconium ileus, 466–468 mediastinal masses, 248 neuropathic bladder, 869 pancreas, 441–442 rectal atresia, 461 tracheomalacia, 260 urogenital sinus, 892 vascular rings, 270–271 radionuclide examinations, 134–135 bile ascites, 498 cystography, 839–840 gastro-esophageal reﬂux, 373 hemangiomas, 668 kidney, 135, 790, 791 (Fig.), 797–798, 802, 819–820 multicystic dysplastic, 809–810 see also DMSA radionuclide examinations neuroblastomas, 722, 723 (Fig.) neuropathic bladder, 869 posterior urethral valves, 790, 859–860 red blood cells, liver tumors, 740 ureterovesical junction obstruction, 824, 825 (Fig.) radiotelemetry monitoring, after fetal surgery, 189 radiotherapy hemangiomas, 670 neuroblastomas, 725 Ramstedt’s pyloromyotomy, 394–395 ranitidine, 375 ranula, 231 rat, cloaca, embryology, 10 Rathke’s pouch, epignathus, 229 recanalization defects, gastrointestinal duplications, 479 recessive inheritance autosomal, 163–164, 170 tumor syndromes, 654–655 see also autosomal recessive polycystic kidney disease X-linked, 164, 165 (Table), 171 reciprocal translocations, 161, 171 recruitment maneuvers, high-frequency oscillatory ventilation, 76 rectorectal anastomosis, rectal atresia, 462 rectosphincteric reﬂex, Hirschsprung’s disease, 520–521 recto-urethral ﬁstulas, 536–537 rectovesical bladder neck ﬁstula, 537–538, 543–544, 545 surgery, 549–551 rectum atresia, 460–462, 538, 540 biopsy, Hirschsprung’s disease, 521, 522 (Fig.) duplications, 485–486 malignancy, 918 pull-through operations hydrometrocolpos, 881–882 see also endorectal pull-through operations stenosis, 538, 540 recurrence risk lymphatic malformations, 694 meconium ileus, 466

sacrococcygeal teratomas, 712 recurrent laryngeal nerve, tracheo-esophageal ﬁstula surgery, 346 red blood cells enzyme deﬁciencies, 154 membrane defects, 154 nucleated, fetal, 16 radionuclide examinations, liver tumors, 740 5α-reductase deﬁciency, 884, 886, 889 gender assignment, 895 reduction glossectomy, 216–217 reﬂux esophagitis, 371 reﬂux nephropathy, 837, 838 regional anesthesia, 64 regression see spontaneous regression rehearsal, separation of conjoined twins, 645 reimplantation of innominate artery, 273 reimplantation of ureter, 824–827 duplication anomalies, 833, 834 neuropathic bladder, 871 after posterior urethral valve ablation, 863 relational potential (ethical standard), 173 remifentanil, 64 renal agenesis, prenatal ultrasound, 794 (Table) renal artery nephrectomy, 813 thrombosis, 152 renal blood ﬂow, changes at birth, 89–90 renal dysplasia imaging, 788 (Fig.) posterior urethral valves, 857, 864 see also multicystic dysplastic kidney renal failure acute, 98 on extracorporeal membrane oxygenation, 322 ﬂuid and electrolytes, 56 posterior urethral valves, 805 postoperative, 82 prune belly syndrome, 639, 640 radionuclide examinations, 790 renal function, posterior urethral valves, 805–806, 857 renal pelvis anteroposterior diameter, fetus, 818 duplication anomalies, 831–836 renal tubular acidosis, ﬂuid and electrolytes, 56 renal vein nephrectomy, 813 thrombosis, 152, 787 Rendell–Baker–Soucek masks, anesthesia, 61 renin intersex, 892 mesoblastic nephromas, 748 renograms see diuretic renograms; DTPA radionuclide examinations; MAG3 radionuclide examinations Replogle sump catheter esophageal atresia, 341 tracheo-esophageal ﬁstula, transport of neonate, 42 resections hemangiomas, 669 intestines hernia, 566 intussusception, 559–560 long-term outcomes, 917–918 Meckel’s diverticulum, 617 meconium ileus, 468 necrotizing enterocolitis, 507 preservation maneuvers, 452–453, 570 liver cysts, 597 liver tumors, 742–744 lung, thoracoscopy, 184 mesoblastic nephromas, 748–750 ovarian tumors, 754–756 right main bronchus, 274 sacrococcygeal teratomas, 708–712 respiratory acidosis, 95 respiratory alkalosis, persistent pulmonary hypertension of neonate, 75 respiratory distress, 47–49

