Handbook of Venous Disorders Guidelines of the American Venous Forum, 3rd edition

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HANDBOOK OF VENOUS DISORDERS

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HANDBOOK OF VENOUS DISORDERS THIRD EDITION Guidelines of the American Venous Forum Edited by

Peter Gloviczki

MD FACS

Joe M. and Ruth Roberts Professor of Surgery, Chair, Division of Vascular and Endovascular Surgery, Director, Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA

Associate Editors: Michael C. Dalsing

MD FACS

E. Dale and Susan E. Habegger Professor of Surgery, Chair, Section of Vascular Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

Bo G. Eklöf

MD PhD

Clinical Professor Emeritus of Surgery, University of Hawaii, USA, and University of Lund, Helsingborg, Sweden

Gregory L. Moneta

MD

Professor of Surgery, Chief of Vascular Surgery, Oregon Health & Science University, Portland, OR, USA

Thomas W. Wakefield

MD FACS

S. Martin Lindenauer Professor of Surgery, Head, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA

First published in Great Britain in 1996 by Chapman & Hall Second edition published in 2001 by Hodder Arnold. This third edition published in 2009 by Hodder Arnold, an imprint of Hodder Education, part of Hachette UK, 338 Euston Road, London NW1 3BH http://www.hoddereducation.com © 2009 Edward Arnold (Publishers) Ltd All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers or in the case of reprographic production in accordance with the terms of licences issued by the Copyright Licensing Agency. In the United Kingdom such licences are issued by the Copyright Licensing Agency: Saffron House, 6–10 Kirby Street, London EC1N 8TS. Hachette Livre UK’s policy is to use papers that are natural, renewable and recyclable products and made from wood grown in sustainable forests. The logging and manufacturing processes are expected to conform to the environmental regulations of the country of origin. 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

978 0 340 938 805

1 2 3 4 5 6 7 8 9 10 Commissioning Editor: Senior Project Editor: Production Controller: Cover Designer: Indexer:

Gavin Jamieson Francesca Naish Joanna Walker Helen Townson Laurence Errington

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To physicians and trainees devoted to the treatment of venous disorders

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Contents

Contributors Foreword Preface Evidence-based guidelines List of abbreviations used PART ONE: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

12. 13. 14. 15. 16.

Edited by Michael C. Dalsing

Venous and lymphatic disease: a historical review Karl A. Illig, Jeffrey M. Rhodes, James DeWeese Development and anatomy of the venous system Peter Gloviczki, Géza Mózes The physiology and hemodynamics of the normal venous circulation Frank Padberg, Jr Classification and etiology of chronic venous disease Robert L. Kistner, Bo Eklöf The physiology and hemodynamics of chronic venous insufficiency of the lower limb Kevin G. Burnand, Ashar Wadoodi Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufficiency Peter J. Pappas, Brajesh K. Lal, Frank T. Padberg Jr., Robert W. Zickler, Walter N. Duran Venous ulcer formation and healing at cellular levels Joseph D. Raffetto Acute venous thrombosis: pathogenesis and evolution Thomas W. Wakefield, Peter K. Henke The epidemiology of and risk factors for acute deep venous thrombosis Mark H. Meissner Epidemiology of chronic venous disorders Eberhard Rabe, Felizitas Pannier

PART TWO: 11.

BASIC CONSIDERATIONS OF VENOUS DISORDERS

xi xv xvii xix xxi

DIAGNOSTIC EVALUATIONS AND VENOUS IMAGING STUDIES

3 12 25 37 47 56 70 83 94 105

Edited by Gregory L. Moneta

Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis Edith Nutescu, Jessica Michaud, Joseph A. Caprini Duplex ultrasound scanning for acute venous disease Sergio X. Salles-Cunha Duplex scanning for chronic venous obstruction and valvular incompetence Babak Abai, Nicos Labropoulos Evaluation of venous function by indirect noninvasive tests (plethysmography) Fedor Lurie, Thom W. Rooke Lower extremity ascending and descending phlebography Curtis B. Kamida, Robert L. Kistner, Bo Eklöf, Elna M. Masuda Computed tomography and magnetic resonance imaging in venous disease Terri Vrtiska, James Glockner

113 129 142 156 160 169

viii Contents

PART THREE: 17. 18. 19. 20. 21.

22. 23. 24. 25. 26. 27.

29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

Edited by Thomas W. Wakefield

The clinical presentation and the natural history of acute deep venous thrombosis Mark H. Meissner Diagnostic algorithm for acute deep venous thrombosis and pulmonary embolism Joann M. Lohr, Daniel Kim, Kelli Krallman Medical treatment of acute deep venous thrombosis and pulmonary embolism Russell D. Hull, Graham F. Pineo Catheter-directed thrombolysis for treatment of acute deep venous thrombosis Anthony Comerota, Jorge L. Martinez Trabal Surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral deep venous thrombosis Bo Eklöf, Robert McLafferty Treatment algorithm for acute deep venous thrombosis: current guidelines Thomas W. Wakefield Current recommendations for prevention of deep venous thrombosis Robert McBane, John Heit The management of axillo-subclavian venous thrombosis in the setting of thoracic outlet syndrome Richard M. Green, Robert Rosen Indications, techniques and results of inferior vena cava filters Lazar J. Greenfield, Venkataramu N. Krishnamurthy, Mary C. Proctor, John Rectenwald Superficial venous thrombophlebitis Anil Hingorani, Enrico Ascher Mesenteric vein thrombosis Waldemar E. Wysokinski, Robert McBane

PART FOUR: 28.

MANAGEMENT OF ACUTE THROMBOSIS

MANAGEMENT OF CHRONIC VENOUS DISORDERS

195 208 221 239

255 265 277 292 299 314 320

Edited by Michael C. Dalsing and Bo Eklöf

Clinical presentation and assessment of patients with venous disease Andrew Bradbury, C. Vaughan Ruckley Diagnostic algorithms for telangiectasia, varicose veins and venous ulcers: current guidelines Robert McLafferty, Andrew D. Lambert Compression therapy for venous ulceration Gregory L. Moneta, Hugo Partsch Drug treatment of varicose veins, venous edema and ulcers Philip D. Coleridge Smith Sclerotherapy in the management of varicose veins of the extremeties J. Leonel Villavicencio Foam sclerotherapy Joshua I. Greenberg, Niren Angle, John J. Bergan Percutaneous laser therapy of telangiectasias and varicose veins Thomas M. Proebstle Surgical treatment of the incompetent saphenous vein Adam Howard, Dominic P.J. Howard, Alun H. Davies Radiofrequency treatment of the incompetent saphenous vein Robert F. Merchant, Robert L. Kistner Laser treatment of the incompetent saphenous vein Nick Morrison Phlebectomy Lowell S. Kabnick Treatment algorithms for telangiectasia and varicose veins: current guidelines Jose I. Almeida, Jeffrey K. Raines Recurrent varicose veins: etiology and management Michel Perrin Local treatment of venous ulcers Thomas F. O’Donnell Jr Surgical repair of deep vein valve incompetence Seshadri Raju

331 342 348 359 366 380 390 400 409 418 429 439 446 457 472

Contents ix

43. 44. 45. 46. 47. 48. 49.

Artificial venous valves Michael C. Dalsing Endovascular reconstruction for chronic iliofemoral vein obstruction Peter Neglén Endovascular reconstruction of complex iliocaval venous occlusions Haraldur Bjarnason Open surgical reconstructions for non-malignant occlusion of the inferior vena cava and iliofemoral veins Peter Gloviczki, Gustavo S. Oderich The management of incompetent perforating veins with open and endoscopic surgery Jeffrey M. Rhodes, Manju Kalra, Peter Gloviczki Percutaneous ablation of perforating veins Steve Elias A treatment algorithm for venous ulcer: current guidelines Ralph G. DePalma

PART FIVE: 50. 51. 52. 53. 54. 55. 56.

58. 59. 60. 61.

LYMPHEDEMA

62. 63. 64. 65.

Index

503 514 523 536 545

553 568 574 583 594 604 617

Edited by Gregory L. Moneta

Lymphedema: pathophysiology, classification and clinical evaluation Thom W. Rooke, Cindy Felty Lymphoscintigraphy and lymphangiography Patrick J. Peller, Claire E. Bender, Peter Gloviczki Lymphedema: medical and physical therapy Gail L. Gamble, Andrea Cheville, David Strick Principles of surgical treatment of chronic lymphedema Peter Gloviczki The management of chylous disorders Purandath Lall, Audra A. Duncan, Peter Gloviczki

PART SEVEN:

491

Edited by Thomas W. Wakefield

Surgical and endovenous treatment of superior vena cava syndrome Manju Kalra, Haraldur Bjarnason, Peter Gloviczki The management of extremity venous trauma David L. Gillespie, Reagan W. Quan Primary and secondary tumors of the inferior vena cava and iliac veins Thomas C. Bower Arteriovenous malformations: evaluation and treatment Byung Boong Lee, James Laredo, David H. Deaton, Richard F. Neville The management of venous malformations Heron E. Rodriguez, William H. Pearce The management of venous aneurysms Heron E Rodriguez, William H. Pearce Management of pelvic venous congestion and perineal varicosities Graeme D. Richardson

PART SIX: 57.

SPECIAL VENOUS PROBLEMS

483

ISSUES IN VENOUS DISEASE

629 635 649 658 665

Edited by Gregory L. Moneta

Outcome assessment in acute venous disease Patrick Carpentier, Peter Gloviczki Outcome assessment in chronic venous disease Robert B. Rutherford, Gregory L. Moneta, Frank T. Padberg Jr., Mark H. Meissner Mapping the future: organizational, clinical and research priorities in venous disease Mark H. Meissner, Bo Eklöf, Peter Gloviczki, Joann M. Lohr, Fedor Lurie, Robert Kistner, Gregory L. Moneta, Thomas W. Wakefield Summary of Guidelines of the American Venous Forum Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Gregory L. Moneta, Thomas W. Wakefield, Joann M. Lohr, Monika L. Gloviczki, Mark H. Meissner

675 684 694 706

723

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Contributors

Editor Peter Gloviczki MD FACS Joe M. and Ruth Roberts Professor of Surgery, Mayo Clinic College of Medicine, Chair, Division of Vascular and Endovascular Surgery, Director, Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA Associate Editors Michael C. Dalsing MD FACS E. Dale and Susan E. Habegger Professor of Surgery, Chair, Section of Vascular Surgery, Indiana University School of Medicine, Indianapolis, IN, USA Bo Eklöf MD PhD Clinical Professor Emeritus of Surgery, University of Hawaii, USA, and University of Lund, Helsingborg, Sweden Gregory L. Moneta MD Professor of Surgery, Chief of Vascular Surgery, Oregon Health & Science University, and Staff Surgeon, Portland VA Medical Center, Portland, OR, USA Thomas W. Wakefield MD FACS S. Martin Lindenauer Professor of Surgery, Head, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA Assistant Editor Monika L. Gloviczki MD Research Fellow, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

John Bergan MD FACS FRCS(hon)Eng FACPh(hon) Professor of Surgery, UCSD School of Medicine, University of California, San Diego, CA, USA Haraldur Bjarnason MD Associate Professor of Radiology, Mayo Clinic College of Medicine, Consultant, Department of Radiololgy, Mayo Clinic, Rochester, MN, USA Thomas C. Bower MD Professor of Surgery, Mayo College of Graduate Medical Education, Consultant and Program Director, Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, MN, USA Andrew W. Bradbury BSc MBA MD FRCSEd Education Dean, Sampson Gamgee Professor of Vascular Surgery and Consultant Vascular Surgeon, Birmingham, UK Kevin G. Burnand MB BS MS FRCS Professor of Surgery, St Thomas’ Hospital, London, UK Joseph A. Caprini MD MS FACS RVT Louis W Biegler Professor of Surgery and Bioengineering, Robert R McCormick School of Engineering and Northwestern University Feinberg School of Medicine and Senior Attending Surgeon, NorthShore University Health System, Skokie, Illinois, USA Patrick Carpentier MD Professor of Vascular Medicine, Grenoble University Hospital, Grenoble, France

Contributing Authors

Andrea L. Cheville MD MSCE Associate Professor, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA

Babak Abai MD Cooper University Hospital, Camden, NJ, USA

Philip D. Coleridge Smith MB BS FRCS British Vein Institute, London, UK

Jose I. Almeida MD Founder, Miami Vein Center and Voluntary Associate Professor of Surgery, Jackson Memorial Hospital, Miami, FL, USA

Anthony J. Comerota MD FACS FACC Director, Jobst Vascular Center, Toledo, OH, USA

Niren Angle MD RVT FACS Assistant Professor of Surgery, University of California, San Diego, CA, USA

Alun H. Davies MA DM FRCS FHEA Professor of Vascular Surgery, Honorary Consultant Surgeon, Faculty of Medicine, Imperial College School of Medicine, Charing Cross Hospital London, UK

Enrico Ascher MD Professor of Surgery, Mount Sinai School of Medicine, Director, Division of Vascular Surgery, Maionides Medical Center, Vascular Surgery, Brooklyn, NY, USA

David H. Deaton MD FACS Associate Professor of Surgery and Chief, Endovascular Surgery Section, Division of Vascular Surgery, Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA

Claire E. Bender MD Professor of Radiology, Mayo Clinic College of Medicine, Consultant, Department of Radiology, Mayo Clinic, Rochester, MN, USA

Ralph G. DePalma MD FACS National Director of Surgery, Department of Veterans Affairs and Professor of Surgery, Uniformed Services University of the Health Services, Washington, DC, USA

xii

Contributors

James A. DeWeese MD Professor of Surgery, Division of Vascular Surgery, University of Rochester Medical Center, Rochester, NY, USA

Adam Howard MB BS BSc FRCS MD Colchester Hospital University NHS Foundation Trust, Colchester, UK

Audra A. Duncan MD Associate Professor of Surgery, Mayo Clinic College of Medicine, Consultant, Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, MN, USA

Dominic P.J. Howard BM BCh MA MRCS Oxford Radcliffe Hospitals Trust, Oxford, UK

Walter N. Duran PhD Vice Chair and Professor, Department of Pharmacology, Physiology and Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA Steve Elias MD FACS FACPh Director, Centers for Vein Disease, Mount Sinai Hospital NY and Englewood Hospital NJ and Associate Professor of Surgery, Mount Sinai School of Medicine, New York, NY, USA Cindy Felty MSN RN CNP CWS Assistant Professor of Medicine, Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA Gail L. Gamble MD Assitant Professor, Northwestern University Feinberg School of Medicine, Department of Physical Medicine and Rehabilitation, Medical Director, Cancer Rehabilitation, Rehabilitation Institute of Chicago, Chicago IL, USA David L. Gillespie MD FACS Assistant Professor, Northwestern University Feinberg School of Medicine, Department of Physical Medicine and Rehabilitation, Professor of Surgery, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA James Glockner MD Assistant Professor of Radiology, Mayo Clinic College of Medicine, Consultant, Department of Radiology, Mayo Clinic, Rochester, MN, USA Richard M. Green MD Chairman, Department of Surgery, Lenox Hill Hospital, Department of Surgery, New York, NY, USA Joshua I. Greenberg MD Vascular and Endovascular Surgery, University of California, San Diego, CA, USA Lazar J. Greenfield MD Professor and Chair Emeritus, Department of Surgery, University of Michigan, Ann Arbor, MI, USA John Heit MD FACP FACC Director, Coagulation Laboratories and Clinic Consultant, Division of Cardiovascular Diseases, Gonda Vascular Center, Professor of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA Peter K. Henke MD Associate Professor of Surgery, University of Michigan, Ann Arbor, MI, USA Anil P. Hingorani MD Clinical Assistant Professor of Surgery, College of Medicine, SUNY Brooklyn and Attending Vascular Surgeon, Maimonides Medical Center, Vascular Surgery, Brooklyn, NY, USA

Russell D. Hull MB BS MSc FRCPC FACP FCCP Professor of Medicine, Hematology and Internal Medicine, Director, Thrombosis Research Unit, Foothills Hospital, Calgary, Alberta, Canada Karl A. Illig MD Professor of Surgery and Neurosurgery, Chief, Division of Vascular Surgery, University of Rochester Medical Center, Rochester, NY, USA Lowell S. Kabnick MD FACS FACPh Associate Professor of Surgery, New York University School of Medicine and Director, NYU Vein Center, New York University Medical Centre, New York, NY, USA Manju Kalra MB BS Associate Professor of Surgery, Mayo Clinic College of Medicine, Consultant, Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, MN, USA Curtis Kamida MD Department of Radiology, Straub Clinic and Hospital, Honolulu, Hawaii, USA Daniel Kim MD John J Crawley Vascular Laboratory, Good Samaritan Hospital, Cincinnati, OH, USA Robert L. Kistner MD Clinical Professor of Surgery, University of Hawaii and Kistner Vein Clinic, Beretania Medical Plaza, Honolulu, HI, USA Kelli Krallman Research Specialist, Hatton Institute for Research and Education, Good Samaritan Hospital, Cincinnati, OH, USA Venkataramu N. Krishnamurthy MD Assistant Professor of Radiology, University of Michigan, Ann Arbor, MI, USA Nicos Labropoulos BSc(Med) PhD DIC RVT Professor of Surgery and Radiology, Director, Vascular Laboratory, Stony Brook University Medical Center, Stony Brook, NY, USA Brajesh K. Lal MD Associate Professor, Department of Surgery, Division of Vascular Surgery, Department of Physiology and Department of Biomedical Engineering UniDNJ, New Jersey Medical School, Newark, NJ, USA Purandath Lall, MB BS FRCS (ed) Veterans Administration Medical Center, Buffalo, NY, USA Andrew D. Lambert Vascular Surgery, Springfield Clinic, Springfield, IL, USA James Laredo MD PhD FACS Assistant Professor of Surgery and Director, Center for Vein, Lymphatics and Vascular Malformation, Department of Surgery, Georgetown University School of Medicine, Washington, DC, USA

Contributors

Byung-Boong Lee MD PhD FACS Professor of Surgery and Co-Director, Center for Vein, Lymphatics and Vascular Malformation, Division of Vascular Surgery, Georgetown University School of Medicine, and Clinical Professor, Georgetown University Hospital, Washington, DC, USA Joann M. Lohr MD RVT FALS John J Crawley Vascular Laboratory, Good Samaritan Hospital, Cincinnati, OH, USA Fedor Lurie MD Vascular Surgeon, Kistner Vein Clinic, Beretania Medical Plaza, and Clinical Assistant Professor, University of Hawaii, Honolulu, HI, USA Robert D. McBane MD Associate Professor of Medicine, Gonda Vascular Center, Division of Cardiology, Mayo Clinic, Rochester, MN, USA Robert B. McLafferty MD Professor of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA Elna M. Masuda MD Associate Professor of Surgery, University of Hawaii and Chief, Vascular Center, Straub Clinic and Hospital, Honolulu, Hawaii, USA Mark A. Mattos MD Detroit Medical Center, Woodbridge, IL, USA

Thomas F. O’Donnell Jr MD Benjamin Andrews Emeritus Professor of Surgery, Tufts University School of Medicine and Director of the Vein Center at Tufts Medical Center and at Dedham Medical Associates, Boston, MA, USA Frank T. Padberg Jr MD Professor of Surgery, Department of Surgery, Division of Vascular Surgery, UMDNJ, New Jersey Medical School, Newark, NJ, USA Felizitas Pannier Academisch Ziekenhuis Maastricht, Afdeling Dermatologie, Maastricht, The Netherlands Peter J. Pappas MD Professor of Surgery, Department of Surgery, Division of Vascular Surgery, UMDNJ, Newark, NJ, USA Hugo Partsch MD Professor of Dermatology, Emeritus Head of the Dermatological Department of the Wilhelminen Hospital, Vienna, Austria William H. Pearce MD Violet R and Charles A Baldwin Professor of Vascular Surgery, Chief, Division of Vascular Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Patrick J. Peller MD Assistant Professor of Radiology, Mayo Clinic College of Medicine, Consultant, Department of Radiology, Mayo Clinic, Rochester, MN, USA

Mark H. Meissner MD Professor of Surgery, University of Washington Medical Center, Seattle, WA, USA

Michel Perrin MD Vascular Surgery, Chassieu, France

Robert F. Merchant MD The Reno Vein Clinic, Reno, NV, USA

Graham F. Pineo MD Division of Hematology and Hematological Malignancies, University of Calgary, Calgary, Alberta, Canada

Jessica Michaud PharmD BCPS Clinical Assistant Professor and Clinical Pharmacist, University of Illinois at Chicago, Chicago, IL, USA Nick Morrison MD FACS FACPh Director, Morrison Vein Institute, Scottsdale, AZ, USA Geza I. Mozes MD PhD (deceased) Assistant Professor of Surgery, Mayo Clinic College of Medicine, Senior Associate Consultant, Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, MN, USA Peter Neglén MD PhD FACS Vascular Surgeon, River Oaks Hospital, Flowood, MS, USA

xiii

Mary C. Proctor MD University of Michigan Medical Center, Ann Arbor, MI, USA Thomas M. Proebstle, MD PhD Dermatology, Phlebology, Professor of Dermatology, University of Pecs, Hungary and Associate Professor of Dermatology, University of Mainz, Germany and Director, Private Clinic Proebstle, Mannheim, Germany Reagan W. Quan MD Servier Traveling Fellow, American Venous Forum and Vascular Surgery, Madigan Army Medical Center, Tacoma, WA, USA

Richard F. Neville MD FACS Professor of Surgery and Chairman, Division of Vascular Surgery, Department of Surgery, Georgetown University School of Medicine, Washington DC, USA

Eberhard Rabe MD President of German Society of Phlebology, President of Union Internationale de Phlébologie, Department of Dermatology, University of Bonn, Bonn, Germany

Edith Nutescu PharmD Department of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

Joseph D. Raffetto MD FACS Chief, Vascular Surgery, VA Boston Healthcare System, West Roxbury, MA, USA

Gustavo S. Oderich MD Assistant Professor of Surgery, Mayo Clinic College of Medicine, Consultant, Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, MN, USA