Index 949 congenital lobar emphysema, 296 neuroblastomas, 721–722 see also airway, obstruction respiratory distress syndrome, 48 (Table) pneumothorax mortality, 280 tracheo-esophageal ﬁstula, 344 respiratory failure acute hypoxic, 76–78 extracorporeal membrane oxygenation criteria, 318 subsequent problems, 323 respiratory function clinical examination, 59–60 postoperative management, 73–78 preoperative assessment, 47–49 after tracheo-esophageal ﬁstula repair, 348–349 respiratory rate, 74 respiratory system, choanal atresia, 201–202 respiratory water loss, 91 resting energy expenditure (REE), 104 postoperative, 105 restriction enzymes, 171 restriction fragment length polymorphism, 171 retinoblastoma gender distribution, 652 two-hit theory, 654 retinoblastoma gene, 653, 654 associated tumors, 656 penetrance, 163 retinopathy extracorporeal membrane oxygenation and, 324 fat in parenteral nutrition, 111 RET proto-oncogene, Hirschsprung’s disease, 515 retracting colostomy, 545 retraction, ribs, lung surgery, 305 retractors, nephrectomy, 812, 813 retrocardiac pneumomediastinum, 278 retrograde endopyelotomy, 822 retrograde genitourethrography, hydrometrocolpos, 877 retrograde pyelography, 820 retroperitoneal hemorrhage, birth trauma, 35 retroperitoneal nephrectomy, laparoscopic, 815 reversal of anesthesia, 65 rhabdomyosarcomas, 735–736 genetics, 658–659 head and neck, 229 Rhesus antibodies, hemolytic disease of newborn, 153 ribosomes, 171 ribs, retraction, lung surgery, 305 Rich’s technique, ureterocele unrooﬁng, 851 right aortic arch esophageal atresia and TEF, 343–344 vascular rings, 269 surgery, 273–274 right atrium, catheterization, 127–128 right descending aorta, with left aortic arch, 268–269, 273 right ductus arteriosus, Down syndrome, 268 right lung to head circumference ratio (LHR), 20, 310, 313 right main bronchus, resection and reanastomosis, 274 right subclavian artery aberrant, 268, 273 atypical origin, 269 rigid bronchoscopy, 329–331 ring chromosomes, 171 ristocetin-induced platelet aggregation, 148 RNA, 158 Robbins, S.L., deﬁnition of teratomas, 703 Robertsonian translocations, 161, 162 (Fig.), 171 rocuronium, 64 Rokitansky anomaly, 907 roller pumps, extracorporeal membrane oxygenation, 320 Roux-en-Y loop, hepatic portoenterostomy, 584, 585 Ruddick, Sara, on maternal interests, 178 S-100 protein, hypertrophic pyloric stenosis and, 391 sacral neural crest cells, 513

sacrococcygeal teratomas, 658, 705–714 fetal surgery, 194, 706 laparoscopic surgery, 187 magnetic resonance imaging, 18, 136 (Fig.), 707–708 prenatal diagnosis, 706 prenatal diagnosis, 17–18, 705–706 sacrum, defects, outcomes, 916 sagittal computed tomography, esophageal atresia, 135 salbutamol, hyperkalemia treatment, 93 salivary glands, tumors, 233 salivary leak, esophageal anastomosis leak, 346 salmon patch, 664 salpingo-oophorectomy, 755–756 saphenous veins cannulation, 124 central venous catheters, 127 sarcoma botryoides, 735 sarcomas, soft-tissue, 733–737 sausage resection, necrotizing enterocolitis, 507 scalp, nevus surgery, 680–681 scanning electron microscopy, embryology of malformations, 6 SCHISIS association, 340 Schwann cell marker D7, hypertrophic pyloric stenosis and, 391 sclerotherapy lymphatic malformations, 690 mesenteric cysts, 495 scoliosis, pectus excavatum, 243 screening cystic ﬁbrosis, 467 Down syndrome, triple test, 16 neuroblastomas, 721 scrotum anomalies, 907 birth trauma, 36 gas, gastric perforation, 406 hypospadias, 11 lymphatic malformations, 693 meconium peritonitis, 474 rhabdomyosarcoma, 735, 736 (Fig.) surgery for torsion of testis, 910 sd-mouse, cloaca, embryology, 10 seal-bark cough, 260 sebaceous nevi, 678–679 Sebastian platelet syndrome, 148 secondary macroglossia, 215 second branchial cleft anomaly, 228 second to fourth rib syndrome, 243 secretory hydrometrocolpos, 875 sedation postoperative, 78–79 for ventilation, 75 segmental dilatation of intestines, congenital, 553–556 segmental pyloric atresia, longitudinal, 384 seizures, extracorporeal membrane oxygenation, 324 self-determination, ethics and, 174 sensorineural handicap, after extracorporeal membrane oxygenation, 323–324 sensory loss, myelomeningocele, 765–766 sensory nerves, bladder, 868 separation, conjoined twins, 645–647 emergent, 643–644 timing, 645 sepsis arterial cannulation, 121 incidence, 139 metabolism, 105–106 on parenteral nutrition, 110 septic shock, ﬂuid and electrolytes, 97–98 sequences (anomalies), 168 sequestration, lung, prenatal diagnosis, 18–19 seromuscular stripping, intestinal, 452, 453 (Fig.) serosal patching, 570 serous cysts, mesenteric, 489 Sertoli cells, 884 Severinghous probe, carbon dioxide tension, transcutaneous monitoring, 72

950 Index sevoﬂurane, 62 sex see gender sex-determining region Y-box gene (SOX10 gene), enteric nervous system defects, 516 sexually transmitted diseases, circumcision and, 904 sham feeding, esophageal atresia, 345 Shh gene (Sonic hedgehog gene), esophageal atresia and TEF, 339 shock, septic, ﬂuid and electrolytes, 97–98 short bowel syndrome, 569–576 gastrostomy, 412 jejuno-ileal atresia repair, 454 short-chain fatty acids, intestinal adaptation, 569 shunt nephritis, 781 shunts see ventriculoperitoneal shunts sialoblastomas, 233 siblings, Hirschsprung’s disease, 515 sickle cell syndromes, 154 sildenaﬁl, 77 silicone membrane oxygenators, 320 silos, 605, 608 spring-loaded, 609 silver staining, cystic mesoblastic nephromas (cellular variant), 747–748 silver sulphadalazine, omphalocele, 610 single-gene disorders inheritance patterns, 163–164 molecular genetics, 166–167 tumors, 654–655 single-lung ventilation, thoracoscopy, 183 single-strand conformational polymorphism (SSCP), tumor mutations, 653 sinuses, neck, 227–228 siphoning, ventriculoperitoneal shunts, 778 skeletal anomalies chest, 244–245 myelomeningocele, 766 Pierre Robin sequence, 211 skeletal survey, neuroblastoma, 722 skin gastrostomy, 418 grafts nasal glioma surgery, 717–718 nevus surgery, 681–684 water loss, 90–91 skin-level devices, gastrostomy, 419–420 skull fracture, birth trauma, 28, 29 slit ventricle syndrome, 781 sludge, biliary, 112, 113 small congenital melanocytic nevi, 676 smallness for gestational age, 46–47, 914 extracorporeal membrane oxygenation and, 317 smooth-muscle cells hypertrophic pyloric stenosis, 392 ureterovesical junction obstruction, 823 soap-bubble appearance, 466 Sober-en-T temporary high urinary diversion, 805 Society for Fetal Urology, hydronephrosis grading, 796, 797 (Fig.), 818 sodium balance, 91–92, 93 neonatal phases, 54 (Table) gastric outlet obstruction, 97 requirements, 93 supplements, timing, 90, 91 sodium nitroprusside, 81 soft-tissue coverage, conjoined twins, 647 soft-tissue sarcomas, 733–737 soiling, after anorectal anomaly surgery, 551 somatostatin, chylothorax, 286 Sonic hedgehog gene, esophageal atresia and TEF, 339 sonography see ultrasound Southern blotting, 166, 171 spastic diplegia, interferon-α, 669 speckled lentiginous nevus, 678 Spectramed transducer system, 121

spermatic cord, paratesticular rhabdomyosarcoma, 735 spherocytosis, hereditary, 154 spider angiomata, 664 spina biﬁda see neural tube defects spina biﬁda cystica see meningocele; myelomeningocele spina biﬁda occulta, 763 (Table), 764 spinal cord birth trauma, 30–31 cloacal exstrophy, 630 compression, neuroblastoma, 722 magnetic resonance imaging, 136 spinal muscular atrophy, polymerase chain reaction, 167 spine neuroblastoma surgery, 726 radiology, neuropathic bladder, 869 spinnaker sail sign, pneumomediastinum, 278 spiral ﬂap pyeloplasty (Culp), 821 Spitz classiﬁcation, esophageal atresia and TEF, 338 Spitz nevi, 679 spleen, birth trauma, 33–34 splenic ﬂexure, classiﬁcation of colonic atresia, 457, 458–459 splenic vein, at pancreatectomy, 443 splinting, trachea, 262–263 split notochord, 479–480, 762 spondylothoracic dysplasia, 245 spontaneous perforation Hirschsprung’s disease, 519 intestines, 508 stomach, 405, 406, 407 spontaneous regression multicystic dysplastic kidney, 800 neuroblastomas, 721 ovarian cysts, 752, 753 pelvi-ureteric junction obstruction, 820 vesico-ureteric reﬂux, 806 spontaneous relaxation of lower esophageal sphincter, 369–370 spring-loaded silos, 609 SRY gene, 885 staging, 733 neuroblastomas, 722 Stamm gastrostomy, 413–415, 416 (Fig.) gastric volvulus, 403 Staphylococcus epidermidis, central venous catheters, 128 staplers, intestinal tapering and lengthening, 571 Starling curve, 80 Starr plication, ureterovesical junction obstruction, 825 steer-horn abnormality, 615 stenting of airways choanal atresia, 203–204 internal, 264 subglottic stenosis, 255 trachea, external, 262–263 sternomastoid muscle, torticollis, 232 sternum, cleft, 239, 241–243 steroids congenital diaphragmatic hernia, 312 hemangiomas, 668 intralesional, 669 prenatal on sodium regulation, 91 on transepidermal water loss, 91 subglottic stenosis, 255 stethoscopes, anesthesia monitoring, 65–66 STING (subureteric Teﬂon injection), 834, 841, 842, 871 stomach duplications, 481–483 esophagoplasty with, 345 gastrostomy complications, 417–418 outlet obstruction, electrolytes, 96–97 perforation, 405–409 after gastrostomy, 418 rupture, 383 transposition, 345 volvulus, 399–404 see also entries beginning gastric . . . stomach bubble, absence, esophageal atresia, 20