Jeffrey K. Raines PhD Director, Vascular Laboratory, Miami Vein Center and Professor Emeritus of Surgery, University of Miami School of Medicine, Miami, FL, USA

xiv

Contributors

Seshadri Raju MD FACS Professor Emeritus and Honorary Surgeon, University of Mississippi Medical Center, Jackson, MS, USA John Rectenwald MD Assistant Professor of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, USA Jeffrey M. Rhodes MD Associate Professor of Surgery, Division of Vascular Surgery, University of Rochester Medical Center, Rochester, NY, USA Graeme D. Richardson MB BS FRACS FRCS Associate Professor of Surgery UNSW, The Rural Clinical School, Wagga Wagga, NSW, Australia Heron E. Rodriguez MD Division of Vascular Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Thom W. Rooke MD Krehbiel Professor of Vascular Medicine, Mayo Clinic College of Medicine, Chair, Division of Vascular Medicine, Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA Robert Rosen MD Chief, Interventional Vascular Oncology and Embolization, Lenox Hill Heart & Vascular Institute, New York, NY, USA C. Vaughan Ruckley MD Emeritus Professor of Vascular Surgery, University of Edinburgh, Edinburgh, UK Robert B. Rutherford MD FACS FRCS(hon) Emeritus Professor of Surgery, Department of Surgery, University of Colorado Medical School, Denver, CO, USA

Sergio X. Salles-Cunha PhD PVT FSVU Compu Diagnostics, Inc, Scottsdale, AZ, USA John Smith BSc MA PhD Consultant Dermatologist, University College Hospital and Research Fellow, University College London, UK David Strick PhD PT Mayo Clinic, Rochester, MN, USA Jorge M. Trabal MD Senior Vascular Fellow, Jobst Vascular Center, The Toledo Hospital, Toledo, OH, USA J. Leonel Villavicencio MD Distinguished Professor of Surgery, Uniformed Services University School of Medicine, Bethesda, MD, USA Terri J. Vrtiska MD Assistant Professor of Radiology, Mayo Clinic College of Medicine, Consultant, Department of Radiology, Mayo Clinic, Rochester, MN, USA Ashar Wadoodi Department of Academic Surgery, St Thomas’ Hospital, London, UK Waldemar E. Wysokinski MD Associate Professor of Medicine, Division of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA Robert W. Zickler MD Assistant Professor of Surgery, Department of Surgery, Division of Vascular Surgery, UMDNJ, New Jersey Medical School, Newark, NJ, USA

Foreword

As one who spent a signiﬁcant part of his professional life treating venous disorders, I take pleasure in recommending this edition of the Handbook of Venous Disorders. I have contributed to this, and to the two previous editions, but, without doubt, this edition has far outdone its predecessors, in my view. This was partly out of necessity, because the management of venous disorders has advanced so signiﬁcantly since the last edition, in which regards it has been thoroughly upgraded. But it also has beneﬁted from a united effort to better deﬁne the ﬁeld, and to not only identify its residual problems but commit to an ongoing effort to resolve them. This still ongoing activity began with a Venous Summit of the American Venous Forum which brought together many of the world’s leaders in this ﬁeld. Held in the interim since the previous edition, it has not only added great impetus and deﬁnition to a ﬁeld moving rapidly forward, with less invasive diagnostic and therapeutic approaches being regularly introduced and anatomic and clinical terminology being standardized. The Venous Summit also identiﬁed a core leadership group to lead in developing these initiatives, which not coincidentally includes all of this handbook’s editorial staff. The authors chosen to contribute to this edition are internationally recognized as leaders in the ﬁeld and for their special areas of expertise and the particular aspects they discuss. As an editor of Vascular Surgery textbooks, I know the importance of choosing uniquely qualiﬁed

contributors, and as a long time member of the American Venous Forum, I can vouch for the special qualiﬁcations of the contributors to this edition. For a number of years the American Venous Forum’s annual program has attracted the best works of European and “third world” authors, as well as those from the United States, providing a great depth of authorship from which to choose for this edition of the Handbook. Thus, this Handbook reﬂects, to a great degree, the initiatives and the ongoing efforts spawned by this Venous Summit and the expertise which has arisen there from. As such, it represents more than just a collection of articles by authors interested in a particular aspect of venous disease, but it is a well focused collection of chapters contributed mainly by those who have participated in a substantive way to this uniﬁed effort to deﬁne this ﬁeld and clarify key aspects of the modern day management of venous disorders, as well as identify those areas in need of further resolution. I enthusiastically recommend this Handbook of Venous Disorders to your reading. I am convinced you will beneﬁt from the special thrust behind the development of this particular edition and trust you will enjoy the perceptive and authoritative views of the modern management of venous disorders that it contains. Robert B. Rutherford MD, FACS, FRCS (hon)

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Preface

Venous disease is receiving long-deserved and increasing recognition worldwide. Venous disorders are among the most prevalent medical conditions and, in the United States alone, each year an estimated 600 000 people have venous thromboembolism – a fact so alarming that the Surgeon General recently issued a Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Increased recognition of venous disease is due to more research in this ﬁeld, to early and accurate diagnosis and to less invasive and more effective treatments. The Third Edition of the Handbook of Venous Disorders brings you evidence-based guidelines on prevention, prediction, diagnosis and treatment of venous and lymphatic disorders. The volume is more comprehensive than any of the previous editions. The chapters are completely revised, updated and 12 new chapters reﬂect the endovenous revolution that has so rapidly transformed management of acute and chronic venous diseases. The Handbook includes the latest information on epidemiology, basic science and investigation of venous and lymphatic disorders, and discusses modern venous imaging studies, including detailed evaluation of acute and chronic venous diseases with duplex scanning. Minimally invasive and endovenous technology has taken over management of venous disease to such an extent that need for some classic open venous surgical procedures has greatly decreased, and some operations are entirely omitted from the book. Discussion is extensive, however, on frequently performed procedures for varicose veins or venous ulcers, such as liquid and foam sclerotherapy or endothermal venous ablation with radiofrequency and laser. Prevention and treatment of acute deep vein thrombosis is presented in detail with latest results of outpatient drug therapies and of catheter-directed thrombolysis, mechanical thrombectomy and venous stenting. Chronic venous occlusions and valvular incompetence as well as unusual problems such as superior vena cava syndrome or venous tumors and lymphedema are discussed in detail; current and future research on venous disease are also presented. The new feature of this fully colored edition is adding evidence-based clinical guidelines to each chapter on evaluation and management, together with evidence scores to help the reader assess the strength of evidence

and the grade of recommendations. The last chapter in the book lists all evidence-based guidelines of the American Venous Forum. This volume would not have been possible without the signiﬁcant collaboration of eminent international experts in venous and lymphatic disease, who contributed their time, efforts and talents to this publication. Most are leaders or honorary members of the American Venous Forum, a society dedicated to the investigation, education and treatment of venous disease. I am particularly grateful to four friends, ﬁrst-time Associate Editors of the Handbook, Michael Dalsing, Bo Eklöf, Greg Moneta and Thom Wakeﬁeld, all Past Presidents of the American Venous Forum, for their invaluable assistance, enthusiasm and generous support of this great project. I would like to thank Dr Robert B. Rutherford for his Foreword to the Third Edition and for being such a leader and role model in the ﬁeld of venous disease and vascular malformations. Special thanks go to the fantastic team at Hodder in London, Francesca Naish and Gavin Jamieson, as well as the proofreader, June Morrison, for their hard work, constant support and particularly for the unbelievable patience they exhibited even to my frequently extreme requests for just another change in the Handbook. Working with them through the editorial process was extremely rewarding. I would also like to add a special thanks to my secretary, Marcia Simonson, for her tremendous help with the editorial process. Finally, I would like to recognize the contribution of two very special people. The ﬁrst is Dr James S.T. Yao, Editor Emeritus of the Handbook and Magerstadt Professor Emeritus of Surgery at Northwestern University Feinberg School of Medicine in Chicago, IL. Without his encouragement and support as Co-Editor of the ﬁrst two editions, this project would have never come to fruition; towards him I will always feel a deep sense of gratitude. The second person to acknowledge is my wonderful wife and Assistant Editor of the Handbook, Dr Monika L. Gloviczki. Her experience and knowledge of venous disease, her editorial skills and, most importantly, her constant love and continuous inspiration made this project a real pleasure; for this I will always be thankful to her. Peter Gloviczki

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Evidence-based guidelines

Evidence-based medicine is the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients.1 Listing evidence-based guidelines of the American Venous Forum is a new addition to the 3rd Edition of the Handbook of Venous Disorders. At the end of each chapter a table summarizes the relevant guidelines, with a letter marking the level of current evidence (A. High quality, B. Moderate quality, C. Low or very low quality). The grade of recommendation of a guideline can be Strong (1) or Weak (2), depending on the risk and burden of a particular diagnostic test or a therapeutic procedure to the patient versus the expected beneﬁt. The words “we recommend” are used for Grade 1, strong recommendations, if the beneﬁts clearly outweigh risk and burdens or vice versa, while the words “we suggest” are used for Grade 2, weak recommendations, when the beneﬁts are closely balanced with risks and burden. These guidelines of the American Venous Forum are based on the GRADE system as it was reported previously by Guyatt et al. (Table 1).2 Chapter 65 gives a summary of all the guidelines of the book. The American Venous Forum, the ﬁrst academic organization in the United States that encompasses the full spectrum of acute and chronic venous and lymphatic disorders, is committed to promote research, education, awareness, prevention and delivery of care. The society has long recognized the need to formulate clinical guidelines based on sound scientiﬁc principles to aid physicians and patients to receive the best and latest information of venous and lymphatic disorders.3,4 Clinical guidelines, published in the 3rd Edition of the Handbook, however, should not be used as dogma when a diagnostic test is selected or a therapeutic procedure is performed. Scientiﬁc evidence should always be combined with the clinical experience of the physician and with the patient’s preference (Fig. 1).5 By formulating evidence-based guidelines, the intentions of the authors and editors of this volume were to help evaluation and treatment of patients with venous and lymphatic disorders with those ideals in mind which were suggested by Dr William J. Mayo in 1910, that “The best interest of the patient is the only interest to be considered.”

Scientiﬁc Evidence

Diagnostic Test or Treatment Physician’s Clinical Experience

Patient’s Preference

Figure 1 Clinical decisions on a diagnostic test or treatment are based on scientiﬁc evidence, the physician’s clinical experience and the patient’s preference

REFERENCES 1. Sackett DL. Evidence-based medicine. Spine 1998; 23: 1085–6. 2. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical practice guidelines: report from an American College of Chest Physicians task force. Chest 2006; 129: 174–81. 3. Gloviczki P. Do we need evidence-based medicine in the ﬁeld of venous diseases? Perspect Vasc Surg Endovasc Ther 2004; 16: 129–33. 4. Meissner MH. “I enjoyed your talk, but. . .”: Evidence-based medicine and the Scientiﬁc Foundation of the American Venous Forum. Presidential Address. J Vasc Surg 2008. on-line (http://www.jvascsurg.org/) 5. Haynes RB, Devereaux PJ, Guyatt GH. Physicians’ and patients’ choices in evidence based practice. BMJ 2002; 324: 1350.

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Evidence-based guidelines

Table 1 Grading Recommendations According to Evidence Grade of Recommendation/ Description

Beneﬁt vs Risk and Burdens

Methodological Quality of Supporting Evidence

Implications

1A/strong recommendation, high-quality evidence

Beneﬁts clearly outweigh risk and burdens, or vice versa

RCTs without important limitations or overwhelming evidence from observational studies

Strong recommendation, can apply to most patients in most circumstances without reservation

1B/strong recommendation, moderate quality evidence

Beneﬁts clearly outweigh risk and burdens, or vice versa

RCTs with important limitations (inconsistent results, methodological ﬂaws, indirect, or imprecise) or exceptionally strong evidence from observational studies

Strong recommendation, can apply to most patients in most circumstances without reservation

1C/strong recommendation, low-quality or very low-quality evidence

Beneﬁts clearly outweigh risk and burdens, or vice versa

Observational studies or case series

Strong recommendation but may change when higher quality evidence becomes available

2A/weak recommendation, high-quality evidence

Beneﬁts closely balanced with risks and burden

RCTs without important limitations or overwhelming evidence from observational studies

Weak recommendation, best action may differ depending on circumstances or patients’ or societal values

2B/weak recommendation, moderate-quality evidence

Beneﬁts closely balanced with risks and burden

RCTs with important limitations (inconsistent results, methodological ﬂaws, indirect, or imprecise) or exceptionally strong evidence from observational studies

Weak recommendation, best action may differ depending on circumstances or patients’ or societal values

2C/weak recommendation, low-quality or very low-quality evidence

Uncertainty in the estimates of beneﬁts, risks, and burden; beneﬁts, risk, and burden may be closely balanced

Observational studies or case series

Very weak recommendations; other alternatives may be equally reasonable

RCT = randomized clinical trials From2, with permission.

List of abbreviations used

ABI ACA ACCP AK APC APG APS aPTT AVF AVM AVP AVVQ bFGF BK BMI C CAIRR CBS CDT CEAP CFD CFN CFV CHF CI CINAHL CIV CM CMS C4b-BP CPO CPT CT ΔCT mouse CV CVD CVI CVM

ankle-brachial pressure index anticardiolipin antibodies American College of Chest Physicians above the knee activated protein C air plethysmography antiphospholipid antibody syndrome activated partial thromboplastin time arteriovenous fistula and American Venous Forum arteriovenous malformation ambulatory venous pressure Aberdeen Varicose Veins Questionnaire basic fibroblast growth factor below the knee body mass index capillary Cooperative Alliance for Interventional Radiology Research cystathione β synthase complex decongestive therapy C, clinical; E, etiology; A, anatomy; P, pathophysiology color-flow duplex ultrasonography fibronectin common femoral vein congestive heart failure confidence interval Cumulative Index to Nursing and Allied Health Literature common iliac vein capillary malformations Center for Medicare and Medicaid Services C4b-binding protein calf pump output Current Procedural Terminology (code book) computed tomography cytoplasmic domain-deleted mouse collecting venule chronic venous disease or chronic venous disorders chronic venous insufficiency congenital vascular malformation

CXCR2KO dAVF DEA DIC dL DS DTI DUMSAD DUS DVT ECM ELS EGF e.g. EMMPRIN EPCR ePTFE EMEA Et ELISAs ET EV EVL EVLT Fb FDA FEU FVL FPDL FV G-CSF °C GI GM-CSF GPIbα GRE GSM GSV GVM

mice with targeted gene deletion of CXC receptor distal arteriovenous fistula dog erythrocyte antigen disseminated intravascular coagulation deciliter duplex scanning direct thrombin inhibitor Duplex Ultrasound in a Multicenter Study of Acute deep vein thrombosis duplex ultrasound deep vein thrombosis extracellular matrix elastic compression stockings epidermal growth factor exempli gratia (for example) extracellular matrix metalloproteinase inducer endothelial cell protein C receptor expanded polytetra-fluoroethylene European Agency for the Evaluation of Medicinal Products endothelial enzyme-linked immunosorbent assays extratruncular ejected volume endovenous laser endovenous laser therapy fibroblasts Food and Drug Administration fibrinogen equivalent unit factor V Leiden mutation flashlamp pumped dye lasers femoral vein granulocyte colony-stimulating factor Celsius degree gastro-intestinal granulocyte–macrophage colony-stimulating factor platelet glycoprotein Ibα gradient recalled echo grayscale median great saphenous vein glomovenous malformations

xxii Abbreviations

GWOT HIPAA HIT HITT HHD HLM HMC HRQL HRT HSE HSLW IBD ICAM1 ICC i.e. ICD ICP ICPVs ICU ICVAL IED IFVT Ig IFN-γ IL-1β IL-8 INR INVEST IPC IPL IPV IRR ISCVS ISR ISR-VDS ISS IV IVC IVUS Kev KO Kt KTP LA LAP LC LDS LFA-1 LHDE LM LMWH LSI

Global War on Terrorism heparin-induced platelet activation assay heparin-induced thrombocytopenia heparin-induced thrombocytopenia and thrombosis hand-held Doppler hemolymphatic malformation human mast cell line health-related quality of life hormone replacement therapy human skin or dermal equivalent hemoglobin-specific laser wavelength inflammatory bowel disease intercellular adhesion molecule 1 immunocytochemical id est (in other words) International Classification of Diseases integrated care pathway incompetent perforating veins intensive care unit Intersocietal Commission for Accreditation of Vascular Laboratories improvised explosive device iliofemoral vein thrombosis immunoglobulin interferon gamma interleukin 1-β interleukin 8 international normalized ratio Investigating Venous Disease Evaluation and Standardization of Testing intermittent pneumatic compression intense pulsed light incompetent perforating vein incidence rate ratio International Society for Cardiovascular Surgery in-stent re-stenosis innovative, screenless, real-time venous duplex system injury severity score iliac vein or intravenous therapy inferior vena cava intravascular ultrasound kiloelectron volt knock-out mice keratinocytes potassium titanylphosphate lupus anticoagulant latency-associated peptide lower calf lipodermatosclerosis lymphocyte function-associated antigen 1 living human dermal equivalent lymphatic malformation low-molecular-weight heparin long saphenous incompetence

LT LTBP Mac-1 MC MCP-1 MAPK MI MHz MIP-2 MLD MMP MP MPFF MRA MRI μm nm J mbq μCi MRV MT-MMPs MTHFR MVO MVT NBCA Nd:YAG NIH NHS-TAS NIVL NSAID OCPs OR OF OTC P20210 pa PA PAA PAD PAI-1 PAPs pca PCS PCV PDGFR-α and -β PDR PE PGE-1 PHA PIN PKO PMNs p.o. PPG

lower thigh latent TGF-β1 binding proteins monoclonal antibody to CD11b macrophages and leukocytes monocyte chemotactic protein-1 mitogen-activated protein kinase myocardial infarction megahertz macrophage-inflammatory protein-2 manual lymph drainage matrix metalloproteinase micro-particle micronized purified flavonoid fraction magnetic resonance angiography magnetic resonance imaging micrometer nanometer Joule megabecquerel microcurie magnetic resonance venography membrane-type matrix metalloproteinases methylene-tetrahydrofolate reductase maximum venous outflow mesenteric vein thrombosis N-butylcyanoacrylate neodymium-doped yttrium aluminum garnet National Institutes of Health National Health Services Health Technology Assessment Survey non-thrombotic iliac vein lesion non-steroidal anti-inflammatory drug oral contraceptive pills odds ratio outflow fraction at 1s outcome relation to thrombus characteristics prothrombin G20210A principal artery plasminogen activator platelet-aggregation assay peripheral arterial disease plasminogen activator inhibitor percutaneous ablation of perforators precapillary arteriole pelvic congestion syndrome postcapillary venule platelet derived growth factor receptor alpha and beta prescription drug reference pulmonary embolism prostaglandin E1 phytohemagglutinin perforation–invagination P-selectin knockout polymorphonuclear neutrophils per os photoplethysmography

Abbreviations

PRA pRb ppRb PRF PSGL rPSGL PT PTA PTFE PTS PTV PV pv PVA PVI PVL QoL RBCS RCC RCT REVAS RF RFA RIJV RR RRR RT-PCR RV SCVS Sa SEPS SA-β-Gal SES SFJ SF-36 SFJT SFM SFP SFD SGP SIR SIS SLE SMCs SNR SPC SPJ SPGR SRA

panel reactive antibody protein retinoblastoma phosphorylated protein retinoblastoma pulse repetition frequency P-selectin glycoprotein ligand-1 receptor antagonist to PSGL-1 prothrombin time percutaneous transluminal balloon angioplasty polytetra-fluoroethylene post-thrombotic syndrome posterior tibial vein perforating vein principal vein polyvinyl alcohol primary venous insufficiency primary venous leiomyosarcoma quality of life red blood cells renal cell carcinoma randomized controlled trial recurrent varices after surgery radiofrequency radiofrequency ablation right internal jugular vein relative risk reduction of the relative risk Reverse Transcription-Polymerase chain reaction residual volume Society for Clinical Vascular Surgery small artery of the microvasculature subfascial endoscopic perforator surgery senescence-associated β-galactosidase staphylococcal enterotoxins saphenofemoral junction Study Short Form-36 saphenofemoral junction thrombophlebitis mid femoral vein proximal femoral vein distal femoral vein strain-gauge plethysmography Society for Interventional Radiology small intestinal submucosa systemic lupus erythematosus smooth muscle cells signal-to-noise ratio superficial posterior fascial compartment saphenopopliteal junction spoiled gradient recalled echo serotonin release assay

SSFP SSV SSVT STD or STS SV SVC SVI SVS SVT T ta Tc Th1 TED TIMP-1 TIMI TLPS TF TGFβ TGC tHcy TNFα tPA TRISS UFH UGS uPA uPAR US VAC VATS VAS VC VCSS VEGF VFI90 VFT VKA VLA-4 VM VO VSDS VTE VV WBBPS WBCs WSLW WT 99mTc-SC

steady-state free precession small saphenous vein suppurative SVT sodium tetradecyl sulfate small vein superior vena cava secondary venous insufficiency Society of Vascular Surgery superficial venous thrombophlebitis truncular terminal arteriole Technetium T helper 1 lymphocyte thromboembolic deterrent tissue inhibitor of metalloprotinese Thrombolysis In Myocardial Infarction transarterial lung perfusion scintigraphy tissue factor transforming growth factor β time gain compensation total plasma homocysteine level tumor necrosis factor α tissue plasminogen activator trauma injury severity score unfractionated heparin ultrasound-guided sclerotherapy urokinase plasminogen activator uPA receptor ultrasound vacuum-assisted closure video-assisted thoracoscopy visual analog scale venous capacitance Venous Clinical Severity Score vascular endothelial growth factor venous filling index venous filling time vitamin K antagonist very late antigen 4 venous malformation venous outflow Venous Segmental Disease Score venous thromboembolism functional venous volume whole body blood pool scintigraphy white blood cells water-specific laser wavelength wild type 99mTc-sulfur colloid

xxiii

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PART

1

BASIC CONSIDERATIONS OF VENOUS DISORDERS Edited by Michael C. Dalsing

1 Venous and lymphatic disease: a historical review Karl A. Illig, Jeffrey M. Rhodes and James A. DeWeese 2 Development and anatomy of the venous system Peter Gloviczki and Géza Mózes 3 The physiology and hemodynamics of the normal venous circulation Frank Padberg 4 Classification and etiology of chronic venous disease Robert L. Kistner and Bo Eklöf 5 The physiology and hemodynamics of chronic venous insufficiency of the lower limb Kevin G. Burnand and Ashar Wadoodi 6 Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufficiency Peter J. Pappas, Brajesh K. Lal, Frank T. Padberg, Jr., Robert W. Zickler and Walter N. Duran 7 Venous ulcer formation and healing at cellular levels Joseph D. Raffetto 8 Acute venous thrombosis: pathogenesis and evolution Thomas W. Wakeﬁeld and Peter K. Henke 9 The epidemiology of and risk factors for acute deep venous thrombosis Mark H. Meissner 10 Epidemiology of chronic venous disorders Eberhard Rabe and Felizitas Pannier

3 12 25 37 47 56 70 83 94 105

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1 Venous and lymphatic disease: a historical review KARL A. ILLIG, JEFFREY M. RHODES AND JAMES A. DEWEESE Introduction Anatomy and pathophysiology Deep venous thrombosis Pulmonary embolus Varicose veins

3 3 4 5 6

INTRODUCTION Venous disease is among the most common medical conditions to affect mankind – approximately 1–3% of the population of the Western world is estimated to have a severe venous problem at some point in their lives.1 Twenty million or more have varicose veins, six million some degree of edema, and an estimated one million have skin changes, in addition to the 500 000 patients who are estimated to have active venous ulcerations at any given time.2 Venous problems have been recognized since antiquity, being mentioned in one form or another in the Old Testament (Isaiah I:6), the Ebers papyrus in 1550 BC, and by Hippocrates ﬁve centuries before Christ.3–5 A chapter of this length can only be a brief overview of the important historical highlights of venous and lymphatic problems. The reader is directed to several excellent collections of original sources relating to the history of the venous and lymphatic systems by Bergan,3,6 Gloviczki,7 Yao,8 Scultetus and Rich,9 and Padberg.10

ANATOMY AND PATHOPHYSIOLOGY Interestingly, the true anatomy of the veins was relatively well understood before the basic concept of circulation of the blood was known – Vesalius published the ﬁrst accurate description of human anatomy, De Humani Corporis Fabrica, in 1543. The person who actually ﬁrst discovered the fact that veins have valves is the subject of a surprising amount of scholarship. Fabricius (Hieronymus Fabricius ab Aquapendente), a student of his, is often credited with the ﬁrst description (in 1603) of the venous

Chronic venous disease Effort thrombosis Lymphatic disease Summary References

6 8 8 9 9

valves and their locations (Fig. 1.1), and with the observation that they were there to prevent reﬂux. However, more recent work has documented that Charles Estienne, a French anatomist, actually left handwritten descriptions of hepatic venous valves as early as 1539 and published his ﬁndings in 1545.9,11 A Spanish anatomist, Ludovicus Vassaeus, likewise published a description of venous valves in 1544, and, to his credit, seemed to have understood their function.11 Detailed, functionally helpful drawings of valves were published in 1585 (Fig. 1.2) It was William Harvey, of course (who, in turn, studied under Fabricius), who brought understanding of the circulatory system into the modern age. He published his preliminary observations in 1616 and his deﬁnitive work (Exercitatio Anatomica De Motu Cordis et Sanguinis), both describing the true anatomy and function of the circulation (Fig. 1.3), in 1628.3,4 The basic pathophysiology of venous disorders seems to have been fairly accurately understood by the ancients, then lost in the dark ages of Galen’s humoral theories. It was Hippocrates who said “it was better not to stand in the case of an ulcer on the leg,”12 and Marianus Sanctus felt that the cause of varicose veins and ulceration was “standing too much before kings.”13 Unfortunately, Galen felt that venous ulcers were caused by an excess of black bile, and, that although excluding this black bile from the ulcer and varicosities was worthy, espoused the theory that tight compression would express these evil humors into the general circulation, making the patient critically ill.3 Luckily, by the seventeenth century, perhaps sparked by the works of Vesalius and Harvey, medicine and treatment of venous disease became grounded on more rational, empiric information and theories.

4

Venous and lymphatic disease: a historical review

Figure 1.2 The ﬁrst drawings of venous valves by Salomon Albertus, published in 1585. From Scultetus et al.9

Figure 1.1 Illustration from Fabricius’ atlas (1603) clearly showing the presence of valves in the veins of the lower extremity. From Bergan.3

DEEP VENOUS THROMBOSIS Elucidation of the pathophysiology of clotting, of course, dates from more modern times. Virchow, in the mid-

1800s, recognized and described the three contributing factors for thrombosis: stasis, endothelial injury, and hypercoagulability.14 Despite a century and a half of research and reﬁnement, this classic triad remains the simplest and best way of approaching any thrombotic process, and is almost literally mentioned every day in every teaching hospital around the world. John Homans’ contributions were critical in understanding all facets of venous disease, especially the causes, effects, and sequelae of deep vein thrombosis (DVT). He produced some of the earliest “modern” descriptions of historical and physical ﬁndings in patients with DVT, recognized and emphasized such classic risk factors as the operation, bedrest, and dehydration, and pointed out the ability of popliteal clots to fatally embolize.15,16 It is, of course, his description in the late 1930s of pain with foot dorsiﬂexion in the presence of DVT that is best remembered today, at least to the casual student in this ﬁeld.16,17 The fact that he was quite speciﬁcally referring to calf vein thrombosis only is unknown to many who refer to and use “Homans’ sign,”

Figure 1.3 Harvey’s drawings illustrating the function of venous valves in the arms and their ability to permit blood ﬂow in only one direction. From Padberg.10

Pulmonary embolus 5

as is the fact that he and others later questioned its value and accuracy.18 Unfortunately, even after Homans’ contributions, history and physical examination remained unreliable methods for the diagnosis of DVT, and it soon became apparent that more objective testing was needed. Although phlebography was ﬁrst described in humans in 1923, it was not until the 1930s that its use became common.19 Because of its low morbidity and high accuracy, and, of course, for want of a better test, it has been regarded as the “gold standard” for the diagnosis of venous disorders in general and DVT speciﬁcally for decades. Because it is not entirely innocuous, however, non-invasive diagnostic testing methods were created. Although venous occlusion plethysmography was ﬁrst used in 1905 to measure arterial blood ﬂow,20 it seems to have been ﬁrst applied for evaluation of venous problems and the diagnosis of DVT in the late 1960s and early 1970s.21,22 Gomez et al.23 ﬁrst described the administration of radioactive (125I-labeled) ﬁbrinogen to identify venous thrombosis in 1963, although this test was limited to actively forming thrombus. Soon after Satomura’s24 original description of arterial blood ﬂow and measurement of velocities using Doppler ultrasound in 1959, clinicians, notably Strandness, beginning in the late 1960s applied this technique to the arterial and venous circulation.25,26 Initial continuouswave devices relied on indirect evidence of obstruction and reﬂux, but with the advent of duplex technology in the 1970s and 1980s the full beneﬁt of ultrasound became apparent. Extensive scientiﬁc work and clinical experience have resulted in reﬁnement of this technique to the point where it has displaced phlebography as the procedure of choice for the diagnosis of DVT at most institutions. Prior to the 1930s, treatment of venous thrombosis was limited to bedrest and elevation, with the only interventional methods attempted being operative clot extraction or venous ligation.27,28 John (Jay) McLean discovered heparin in 1916 while a 24-year-old medical student at Johns Hopkins, but never followed up on this line of work. Howell, Holt, and Best at the University of Toronto expanded his results, purifying and characterizing it, while Murray, also at Toronto, conducted the ﬁrst largescale clinical trials.5 Warfarin was discovered after a veterinary observation that blood failed to clot in cattle that had eaten moldy sweet clover hay. Dicoumarol was isolated and synthesized by Stahmann in 1941, and clinical results of its use were published in 1942.29

patients with deep venous thrombosis by Homans in 1934.15 Because venous ligation was associated with a high incidence of severe venous stasis and recurrent, often fatal, embolization, Dale suggested temporary caval ligation, but this never proved practical. Because of these problems, solutions were proposed in the late 1950s and early 1960s that involved partial caval interruption, allowing ﬂow of liquid blood but entrapment of larger emboli. Marion “Bill” DeWeese developed a technique whereby interrupted silk sutures were placed but not tightened, producing an intraluminal “harp-grid” network to trap emboli, and thus performed the ﬁrst intravascular partial venous interruption. Spencer suggested plicating the cava with interrupted sutures, while Moretz and Miles both developed plastic clips to narrow the vena cava. Subsequently, Adams and Jim DeWeese (Bill DeWeese’s brother) combined the best elements of both to arrive at what became the most widely used such device (Fig. 1.4).30 Interestingly, as late as 1974, Richard Nixon was treated with unilateral iliac clipping (using a Miles clip) and apparently did surprisingly well, with “no signiﬁcant edema or other postphlebitic symptoms in the affected leg” for 19 years before his death.31

PULMONARY EMBOLUS

Figure 1.4 Early techniques of caval interruption. (a) M. S. “Bill” DeWeese’s “harp-grid” method of caval ﬁltration. (b) Spencer’s technique of caval plication, which differs from DeWeese’s in that the knots are tightened, and the caval lumen itself is much smaller. (c) Moretz’s smooth clip. (d) Miles’ doubly serrated clip, dividing the cava into three or four channels. From Illig, DeWeese.30

Ligation of the inferior vena cava was apparently ﬁrst performed by Trendelenburg in 1906 as part of the treatment of a woman with puerperal sepsis, but routine femoral venous ligation was ﬁrst generally advocated as a speciﬁc treatment for prevention of pulmonary embolus in

6

Venous and lymphatic disease: a historical review

Described in 1969, the Mobin–Uddin umbrella, a plastic disc with small holes allowing blood ﬂow, was the ﬁrst practical method of caval interruption able to be introduced through a remote access site without the need for major operation.32 Although complete caval occlusion frequently occurred, the development of modern devices, pioneered by Greenﬁeld’s original steel Greenﬁeld ﬁlter and now joined by multiple similar devices, has almost eliminated this problem.33 In recent years, systemic and catheter-directed thrombolysis has been increasingly used in an effort to quickly reduce clot burden and ameliorate postphlebitic problems in many patients,34 but this has yet to be universally applied.

VARICOSE VEINS Varicose veins have been recognized since very early in recorded history. There is a stone votive offering in the National Museum in Athens, Greece, dedicated to a physician by a grateful patient, which clearly shows a long varicose saphenous vein (apparently with an incompetent perforator distal to the area that is being compressed) (Fig, 1.5).3 Although multiple methods for their treatment have been investigated, the Arab statement dating from c. 400, “cut skin, expose varix, insert probe under it … pull out varix and cut”4 has perhaps not been improved upon as we enter the twenty-ﬁrst century. Homans35 eloquently described the pathophysiology, etiology, and treatment of varicose veins in 1916, using ideas and descriptions that remain startlingly modern today. For decades, perhaps centuries, varicose veins were treated by surgical removal, often (as late as the 1990s) by surprisingly large incisions. It was recognized that these veins, being under low pressure, could simply be pulled out, with hemostasis achieved by means of pressure and elevation, and in the latter part of the twentieth century “stab-avulsion” or “microphlebectomy” techniques were adopted, allowing superﬁcial varicosities to be removed using incisions of a few millimeters in length on an ambulatory basis. Sclerotherapy was ﬁrst described in 1864.36 Although liquid sclerotherapy and stab-avulsion phlebectomy probably remain the gold standard in the twenty-ﬁrst century, new techniques such as endovenous ablation and foam sclerotherapy have arisen to further simplify and/or improve the results of these techniques.

CHRONIC VENOUS DISEASE As discussed above, the observation that venous ulceration and edema are made worse with standing seems to have been made well before the birth of Christ. Compression therapy is mentioned in the Old Testament (Isaiah I: 6), and Roman foot soldiers knew that tightly wrapping their legs alleviated discomfort induced by prolonged standing. Both Celsus (before Christ) and Chauliac (1363) used

Figure 1.5 Votive offering from a grateful Greek patient to his doctor, apparently commemorating successful treatment of a varicose vein. From Bergan.3

linen and plaster wraps for chronic venous disease, obviously antedating Unna by many centuries. Apart from its spelling, Paré’s observation in the sixteenth century that “[in bandaging, wrap] the leg beginning at the foote and ﬁnishing at the knee, not forgetting a little bolster upon the varicose veins” remains an absolutely perfect statement today.3 Brodie (1846) was the ﬁrst to succinctly describe the signs and symptoms of chronic venous insufﬁciency in a scientiﬁc manner and described visible superﬁcial venous reﬂux. Following was Trendelenburg’s classic clinical test to distinguish superﬁcial from deep reﬂux in 1891.3,37 Once again, Homans was among the ﬁrst to accurately describe the relationship between varicose veins, deep venous thrombosis, and venous ulceration. He also pointed out that valvular incompetence does not necessarily have to follow deep venous thrombosis.35 Interestingly, he also seems to have been the ﬁrst to point out [anticipating the results of the North American

Chronic venous disease 7

subfascial endoscopic perforator surgery (SEPS) registry by many decades] that venous ulcers behave quite differently whether they are associated with superﬁcial reﬂux only or follow deep vein thrombosis and recanalization.38 Although many others contributed, it was Linton in 1953 who most eloquently described what has become the best-accepted modern pathophysiologic theory of chronic venous ulceration and dermatitis, apparently coining the term “ambulatory venous hypertension” in the process.39 As discussed above, even the Romans empirically knew the value of compression therapy for venous insufﬁciency. Richard Wiseman, surgeon to Charles II king of Great Britain and Ireland, introduced a lace-up boot for venous compression for “varicose ulcers” in 1676 (Fig. 1.6),3 and Gay coined the term “venous ulcer” in 1867 and pointed out that such ulcers can occur in the absence of varicose veins.40 Unna’s boot, a combination of a moist, occlusive dressing and leg compression, was described in 1854 and remains effective and thus modern.41

Figure 1.6 Compression boot developed by Wiseman, surgeon to Charles II (c. 1676), consisting of a laced-up soft leather boot. From Bergan.3

Elastic stockings were ﬁrst introduced in the twentieth century when such ﬁbers became available. The original stockings were crude “one-size-ﬁts-all” and did not signiﬁcantly improve outcome. Conrad Jobst, a successful engineer, developed refractory varicose veins and ulcerations in the 1930s, apparently suffering recurrences and non-healing despite superﬁcial venous ablation. He noticed that his symptoms were alleviated while standing in his pool, and came to the conclusion that the graduated pressure naturally created by the increasing depth of the water was the “active ingredient” involved. After experimentation and invention, he made his own graduated compression stockings, which promptly alleviated his symptoms.42 Despite other advances, graduated compression stockings remain the essential and most widely accepted therapeutic option for chronic venous insufﬁciency today. Operative therapy for hemodynamically signiﬁcant venous disease also dates from the early part of the twentieth century. It is hard to pinpoint exactly when saphenous vein incompetence was recognized as the cause of chronic venous disease, but Trendelenburg advocated saphenofemoral junction ligation in 1891.43 Long the standard of care, simple ligation was increasingly recognized as inadequate because of the persistence of peri-junctional branches allowing transmission of reﬂux distally, as well as the not infrequent problem of recanalization. Formal high ligation and stripping of the entire great saphenous vein became the standard of care for this reason in the last few decades of the twentieth century, modiﬁed in turn to the level of the knee only in order to reduce the problem of saphenous neuralgia. Within the past decade less invasive intraluminal techniques for ablating the vein in situ, such as radiofrequency ablation (RFA) and endovenous laser ablation therapy (EVLT) have very quickly become standard therapy. With good long-term results, minimal morbidity, and the ability to perform these interventions under tumescent anesthesia, these techniques have replaced conventional saphenous stripping in many practices.44,45 It is interesting to note that we have come full circle – maintaining patency of the epigastric vein is now our goal, but enough time has not yet elapsed to tell what the long-term recurrence rate will be. Gay described the perforators in 1867,40 and although perforator interruption had apparently been practiced before, Robert Linton ﬁrst widely publicized the procedure in 1938.46 Originally involving three separate incisions as well as ligation of the superﬁcial femoral vein, the “modern” Linton procedure eventually included division of the medial perforators only.39 Of course, wound complications proved the major problem, which prompted Linton to carefully note that all ulcers must be healed and the skin in as good a condition as possible before proceeding. Galen (AD 130–200) said “The veins lying above it which were varicose, were excised. Immediately the ulcer healed, yet the incision … did not

8

Venous and lymphatic disease: a historical review

get well.”6 Although not describing perforators, he very nicely expresses the problem at hand. Modiﬁcations were designed to reduce wound complications, including DePalma’s parallel transverse incisions and Rob and Felder’s posterior, “stocking-seam” approach,6 but operative perforator ligation remained morbid and cumbersome, and hence little used by the majority of surgeons. Edwards47 ﬁrst seems to have thought of dividing the perforators through a remote incision. His technique was to blindly shear the perforators with a “phlebotome” inserted proximally into the superﬁcial posterior compartment, and the results were acceptable. With the advent of improved technology and familiarization with endoscopic techniques, attention shifted to this method as a way of gaining visual access to the perforators without a long incision (Fig. 1.7). Extensive clinical work has been carried out by Hauer, Rhodes, and Gloviczki, O’Donnell and Iafrati, Bergan, and Padberg, among others, in the USA, and by groups in Germany, England, and the Netherlands.48,49 Although proponents of SEPS believe it offers signiﬁcant clinical beneﬁt over non-operative therapy and superﬁcial venous ablation alone, this has not been proven. Within the past few years, RFA and EVLT have been used to ablate incompetent perforators, as well, and their roles will be clariﬁed as results accumulate. Efforts have also been directed toward correction of incompetence in the deep system, by means of direct valvular reconstruction (Kistner) or transposition of a venous segment bearing functional valves (Raju and others), techniques that date from the 1970s and 80s, respectively.50,51 Bypass for occluded infrainguinal veins (most commonly the superﬁcial femoral vein) was ﬁrst discussed as early as 1954,52 and popularized in the 1970s as the May–Husni operation.53 Crossover femoral grafts (the contralateral saphenous; Palma operation; ipsilateral

saphenous, or even prosthetic) with or without arteriovenous ﬁstulae for iliac occlusion were similarly popularized in the 1960s54 and continue to be performed today in appropriate settings.

EFFORT THROMBOSIS Venous thrombosis of the upper extremity was ﬁrst described by Paget and von Schröetter in 1875 and 1884, respectively,55 but seems not to have been widely recognized as an important clinical entity until 1949,56,57 even though the observation that intermittent axillosubclavian venous obstruction can be caused by careful positioning of the arm in a substantial number of persons had been recognized in late 1930s.58 Because exercise is often associated with its acute clinical presentation or exacerbates chronic symptoms, this entity is today most commonly referred to as “effort thrombosis.”56 Treatment was originally entirely conservative, but after it became apparent that these patients have a substantial risk both of pulmonary embolus and functional morbidity, anticoagulation was adopted.57 What differentiates these patients from those with a lower extremity clot, however, is that there is a correctable causative factor, compression at the thoracic outlet, in many or most such patients. In the 1980s and 1990s, various methods for alleviating this compression, usually by resection of the ﬁrst rib or medial clavicle, sometimes combined with venous thrombectomy, were used. With the advent of thrombolysis and its success in this situation, a more aggressive attempt to clear the axillary vein of thrombus and subsequently relieve the compression and reconstruct the vein, if necessary, has become the standard of care.59 Although several controversies regarding details remain, the results in general are quite good.60,61

LYMPHATIC DISEASE

Figure 1.7 Illustration of a venous perforator, exposed endoscopically, being identiﬁed, clipped, and divided.

Once again, it was Hippocrates who seems to have ﬁrst left a historical record of the lymphatics, describing “glands, that everybody has in the armpit” and “white blood.”62 Although several others described lymphatics before the birth of Christ, the discovery of the lymphatic system in a scientiﬁcally accurate sense is attributed to Asellius, who observed and described the mesenteric lymphatic in a wellfed dog. Pecquet subsequently described the cysterna chyli and thoracic duct (1651), while Bartholin (1653) and Rudbeck (1942) clariﬁed the anatomy of the major lymphatic structures (Fig. 1.8). Finally, Hunter in the eighteenth century, Starling in the nineteenth, and Rusznyák, Földi, and Szabó in the twentieth all elucidated modern concepts of lymphatic physiology.7 Diagnosis and treatment of lymphatic disorders have only been relatively recent developments. Direct contrast

References 9

drainage, either by direct lymphatic reconstruction66 or transposition of lymphatic-rich tissues67,68 to drainage basins, have been described since the 1970s, but only a few centers have had much experience with them. “Reduction,” or debulking operations, have been performed since the early 1900s. Early attempts involved complete excision of all tissue, including skin, to the level of the fascia, with reconstruction by grafting. Originally described by Charles in 1912 and still bearing his name, this procedure is still sometimes used today for selected patients.69 Thompson70 described (in 1962) and later popularized his “buried dermal ﬂap” procedure, designed both to debulk the limb and provide improved drainage, and Sistrunk71 described a straight debulking procedure for excision of the involved tissue alone. Homans72 modiﬁed and popularized this procedure in 1936, and it now bears his name and has become the most commonly used debulking operation in this situation.

SUMMARY

Figure 1.8 One of Bartholin’s illustrations (1653) depicting the cysterna chyli and thoracic duct. From Gloviczki.7

Venous and lymphatic disease certainly deserves a prominent position as one of the medical conditions best known in antiquity. Although names such as Hunter, Virchow, Homans, Linton, Jobst, and others are rightly associated with modern knowledge in this ﬁeld, so too are Hippocrates, Celsus, Estienne, and the anonymous Greeks, Romans, and Arabs whose writings have survived to this day. Although progress continues, sparked in part by the increasing operative options available for both problems, it is impressive to note how well developed the knowledge was regarding the pathophysiology and treatment of venous and lymphatic problems even before the scientiﬁc age.