Index 951 strangulation inguinal hernia, 562 midgut volvulus, 435, 436, 437 strawberry capillary hemangioma, 665 strawberry marks, 665 streptokinase, blockage clearance, 128 strictures esophagus anastomotic, 347, 371 balloon dilatation, 137 necrotizing enterocolitis, 509 urethra, 864 stridor, 329–330 gastro-esophageal reﬂux, 371, 372 stroke volume, 79 pneumoperitoneum, 185 ‘stuck twin’, fetal surgery, 194 Sturge-Weber syndrome, 667 subarachnoid hemorrhage, birth trauma, 29 subcapsular hematoma, liver, 33, 507–508 subclavian artery direct catheterization, 128 left, aberrant, 269, 273 right aberrant, 268, 273 atypical origin, 269 subdural hemorrhage, birth trauma, 29–30 subdural tapping, 30 subepithelial ﬁstula, midline raphe, 535, 536 (Fig.), 541 subglottic hemangioma, 666 subglottic stenosis, 253–258 tracheostomy for, 224, 255 submucous plexus, Hirschsprung’s disease, 513, 518 substrate adhesion molecules, embryogenesis, 5 subureteric Teﬂon injection, endoscopic, 834, 841, 842, 871 suctioning endotracheal tubes, 72–73 on extracorporeal membrane oxygenation, 321 tracheostomy, 223 suction rectal biopsy, 521, 522 (Fig.) sudden death, Pierre Robin sequence, 211 sudden infant death syndrome, gastro-esophageal reﬂux, 371 sulphonylurea receptor gene (SUR gene), hyperinsulinism, 441 sump catheter see Replogle sump catheter superior mesenteric artery, neuroblastoma surgery, 729 superior mesenteric vessels, malrotation, 436 superior vena cava, thrombosis, chylothorax and, 286 Supertygon, 320 support groups, esophageal atresia and TEF, 349 suppressors, 171 supraumbilical skin fold incision, pyloromyotomy, 394–395 surfactant congenital diaphragmatic hernia, 310, 311 fetal tracheal occlusion on, 312 replacement therapy, 49, 77–78 surgical trauma, energy requirements, 104–105 sutures gastrostomy, 415 heminephro-ureterectomy, 853 reduction glossectomy, 217 tracheostomy, 221, 222 suxamethonium, 63 swallowing disorders, gastrostomy, 412–413 gastro-esophageal reﬂux, 369 sweating, 90 electrolytes, 55 (Table) ‘Swedish noses’ (condenser humidiﬁers), 73 Swenson’s pull-through operation, 524–526 Swyer syndrome, 891 sympathetic nervous system, bladder, 868 synapses, hypertrophic pyloric stenosis and, 390–391 synchronized ventilation, 75 syndrome of inappropriate antidiuretic hormone secretion (SIADH), 92 postoperative, 97