REFERENCES lymphangiography was the ﬁrst diagnostic method investigated, being ﬁrst described in 1944,63 but it is now felt to contribute to further lymphatic damage. For this reason, lymphoscintigraphy, ﬁrst described by Taylor64 in 1957, has become the diagnostic test of choice. Although his original report described injection of 131I-labeled protein, imaging today is usually performed using 99technetium. Treatment of lymphedema in antiquity is not widely described (perhaps because the entity was confused with or lumped together with venous insufﬁciency), although undoubtedly elevation and compression therapy were used. Modern treatment strategies designed to directly treat the swelling itself date from the 1960s and 1970s, when various algorithms, including manual lymphatic drainage and general limb massage, pneumatic compression devices, simple and adjustable compression stockings, and elevation were all used in various protocols.63,65 Operative attempts to improve lymphatic

1. Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J 1985; 290: 1855–6. 2. Coon WW, Willis PV, Keller JB. Venous thromboembolism and other venous diseases in the Tecumseh community health study. Circulation 1973; 48: 838–46. 3. Bergan JJ. Historical highlights in treating venous insufﬁciency. In: Bergan JJ, Yao JST, eds. Venous Disorders. Philadelphia, PA: WB Saunders, 1991: 3–15. 4. Gloviczki P. Management of venous disorders: Introduction and general considerations. In: Rutherford RB, ed. Vascular Surgery, 6th edn. Philadelphia, PA: Elsevier Saunders, 2005: 2111–23. 5. DeWeese JA. Treatment of venous disease: the innovators. J Vasc Surg 1994; 20: 675–83. 6. Bergan JJ, Ballard JL. Historical perspectives. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer-Verlag, 1998: 1–13.

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Venous and lymphatic disease: a historical review

7. Gloviczki P. The management of lymphatic disorders. Lymphedema: an overview: In: Rutherford RB, ed. Vascular Surgery, 6th edn. Philadelphia, PA: Elsevier Saunders, 2005: 2111–23; 1883–8. 8. Yao JST. Presidential address: venous disorders – reﬂections of the past three decades. J Vasc Surg 1997; 26: 727–35. 9. Scultetus AH, Villavicencio L, Rich NM. Facts and ﬁction surrounding the discovery of the venous valves. J Vasc Surg 2001; 33: 435–41. 10. Padberg FT. Improving management of chronic venous disorders: Exploration, description, and understanding – parallels in the worlds of the Renaissance and the American Venous Forum. J Vasc Surg 2005; 41: 355–65. 11. Caggiati A, Bertocchi P. Regarding “fact and ﬁction surrounding the discovery of the venous valves.” J Vasc Surg 2001; 33: 1317 [and reply]. 12. Adams F. The Genuine Works of Hippocrates. Baltimore, MD: Williams and Wilkins, 1939: 333. 13. Dodd H, Cockett FB. The Pathology and Surgery of the Veins of the Lower Limb. Edinburgh: E&S Livingstone, 1956: 8. 14. Virchow R. Neuer fall von todlicher Emboli der Lungenarterie. Arch Path Anat 1856; 10: 225–8. 15. Homans J. Thrombosis of the deep veins of the lower leg, causing pulmonary embolism. N Engl J Med 1934; 211: 993–7. 16. Homans J. Thrombophlebitis of the leg. N Engl J Med 1938; 218: 594–9. 17. Homans J. Exploration and division of the femoral and iliac veins in the treatment of thrombophlebitis of the leg. N Engl J Med 1941; 224: 179–86. 18. Barner HB, DeWeese JA. An evaluation of the sphygmomanometer pain test in venous thrombosis. Surgery 1960; 48: 915–24. 19. Neiman HL. Phlebography in the diagnosis of venous thrombosis. In: Bergan JJ, Yao JST, eds. Venous Problems. Chicago, IL: Year Book Medical Publishers, 1978: 111–22. 20. Brodie TG, Russell AE. On the determination of the rate of blood ﬂow through an organ. J Physiol 1905; 32: 47P. 21. Eriksson E. Plethysmographic studies of venous diseases of the legs. Acta Chir Scand 1968; 398 (Suppl): 7–18. 22. Mullick SC, Wheeler HB, Songster GP. Diagnosis of deep venous thrombosis by measurement of electrical impedance. Am J Surg 1970; 119: 417–22. 23. Gomez RL, Wheeler HB, Belko JS, Warren R. Observations on the uptake of a radioactive ﬁbrinolytic enzyme by intravascular clots. Ann Surg 1963; 158: 905–11. 24. Satomura, S. Study of the ﬂow patterns in peripheral arteries by ultrasonics. J Acoust Soc Japan 1959; 15: 151. 25. Sigel B, Popky GL, Boland JP, et al. Diagnosis of venous disease by ultrasonic ﬂow detection. Surg Forum 1967; 18: 185–7. 26. Strandness DE, Sumner DS. Ultrasonic velocity detector in the diagnosis of thrombophlebitis. Arch Surg 1972; 104 (2): 180–3. 27. Homans J. Diseases of the veins. New Engl J Med 1944; 231 (2): 51–60.

28. DeWeese JA, Jones TI, Lyon J, Dale WA. Evaluation of thrombectomy in the management of iliofemoral venous thrombosis. Surgery 1960; 47 (1): 140–59. 29. Johnsson H, Schulman S. Anticoagulation treatment in deep vein thrombosis. In: Eklöf B, Gjores JE, Thulesius O, Bergqvist D, eds. Controversies in the Management of Venous Disorders. London; Butterworth, 1989: 105–14. 30. Illig KA, DeWeese JA. Operative inferior vena caval interruption. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery, 4th ed. St Louis, MO: Mosby, 2001; 892–4. 31. Barker WF, Hickman EB, Harper JA, Lungren J. Venous interruption for pulmonary embolism: the illustrative case of Richard M. Nixon. Ann Vasc Surg 1997; 11: 387–90. 32. Mobin-Uddin H, McLean R, Bolooki H, Jude JR. Caval interruption for prevention of pulmonary embolism. Arch Surg 1969; 99: 711–5. 33. Whitehill TA. Caval interruption methods: comparison of options. Sem Vasc Surg 1996; 9 (1): 59–69. 34. Semba CP, Dake MD. Venous thrombolysis. In: Ouriel, K, ed. Lower Extremity Vascular Disease. Philadelphia, PA: WB Saunders, 1995: 321–30. 35. Homans J. The operative treatment of varicose veins and ulcers, based upon a classiﬁcation of these lesions. Surg Gyn Obstet 1916; 22: 143–58. 36. Browse NL, Burnand KG, Lea TM. Diseases of the Veins. London: EH Arnold, 1988: 1–21. 37. Green RM, Ouriel K. Venous and lymphatic disease. In: Schwartz SI, Shires GT, Spencer FC, eds. Principles of Surgery, 7th ed. New York; McGraw-Hill, 1999: 1005–32. 38. Homans J. The etiology of treatment of varicose ulcer of the leg. Surg Gyn Obstet 1917; 24: 300–11. 39. Linton RR. The post-thrombotic ulceration of the lower extremity: its etiology and surgical treatment. Ann Surg 1953; 138: 415–32. 40. Wittens CHS, Pierik RGJM, van Urk H. The surgical treatment of incompetent perforating veins. Eur J Vasc Endovasc Surg 1995; 9: 19–23. 41. Kitka MJ, Schuler JJ, Meyer JP, Durham JR, EldrupJorgensen J, Schwarcz TH, Flanigan DP. A prospective, randomized trial of Unna’s boots versus hydroactive dressing in the treatment of venous stasis ulcers. J Vasc Surg 1988; 7: 478–86. 42. Bergan JJ. Conrad Jobst and the development of pressure gradient therapy for venous disease. In: Bergan JJ, Yao JST, eds. Surgery of the Veins. Orlando, FL: Grune and Stratton, 1985: 529–40. 43. Trendelenberg F. Uber die Unterbindung der Vena Saphena Magna bie Unterschenkel Varicen. Beitr Z Clin Chir 1891; 7: 195. 44. Lurie F, Creton D, Eklöf B, et al. Prospective randomized study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year followup. Eur J Vasc Endovasc Surg 2005; 29: 67–73. 45. Ravi R, Rodriguez L, Lopez JA, et al. Endovenous ablation of incompetent saphenous veins: a large single-center experience. J Endovasc Ther 2006; 13: 244–8.

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46. Linton RR. The communicating veins of the lower leg and the operative technique for their ligation. Ann Surg 1938; 107: 582–93. 47. Edwards JM. Shearing operation for incompetent perforating veins. Br J Surg 1976; 63: 885–6. 48. Rhodes JM, Gloviczki P, Canton L, et al. Endoscopic perforator vein division with ablation of superﬁcial reﬂux improves venous hemodynamics. J Vasc Surg 28: 839–47. 49. Gloviczki P, Bergan JJ, Rhodes JM, et al. Mid-term results of endoscopic perforator vein interruption for chronic venous insufﬁciency: lessons learned from the North American Subfascial Endoscopic Perforator Surgery registry. J Vasc Surg 1999; 29: 489–502. 50. Kistner RL. Surgical repair of the incompetent femoral valve. Arch Surg 1975; 110: 1336–42. 51. Raju S. Valvuloplasty and valve transfer. Int Angiol 1985; 4: 419–24. 52. Warren R, Thayer T. Transplantation of the saphenous vein for postphlebitic stasis. Surgery 1954; 35: 867–76. 53. Husini EA. In situ saphenopopliteal bypass graft for incompetence of the femoral and popliteal veins. Surg Gyn Obstet 1970; 130 (2): 279–84. 54. Palma EC, Esperon R. Vein transplants and grafts in surgical treatment of the postphlebitic syndrome. J Cardiovasc Surg 1960; 1: 94–107. 55. Adams JT, DeWeese JA. “Effort” thrombosis of the axillary and subclavian veins. J Trauma 1971; 11: 923–30. 56. Kleinsasser L. “Effort” thrombosis of axillary and subclavian veins: analysis of 16 personal cases and 56 cases collected from the literature. Arch Surg 1949; 59: 258–74. 57. Adams JT, McEvoy RK, DeWeese JA. Primary deep venous thrombosis of the upper extremity. Arch Surg 1965; 91: 29–42. 58. McLaughlin CW, Popma AM. Intermittent obstruction of the subclavian vein. JAMA 1939; 113: 1960–3. 59. Green RM. Acute axillosubclavian venous thrombosis: twenty years of progress. In: Yao JST, Pearce WH, eds. Progress in Vascular Surgery. Stamford, CT: Appleton and Lange, 1997: 505–14.

60. Molina JE, Hunter DW, Dietz CA. Paget-Schrotter syndrome treated with thrombolytics and immediate surgery. J Vasc Surg 2007; 45: 328–34. 61. Doyle A, Wolford HY, Davies MG, et al. Management of effort thrombosis of the subclavian vein: today’s treatment. Ann Vasc Surg 2007; 21: 723–9 62. Kanter MA. The lymphatic system: an historical perspective. Plast Reconstr Surg 1987; 79: 131. 63. Gamble GL, Rooke TW, Gloviczki P. Nonoperative management of chronic lymphedema. In: Rutherford RB, ed. Vascular Surgery, 6th ed. Philadelphia, PA: WB Saunders, 2005: 2416–27. 64. Taylor GW, Kinmonth JB, Rollinson E. Lymphatic circulation studied with radioactive plasma protein. Br Med J 1957; 1: 133–7. 65. Felty CL, Rooke TW. Modern treatment of lymphedema. In: Yao JST, Pearce WH, eds. Progress in Vascular Surgery. Stamford, CT: Appleton and Lange, 1997: 535–47. 66. Gloviczki P, Fisher J, Hollier LH, Pairolero DC, Schirger A, Wahner HW. Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 1988; 7: 647–52. 67. Goldsmith, HS. Long-term evaluation of omental transposition for chronic lymphedema. Ann Surg 1974; 180: 847–9. 68. Hurst PAE, Stuart G, Kinnmonth JB, Browse LN. The longterm results of the enteromesenteric bridge operation in the treatment of primary lymphedema. Br J Surg 1985; 72: 272–4. 69. Gloviczki P, Noel A. Surgical treatment of chronic lymphedema and primary chylous disorders. In: Rutherford RB, ed. Vascular Surgery, 6th ed. Philadelphia, PA: WB Saunders, 2005: 2428–46. 70. Thompson N. Surgical treatment of chronic lymphedema of the lower limb. With preliminary report of a new operation. Br Med J 1962; 2: 1566–73. 71. Sistrunk WE. Further experiences with the Kondoleon operation for elephantiasis. JAMA 1918; 71: 800–6. 72. Homans J. The treatment of elephantiasis of the legs. N Engl J Med 1936; 215: 1099–104.

2 Development and anatomy of the venous system PETER GLOVICZKI AND GÉZA MÓZES* *Deceased

Introduction Development of the venous system Anatomy

12 12 14

INTRODUCTION In the last decade, progress in modern imaging studies, such as duplex scanning, three-dimensional computed tomography and magnetic resonance imaging, has provided an improved insight into our understanding of the anatomy of the venous system.1–3 Increasing use of minimally invasive catheter-based therapies has furthermore required a more thorough knowledge of the venous anatomy to optimize outcome and minimize thromboembolic complications. Since the current Terminologia Anatomica4 suggests terms that are frequently different from those used in clinical practice, a new international anatomic terminology has been developed to avoid confusion for those clinicians who treat patients with acute deep vein thrombosis and chronic venous disease.5–7 Recent international efforts have also resulted in a consensus document on duplex anatomy of the venous system of the lower limbs.2 This chapter includes a review of the development of the venous system, followed by a description of the anatomy of the veins of the lower limb and pelvis. We also discuss relevant venous anatomy of the trunk and the upper limbs. The goal of the American Venous Forum is to entice venous specialists around the world to adopt the new terminology of leg veins to improve the safety and outcome of treatments for venous disease and to permit international collaboration and communication among scientists interested in clinical venous research.

DEVELOPMENT OF THE VENOUS SYSTEM Primitive vascular channels in the limb ﬁrst appear in the third week of gestation. During development, the vascular system undergoes differentiation through multiple stages,

Histology References

21 23

ﬁrst described by Woolard8 in 1922. Stage 1 is the undifferentiated stage, with only a capillary network being present. Stage 2 is the retiform stage, when large plexiform structures can be seen, and by the third week of gestation Stage 3, the maturation stage, includes the development of large channels, arteries, and veins. Vascular endothelial growth factor (VEGF) secreted by keratinocytes has been found to induce the penetration of capillary vessels into the avascular epidermis.9 The venous system ﬁrst appears in the trunk as bilaterally symmetrical vessels, with the left vessels regressing and the right vessels dominating as the superior and inferior vena cavae.10 These patterns of development lend themselves to the anatomic variants found among individuals.

Veins of the trunk SUPERIOR VENA CAVA AND TRIBUTARIES

Blood is initially returned to the heart tube via the paired sinus venosus.11 The portion of the body cranial to the developing heart drains through the bilateral anterior cardinal veins, and the caudal portion of the body drains forward through the bilateral posterior cardinal veins (Fig. 2.1). The anterior and posterior cardinal veins join to form the common cardinal veins, with the right and left common cardinal veins draining centrally into the sinus venosus. The common cardinal veins also receive the vitelline and umbilical veins; the vitelline veins form later into the hepatic portal system. The anterior cardinal veins connect the left anterior cardinal vein with the right anterior cardinal vein. This left to right channel becomes the left brachiocephalic vein. The portion of the left anterior cardinal vein caudal to this

Development of the venous system 13

Figure 2.1 Development of the major veins. (Redrawn from Avery LB. Developmental Anatomy, revised 7th edn. Philadelphia W.B. Saunders, 1974.)

anastomosis regresses but does not disappear; it forms the oblique vein of the left atrium (vein of Marshall) and the coronary sinus. Persistence of the left caudal anterior cardinal vein results in a double superior vena cava (Fig. 2.2a).3 In the absence of the right proximal superior vena cava; the blood from the right upper body is drained into a left superior vena cava (Fig. 2.2b). INFERIOR VENA CAVA AND TRIBUTARIES

The inferior vena cava develops from multiple segments. The paired posterior cardinal veins originally extend into the region that will become the pelvis, and are joined together at the iliac anastomosis (Fig. 2.1). Most of the posterior cardinal veins disappear; the most cranial portion on the right persists as the arch of the azygos. The very caudal portion of the posterior cardinal veins and iliac anastomosis form the common, external, and internal iliac veins and the median sacral vein. The posterior cardinal veins are mostly replaced by the ventral subcardinal and the dorsal supracardinal veins. Drainage of the more

Figure 2.2 Anomalies of the vena cava. (a) double superior vena cava; (b) left superior vena cava; (c) double inferior vena cava; (d) left inferior vena cava. (a, b) posterior view; (c, d) anterior view.

14

Development and anatomy of the venous system

cranial region of the abdomen goes mostly into the subcardinal and that of the more caudal portion into the supracardinal veins. Most of the azygos system develops from the supracardinal veins. Lastly, veins of the left side generally regress resulting in a right-sided inferior vena cava. The most inferior portion of the inferior vena cava, the post-renal segment, develops from the right supracardinal vein; therefore, it is relatively posterior in position. This is demonstrated by the conﬂuence of the common iliac veins forming behind the common iliac arteries. At the level of the kidneys, the inferior vena cava is formed from the right sub-supracardinal anastomosis (renal segment), thereby becoming more anterior in position. Above the kidneys, the inferior vena cava is formed from the right subcardinal vein (prerenal segment), which is still more anterior as is demonstrated by the inferior vena cava diverging anterior to the aorta. The hepatic segment of the inferior vena cava is formed directly by hepatic sinusoids. Since the inferior vena cava develops from bilateral veins, with the right veins usually persisting, variations are to be expected, although they are unusual. If the right subcardinal vein fails to make a connection with the liver, absence of the suprarenal inferior vena cava results, so that the inferior vena cava drains into the arch of the azygos and the hepatic veins drain independently through the diaphragm to the right atrium.3 Double inferior vena cava (2–3%) occurs usually in the infra-renal portion because of bilateral persistence of the supracardinal veins (Fig. 2.2c). A left inferior vena cava (< 0.5%) results from caudal regression of the right supracardinal vein with persistence of the left supracardinal vein (Fig. 2.2d). Renal vein anomalies include the persistent (circumaortic) renal collar (1–9%) and the posterior (retroaortic) left renal vein (1–2%) (Fig. 2.3).

Veins of the limbs The general pattern for the development of the vasculature of the limbs begins as a ﬁne capillary network arising from several segmental branches of the aorta. As the limb begins to extend from the body, a channel from within this network predominates as the axial or central artery. The blood returning to the body from capillary networks is ﬁrst collected in a marginal sinus that extends around the apex of the limb bud, just deep to the apical ectodermal ridge. The capillary networks and the marginal sinus itself send out new vascular sprouts in response to growth of the limbs. Early on, blood drains from the marginal sinuses of the limbs into superﬁcial venous plexuses of the body, but the blood is progressively shunted into deeper channels as development progresses and deep veins, frequently paired, develop along major arteries. Valves form in the veins relatively early. It is thought that the deﬁnitive number of valves is reached by the sixth month of fetal life. Development of the veins of the limb is likely preceded by development of major nerves. Gillot proposed that venous development is induced by major nerves; in the embryo, these angioguiding nerves are the femoral, the sciatic and the posterior femoral cutaneous nerves.3,12 Many of the embryonic veins regress during development; their persistence (sciatic vein, lateral marginal vein, etc.) is, however, frequently seen in patients with venous malformations.13–16 The axial artery of the upper limb forms the brachial artery in the arm and the interosseous artery in the forearm, with the ulnar and radial arteries forming later. As the digits are forming, the apical marginal sinus regresses, but the proximal marginal channels persist as the cephalic and basilic veins.

ANATOMY Veins of the lower extremity

Figure 2.3 Circumaortic renal collar.

The veins of the lower extremity are composed of the superﬁcial, the deep and the perforating veins. Perforating veins connect the superﬁcial to the deep venous system. They pass through the deep fascia which separates the superﬁcial compartment from the deep. Communicating veins connect veins within the same system. Recent development of evaluation of the veins with duplex scanning resulted in recognition of the saphenous subcompartment and the saphenous fascia.1,2,7 The saphenous fascia covers the saphenous subcompartment and separates the great saphenous vein from other veins in the superﬁcial compartment. Bicuspid valves are important structures in the leg veins, assisting unidirectional ﬂow in the normal venous system.

Anatomy 15

Figure 2.4 Venous networks in the lower extremity. Capillaries of dermal papillae are drained by the subpapillary venous plexus, which in turn joins to the reticular venous plexus. Superﬁcial veins (a) drain dermal veins and empty into the deep axial veins through direct perforating veins (b). Perforating veins communicate with each other through small branches. Muscular venous sinuses ﬁll from the superﬁcial veins or from the reticular venous plexus through indirect perforating veins (c) and they are drained into the deep axial veins.

Cutaneous microcirculation Cutaneous branches of arteries reach the skin either directly or following the penetration of skeletal muscles. In the skin, the arterioles form a reticular and a more superﬁcial subpapillary dermal plexus.17 Capillary loops of the dermal papillae emerge from the latter plexus and drain through venules into the subpapillary venous plexus, which again drains into the deeper reticular venous plexus at the dermal–subcutaneous junction (Fig. 2.4). Vertically oriented, small-valved veins connect the reticular venous plexus to the superﬁcial veins.

The GSV begins just anterior to the medial ankle, crosses in front of the tibia and ascends medial to the knee (Fig. 2.6). Proximal to the knee, the GSV ascends on the medial side of the thigh and enters the fossa ovalis 3 cm inferior and 3 cm lateral to the pubic tubercle. The GSV is doubled in the calf in 25% of the population and in the

Superficial veins of the leg Few veins of the human body have more variability in their gross anatomy than the superﬁcial veins of the leg. Superﬁcial veins, the great and the small saphenous veins and their tributaries, course in the subcutaneous fat outside the deep fascia and drain blood from the skin and subcutaneous tissues (Figs 2.5 and 2.6, Table 2.1).17–20 The superﬁcial venous system of the foot is divided into the dorsal and plantar subcutaneous venous network (Fig. 2.5). Superﬁcial vein tributaries drain blood into the dorsal venous arch on the dorsum of the foot at the level of the proximal head of the metatarsal bones. The medial and lateral end of this arch continues through the medial and lateral marginal vein into the great saphenous vein (GSV) and small saphenous vein (SSV), respectively.

Figure 2.5 Superﬁcial and perforating veins of the foot.

16

Development and anatomy of the venous system

Table 2.1 New terminology of lower extremity veins Old, historic terms or eponyms Superﬁcial femoral vein Greater or long saphenous vein Lesser or short saphenous vein Saphenofemoral junction Giacomini’s vein Posterior arch vein or Leonardo’s vein Cockett perforators (I, II, III) Boyd’s perforator Sherman’s perforators “24 cm” perforators Hunter’s and Dodd’s perforators May’s or Kuster’s perforators

Figure 2.6 Medial superﬁcial and perforating veins of the leg.

thigh in 8%.18 The saphenous nerve runs in close proximity to the GSV in the distal two-thirds of the calf. The accessory great saphenous veins are frequently present and run parallel to the GSV both in the thigh and in the

“New” terms Femoral vein Great saphenous vein (GSV) Small saphenous vein (SSV) Conﬂuence of the superﬁcial inguinal veins Intersaphenous vein Posterior accessory great saphenous vein of the leg Posterior tibial perforators (lower, middle, upper) Paratibial perforator (proximal) Paratibial perforators Paratibial perforators Perforators of the femoral canal Ankle perforators

leg. The veins lie anterior, posterior or superﬁcial to the main trunk. The posterior accessory GSV of the leg (Leonardo’s vein or posterior arch vein) is a common tributary, it begins posterior to the medial malleolus and ascends on the posteromedial aspect of the calf to join the GSV distal to the knee (Fig. 2.6). The anterior accessory GSV of the leg drains the anterior aspect of the leg below the knee. The posterior accessory GSV of the thigh, if present, drains the medial and posterior thigh.11 The anterior accessory GSV of the thigh collects blood from the anterior and lateral side of the thigh (Fig. 2.6). The anterior and posterior accessory GSVs join the GSV just before it ends at the conﬂuence of superﬁcial inguinal veins (saphenofemoral junction) (Fig. 2.7). The superﬁcial circumﬂex iliac, superﬁcial epigastric, and external pudendal veins join each other and the distal GSV to form the conﬂuence of superﬁcial inguinal veins (saphenofemoral junction). Rarely, the GSV terminates high on the lower abdomen or joins the femoral vein very low and the superﬁcial inguinal veins empty individually into the femoral vein. Other occasional tributaries of the GSV in the groin include the posterior and anterior thigh circumﬂex veins The SSV lies lateral to the Achilles tendon in the distal calf (Fig. 2.8). In the lower two-thirds of the calf, the SSV runs in the subcutaneous fat and then pierces the fascia to run between the two heads of the gastrocnemius muscle.20 In the popliteal fossa at about 5 cm proximal to the knee crease, the main trunk of the SSV drains into the popliteal vein. A smaller vein, the cranial extension of the SSV, frequently continues in a cephalad direction. Uncommonly, the main trunk of the SSV continues without draining into the popliteal vein and eventually empties into the femoral vein or GSV. The intersaphenous vein (vein of Giacomini) is a communicating vein connecting the SSV to the GSV in the posteriomedial thigh; this vein, present in two-thirds of limbs with venous

Anatomy 17

Figure 2.7 Most common anatomic variations of the conﬂuence of superﬁcial inguinal veins. (a) 33%; (b) 15%; (c) 15%; (d) 13%).

Figure 2.9 Deep and perforating veins of the lower extremity.

Figure 2.8 Posterior superﬁcial and perforating veins of the leg.

disease, usually ascends subfascially and perforates the fascia to join the superﬁcial system.21 The sural nerve courses along the SSV in the distal calf. Superﬁcial veins of the lateral leg and thigh form the lateral venous system. The lateral venous system is drained through multiple small tributaries into the GSV and SSV or through perforating veins into the deep system. In the superﬁcial veins, bicuspid valves secure unidirectional venous blood ﬂow towards the heart. There are more constant valves, which are usually placed at the termination of the major venous trunks. These valves have strong, white cusps and marked sinusoid dilatation of the venous wall at the origin of the valves. Other valves are delicate, almost transparent structures. In the GSV, there are usually at least six valves (maximum 14–25). A constant valve is present in the GSV within 2–3 cm to the saphenofemoral junction in about 85% of veins.22 The frequency of valves is greater below than above the knee. In the SSV, valves are numerous (median 7–10, range 4–13) and more closely spaced. The highest valve is usually

18

Development and anatomy of the venous system

Figure 2.10 Relation of the medial direct perforating veins to the deep and superﬁcial posterior fascial compartments (SPCs). PTVs, posterior tibial veins.

situated close to the termination of the small saphenous vein. Valves in communicating tributaries between the two saphenous veins are always oriented to direct blood from the SSV to the GSV.

Deep veins of the leg Deep veins accompany the corresponding arteries, frequently in a paired fashion. On the sole, the richly anastomosing deep plantar venous arch collects blood from the toes and the metatarsals. The deep plantar venous arch continues into the medial and lateral plantar veins, which become the posterior tibial veins behind the medial ankle (Fig. 2.9). On the dorsum of the foot, the major deep veins, the dorsalis pedis veins, continue into the anterior tibial veins. In the calf, the paired posterior tibial veins run between the edges of the ﬂexor digitorum longus and tibialis posterior muscles and under the fascia of the deep posterior compartment (Fig. 2.10). They drain the muscles of the deep and superﬁcial posterior compartments and are connected to the GSV and posterior accessory saphenous vein by perforators. The posterior tibial veins pierce the soleus muscle close to its bony adherence (soleal arcade) and continue into the popliteal vein. The anterior tibial veins ascend in the anterior compartment. Distally there is a constant connection between the anterior tibial and the peroneal veins. The peroneal veins originate in the distal third of the calf and ascend deep to the ﬂexor

hallucis longus muscle. They receive the peroneal perforators and several large veins from the soleus muscle. The posterior tibial and peroneal veins form the short tibioperoneal trunk which joins the anterior tibial veins to form the popliteal vein. The popliteal and femoral veins are usually duplicated in segments of various lengths and form a plexus around the corresponding arteries similarly to the deep veins of the calf (Fig. 2.9). The gastrocnemius vein and the SSV are the main tributaries of the popliteal vein. In the adductor canal, the popliteal vein becomes the femoral vein and runs initially lateral and then medial to the femoral artery. The femoral vein unites with the profunda femoris (deep femoral) vein at about 9 cm below the inguinal ligament. In the adductor canal or sometimes more distally, there is a consistent (~84%) anastomosis between the profunda femoris and the femoral or popliteal veins that provides an important collateral channel in case of deep venous thrombosis. The common femoral vein is the continuation of the femoral vein after it joins the deep femoral vein. The GSV empties into the common femoral vein at the conﬂuence of the superﬁcial inguinal veins. Further tributaries of the common femoral vein are the lateral and medial circumﬂex femoral veins, which can anastomose with the internal iliac vein. The common femoral vein is medial to the corresponding artery and ends at the inguinal ligament where it continues as the external iliac vein. The frequency of valves in deep veins increases from proximal to distal. Deep veins of the foot, the posterior

Anatomy 19

and anterior tibial, and the peroneal veins are profusely valved, containing valves at about 2 cm intervals. The popliteal vein and the most distal part of the femoral vein have usually one or two valves. There are an additional three or more valves in the femoral vein up to the junction with the profunda femoris vein. One of these valves is constantly (~90%) found just distal to this junction.23 In the common femoral vein there is usually only one valve. It is important to emphasize that in the external iliac and common femoral veins proximal to the saphenofemoral junction there is only one valve or, in 37% of cases, there is no valve at all. The common iliac and cava veins are valveless.

Perforating veins There are more than 150 perforating veins (PVs) in the lower extremity; however, the medial PVs are most signiﬁcant and have been the center of debate for decades.24–32 Their role in the development of chronic venous insufﬁciency and venous ulcers is still not well deﬁned. Signiﬁcant variation exists in the location of leg perforators; however, distribution of clusters of PVs follows a predictable pattern (Table 2.2). Dorsal, plantar, medial, and lateral foot perforators are the main groups of PVs in the foot. A large PV runs between the ﬁrst and second metatarsal bones and connects the superﬁcial dorsal venous arch to the pedal vein. Clusters of PVs at the ankle are the anterior, medial and lateral ankle perforators . The medial calf perforators have two groups: posterior tibial and paratibial PVs. Three groups (lower, middle, upper) posterior tibial PVs (Cockett I–III perforators) connect the posterior accessory GSV to the posterior tibial veins (Fig. 2.10). The paratibial perforators drain the GSV into the posterior tibial veins. Other perforators of the leg below the knee are the anterior, lateral, medial, and lateral

gastrocnemius, intergemellar, and Achillean PVs . Infra- and suprapatellar and popliteal fossa PVs are located around the knee. Perforators of the femoral canal connect tributaries of the GSV to the femoral vein (Fig. 2.9). Inguinal perforators drain into the femoral vein in the proximal thigh.

Venous sinuses of calf muscles Venous sinuses are thin-walled, large veins in the calf muscles. They have a capacity to hold great volumes of venous blood. They are embedded in skeletal muscles which contract rhythmically during ambulation; therefore, they serve as “chambers” of the “peripheral heart,” the calf muscle pump. The soleus muscle is particularly rich in venous sinuses; it may contain 1–18 such sinuses. They are less developed in the gastrocnemius muscle. Venus sinuses are ﬁlled from the superﬁcial veins and from the reticular venous plexus through indirect, muscular perforators and from the muscles through postcapillary venules and small muscular veins. Venous sinuses of the soleus muscle are drained into the posterior tibial and peroneal veins by the soleus veins (Fig. 2.9). Soleus veins are large, short, and tortuous to accommodate the considerable range of muscular movements. In the lower third of the leg, soleus veins frequently join directly into perforating veins before entering the deep veins. Bilateral gastrocnemius veins draining the two heads of the gastrocnemius muscle usually empty into the popliteal vein, distal to the conﬂuence of the small saphenous vein with the popliteal trunk (Fig. 2.9). The venous sinuses themselves are valveless; however, the small intramuscular veins linking them and the muscular veins draining venous sinuses into the deep veins contain numerous valves. Indirect perforating veins feeding venous sinuses are also valved. Valvular competence plays a critical role in the efﬁcient work of the calf muscle pump.

Table 2.2 Studies on the location of direct medial perforating veins in the leg First author (year)

Number of legs Anatomic Surgical dissections ﬁndings

Linton (1938) Sherman (1948) Cockett (1953) O’Donnell (1977)

10 92 21 –

50 901 201 39

Fischer (1992) Mózes (1996)

– 40

194 –

middle posterior tibial perforator

Location of medial perforating veins* upper posterior proximal paratibial perforating tibial perforator veins

Distal third of the leg Middle third of the leg Proximal third of the leg 13.5 cm 18.5 cm 24 cm, 30 cm, 35 cm, 40 cm 13–14 cm 16–17 cm At the knee Half of the incompetent perforating veins is Few incompetent perforating between 10 and 15 cm† (15–20 cm*) veins Random distribution of incompetent perforating veins 7–9 cm† (12–14 cm*) 10–12 cm† (15–17 cm*) 18–22 cm,† 23–27 cm,† 28–32 cm† (23–27 cm*), (28–32 cm*), (33–37 cm*)

*Distances measured from the sole. †Distances measured from the lower tip of the medial malleolus.

20

Development and anatomy of the venous system

Veins of the abdomen and pelvis The external iliac vein begins at the inguinal ligament, courses along the pelvic brim, and ends anterior to the sacroiliac joint by joining the internal iliac to form the common iliac vein.33 Its tributaries are the (deep) inferior epigastric, the deep circumﬂex iliac and the pubic veins, which freely anastomose with the corresponding superﬁcial veins and with the obturator vein. The internal iliac vein is a short trunk, formed by the union of its extraand intrapelvic tributaries. The extrapelvic tributaries are the gluteal (superior and inferior), the internal pudendal, and the obturator veins. The gluteal veins anastomose with the medial circumﬂex femoral vein and receive numerous perforating veins from the corresponding superﬁcial veins (Fig. 2.11). Intrapelvic tributaries of the internal iliac vein,

such as the lateral sacral and several visceral (middle rectal, vesical, uterine, and vaginal) veins, drain the presacral venous plexus and the pelvic visceral plexuses (rectal, vesical, prostatic, uterine, and vaginal). These plexuses and the additional superﬁcial (pudendal) plexus provide free communication for venous ﬂow between the two sides of the pelvis.34 The common iliac veins begin at the sacroiliac joints and form a conﬂuence at the right side of the ﬁfth lumbar vertebra to form the inferior vena cava. The only tributary of the right common iliac vein is the right ascending lumbar vein, whereas the left drains the median sacral vein too. The ascending lumbar vein runs vertically along the vertebral column, collects blood from lumbar veins and proximally anastomoses with the azygos system. The inferior vena cava ascends on the right side of the vertebral column and terminates in the right atrium soon after passing through the diaphragm (Fig. 2.11). Its tributaries are the lumbar veins, the right gonadal vein, the renal veins, the right suprarenal, the right inferior phrenic, and the hepatic veins. The left gonadal and suprarenal veins join the left renal vein, and the left inferior phrenic opens into the left suprarenal vein. In case of inferior vena cava obstruction, anastomoses between the veins of the chest and abdominal wall (thoracoepigastric, internal thoracic, and epigastric veins), the lumbar–azygos connections and the vertebral plexuses can provide important collateral avenues.

Veins of the upper extremity and the thorax UPPER EXTREMITY VEINS

Figure 2.11 Major veins of the pelvis, abdomen and thorax.

Venous return from the arm is mostly maintained by the work of the heart. Valves do not play an important role in this venous circulation. Deep veins of the arm are paired and follow their corresponding arteries. Perforators between the deep and superﬁcial veins are less numerous in the arm than in the leg. Superﬁcial veins of the upper limb are the cephalic and basilic veins and their tributaries (Fig. 2.12). The dorsal venous plexus of the hand continues into the cephalic vein on the radial and into the basilic on the ulnar side. The cephalic vein begins at the “anatomical snuff box”; it courses over the distal radius to the ventral aspect of the forearm, ascends on the lateral side of the arm and in the deltopectoral groove. It enters the infraclavicular fossa, pierces the clavipectoral fascia, and empties into the axillary vein. The basilic vein ascends on the ulnar side of the forearm, it perforates the deep fascia about midway in the arm, and after receiving the deep brachial vein it continues into the axillary vein. The median cubital vein connects the cephalic and basilic veins in front of the elbow. Variations are common, including the presence of additional major venous trunks, such as the accessory cephalic or antebrachial veins. The deep veins (radial, ulnar,

Histology 21

The superior intercostal vein drains the upper intercostal veins; it opens into the brachiocephalic vein on the left, whereas on the opposite side it joins the azygos vein. The superior vena cava is formed behind the ﬁrst right costal cartilage by the union of the brachiocephalic veins. It descends right of the ascending aorta and opens into the right atrium at the level of the third right costal cartilage. Halfway along its length, before it enters the pericardium, it receives the azygos vein from behind. AZYGOS VEINS

The origin of the azygos vein is not constant. It may arise from the back of the inferior vena cava at the level of the renal veins or it may be the continuation of the right ascending lumbar vein (Fig. 2.11). The azygos vein ascends on the right side of the body until the fourth thoracic vertebra, and then passes anteriorly to join the superior vena cava. Major tributaries of the azygos vein are the right superior intercostal, the hemiazygos, and the accessory hemiazygos veins. The hemiazygos vein courses on the left side of the vertebral column; its origin is similar to that of the azygos vein. At the level of the eighth thoracic vertebra, it crosses the column and joins the azygos vein. Often the left renal vein communicates with the hemiazygos vein. The accessory hemiazygos vein descends left to the vertebral column and parallel with the azygos vein. Proximally, it anastomoses with the left brachiocephalic vein and ends distally when it joins to the azygos or the hemiazygos veins at the level of the seventh thoracic vertebra. The azygos veins drain the intercostal veins on both sides, receive several visceral tributaries and freely anastomose with the vertebral venous plexuses. The azygos veins and their tributaries provide an important collateral circulation in the face of superior or inferior vena cava obstruction.

HISTOLOGY Figure 2.12 Superﬁcial veins of the upper extremity.

brachial, and axillary veins) are usually paired and follow the course of the main arteries of the arm The axillary vein begins at the lower border of the teres major, which corresponds with the lateral border of the scapula on an anteroposterior chest radiograph. At the outer border of the ﬁrst rib, it becomes the subclavian, which ends at the medial border of the scalenus anterior muscle, where it joins the internal jugular vein to form the brachiocephalic vein. The brachiocephalic (innominate) vein begins behind the sternoclavicular joint. The left brachiocephalic vein descends obliquely to join the right one. Constant tributaries of the brachiocephalic vein are the vertebral, internal thoracic, and inferior thyroid veins.

The venous wall is three layered: intima, media, and adventitia.35,36 The intima uniformly consists of a single layer of endothelial cells resting on scant connective tissue. The internal elastic lamina, a layer of thick elastic ﬁbers at the base of the intima, is frequently incomplete in medium-sized veins and absent in the smaller ones. Venous valves are bicuspid infoldings of the intima covered by endothelium on both sides with an intervening connective tissue skeleton (Fig. 2.13 a,b and Fig. 2.14). At the origin of valves, veins may be focally distended forming small sinusoid dilations probably in response to the hemodynamic consequences of focally reversed ﬂow. The media is composed of layers of smooth muscle cells and connective tissue. The relative thickness of the media as well as the proportion of the two major components varies considerably with different size and function. Major superﬁcial veins, such as the greater and lesser saphenous, have thick muscular media providing an ability to contract

22

Development and anatomy of the venous system

(a)

(b)

Figure 2.13 Proximal (a) and distal (b) aspect of a venous valve (stereomicroscopy, magniﬁcation ×11.2).

Figure 2.14 Histology of a venous valve (Orcein, magniﬁcation ×2.5).

and to resist the development of varicosities. Tributaries of the saphenous veins have thinner media and can become more easily varicosed. The media of the deep veins of the calf contain as much smooth muscle as in saphenous veins; however, their collagen content is more abundant resulting in a more rigid wall. The larger deep veins (femoral, iliac, axillary, subclavian, innominate) contain less and less smooth muscle cell mass and the almost complete lack of these cells in the media of the caval veins is remarkable.13 The adventitia is poorly demarcated and contains loose connective tissue with lymphatics, vessels (vasa vasorum), and adrenergic nerve ﬁbers. The GSV is ensheathed in further layers of ﬁbrous tissue associated with the deep fascia, which makes this vein even more resistant to the development of varicosities.37

Guidelines 1.1.0 of the American Venous Forum on development and anatomy of the venous system No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

1.1.1 The main deep vein of the thigh between the popliteal and the common femoral vein is the femoral vein. The old term “superﬁcial femoral vein” should be abandoned

1

1.1.2 The main superﬁcial veins of the lower limbs are the great saphenous vein and the small saphenous vein

1

1.1.3 The old terms “Cockett” and “Giacomini” veins should be replaced by the new terms “posterior tibial perforating vein” and “intersaphenous vein”, respectively. The use of eponyms is discouraged

1

References 23

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

1. Caggiati A. Fascial relationships of the long saphenous vein. Circulation 1999; 100: 2547–9. ★2. Cavezzi A, Labropoulos N, Partsch H, et al. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs – UIP consensus document. Part II, Anatomy. Eur J Vasc Endovasc Surg 2006; 31: 288–99. 3. Uhl J-F, Gillot C. Embryology and three dimensional anatomy of the superﬁcial venous system of the lower limbs. Phlebology 2007; 22: 194–206. 4. International Anatomical Terminology, Federative Committee on Anatomical Terminology. Terminologia Anatomica. Stuttgart: Thieme, 1998. ★5. Caggiati A, Bergan JJ, Gloviczki P, et al. International Interdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement. J Vasc Surg 2002; 36: 416–22. ★6. Caggiati A, Bergan JJ, Gloviczki P, et al. International Interdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limb: extensions, reﬁnements, and clinical application. J Vasc Surg 2005; 41: 719–24. ◆7. Mozes G, Gloviczki P. New discoveries in anatomy and new terminology of leg veins: clinical implications. Vasc Endovasc Surg 2004: 38: 367–74. 8. Woollard RH, The development of the principal arterial stems in the forelimb of the pig. Carnegie Institution of Washington: contributions to embryology, 1992; 14 (70): 139–54. 9. Ballaun C, Weninger W, Uthman A, Weich H, Tschachler E. Human keratinocytes express the three major splice forms of vascular endothelial growth factor. J Invest Dermatol 1995; 104: 710. 10. Nicholson CP, Gloviczki P. Embryology and development of the vascular system. In: White RA, Hollier LH, eds, Vascular Surgery: Basic Science and Clinical Correlations, Philadelphia, PA: JB Lippincott, 1994: 3–20. 11. Carlson BM. The development of the circulatory system. In: Carlson BE, ed. Patten’s Foundations of Embryology, 5th edn, New York: McGraw-Hill, 1988: 586–627. 12. Gillot C. Multimedia Atlas of the Superﬁcial Venous Networks of the Lower Limb. Editions Phlebologiques Fancaises. Cabourg: Colret Editeur, 1998. ◆13. Browse NL BK, Irvine AT, Wilson NM. Embryology and radiographic anatomy. In: Browse NL BK, Irvine AT, Wilson NM, eds. Diseases of the Veins. 2nd edn. London: Arnold, 1999; 23–48. 14. Noel AA, Gloviczki P, Cherry KJ, et al. Surgical treatment of venous malformations in Klippel-Trenaunay syndrome. J Vasc Surg 2000; 32: 840–7.