syndromes, 168 synovial sarcoma, 737 systemic vascular resistance, dopamine on, 80 Tamilnadu (India), rectal atresia incidence, 460 tamponade see cardiac tamponade Tank’s technique, ureterocele unrooﬁng, 850 tapering megaureter, 803 short bowel syndrome, 571–572 ureterovesical junction obstruction, 825 taurine, parenteral nutrition, 108 Teﬂon injection, subureteric, endoscopic, 834, 841, 842, 871 teicoplanin, sepsis on parenteral nutrition, 110 telomeres, 171 temperature hyperthermia, neural tube defects, 763 maintenance, 47 postoperative, 83 in theater, 60 see also hypothermia Tennell test, 123 tension pneumomediastinum, 278 tension pneumothorax, 279 congenital lobar emphysema vs, 297 teratogenic factors, 4 neural tube defects, 763 teratomas, 658 anterior mediastinum, 248, 249 (Fig.) cervical, 697–703 prenatal diagnosis, 17 deﬁnitions, 705 gender distribution, 652 testis, 906 see also sacrococcygeal teratomas tertiary centers, receiving transported neonates, 41 test feeding, hypertrophic pyloric stenosis, 392–393 testicular dysgenesis, 889 testicular feminization syndrome, 884 testis cloacal exstrophy, 631 descent, 903, 905 exstrophy, 906 inguinal hernia iatrogenic ascent, 566 infarction, 562 management, 566 prune belly syndrome, 639 rare anomalies, 906–907 torsion, 909–911 inguinal hernia vs, 563 tumors, 906 undescended see cryptorchidism see also paratesticular rhabdomyosarcoma testis-determining factor, 884, 885 translocation, 889 testolactone, 894 testosterone, 884–885 human chorionic gonadotrophin stimulation test, 893 intestinal adaptation, 570 true hermaphroditism, 890–891 tetraploidy, 161 thalidomide, 4 thermal environment, 47 thickening of feeds, gastro-esophageal reﬂux therapy, 374 thiopentone, 63 third branchial cleft anomaly, 228 third space ﬂuid losses, 54, 97 intraoperative, 66 third ventriculostomy, endoscopic, 781–782 thoracentesis, fetal pleural effusion, 289–290 thoracic duct, 283, 284 ligation, 289 thoracic ectopia cordis, 239–240, 242–243 thoraco-abdominal ectopia cordis (Cantrell pentalogy), 239, 240–241, 606

952 Index thoracoamniotic shunting, congenital cystic adenomatoid malformation, 19, 299 thoracopagus conjoined twins, 644 (Table) thoracoscopy, 183–185 esophageal duplication cysts, 184, 363 video-assisted surgery chylothorax, 289 double aortic arch, 272 thoracostomy chylothorax, 286 pneumothorax, 280 thoracotomy central venous catheterization, 127–128 congenital esophageal stenosis, 355–356 esophageal atresia and TEF surgery, 341–343 esophageal duplication cysts, 362 lung, 304–306 neuroblastoma, 251 3-prime (genetics), 170 thrombocytopenia, 147–150 neuroblastoma, 722 thrombocytopenia with absent radii, 149 thrombosis central venous catheters, 128, 152 in ECMO oxygenators, 320 renal artery, umbilical artery catheters, 152 renal vein, 152, 787 superior vena cava, chylothorax and, 286 thrombotic states, 151–153 thymocyte-associated antigen (CD38), 141–142 thymus, hyperplasia, 248 thyroglossal duct, cysts and sinuses, 228 thyroid congenital goitre, 232–233 lingual, 232 tissue expansion conjoined twins, 647 nevus surgery, 680–681 tissue plasminogen activator, blockage clearance, 128 T-lymphocytes, 139, 140 responses, 140–141 TNM staging, 733 tocolytic therapy, fetal surgery, 191 complications, 189 tongue anastomosis to lip, Pierre Robin sequence, 209 breathing, 201 lesions, 229–232 lymphatic malformations, 693 see also macroglossia TORCH syndromes see intrauterine viral infections torsion ovarian cyst, 751, 752–754, 755 testis, 909–911 inguinal hernia vs, 563 torticollis, 232 total body water, 53 total parenteral nutrition see parenteral nutrition total urogenital mobilization, 550 toxic megacolon, Hirschsprung’s disease, 518 trachea agenesis, 219 atresia, embryology, 7 blood supply, 296 diameter vs resistance, 253 embryology, 339 external stenting, 262–263 fetus minimal-access surgery, 191 occlusion (procedure), 20, 193, 312 gas insufﬂation congenital diaphragmatic hernia, 78 see also intratracheal pulmonary ventilation granulation tissue, tracheostomy, 224 stenosis, tracheostomy for, 224 tracheobronchial remnants, congenital esophageal stenosis with, 353, 354

tracheobronchomalacia, aortopexy, 262, 263–264 tracheo-esophageal ﬁstula, 48 (Table), 337–352 contrast radiography, 132 embryology, 6–7 ﬂuid and electrolytes, 55 (Table) H-type, 346 recurrence, 348 thoracoscopy, 184–185 tracheomalacia with, 260 transport of neonate, 42 tracheomalacia, 219, 220, 224, 259–265 esophageal atresia, 259–260, 347–348 tracheostomy, 219–225 cervical teratomas, 699 decannulation, 224–225 dislodgement, 223 Pierre Robin sequence, 209–210 reinsertion, 225 subglottic stenosis, 224, 255 traction, pelvic osteotomies, 623 transanal endorectal pull-through operations, Hirschsprung’s disease, 526 transanal end-to-end rectorectal anastomosis, rectal atresia, 462 transanastomotic tubes, jejuno-ileal atresia, 452 transcription (genetic), 159, 171 transcutaneous blood gas monitoring, 72 transepidermal water loss, 90–91 transfer RNA, 159 transforming growth factor-α embryogenesis and, 6 hypertrophic pyloric stenosis, 392 transforming growth factor-β, embryogenesis and, 6 transhepatic venous sampling, pancreas, 441–442 transillumination hydrocephalus, 776 percutaneous endoscopic gastrostomy, 417 pneumothorax, 279 translocations, 161, 171 testis-determining factor, 889 transperitoneal nephrectomy, laparoscopic, 814–815 transplantation heart, conjoined twins, 646 intestines short bowel syndrome, 570, 574 TPN-related cholestasis, 113 liver, biliary atresia, 579–580, 587 mucosa, 570 see also grafts transport of surgical neonate interhospital, 39–44 teams, 40 to operating theater, 60 transverse innominate osteotomy, 623 transverse testicular ectopia, 907 trauma birth trauma, 28–36 chylothorax, 284 fetal, 27, 28 (Fig.) gastric perforation, 405 triad of Borchardt, gastric volvulus, 401 trichterbrust (pectus excavatum), 243 triglycerides, chyle, 284 triple test, screening for Down syndrome, 16 triplet repeat expansions, unstable, 165–166 triploidy, 161, 171 trisomy syndromes, 161, 171 genetics, 161, 162 omphalocele, 606 prune belly syndrome theory, 637 thrombocytopenia, 149 trocars, laparoscopy, 186 trunk nevus surgery, 681–682 rhabdomyosarcoma, 735–736 T tubes, gastrostomy, 415

Index 953 tuberous sclerosis, renal ultrasound, 788 tubing, extracorporeal membrane oxygenation, 320 d-tubocurarine, 64 tubular sodium reabsorption, changes at birth, 91 tumor bed re-excision, 734–735 tumor markers, neuroblastomas, 723–724 tumor necrosis factors, 141 (Table) tumors, 651–662 circumcision, prevention, 904 gonadal dysgenesis, 891, 895 intracranial, 776 liver, 739–745 see also hepatoblastomas multicystic dysplastic kidney, 800–801, 811 nasal, 715–720 ovary, 751–757 parotid gland, 233 hemangiomas, 665 presacral, 707 from radiotherapy, 670 salivary glands, 233 testis, 906 tongue and oropharynx, 229–232 see also malignancy tunica vaginalis, 905 birth trauma, 36 tunneling, central venous catheters, 126 Tunstall connectors, Pierre Robin sequence airway management, 208, 209 (Fig.) Tween 80, Gastrograﬁn, 467 twelfth rib, at nephrectomy, 812 twins cloacal exstrophy, 630 conjoined, 643–648 see also partial twinning twin-to-twin transfusion syndrome, fetal surgery, 194 two-hit theory, 654, 657 two-stage operation of Lehbein, meconium peritonitis, 474–475 type 2B von Willebrand’s disease, 148 tyrosine, parenteral nutrition, 108 UJ13A monoclonal antibody, neuroblastoma localization, 722 ultrafast computed tomography tracheomalacia, 261 vascular rings, 271 ultrasound, 133–134 abdominal cysts, 491–492 adrenal hemorrhage, 35 bladder, 787 neuropathic, 869 prenatal, 794 chylothorax, 285 congenital biliary dilatation, 591 congenital cystic adenomatoid malformations, 298 congenital diaphragmatic hernia, 192–193 duodenal obstruction, 424, 426 (Fig.) ECMO catheter placement, 319 hydrocephalus, 776 hydrometrocolpos, 877 hypertrophic pyloric stenosis, 393 interventional techniques, 138 kidney, 133, 134 (Fig.), 787–789, 792, 796–797, 818–819 prenatal, 795, 817–818 liver abscess, 599 malrotation, 436 multicystic dysplastic kidney, 809 myelomeningocele, 22 neuroblastomas, 723 ovarian cyst torsion, 752 posterior urethral valves, 804, 858, 861 prenatal diagnosis, 15–16, 45, 133 pyloric atresia, 383 pyloric duplications, 483 sacrococcygeal teratoma, 18, 194 ureterocele, 832 (Fig.) ureterovesical junction obstruction, 824