15. Cherry KJ, Gloviczki P, Stanson AW. Persistent sciatic vein: diagnosis and treatment of a rare condition. J Vasc Surg 1996; 23: 490–497. 16. Gloviczki P. Vascular malformations. In: Moore WS, ed. Vascular and Endovascular Surgery: a comprehensive review, 7th edn. Philadelphia, PA: Saunders, 2005. 17. Braverman IM.The cutaneous microcirculation: ultrastructure and microanatomical organization. Microcirculation 1997; 4: 329–40. 18. Thomson H. The surgical anatomy of the superﬁcial and perforating veins of the lower limb. Ann R Coll Surg Engl 1979; 61: 198–205. ●19. Caggiati A, Bergan JJ. The saphenous vein: derivation of its name and its relevant anatomy. J Vasc Surg 2002; 35: 172–5. ●20. Caggiati A. Fascial relationships of the short saphenous vein. J Vasc Surg 2001: 34: 241–6. ●21. Delis KT, Knaggs AL, Khodabakhsh P. Prevalence, anatomic patterns, valvular competence, and clinical signiﬁcance of the Giacomini vein. J Vasc Surg 2004: 40: 1174–83. 22. Pang AS. Location of valves and competence of the great saphenous vein above the knee. Ann Acad Med Singapore 1991; 20: 248–50. 23. Basmajian JV. Distribution of valves in femoral, external iliac and common iliac veins and their relationship to varicose veins. Surg Gyn Obstet 1952; 95: 537–42. ●24. Linton RR. The communicating veins of the lower leg and the operative technique for their ligation. Ann Surg 1938; 107: 582–93. 25. Sherman RS. Varicose veins: further ﬁndings based on anatomic and surgical dissections. Ann Surg 1949; 130: 218–32. 26. Cockett FB, Jones DEE. The ankle blow-out syndrome: A new approach to the varicose ulcer problem. Lancet 1953; 1: 17–23. ◆27. Dodd H, Cockett FB. Surgical anatomy of the veins of the lower limb. In: Dodd H, Cockett FB (eds.) The pathology and surgery of the veins of the lower limb. London: E & S Livingstone, 1956: 28–64. ●28. O’Donnell TF, Burnand KG, Clemenson G, et al. Doppler examination versus clinical and phlebographic detection of the location of incompetent perforating veins. Arch Surg 1977; 112: 31–5. 29. May R. Nomenclature of the surgically most important connecting veins. In: May RPH, Staubesand J, eds. Perforating Veins. Baltimore, MD: Urban & Schwarzenberg, 1981; 13–18. 30. Fischer R, Fullemann HJ, Alder W. About a phlebological dogma of the localization of the Cockett perforators [in French]. Phlébologie 1992; 45: 207–12. ●31. Mozes G, Gloviczki P, Menawat SS, et al. Surgical anatomy for endoscopic subfascial division of perforating veins. J Vasc Surg 1996; 24: 800–8. 32. Mozes G, Gloviczki P, Kadar A, Carmichael SW. Surgical anatomy of perforating veins. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer-Verlag, 1998: 17–28.

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33. Gabella G. Venous system. In: Gray’s Antomy, 38th edn. New York: Churchill Livingstone, 1995: 1574–605. 34. Mavor GE, Galloway JM. Collaterals of the deep venous circulation of the lower limb. Surg Gynecol Obstet 1967; 125: 561–71. 35. Patrick JG. Blood vessels. In: Strenberg SS, ed. Histology for Pathologist. New York: Raven Press, 1992: 195–213.

36. Parum DV, Histochemistry and immunochemistry of vascular disease. In: Stehbens WE, Lie JT, eds. Vascular Pathology. London: Chapman & Hall, 1995: 313–327. 37. Thomson H. The surgical anatomy of varicose veins. Phlebologie 1982; 35: 11–8.

3 The physiology and hemodynamics of the normal venous circulation FRANK PADBERG Introduction Venous return Physiologic components of the return circulation The peripheral muscle pump mechanism

25 25 26 29

INTRODUCTION Although venous disease has been recognized since antiquity, it is only in the last 150 years that substantial progress in therapy and understanding has been realized. Anatomy and function are better appreciated now from the perspective of twentieth-century testing modalities. Many studies from the middle of the twentieth century assess useful and unique physiological concepts. Although somewhat limited by the available diagnostic modalities of the time, small sample size and minimal descriptive statistics, these studies continue to offer valuable physiologic and hemodynamic data on normal individuals. Ambulatory pressure manometry, dynamic phlebography, plethysmographic evaluations, color ﬂow duplex ultrasound, computed tomography (CT), and magnetic resonance venography have contributed substantially to the advancement of current knowledge. Detailed discussions of the major pathological conditions affecting the venous circulation – obstruction and reﬂux – will be found in later chapters. The primary purpose of the venous circulation is to return blood to the heart for reoxygenation and recirculation. Understanding volume and pressure relationships are essential for understanding normal and abnormal venous function. The enormous capacity of the venous reservoir plays a major role in maintenance of cardiovascular homeostasis by accommodating volume shifts. Regulation of venous tone is an important aspect of volume accommodation and works in concert with arterial control mechanisms that effect changes in the distribution of cardiac output. Sympathetic mediated adjustments of smooth muscle tone are most pronounced in the

Physiologic compensations Summary References

32 35 35

splanchnic and cutaneous distributions, which are also the most densely innervated. In the upright posture, the physiological effects of gravity and hydrostatic pressure would appear to oppose return ﬂow, but these effects are largely offset by valves and an efﬁcient peripheral pump mechanism.

VENOUS RETURN Venous return is deﬁned as the rate of blood ﬂow toward the heart, which in homeostatic circumstances must equal cardiac output. It is expressed as volume per unit time, and varies with age, gender, and physical conditioning. The resting cardiac output (5040 mL/minute) is the product of stroke volume (70 mL) and heart rate (72 bpm).1 Increasing ﬁber length (volume) or heart rate will increase cardiac output. Active venoconstriction of capacitance vessels was once thought to have been a major contributor to changes in cardiac output. The accumulated evidence has now demonstrated that reﬂex-mediated control of the resistance (precapillary) vessels is the major determinant of the distribution of the circulation.2–4 However, depending on activity and posture, 60–80% of human resting blood volume (70 mL/kg in men and 65 mL/kg in women) resides in the venous system. 25–50% of this volume resides in the smaller post-capillary venules and their collecting systems. Approximately 25% (18 mL/kg) resides in the splanchnic network.1–3 The interaction of multiple components is required for effective venous return: a central pump, a pressure gradient, a peripheral venous pump, and venous valves.

26

The physiology and hemodynamics of the normal venous circulation

Central Blood moves through both arteries and veins because of the pumping action of the heart. Fluid ﬂow follows this dynamic pressure gradient toward the entry port of the central pump – the right atrium. In the normal individual, atrial pressures of 4–7 mmHg are relatively constant regardless of position. When supine, pressures at the venular end of the capillary bed are estimated to be 12– 18 mmHg, which is consistent with venous pressure measured in ankle veins.5–8 Thus, ﬂow moves toward the lower pressures of the right atrium. Pressures in the upper extremity in the upright posture are increased by approximately 6 mmHg, at the level of the ﬁrst rib.1,6 In an upright posture, or in the raised arm, gravitational or hydrostatic forces propel upper extremity and cerebral blood toward the heart. The pliable venous wall collapses above the height of the central venous pressure, a fact utilized clinically during bedside estimation of this pressure in the jugular vein. Whether standing or sitting, gravity is additive to both arterial and venous pressures in the lower extremity. However, since the force of gravity is equilibrated between the arterial and venous circulation, it is not a signiﬁcant factor when considering the pressure gradients inﬂuencing venous return in the normal lower extremity. Venous return is enhanced by negative and neutral (usually 0 mmHg) intra-abdominal and intrathoracic pressures. However, during inspiration, the increase in intra-abdominal pressure causes a transient reduction in ﬂow from the lower extremities to the right atrium by acting as an external compressive force on ﬂow through a collapsible tube such as the inferior vena cava (IVC).9 Chronic, sustained elevation of intra-abdominal pressure occurs with clinical conditions such as ascites and morbid obesity; venous pressure in the lower extremities must rise above this chronically elevated pressure to effect ﬂow through an IVC that has collapsed because of external pressure. In normal circumstances, a pressure gradient begins with 12–18 mmHg at the venous end of the capillary, and falls steadily to 5.5 mmHg at the extrathoracic great veins.10 When blood reaches the right atrium, it is actively pulled into the pump, oxygenated in the pulmonary circuit, and recirculated. Since there are no valves in the large venous conduits, the pathophysiologic consequences are generally those of obstruction to venous ﬂow. The consequences of elevated central venous pressures are well characterized by congestive heart failure, ascites, Budd–Chiari syndrome, morbid obesity, and superior vena cava syndrome.

Peripheral Venous return from the dependent lower extremity is achieved by active pumping of the calf muscle assisted by competent venous valves. Normal valve closure effectively

prevents retrograde ﬂow of blood. In the normal extremity, competent saphenofemoral and saphenopopliteal valves make consideration of lower extremity venous return primarily a function of the deep veins. Valves are distributed throughout upper and lower extremity veins and seem to be more numerous in the more distal segments. The anatomic distribution and extent of valvular incompetence necessary to produce clinical symptoms remains incompletely understood. As might be anticipated, the greater the valvular dysfunction or reﬂux, the greater the likelihood of symptoms from peripheral venous insufﬁciency.11–15 The plantar venous plexus probably serves to ﬁll or prime the calf pump. Since most investigators have focused on the calf pump, the role of the foot and thigh components are less well deﬁned. The calf pump is very efﬁcient in the normal limb; however, it is unknown whether or how it might compensate for deﬁciencies such as outﬂow obstruction, proximal valvular failure, distal valvular failure, or muscle weakness.

PHYSIOLOGIC COMPONENTS OF THE RETURN CIRCULATION The prominent role of hydrostatic pressure and capacitance are unique to the venous circulation. Both interact with other physiologic and hemodynamic factors to exert a variable inﬂuence relative to circumstances such as posture, volume depletion, physical exercise, and ambient temperature. Adrenergic-mediated reﬂexes largely control the splanchnic circulation; blood ﬂow to the skin and skeletal muscle ﬂuctuates over a wide range of volumes in response to local, hormonal, and reﬂex stimuli.2,3,4,16,17

Hydrostatic and dynamic pressure relationships Although local venous pressure varies with the recumbent, sitting, and standing positions, venous ﬂow still follows a pressure gradient. The peripheral calf muscle pump/valvular mechanism is quite effective at returning venous blood, but it only functions when there are active muscle contractions. When active movement is artiﬁcially constrained, the capacitance increases, and the pressure slowly rises to that produced by gravity – the hydrostatic pressure. Sustained exposure to elevated hydrostatic pressures is transmitted to the capillary bed where the balance of ﬁltration favors transudation into the extracellular ﬂuid. Transient inactivity of this mechanism may lead to edema in otherwise normal individuals when the extremity is immobilized for an extended period of time, such as an intercontinental ﬂight in the “economy” or coach section. Likewise, most individuals will appreciate fatigue of the return system by an increasingly snug ﬁt of their footwear near the end of the day.

Physiologic components of the return circulation 27

This pressure, the static or hydrostatic pressure, represents the weight of the column of blood from the point where active recirculation begins – usually the right atrium. Topographically this is assigned to the level of the fourth costosternal junction. The hydrostatic pressure at a given anatomic point is determined by measuring the vertical distance below this landmark.5,18 The effect of gravity increases 0.77 mmHg/cm of height below the atria; the constant being derived from the product of the density of blood (1.056 g/cm3) times the acceleration of gravity (980 cm/second2) divided by 1334 dynes/cm2.1,10 As demonstrated in Fig. 3.1, the hydrostatic pressure at the distal calf in the average 174 cm tall American male is 94 mmHg when standing.6 Chronic, sustained venous pressure elevation, or venous hypertension, is closely associated with pathologic consequences. In the peripheral venous circulation, the major outcomes are reﬂected in the skin and subcutaneous tissues and include the typical changes described in CEAP clinical classiﬁcations 3–6: edema, pigmentation, ﬁbrosis, and ulceration. The frequency of cutaneous ulceration increases with increasing endexercise venous pressures above 30 mmHg;14 this condition, termed venous hypertension, is not the only abnormality producing these symptoms, but remains a

major focus for surgical correction.6,11,15 Reﬂux, the most common pathophysiology associated with venous hypertension, may result from valvular insufﬁciency of either the deep or the superﬁcial system.

Capacitance and pressure relationships The total body venous reservoir has an enormous capacity for ﬂuid variation, which permits accommodation of as much as 20–30% additional volume in the normal individual.1,2 The normal blood volume is approximately 65 mL/kg in women and 70 mL/kg in men, of which 60–80% resides in the venous circulation. The change to upright posture alone is responsible for a 10% volume shift (7 mL/kg or 250–500 mL) into the lower extremity.2,3 The shape of the venous wall varies greatly depending upon pressure, volume, and ﬂow as demonstrated in Fig. 3.2.9 When empty or ﬂaccid, the walls are coapted and the pressure low. As the cross-sectional proﬁle changes to that of a dumbbell or ellipse, large shifts in ﬂow (or volume) are accommodated with minimal change in pressure. Until the vein becomes circular in shape, the pressures remain low. The enormous ﬂow carried by an incompletely distended vein can be deceiving; just ask any surgeon who has nicked a ﬂaccid iliac vein or the vena cava! Once a circular geometry is achieved, further distention is accompanied by a rather sharp increase in pressure per unit volume (Fig. 3.2). Over the normal pressure range of 5–25 mmHg, capacitance volume may change in large amounts without affecting ﬂow or pressure.2,9 As a result, within the range of normal pressures, the venous hydrostatic pressure becomes an inactive factor in the

Volume (ml) 14 12 10 8 6 4 2

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Figure 3.1 The relative pressures generated by dynamic (cardiac pump) and hydrostatic (positional) inﬂuences are illustrated in this schematic. The ﬁgure has been standing motionless with the dependent veins ﬁlling by gravity. Upper extremity pressures vary with position of the arm. From Meissner et al.6 DP, dynamic pressure; Ht, height; HP, hydrostatic pressure; RA, right atrium.

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Figure 3.2 Pressure/volume relationships in the distensible venous lumen are reﬂected in this diagram. Considerable volume is introduced before pressure rises: pressures begin to rise as the vein becomes elliptical and increase further as a circular conﬁguration is reached. Katz et al.9

28

The physiology and hemodynamics of the normal venous circulation

mechanics of venous return. The higher pressure needed to produce circular distention of the vein approximates that deﬁned as “abnormal” by ambulatory venous pressure studies (30 mmHg).14 Likewise, this threshold is similar to the pressures associated with pulmonary dysfunction from obstructive or regurgitant valvular disease and the threshold for neuromuscular dysfunction in compartmental syndromes. The venous wall is considerably thinner than the arterial wall, but consists of the same elements – intima, media, and adventitia. The walls of the subfascial deep veins have a relatively uniform thickness; in comparison, the walls of the major superﬁcial venous trunks, the saphenous and cephalic veins, are relatively thick. Pliability is a key feature of venous or capacitance vessels. However, when fully distended with high pressures, a vein loses this pliability and becomes as stiff as an artery.10 Another key feature related to capacitance function is the capacity to constrict or dilate over a wide range of diameters For example, venoconstriction often follows failed venipuncture or exposure for harvest in the operating room; venodilation often follows increased ambient temperature, warmed acoustic gel, and general anesthesia.

Physiological control: reflex, hormonal and local mechanisms In response to various stimuli, ﬂow through splanchnic, muscle, and cutaneous veins can vary by an enormous volume. Reﬂex impulses are transmitted through sympathetic nerves, which predominantly exert their effects as arterial constriction. Baroreceptor- and chemoreceptor-mediated effects are the most effective acute adjustments to distribution of blood ﬂows.1 Fluid shifts and hormonal mechanisms become more important with later adjustments to volume status. Although ﬂow is largely controlled by the small resistance arterial beds, capacity is largely adjusted by dilation or constriction of the venous network. Adrenergic innervation is distributed to both arteries and veins. Furness et al.,19 in an elegant physiologic/ anatomic study demonstrated that the relative density of these adrenergic endings in the microcirculatory bed is far greater in the arterial (resistance) circulation (Fig. 3.3). The splanchnic and cutaneous distributions receive the greatest venous concentration of adrenergic ﬁbers. These distributions also have the largest complement of smooth muscle.1 Marked arteriolar smooth muscle hypertrophy facilitating precapillary venoconstriction is one of many adaptations in the extremity skin of the giraffe, which facilitates the animal’s adaptation to extreme vertical physiologic stress.20 The splanchnic circulation normally contains approximately 18 mL/kg or about 25% of the total blood volume and accounts for approximately 27% of the total blood ﬂow. Although normal splanchnic demand is

pv

pa sv

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cv

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Figure 3.3 Diagrammatic representation of the relationship between adrenergic nerves and the mesenteric blood vessels: pa, principal artery; pv, principal vein; sa, small artery of the microvasculature; ta, terminal arteriole; pca, precapillary arteriole; c, capillary; cv, collecting venule; sv, small vein. The adrenergic nerves are represented by the heavy lines. Arrows indicate the direction of blood ﬂow. Note that the precapillary arterioles and the collecting venules are not innervated. Reproduced with permission from Furness JB, Marshall JM.19

determined from local regulatory mechanisms, acute adjustments of splanchnic volume may be mediated by baroreceptors via adrenergic ﬁbers.2,4 In severe hypotension, circulating vasopressin and catecholamines may exert a substantial additive effect to the splanchnic adjustments. These redistributions account for approximately 50% of the acute volume compensation following an acute hemorrhage. Although a small proportion of this volume shift may result from active venoconstriction, the majority results from passive elastic recoil and redistribution of arterial ﬂow. The blood ﬂow to inactive skeletal muscle is only 3 mL/minute/100 g of tissue, but because of its large tissue mass this accounts for approximately 15% of the total blood volume. Adrenergic stimulation has little inﬂuence on skeletal muscle ﬂow, which is primarily controlled by locally mediated stimuli.1,2 Skeletal muscle ﬂow may increase by as much as 20-fold to 80 mL/minute/100 g tissue with sustained exercise. Venoconstriction occurs in response to exercise, although local heating abolishes this response in active muscle.3 The increased volume of ﬂow

The peripheral muscle pump mechanism 29

with exercise, along with the heat generated, secondarily recruits dilation of the cutaneous venous network. Core temperature is maintained at a constant 36–37.5°C, whereas skin temperature varies markedly with the ambient temperature. Overall, temperature control is maintained by the hypothalamus, whereas cutaneous circulation responds to both reﬂex innervation and direct local stimuli. Cutaneous blood ﬂow may vary by as much as 30-fold. Cutaneous blood ﬂow is approximately 3 mL/minute/100 g of tissue in cool weather, which accounts for approximately 6% of the total blood ﬂow.16 Conservation of body heat is achieved by constriction of the cutaneous network that lowers ﬂow even further. The deep veins are unaffected by cold.17 Thus, extreme cold also concentrates venous ﬂow in the deep veins, where a countercurrent heat exchange efﬁciently preserves thermal energy. A reduction in body temperature markedly enhances venoconstriction in response to local cooling through potentiation of the threshold of the adrenergic receptors of cutaneous veins.17 In a warm environment, heat loss is facilitated to maintain homeostatic body temperature. Skin blood ﬂow increases with reduced adrenergic impulses, leading to both arterial and venous dilation.16 In severe heat stress, the skin blood ﬂow may reach 2–3 L/minute. Local injury leads to release of histamine and bradykinin, which produce localized vasodilation. There is mounting evidence to suggest that the vasodilatory actions of progesterone seem to increase venodilation and even the incidence of varicose veins.4 Although evaluated by a number of investigators, only a limited role has been identiﬁed for nitric oxide in venous regulation.21,22

THE PERIPHERAL MUSCLE PUMP MECHANISM Flow against gravity is maintained using a system of muscle pumps to eject the blood and internal valves to prevent retrograde ﬂow (Fig. 3.4). In normal individuals, this mechanism is remarkably efﬁcient. The complex relationship between pressure and volume is integral to comprehension of venous function.

Valvular function Duplex surveys have deﬁned normal valvular function as a duration of retrograde ﬂow that is < 0.5 seconds for all deep and superﬁcial veins of the lower extremities, except the common femoral vein (< 1.5 seconds).23,24 Soleal sinuses have no valves and a relatively ﬁxed volume.25 The paired gastrocnemius muscles also have sinuses, but apparently of less volume and number. Although the role of valves in the prevention of reﬂux ﬂow is obvious, the importance of dysfunction (incompetence) of a single or even several valves is not clear. Incompetence of a single valve produces no known physiological consequence.23

(a)

(b)

(c)

Figure 3.4 Drawing illustrating “operation of the muscle pump.” (a) resting (b) muscle contraction (c) muscle relaxation. Venous pressure in the distal leg is indicated by the length of the hydrostatic column. Sumner DS, Zierler E. Vascular physiology: essential hemodynamic principles. In: Rutherford RB, ed. Vascular Surgery, 6th edn, Philadelphia, PA: Saunders-Elsevier, 2005.

The importance of various anatomic sites of valvular dysfunction is incompletely resolved. Although some have ascribed great pathophysiological signiﬁcance to the femoral and popliteal valves, others have emphasized abnormalities of the distal valves.23,26–28 In an analysis of 155 patients from a series of randomized trials, incompetence of the popliteal vein valve was the only signiﬁcant risk factor for delayed healing.26 Rosfors28 determined that distal valvular dysfunction was of greater signiﬁcance than popliteal valvular dysfunction, but, combined disease categories were most likely to be associated with severe chronic venous insufﬁciency (CVI).13 The increased number of valves in the infrapopliteal segments suggests that their functional importance is greater in that location. Perforating vein valves prevent outward ﬂow when functioning properly.25,29 This concept is consistent with the pressure/ﬂow relationships of the calf pump. Cockett25 colorfully captured the image of perforating vein malfunction, with his description of the “ankle-blow-out” syndrome.