urinary tract, 787–789, 792 prenatal, 794–795 vesico-ureteric reﬂux, 838, 839 (Fig.) see also Doppler ultrasound; echocardiography umbilical artery catheters, 52, 79, 122–123 renal artery thrombosis, 152 renal damage and, 89 umbilical cord, management, bladder exstrophy, 622 umbilical fold incision see supraumbilical skin fold incision umbilical vein cannulation, 124 liver abscesses, 598 transport of neonate, congenital diaphragmatic hernia, 43 umbilicus excision at gastroschisis surgery, 913, 917 ﬁstula, 615–616 hemangiomas, 666 hernia, bladder exstrophy, 620 polyp, 616–617 uncinate process, pancreas, excision, 443 unrooﬁng liver cysts, 598 ovarian cysts, 756 ureterocele, 850–851, 853 upper airway obstruction, 48 (Table) epignathus, 229 lateral cervical cyst, 228 lymphangiomatous macroglossia, 215, 216 (Fig.) Pierre Robin sequence, management, 208–210 ureter bladder exstrophy, 621 surgery, 626 duplication anomalies, 831–836 enlargement with hydronephrosis, 801–804 grading, 819 opening pressure, ureterovesical junction obstruction, 824 posterior urethral valves, 857 prune belly syndrome, 638 see also megaureter; reimplantation of ureter ureteral bud, 793 ureterectomy (heminephro-ureterectomy), 850, 852–853 ureterocele, 801, 832, 845–854 management, 835 prenatal ultrasound, 794 (Table) see also ectopic ureterocele ureterocystoplasty, 872 ureteropelvic junction obstruction see pelvi-ureteric junction obstruction ureterostomy, posterior urethral valves, 864 uretero-ureterostomy, duplication anomalies, 833 ureterovesical junction obstruction, 823–827 after posterior urethral valve treatment, 864 urethra anomalies, 905 atresia, 796 bladder exstrophy, reconstruction, 626 embryology, 11 exstrophy, 906–907 iatrogenic stricture, 864 prune belly syndrome, 638–639 recto-urethral ﬁstulas, 536–537 see also posterior urethral valves urethral sounds, pediatric, choanal atresia surgery, 203 urethrovaginal folds, 855 urinary ascites, 497, 858 urinary diversion continent, 872 posterior urethral valve ablation and, 863–864 Sober-en-T, 805 urinary hydrometrocolpos, 875 urinary incontinence anorectal anomaly surgery, 551 myelomeningocele, 768 posterior urethral valves, 805, 864 sacrococcygeal teratoma, 712 ureterocele, 845 vaginoplasty and, 896

954 Index urinary tract bladder exstrophy, 621 cloacal exstrophy, management, 634 conjoined twins, 647 duplication anomalies, 831–836 imaging, 790 ureterocele, 845, 846, 848 imaging, 787–792 infections circumcision and, 904 duplication anomalies, 833 gender, 838 neuropathic bladder, 870 renal scarring, 837 myelomeningocele, 766 obstruction see obstructive uropathy perforation, 497 prenatal ultrasound, 794–795 prune belly syndrome, 638–639, 639, 640 urine fetal, 192, 793–794 analysis, 796, 818, 860 posterior urethral valves, 22 output and osmolarity, 90 normal, 92 postoperative, 82 preoperative, 53–54 urodynamics neuropathic bladder, 869–870 see also pressure-ﬂow studies urogenital sinus persistent, 875 (Fig.) radiology, 892 urokinase, blockage clearance, 128 parenteral nutrition, 111 ursodeoxycholic acid, TPN-related cholestasis, 113 uterus closure, fetal surgery, 189 double, 541 endoscopy, 190 vaccines, neonates, 143 VACTERL association adriamycin, 4, 339 duodenal atresia, 424 esophageal atresia and TEF, 340 vacuum-glossoptosis-apnea, choanal atresia, 201 vagal neural crest cells, 513 vagina abdominoperineal pull-through, 880–882 bladder exstrophy, 621 cloacal exstrophy, reconstruction, 634 double, 541 ﬁstula, 540 rhabdomyosarcoma, 735 vestibular ﬁstula, 539 vaginoplasty, 896–897 valproate, neural tube defects, 763 values history, 176 ‘valve bladder’, 805 valved jejunal interposition hepatoduodenostomy, 593 valves artiﬁcial, intestinal, 573–574 see also posterior urethral valves valve systems, ventriculoperitoneal shunts, 778 vanillylmandelic acid, neuroblastomas, 723 vanishing testis, 906 vascular access see central venous catheters; intravenous access; umbilical artery catheters vascular endothelial growth factor, pulmonary stretch, 312 vascular malformations, 663, 664 liver, 739 vascular occlusion atresia etiology colonic, 457 jejuno-ileal, 445