The calf pump The contracting gastrocnemius and soleus muscles expel blood into the large capacity popliteal vein. The normal limb has a calf volume ranging from 1500 to 3000 mL, a venous volume of 100–150 mL, and ejects over 60% of the

30

The physiology and hemodynamics of the normal venous circulation

venous volume with a single contraction.12,30,31 Christopoulos30 normalized the reporting of air plethysmographic volumes to facilitate comparison of clinical groups and eliminate such effects as edema and variance in calf size. An ejection volume of 2.5–3.7 mL/ 100 mL of calf tissue volume was described for normal limbs. Expressing the ejection fraction as a ratio serves the same comparative function. Beginning at the resting hydrostatic pressure, the venous pressure is substantially reduced after the initial contractions (Fig. 3.5).5 The end-exercise pressure, referred to as the ambulatory venous pressure (AVP), is maintained at a lower value by repetitive contractions. When active contraction ceases, 31 seconds are required to restore hydrostatic pressure in the normal limb. Measurements of changes in venous pressure and volume during repetitive contractions of the normal calf transcribe similar curves (Fig. 3.6a–c).5,6,30,31 Separation of venous pressure relationships from musculofascial pressures is accomplished by simultaneous measurement of compartmental and venous pressures.31,32 Restoration of > 90% of volume requires over 70 seconds to reﬁll the calf.30 In the normal resting state, the veins of the calf are ﬁlled at a rate of 1–2 mL/second both by active and passive mechanisms. The calf pump is actively primed by compression of the plantar venous plexus. Passive ﬁlling occurs during muscle relaxation when blood ﬂows into the just emptied deep veins from the muscle itself, the distal deep veins, and the superﬁcial veins. Venous blood ﬂows through perforating veins to follow the pressure gradient from elevated hydrostatic pressures in the superﬁcial veins to the rhythmically decreased mean pressure in the deep veins of the calf. Not all perforating veins have valves, but those that do are oriented to prevent ﬂow from the deep to the superﬁcial system.25 Abnormal function of either the deep or superﬁcial venous system will commonly result in an increased venous pressure, an increased venous

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Figure 3.5 The drawing illustrates mean pressure changes in the dorsal foot vein during standing, calf exercise, and the subsequent resting state. From Pollack and Wood.5

70

volume, and a shortened reﬁll time.5,14,30 Notably, external compression would beneﬁt this ﬂow pattern by actively encouraging ﬂow into the deep system and reducing calf volume, thus effectively priming the peripheral pump. Radiographic visualization of contrast movement during active calf contraction was described by Almén.29 The intramuscular soleal and gastrocnemial sinuses ﬁll from the deep muscle compartment and empty completely with a single calf contraction. The intermuscular, paired, deep tibial veins, which lie between the muscle bundles, are substantially compressed, but are never completely empty (Fig. 3.4). The proximal valves open during active calf contraction. The distal deep vein valves close during active calf contraction, along with those in the perforating veins, thus preventing retrograde or outward ﬂow during the contraction cycle.29 In addition, phlebography of the foot suggests a major role for the plantar venous plexus in ﬁlling the deep tibial veins.33 The use of direct pressure measurements in the tibial, popliteal, and saphenous veins has provided invaluable measures of hydrostatic pressure, pressure reduction with single and multiple calf contractions, and time for recovery of resting pressure. However, despite innovative and extensive experimental observations, the invasive aspects of these investigations have precluded repetitive examination. Plethysmography, whether by foot volume, air, or strain gauge is well accepted, such that longitudinal data with these non-invasive methods is now appearing. Various authors have described the volume changes associated with elastic compression, surgical intervention, CEAP clinical class, late-day deterioration of venous function, and diminished joint function.11,12,15,30,34,35

Thigh and foot contributions to the peripheral venous pump Although the thigh veins are surrounded by muscle, the contribution of active contraction of thigh muscle to venous return is thought to be minimal. Ludbrook31 was surprised by his data demonstrating that it required less than 10 seconds for normal venous ﬁlling in the thigh compared with over a minute for the calf. The virtually instantaneous reﬁll of this segment is consistent with endexercise pressure measurements in the popliteal vein.18,36 A thigh segment ejection fraction of 20% was measured with a 15 cm air plethysmographic cuff.31 Considerably less efﬁcient venous return from the thigh segment was attributed to the observed rapid reﬁll and less compressible intermuscular location of the deep veins in the thigh. Compression of the plantar venous plexus actively pumps blood proximally.33 Although the medial and lateral plantar veins are also intermuscular in location, intrinsic muscle contraction coincides with the timing of maximal weight bearing on the full foot; compression then forces blood out of the foot. Blood ﬂow from the plantar venous plexus is primarily directed into the paired, deep

The peripheral muscle pump mechanism 31

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tibial veins; however, there is disagreement about whether it is all retained in the deep system. Several investigators describe ﬁndings which suggest that ﬂow passes from these and other deep foot veins both into the deep and the superﬁcial venous networks.37,38 Kuster et al.38 studied the veins communicating between the deep and suprafascial systems of the foot in 10 unembalmed limbs and identiﬁed 6–12 veins per foot. Approximately 50% of these veins had valves that, unlike the perforating veins of the calf and thigh, only allowed ﬂow from the deep veins toward the superﬁcial veins. Even with intraosseus tarsal phlebography, an ankle tourniquet was still needed to direct ﬂow into the deep veins.37 Although the interaction between the various leg pumps is not fully understood, all work with competent valve function to return the venous blood from one segment of the extremity to another.

Figures 3.6 (a–c) The pressure and volume changes with activation of the calf muscle pump are demonstrated. Beginning in the standing posture, the hydrostatic pressure baseline is demonstrated in a dependent, but non-weight bearing limb. The subject then performs 10 tip-toe (heel raising) maneuvers and resumes the non-weight-bearing posture. (a) Pressure changes during these maneuvers are illustrated in this recording from cannulation of a dorsal foot vein reported in mmHg. (b) Volume changes during these maneuvers are illustrated in this air plethysmographic examination. The volume remaining in the limb after exercise divided by the venous volume standing still is reported as the residual volume fraction (RVF, %). (c) This schematic compares the pressure and volume changes along a concomitant timeline. Note the efﬁciency of the calf pump in rapidly reducing either volume or pressure upon commencement of muscle activity. Although volume ﬁlling begins within 5–7 seconds, pressure does not rise substantially for 30–40 seconds. Alterations in these relationships can generate chronic, sustained venous pressure elevations, the end products of which are the symptoms and ﬁndings of chronic venous insufﬁciency.

Stroke volume and calf pump output Like many biological systems, the provision for normal venous return from the peripheral muscle pump greatly exceeds the minimum required for normal function. If we postulate a conservative normal walking cadence of 100 steps/minute, and a median ejection volume of 3.0 mL/ 100 mL in a 2.0 L calf, the calf pump output (CPO) would be 6.0 L/minute. The CPO per limb would be half of this, or 3.0 L/minute. Even by employing these conservative assumptions, the estimated CPO exceeds the resting cardiac output. Logically, if the proportion ejected were reduced, the result would be a less efﬁcient pump and a decreased CPO. For example, in deep venous insufﬁciency, if the median ejection volume were decreased to 1.7 mL/ 100 mL, the CPO would still be 3.4 L/minute.

32

The physiology and hemodynamics of the normal venous circulation

Pressure relationships in the lower extremity In the normal limb, the pressure is reduced from the resting hydrostatic pressure to a mean of 22 mmHg with ambulatory calf contractions, a value that is reached within 7–12 steps.5 Similar pressure changes were observed with standing ankle plantar ﬂexion or heel raising which transfers weight to the forefoot (the tip-toe maneuver).5,6,14 When resuming a static standing position, the hydrostatic pressure is restored in a mean of 31 seconds (Fig. 3.6a–c). As a practical matter, venous pressure studies have generally been obtained from the dorsal foot veins, assuming that the pressure accurately reﬂects pressure determined from direct cannulation of the deep veins of the calf (posterior tibial). Several authors have compared simultaneous pressures from deep and superﬁcial vein catheters placed at the same anatomic height.8,18,36,38 Although these investigations demonstrated different patterns in deep and superﬁcial veins, the pressures measured in the superﬁcial veins at the ankle were essentially unchanged. Despite these apparent pattern differences, it is pressures measured in the skin and subcutaneous (superﬁcial) venous network that are most likely to be associated with dermal pathophysiologic changes. The incidence of ulceration has a linear relationship to increases in ambulatory venous pressures above 30 mmHg; ulceration and an increased AVP was also associated with a 90% reﬁll time of < 20 seconds.14 In addition, rapid reﬂux (i.e., venous ﬁlling of greater than 7 mL/second) is also associated with a high incidence of ulceration.30 Contracting muscle and an intact limb fascia are integral components of the peripheral musculovenous pump. During maximal contraction, intramuscular pressures of 250 mmHg are generated in the soleus muscle, and 215 mmHg in the gastrocnemius.31 More recent studies have suggested that pressures measured within the fascial envelope of the leg ranged from 80 to 90 mmHg in various postural positions.32 Intravenous pressures taken from the proximal posterior tibial vein rise to > 200 mmHg during initial calf contraction, with subsequent peak pressures of > 150 mmHg on repetitive contractions. The pressures were 30 mmHg on relaxation.18 Saphenous vein measurements at the same anatomic height had a lesser initial peak pressure and demonstrated declining peak pressures with each contraction. The pressure gradient thus favors superﬁcial to deep ﬂow only during the postcontraction, relaxation phase of the calf muscle cycle. Pressures in the popliteal vein demonstrate a short rise during the initial calf contraction, which corresponds to expulsion of blood from the calf, but popliteal pressures do not decrease following relaxation; thus, the baseline, resting popliteal vein pressure remains close to the hydrostatic pressure for the greater proportion of the walking cycle.18,36 The ﬁxed, non-elastic investing fascia of the lower leg provides an unyielding envelope that permits generation of these high pressures, but also prevents

dilation of the capacitance chamber, thus eliminating an increase in stroke volume as a potential compensatory mechanism for calf pump failure. Unlike the fascia, normal skin is elastic and can stretch in response to a sustained increase in subcutaneous pressure. The combination of stretched skin, edema, venous hypertension, and minor injury may predispose to ulceration. In contrast to man, the giraffe exhibits several physical adaptations to its exaggerated physiological demands; these include an elevated interstitial ﬂuid pressure (mean 40–50 mmHg) and a skin structure characteristic of a tight and unyielding fascia.20 Clinically, these considerations are incorporated into therapeutic devices, such as the adjustable velcro wrap and Unna’s boot, that also provide an unyielding external envelope. The gradient compression stocking utilizes elastic to provide similar external support.

PHYSIOLOGIC COMPENSATIONS Compensation for upright posture In man, the primary peripheral circulatory adaptation to assumption of upright posture is made by changes in arterial resistance and not by adjustments in venous tone or capacitance.3,39 Circulatory homeostasis with this change in position is largely achieved by immediate changes in heart rate and then adjustment in arterial resistance.2,5,39 When the dependent capacitance vessels (veins) are allowed to continue to ﬁll passively without emptying, the resulting redistribution of blood volume may result in syncope, a common problem in fresh military recruits learning to stand in formation. Normal individuals, standing in a static position, ﬁdget and shift weight from one leg to another at least once per minute; this frequency was not diminished by extremes of heat or cold.36,40

Volume depletion: hemorrhage (acute), dehydration (chronic) Compensation for acute reduction in blood volume and the resulting decrease in venous return is mediated by baroreceptor stimulation and increased sympathetic output. Loss of approximately 10% of circulating volume may be accommodated without changes in cardiac output or systemic pressure by sympathetic mediated arteriolar constriction and venoconstriction and increases in heart rate. Acute loss of approximately 30–40% of the volume can be tolerated without death, but requires maximal utilization of compensatory mechanisms. Reﬂex vasoconstriction, which is most prominent in the splanchnic and cutaneous distributions, is accompanied by circulating catecholamines in severe acute blood loss. Canine studies suggest that acute volume depletion of

Physiologic compensations 33

approximately 29% (20 mL/kg) can be compensated by the combination of vasoconstriction and transcapillary ﬂuid reabsorbtion (6 mL/kg). Thus, 10–15 mL/kg is compensable by active venoconstriction and passive elastic recoil resulting from both reduced arterial pressure and vasoconstriction.1,2 Over a prolonged time interval, an individual can compensate for loss of almost 50% of blood volume (35 mL/kg). The transfer of extracellular ﬂuid volume to the circulating volume and the hormonal effects of aldosterone and the renin–angiotensin system are both involved in the accommodation of chronic volume loss of this degree.1,2 Both acute and chronic adjustments to volume depletion are primarily achieved through the control of arterial resistance, with veins playing a passive, but essential role.

Musculoskeletal activity To supply the enormous blood ﬂow required by exercising muscle, three major circulatory accommodations take place.1 First, cardiac output may increase ﬁve to seven times normal resting values. Second, the mean arterial pressure rises 20–80 mmHg. Third, the mass sympathetic discharge produces diffuse arteriolar constriction and venoconstriction. Local effects produce vasodilation of the muscle arterioles because local metabolic effects override the sympathetic signals to vasocontriction. In contrast, deterioration of calf pump function at the end of the day was reported using both photo- and airplethysmography.34,35 Although the variance was relatively limited, these ﬁndings suggest that venous return from the limb deteriorates with prolonged upright activity. The explanation for these ﬁndings may be related to stress relaxation of venous smooth muscle. It is probable that the calf pump mechanism normally compensates for venous insufﬁciency, whether reﬂuxive or obstructive in nature. However, calf pump function and ankle range of motion are progressively diminished with increasing severity of CVI.6,7,11,12 Although the potential role of the calf pump in venous insufﬁciency has been known for some time, little has been done in a direct attempt to effect a therapeutic intervention. The hypothesis that physical conditioning, directed to improve calf pump function, could be of therapeutic value was addressed in a small, randomized controlled trial; both improved calf pump function and muscle strengthening were observed.41

Temperature adjustment Regulation of heat loss from the body is a major determinant of skin blood ﬂow. A decrease in temperature produces cutaneous arterial vasoconstriction as well as subcutaneous venoconstriction. The combined effects of

local and central effects can reduce skin blood ﬂow to less than 3 mL/100 g/minute.16 Additional physiologic compensations for cold include shivering, hunger, and catecholamine secretion. Compensatory mechanisms to achieve heat loss include increased cutaneous arterial ﬂow and increased subcutaneous venous capacitance. Maximal skin blood ﬂow may increase by over 10-fold to 30 mL/100 g/minute with ﬂows of 2–3 L/minute.16 Additional physiologic compensations for heat include sweating, increased respiration, and decreased activity. At the extremes of ambient temperature (0–55°C), venous pressure measurements in normal individuals exhibit pathological ﬁndings.40 By gradually adjusting ambient temperatures between 0°C and 55°C, toe temperatures of 22°C and 40°C respectively were recorded, although subjects were stressed to the clinical end-points of shivering or sweating (Fig. 3.7).40 A cold extremity never achieved a full hydrostatic pressure head and required prolonged ﬁlling to reach even a reduced hydrostatic pressure. A warm extremity achieved a full hydrostatic pressure almost immediately, making assessment of post-exercise pressures difﬁcult.40 Although speciﬁcally determined in relatively extreme temperatures, these ﬁndings for ambulatory venous

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Figure 3.7 The three panels illustrate the changes in an ambulatory venous pressure tracing at extremes of ambient temperature (the temperature markings indicate toe temperatures). Note the absence of a return to the baseline hydrostatic pressure (93 mmHg) in (a), cold; and the immediate return to baseline hydrostatic pressure in (c), hot. From Henry and Gauer.40

34

The physiology and hemodynamics of the normal venous circulation

pressure determinations have implications for other methods of venous testing as well. For these reasons, the rooms used for these examinations must be maintained within a reasonable range of comfortable ambient temperatures.

mediated by the adrenergic (sympathetic) nervous system.3 Ongoing research continues to seek effective pharmacological solutions for venotonic therapy.4 Although a speciﬁc neural pathway for venodilation has not been identiﬁed in humans, the paracrine mechanism of the endothelial-derived relaxing factor has been an important focus of recent research. Now recognized as nitric oxide, the vasodilator effect in the venous circulation is minimal compared with its effects in the arterial circulation. A clinical correlate was described by Lüscher,22 who studied internal mammary arteries, internal

Other Active venoconstriction occurs with hyperventilation, cold showers, strong emotion, and muscular exercise; it is Without endothelium (n 9)

(a)

Without endothelium (n 9)

(b)

Relaxation % of contraction to norepinephrine

0

20 With endothelium (n 22) 40

50

80 With endothelium (n 27) 100 9

8

7

6

5

4

9

8

7

6

5

4

Acetylcholine (logM)

Figure 3.8 Fig 2, page 464. Endothelium-dependent relaxation responses to ACH in human internal mammary arteries (䊏, 䊐) and saphenous veins (䉱, 䉮). From Lüscher et al.22

Guidelines 1.2.0 of the American Venous Forum on physiology and hemodynamics of the normal venous circulation No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.2.1 Venous return follows a continued dynamic pressure gradient. The majority of the energy imparted by the pumping action of the heart is dissipated in the arterial distribution

A

1.2.2 The hydrostatic pressure in the venous system is directly related to the height of the column of blood in relation to the zero point of the right atrium

A

1.2.3 Venous return against gravity is accomplished by the combined action of active extremity muscular pumps and the function of one-way venous valves

A

1.2.4 The plantar venous pump acts to prime the calf muscular pump

C

1.2.5 The thigh muscular pump contributes little to venous return

B

1.2.6 The anatomic structure of the vein allows for great variation in its diameter and thus the capacity of the venous system. This facilitates the response of the venous system to acute volume changes and to adjusting temperature

A

1.2.7 External pressure on collapsible proximal veins increases distal venous pressure

B

References 35

mammary veins, and saphenous veins harvested for coronary arterial bypass grafts. The relaxation response of the veins was markedly reduced compared with the artery (Fig. 3.8). They postulated that these physiologic characteristics inﬂuenced patency of the bypass grafts.

SUMMARY Understanding the normal venous circulation requires mastery of complex hemodynamic and physiologic concepts. Gravity-induced hydrostatic pressure encourages ﬂow into the dependent capacitance network. The distensibility of the venous wall permits the system to accept (or contribute) large volume adjustments with a minimal rise (or fall) in pressure. Venous return ﬂows along a pressure gradient, just as the arterial and microcirculations do. The return of venous blood against gravity is accomplished by breaking the system into multiple pumped segments with internal valves preventing the return of ejected blood. The muscle pumping mechanism is very efﬁcient, and empties into a capacious, valved popliteal vein. Acute circulatory adjustments associated with standing, volume deﬁciencies, or changes in temperature are largely compensated by reﬂex alterations in resistance vessels, in conjunction with adjustments of venous tone. The complex physiologic interactions of the return circulation provide a homeostatic milieu that supports reasonable human function in a wide variety of circumstances.

REFERENCES ● ◆

= Key primary paper = Major review article 1. Guyton AC, Hall J. Medical Physiology, 9th edn. Philadelphia, PA: Saunders, 1996. ◆2. Rothe CF. Venous System: Physiology of the capacitance vessels. In: Shepherd JT and Abboud FM, eds. Handbook of Physiology, vol. III, Peripheral Circulation and Organ blood ﬂow, section 2, The Cardiovascular System. Bethesda, MD: American Physiological Society, 1983: 397–452. ◆3. Shepherd JT. Role of the veins in the circulation. Circulation 1966; 33: 484–91. 4. Vanhoutte PM. Venous wall and venous disease. In Vanhoutte PM, ed. Return Circulation and Norepinephrine: An Update. Paris: John Libbey, 1991: 1–14. ●5. Pollack AA,Wood EH. Venous pressure in the saphenous vein at the ankle in man during exercise and changes in posture. J Appl Physiol 1949; 1: 649–62. ◆6. Meissner MH, Moneta G, Burnand K, et al. The Hemodynamics and Diagnosis of Venous Disease. J Vasc Surg 2007; 46 (Suppl): 4S–24S.

7. Kügler C, Strunk M, Rudofsky G. Venous pressure dynamics of the healthy human leg. J Vasc Res 2001; 38: 20–9. 8. Neglén P, Raju S. Differences in pressures of the popliteal, long saphenous, and dorsal foot veins. J Vasc Surg 2000; 32: 894–901. ●9. Katz AI, Chen Y, Moreno AH. Flow through a collapsible tube; experimental analysis and mathematical model. Biophys J 1969; 9: 1261–79. ◆10. Sumner DS. Hemodynamics and pathophysiology of venous disease. In: Rutherford RB, ed. Vascular Surgery 4th edn. Philadelphia, PA: WB Saunders, 1995; 1673–95. 11. Araki C, Back TL, Padberg FT, et al. Signiﬁcance of calf muscle pump function in venous ulceration. J Vasc Surg 194; 20; 872–9. 12. Back T, Padberg F, Araki C, et al. Ankle range of motion and reduced venous function is associated with progression of chronic venous insufﬁciency. J Vasc Surg 1995; 22: 519–23. 13. Lees TA, Lambert D . Patterns of venous reﬂux in limbs with skin changes associated with chronic venous insufﬁciency. Br J Surg 1993; 80: 725–8. 14. Nicolaides AN, Hussein MK, Szendro G, et al. The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 1993; 17: 414–19. 15. Padberg F. Surgical intervention in venous ulceration. Cardiovasc Surg 1999; 7: 83–90. 16. Roddie IC. Circulation to skin and adipose tissue. In: Shepherd JT, Abboud FM, eds. Handbook of Physiology, vol. III, Peripheral Circulation and Organ blood ﬂow, section 2, The Cardiovascular System. Bethesda, MD: American Physiological Society, 1983: 285–317. 17. Vanhoutte PM, Shepherd JT. Thermosensitivity and veins. J Physiol (Paris) 1971; 63: 449–51. 18. Arnoldi CG. Venous pressure in the leg of healthy human subjects at rest and during muscular exercise in the nearly erect position. Acta Chir Scand 1965; 130: 570–83. 19. Furness JB, Marshall JM. Correlation of the directly observed responses of mesenteric vessels of the rat to nerve stimulation and noradrenaline with the distribution of adrenergic nerves. J Physiol 1974; 239: 75–88. 20. Hargens AR, Millard RW, Petterssen K, Johansen K. Gravitational hemodynamics and edema prevention in the giraffe. Nature 1987; 329: 59–60. 21. DeMey JG, Vanhoutte PM. Heterogenous behavior of the canine arterial and venous wall: importance of the endothelium. Circ Res 1982; 51: 439–47. ●22. Lüscher TF, Diederich D, Siebenmann R, et al. Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med 1988; 319: 462–7. 23. Araki C, Back TL, Padberg FT. Reﬁnements in detection of popliteal vein reﬂux. J Vasc Surg 1993; 18: 742–8. 24. VanBemellen PJ, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reﬂux with the duplex ultrasound scanner. J Vasc Surg 1989; 10: 425–31.