rectum, 460 see also blood supply vascular rings, 267–276 vas deferens, absence, 907 vasoactive drugs, low cardiac output, 79–82 vasoactive intestinal peptide (VIP), absence in hypertrophic pyloric stenosis, 390 vasoconstriction, epinephrine, 81 vasodilators, low cardiac output states, 81–82 VATER association, 168, 339–340 VCU see micturating cystourethrography vecuronium, 63 vein of Galen, malformation, 776 venous access see intravenous access venous sampling, transhepatic, pancreas, 441–442 veno-venous extracorporeal membrane oxygenation, vs veno-arterial, 318–319 veno-venous hemoﬁltration, 82–83 ventilation anesthesia, 61 monitoring, 66 settings, 65 carbon dioxide pneumoperitoneum, 185 congenital diaphragmatic hernia, 78, 310–311 transport of neonate, 43 on extracorporeal membrane oxygenation, 320–321 extracorporeal membrane oxygenation vs, 318 ﬂuid therapy on, 82 high-frequency jet ventilation, 77 lung injury from, 75–76 non-invasive, 78 pneumothorax, 279 postoperative, 73–77 pulmonary interstitial emphysema, 278 thoracoscopy, 183–184 see also high-frequency oscillatory ventilation; life support, withdrawal ventriculoatrial shunts, 778, 780–781 ventriculoperitoneal shunts, 778–781 complications, 780–781 liver abscesses, 598 over-drainage, 781 tapping, 781 Venturi principle, airways, 259 verrucous lesions, lymphangiomatous macroglossia, 215 vertebrae neurenteric cysts and, 360 neuroblastoma, 722 very-low-birth-weight babies hyperglycemia, 95–96 hypothermia, 39 vesico-amniotic shunting, 22, 796 posterior urethral valves, 860–861 prune belly syndrome, 639 vesicostomy neuropathic bladder, 871 posterior urethral valves, 805 ablation, 863 prune belly syndrome, 640 vesico-ureteric reﬂux, 806, 837–844 bladder exstrophy, 621 contralateral ureterocele, 845 duplication anomalies, 833 micturating cystourethrography, 834 (Fig.) grading, 840 imaging, 789 neuropathic bladder, 871 pelvi-ureteric junction obstruction, secondary, 817 posterior urethral valves, 804, 857 post-treatment, 864 postoperative, ureterocele treatment, 849 prenatal ultrasound, 794 (Table) vestibular ﬁstula, 539 repair, 547–548 vaginal ﬁstula vs, 540 video-assisted choledochal cyst excision, 594

Index 955 video-assisted thoracoscopic surgery chylothorax, 289 double aortic arch, 272 video esophagogram, prone, 346 viral infections, intrauterine, thrombocytopenia, 149–150 vitamin(s), neural tube defects, 762–763 vitamin B12 malabsorption, ileal resection, 917–918 vitamin E, congenital diaphragmatic hernia, 312 vitamin K, 51, 60, 151 voiding cystourethrography see micturating cystourethrography volume preset ventilators, 74 volume replacement, intraoperative, 66 volvulus ﬂuid and electrolytes, 55 (Table) gastric, 399–404 midgut loop, 427, 435, 436, 437 vomiting duodenal obstruction, 426 gastric volvulus, 401 gastro-esophageal reﬂux, 371–372 hypertrophic pyloric stenosis, 392 hypochloremic alkalosis, 55 meconium ileus, 466 von Hippel–Lindau syndrome, 666, 667 von Willebrand’s disease, 151 type 2B, 148 VURD syndrome, 805 Waardenberg–Shah syndrome, 516 WAGR syndrome, 657 waiter’s tip posture, Erb’s palsy, 31 warfarin, 153 warming mattresses, 60 water balance, 89, 90–91 extracorporeal membrane oxygenation, 320 intraoperative, 66 neonatal phases, 54 (Table) parenteral nutrition, 106 postoperative management, 82–83 see also hydration water bath humidiﬁers, 73

weaning extracorporeal membrane oxygenation, 322 parenteral nutrition, 114 ventilation, 75 webs, esophagus, 353 Weigert–Mayer law, 831 weight see body weight well-tempered renograms, 797 wet purpura, 151 Whitaker–Sherwood diathermy hook, posterior urethral valves, 862 Whitaker test see pressure-ﬂow studies whole-chromosome paints, 162 Willis, R.A., deﬁnition of teratomas, 703 Wilms’ tumor, 657, 747–750 genetics, 655–656 multicystic dysplastic kidney, 811 windsock membranes duodenal, 423, 427 (Fig.), 429 jejuno-ileal, 446 pyloric and antral, 386 Wiskott–Aldrich syndrome, 148 variants, 148 withholding vs withdrawing treatment, 179 Wolfﬁan duct prune belly syndrome theory, 637 ureteric anomalies, 831 Wolfﬁan structures, 885 wound dehiscence gastrostomy, 418 myelomeningocele, 768 WT1 gene, 655, 657 xiphopagus conjoined twins, 644 (Table) X-linked inheritance dominant, 165 recessive, 164, 165 (Table), 171 X-linked thrombocytopenia, 148 Young’s classiﬁcation, posterior urethral valves, 855–856 Y pyeloplasty (Foley), 821 zaprinast, 77