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The physiology and hemodynamics of the normal venous circulation

25. Cockett FG. The pathology and treatment of venous ulcers of the leg. Br J Surg 1955; 43: 260–78. 26. Brittenden J, Bradbury AW, Allan PL, et al. Popliteal vein reﬂux reduces healing of chronic venous ulcer. Br J Surg 1998; 85: 60–2. 27. Dalsing MC, Raju S, Wakeﬁeld TW, Taheri S. A multicenter, Phase I evaluation of cryopreserved venous valvular allografts for treatment of chronic deep venous insufﬁciency. J Vasc Surg 1999; 30: 854–66. 28. Rosfors S, Lamke L-O, Nordström E, Bygdman S. Severity and location of venous valvular insufﬁciency: The importance of distal valve function. Acta Chir Scand 1990; 156: 689–94. 29. Almén T, Nylander G. Serial phlebography of the normal lower leg during muscle contraction and relaxation. Acta Radiol 1963; 57: 264–72. 30. Christopoulos DG, Nicolaides AN, Szendro G, et al. Airplethysmography and the effect of elastic compression on venous hemodynamics of the leg. J Vasc Surg 1987; 5: 148–59. ●31. Ludbrook J. Musculovenous pumps of the human lower limb. Am Heart J 1966; 71: 635–41. 32. Alimi YS, Barthelemy P, Juhan P. Venous pump of the calf: A study of venous and muscular pressures. J Vasc Surg 1994; 20: 728–35.

33. White JV, Katz ML, Cisek P, Kreither J. Venous Outﬂow of the leg: Anatomy and physiologic mechanism of the plantar venous plexus. J Vasc Surg 1996; 24: 819–24. 34. Bishara RA, Sigel B, Rocco K, et al. Deterioration of venous function in normal lower extremities during daily activity. J Vasc Surg 1986; 3: 700–6. 35. Katz ML, Comerota AJ, Kerr RP, Caputo GC. Variability of venous hemodynamics with daily activity. J Vasc Surg 1994; 19: 361–5. 36. Höjensgård IC, Stürup H. Static and dynamic pressures in superﬁcial and deep veins of the lower extremity in man. Acta Physiol Scand 1953; 27: 49–67. 37. Jacobsen BH. Venous drainage of the foot. Surg Gynecol Obstet 1970; 131: 22–4. 38. Kuster G, Lofgren EP, Hollinshead WH. Anatomy of the veins of the foot. Surg Gynecol Obstet 1968; 127: 817–23. 39. Samuelhoff SI, Browse NL, Shepherd JT. Response of capacity vessels in human limbs to heal up tilt and suction on the lower body. J Appl Physiol 1966; 21: 47–54. 40. Henry JP, Gauer OH. The inﬂuence of temperature upon venous pressure in the foot. J Clin Inv 1950; 29: 855–61. 41. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufﬁciency: a randomized trial. J Vasc Surg 2004; 39: 79–87.

4 Classification and etiology of chronic venous disease ROBERT L. KISTNER AND BO EKLÖF Introduction Development of the CEAP classiﬁcation “Revised” CEAP document Terminology and new deﬁnitions Writing CEAP

37 37 38 39 40

INTRODUCTION The need for an accurate classiﬁcation system in venous disease is fundamental to understanding of the clinical disease processes and to interinstitutional communication about the separate entities. The imprecise diagnoses that were the norm in venous disease throughout the ages have been replaced by accurate imaging studies since the introduction of non-invasive ultrasound scans in the 1980s. Once presented with the ability to make accurate diagnoses of the cause and mechanism of chronic disease in the individual segments of the lower extremity veins, it was necessary to devise a classiﬁcation system capable of organizing the data in a meaningful way. In 1994 the American Venous Forum convened a subcommittee of world experts in chronic venous disease to address this challenge. Recognizing that a modern classiﬁcation of chronic venous disease (CVD) must now embrace more than just the clinical state of the patient, this committee created the “CEAP” (C, clinical; E, etiology; A, anatomy; P, pathophysiology) classiﬁcation, which provides a system where the multiple variations of CVD can be communicated in a clinically and scientiﬁcally meaningful manner, allowing analysis and comparison of treatment modalities for like conditions.1 Because identical clinical presentations of CVD spring from different etiologies, and the distribution of speciﬁc pathologic processes have different implications for treatment and long-term prognosis, the CEAP classiﬁcation organizes these elements into the methodology. In the CEAP system the clinical state is amended by the etiologic basis for the disease in each case and this is

Clinical application of CEAP Importance of deﬁning etiology Comparison of primary and secondary CVD Conclusions References

41 41 41 44 45

described in terms of the anatomic distribution of the pathophysiologic process throughout the axial venous drainage from the calf to the diaphragm. This organization of information has been successfully promulgated around the world by the international representation that devised it. Its wide acceptance has become fundamental to interinstitutional communication and to the description of chronic venous disorders.

DEVELOPMENT OF THE CEAP CLASSIFICATION The CEAP classiﬁcation, which was introduced in 1994,1 provides a framework around which the clinical manifestations found in CVD are paired with key pathologic elements of causation and physiologic mechanism in speciﬁc anatomic locations of the lower extremity. Speciﬁcally, for each clinical condition it ●

●

●

distinguishes primary from secondary and from congenital causes of the problem, distinguishes reﬂux from obstructive pathophysiology, and identiﬁes the precise anatomic segments affected by reﬂux or obstruction through 18 named segments of the lower extremity venous tree.

In this way, clinical manifestations are coupled with the precise pathological entity from which the natural history of the pathologic processes and the effects of management alternatives for like clinical states can be identiﬁed and studied. The classiﬁcation describes the status of the

38

Classiﬁcation and etiology of chronic venous disease

disease process at a point in time; these details can change over time with the introduction of interval treatments and with the natural history of the disease process. By interval CEAP examination the longitudinal changes that occur over time or after interventions can be documented. This classiﬁcation addressed the considerations imposed by modern diagnostic and treatment capabilities. It was incorporated into the updated Reporting Standards for Venous Disease in 19952 and became known as the CEAP classiﬁcation. Its acceptance was engendered around the world by venous authorities in Europe, America, and Asia, and has now been published in at least 11 languages on ﬁve continents (Chinese, English, French, German, Greek, Italian, Japanese, Polish, Portuguese, Spanish, and Swedish). The fact of worldwide dissemination addresses the need for a universal classiﬁcation to enable accurate communication between institutions and countries about the details of CVD and the results of different forms of treatment. The CEAP classiﬁcation was originally intended as a dynamic document with the intent that it be amended in the future light of experience with its usage. During this period several evaluations of the clinical categories3 and of the appended scoring systems4 that were based upon CEAP have been published5–7 and have provided both validity and critique to their content. After the ﬁrst 10 years, CEAP’s validity and usefulness underwent its ﬁrst critical review with the intent to make needed revisions in 2004 by a new international subcommittee of the American Venous Forum chaired by Professor Bo Eklöf. In this revision8 the fundamental structure of the CEAP categories was afﬁrmed and retained; additions to the classiﬁcation included speciﬁc deﬁnitions of terms, clariﬁcation of details within the C Class, and improvements in the method of recording the ﬁndings to render the classiﬁcation more complete in its long form, and more user friendly in its short form. This chapter will present the recently approved revised format of CEAP and will examine the fundamental importance of deﬁning the etiologic basis of the clinical problem.

“REVISED” CEAP DOCUMENT8 The CEAP classiﬁcation reduces CVD into its component parts of clinical manifestations, etiologic basis for the disease, anatomic distribution of the disease, and pathophysiologic mechanism operating in the involved venous segments affected by the disease. Each of these elements of CVD are speciﬁcally deﬁned within the classiﬁcation in order to achieve uniform reporting wherever the classiﬁcation is used and thereby enable interinstitutional communication about like problems throughout the world. It is important to recognize the classiﬁcation is a time-speciﬁc qualitative assessment of the disease process that requires interval updating for follow-up assessment of the individual case or for

longitudinal studies of the natural history of a disease entity. The contents of the revised tables follow. C (Table 4.1): The clinical classiﬁcation is divided into seven classes of progressive severity ranging from C0 representing no diagnosable venous disease to telangiectases/reticular veins, varicose veins, venous edema, mild and severe skin changes, and venous ulcer divided into healed ulcer and active ulcer categories. The clinical category is amended by a notation to indicate whether the diagnosed abnormalities were accompanied by symptoms (s) or were asymptomatic (a). This ordering of the severity of the clinical manifestations was proposed in the initial report of the CEAP classiﬁcation and has been retained in validity studies on disease severity scoring.4,5 Table 4.1 Clinical classiﬁcation CO C1 C2 C3 C4a C4b C5 C6 S

A

No visible or palpable signs of venous disease Telangiectases or reticular veins Varicose veins Edema Pigmentation and/or eczema Lipodermatosclerosis and/or atrophie blanche Healed venous ulcer Active venous ulcer Symptoms including ache, pain, tightness, skin irritation, heaviness, muscle cramps, as well as other complaints attributable to venous dysfunction Asymptomatic

E (Table 4.2): The etiologic classiﬁcation is divided into 3 classes of congenital, primary, and secondary categories and a new designation to indicate instances in which no etiologic basis could be identiﬁed. Congenital disease refers to named recognized problems where the vessels themselves are deformed from birth, such as the Klippel–Trenaunay deformity. Primary disease refers to cases with degeneration of elements of the normally formed vein wall with valvular reﬂux, typiﬁed by varicose veins. Secondary disease refers to acquired deformities of the veins in which elements of obstruction and reﬂux often coexist, as in post-thrombotic veins. Table 4.2 Etiologic classiﬁcation Ec Ep Es En

Congenital Primary Secondary (post-thrombotic) No venous etiology identiﬁed

A (Table 4.3): The anatomic classiﬁcation is divided into three categories to denote superﬁcial, perforator, and deep vein involvement, and a new category to indicate that no anatomical category could be assigned. This simple anatomical classiﬁcation is supplemented by 18 named

Terminology and new deﬁnitions 39

segments (see Table 4.5) of the veins from the infradiaphragmatic inferior vena cava to the crural veins, which are used in the following section to locate the segments of reﬂux and obstruction. Table 4.3 Anatomic classiﬁcation As Ap Ad An

Superﬁcial veins Perforating veins Deep veins No venous location identiﬁed

P (Table 4.4): The pathophysiologic classiﬁcation is divided into two categories of reﬂux and obstruction and a third category when elements of both reﬂux and obstruction coexist. A new category (An) is added in the revised format to indicate that no determination was made for reﬂux and obstruction. Table 4.4 Pathophysiologic classiﬁcation Pr Po Pr,o Pn

Reﬂux Obstruction Reﬂux and obstruction No venous pathophysiology identiﬁable

When reﬂux or obstruction is found, the anatomic segments afﬂicted with each problem are identiﬁed by using the 18 designated segments described under anatomic classiﬁcation above (Table 4.5).

It is recognized that post-thrombotic disease is a dynamic process in which elements of obstruction become altered by the process of recanalization and maturation of the thrombus to yield a variable mix of reﬂux and obstruction in the later stages. This evolution of postthrombotic changes may present as reﬂux, obstruction, or a mixture of both; the CEAP system allows for segmentby-segment classiﬁcation of these ﬁndings at the time of the examination. Serial examinations can be used to catalogue the dynamic changes of reﬂux and obstruction that occur in the speciﬁc case over time.

TERMINOLOGY AND NEW DEFINITIONS8 New definitions CVD, chronic venous disorders: embraces C1–C6. CVI, chronic venous insufﬁciency: limited to C3–C6. The CEAP classiﬁcation deals with all forms of chronic venous disorders. The term chronic venous disorder includes the full spectrum of morphological and functional abnormalities of the venous system from telangiectases to venous ulcers. Some of these, like telangiectases, are highly prevalent in the normal adult population and in many cases the use of the term “disease” is not appropriate. The term chronic venous insufﬁciency implies a functional abnormality of the venous system and it should be reserved for patients with more advanced disease, including those with edema (C3), skin changes (C4), or venous ulcers (C5–6).

Table 4.5 Venous anatomic segment classiﬁcation Superﬁcial veins 1 Telangiectases/reticular veins 2 Great saphenous vein (GSV) above knee 3 GSV below knee 4 Small saphenous vein 5 Non-saphenous veins Deep veins 6 Inferior vena cava 7 Common iliac vein 8 Internal iliac vein 9 External iliac vein 10 Pelvic: gonadal, broad ligament veins, other 11 Common femoral vein 12 Deep femoral vein 13 Femoral vein 14 Popliteal vein 15 Crural veins: anterior tibial, posterior tibial, peroneal veins (all paired) 16 Muscular veins: gastrocnemius, soleal, other Perforating veins 17 Thigh perforator veins 18 Calf perforator veins

More precise definitions Telangiectasias: a conﬂuence of dilated intradermal venules of less than 1 mm in caliber. Synonyms include spider veins, hyphen webs, and thread veins. Reticular veins: dilated bluish subdermal veins usually from 1 mm in diameter to less than 3 mm in diameter. They are usually tortuous. This excludes normal visible veins in people with thin, transparent skin. Synonyms include blue veins, subdermal varices, and venulectases. Varicose veins: subcutaneous dilated veins equal to or more than 3 mm in diameter measured in the upright position. These may involve saphenous veins, saphenous tributaries, or non-saphenous superﬁcial leg veins. Varicose veins are usually tortuous, but tubular saphenous veins with demonstrated reﬂux may be classiﬁed as varicose veins. Synonyms include varix, varices, and varicosities. Corona phlebectatica: a fan-shaped pattern of numerous small intradermal veins on the medial or lateral aspects of

40

Classiﬁcation and etiology of chronic venous disease

the ankle and foot. This is commonly thought to be an early sign of advanced venous disease. Synonyms include malleolar ﬂare and ankle ﬂare. Edema: a perceptible increase in the volume of ﬂuid in the skin and subcutaneous tissue, characteristically indented with pressure. Venous edema refers to edema in leg, ankle, or foot associated with identiﬁable reﬂux or obstruction in the veins appropriate to the site of swelling. It usually occurs in the ankle region, but it may extend to the leg and foot. Pigmentation: a brownish darkening of the skin resulting from extravasated blood, which usually occurs in the ankle region but may extend to the leg and foot. Eczema: an erythematous dermatitis, which may progress to a blistering, weeping, or scaling eruption of the skin of the leg. It is most often located near varicose veins but may be located anywhere in the leg. Eczema is usually seen in uncontrolled CVD but may reﬂect sensitization to local therapy. Lipodermatosclerosis (LDS): localized chronic inﬂammation and ﬁbrosis of the skin and subcutaneous tissues of the lower leg, sometimes associated with scarring or contracture of the Achilles tendon. LDS is sometimes preceded by diffuse inﬂammatory edema of the skin that may be painful and which is often referred to as hypodermitis. This condition must be distinguished from lymphangitis, erysipelas, or cellulitis by their characteristically different local signs and systemic features. LDS is a sign of severe CVD. Atrophie blanche or white atrophy: localized, often circular whitish and atrophic skin areas surrounded by dilated capillaries and sometimes hyperpigmentation. This ﬁnding is a sign of severe CVD and not to be confused with healed ulcer scars. Scars of healed ulceration may also have atrophic skin with pigmentary changes but are distinguishable by history of ulceration and appearance from atrophie blanche and are excluded from this deﬁnition. Venous ulcer: full thickness defect of the skin most frequently in the ankle region that fails to heal spontaneously and is sustained by CVD.

WRITING CEAP The method of recording the CEAP classiﬁcation is important. When this was addressed in the 2004 revised CEAP, a simpliﬁed “basic CEAP” was added to the original “full CEAP” method of recording. The revised format8 has three basic elements to be included in the CEAP recording:

1. the C-E-A-P ﬁndings 2. date of the examination 3. diagnostic “level” of the examination: ● Level 1: history, physical, Doppler examination (hand-held) ● Level 2: non-invasive: duplex scan, plethysmography ● Level 3: invasive: venography, venous pressure, intravascular ultrasound (IVUS), spiral CT, magnetic resonance venography (MRV).

Full CEAP The full (advanced) CEAP classiﬁcation system is essential for standardized reporting in scientiﬁc journals and for the researcher. It allows grouping of patients so that similar types of patients can be analyzed together for study of both group and sub-group elements of C, E, A, and P. This complete classiﬁcation, for example, allows any of the 18 named venous segments to be identiﬁed as the location of venous pathology. Consider a patient with pain, varicose veins and lipodermatosclerosis where a duplex scan conﬁrms primary reﬂux of the great saphenous vein (GSV) and incompetent perforators in the calf. The classiﬁcation here would be C2,4b-S; Ep; As,p; Pr2,3,18.

Basic CEAP This format provides simpliﬁcations of the full format for more informal usage. It is meant to replace the habit of simply using the highest clinical class to denote the venous problem, a practice discouraged as being too incomplete. Basic CEAP applies two simpliﬁcations. 1. The single highest descriptor can be used for clinical classiﬁcation. For example, a patient with varicose veins, swelling and lipodermatosclerosis would be C4b (as opposed to the full CEAP format of C2,3,4b). 2. The anatomic segments are deleted. For example, the full CEAP format of C2,4b-S; Ep; As,p; Pr2,3,18 would be simpliﬁed to C4b-S; Ep; As,p; Pr. Venous disease is often considered to be a simple problem undeserving of a multicategory classiﬁcation format. The truth is that venous disease is not so simple and it demands well-deﬁned categorical descriptions to be understood. In modern phlebological practice the majority of patients should have a duplex scan of the leg veins carried out in a manner to diagnose the E, A, and P categories of the CEAP classiﬁcation.

Identifying date and method of examination CEAP is not a static classiﬁcation; it can be altered by factors such as a corrective treatment or a more deﬁnitive

Comparison of primary and secondary CVD

test, or just the effect of the passage of time on the natural evolution of the disease process. For this reason, the date and the method of testing (Doppler, duplex scan, venography) used for a particular classiﬁcation should be recorded. METHOD OF INVESTIGATION

The accuracy of the diagnosis increases with the addition of imaging and invasive testing in CVD. Three “levels” of testing are outlined. Level 1 the ofﬁce visit with history and clinical examination, which may include use of a handheld Doppler. Level 2 the non-invasive vascular laboratory, which includes duplex color scanning and plethysmography. Level 3 invasive investigations or more complex imaging studies, including varicography, ascending and descending venography, venous pressure measurements, IVUS, spiral CT scan, or MRV. Recording of the date and method used can be added in parentheses after the CEAP recording as follows: Basic form: C4b-S; Ep; As,p; Pr (Level 2; 8/21/2003) Full form: C2,4b-S; Ep; As,p; Pr2,3,18. (Level 2; 8/21/2003)

CLINICAL APPLICATION OF CEAP Example: a patient presents with painful swelling of the leg and varicose veins, lipodermatosclerosis, and active ulceration. Duplex scanning on May 17 2004 showed axial reﬂux of the GSV above and below the knee, incompetent calf perforators and axial reﬂux in the femoral and popliteal veins. No signs of post-thrombotic obstruction. This example is presented in CEAP as follows: ●

Classiﬁcation according to full CEAP: C2,3,4b,6-S; Ep; As,p,d; Pr2,3,18,13,14 (L2; 5/20/2004).

●

Classiﬁcation according to basic CEAP: C6-S; Ep; As,p,d; Pr (L2; 5/20/2004).

Fig. 4.1 shows six patients with severe skin changes typical of advanced C4–6 disease. From inspection alone the clinical class of C4–6 venous disease would be diagnosed, and many physicians would assume all of these are due to post-thrombotic disease. After full investigation six different diagnoses emerged (Table 4.6). These cases illustrate that the full CEAP classiﬁcation is needed to identify the actual entity behind similarappearing clinical conditions. The clinical class is C4–6 in all six cases but the details of E, A, and P vary widely. Treatment of these cases could range from simple ablation of the GSV or perforator veins for cases 1, 2, and 3, to the potential for extensive deep vein reconstruction in cases 5 and 6, to no venous treatment at all for case 4.

IMPORTANCE OF DEFINING ETIOLOGY Knowledge of the etiologic basis of the CVD process is fundamental to understanding the clinical progress and treatment of the disease. The three categories within etiology are entirely different in that the congenital cases represent malformation of the blood vessels, the primary cases represent a degenerative process in the normally formed vessel walls and valves, and the secondary cases represent an acquired inﬂammatory destructive process that incorporates destructive and reparative elements in its disease progression. Congenital cases are distinctive and relatively rare and are not further detailed in this discussion.

COMPARISON OF PRIMARY AND SECONDARY CVD In primary and secondary CVD, the natural history and the treatment alternatives have major differences but the clinical manifestations can be similar to the point of being indistinguishable (Fig. 4.1). For too long the concept has been accepted that the difference between primary venous insufﬁciency (PVI) and secondary venous insufﬁciency

Table 4.6 CEAP classiﬁcation and diagnosis of 6 patients with leg ulcers (Fig. 4.1) Case 1 2 3 4 5 6

Isolated perforator reﬂux GSV and perforator reﬂux GSV reﬂux No venous disease P–T reﬂux: deep and perf Primary reﬂux: deep, perf and GSV

41

CEAP C2,3,4b,6-s; Ep; As,p; Pr18 C2,3,4b,6,-s; Ep; As,p; Pr2,3,18 C2,3,4b,6,-s; Ep; As,p; Pr2,3 C3,4b,6-s; En; An; Pn C2,3,4b,6,-s; Es; As,p,d; Pr2,3,11,13,14,15,18 C2,3,4b,6,-s; Ep; As,p,d; Pr2,3,11,13,14,15,18

42

Classiﬁcation and etiology of chronic venous disease

1

2

3

4

5

6

Figure 4.1 Six patients with leg ulcers (Table 4.6).

(SVI), or post-thrombotic disease, is of little relevance since practical treatment for the two conditions is largely limited to providing external support for the duration of active life. The earliest report of the striking clinical similarities and the marked pathological differences between primary and secondary disease was beautifully described by Bauer9 in 1948 when he recognized that 58% of his cases of advanced venous insufﬁciency were due to non-post-thrombotic disease, using descending venography for diagnosis. With the development of noninvasive imaging through ultrasound to correctly diagnose reﬂux and its apparent etiologic basis, the current standard of practice is to be accurate in diagnosis and speciﬁc in treatment for chronic venous conditions. The need to know the natural history of the clinical problem to employ

preventative therapies such as anticoagulation or to target speciﬁc sites for corrective surgery is compelling if progress is to be made in management of chronic venous disorders. A comparison between PVI and SVI is shown in Tables 4.7 and 4.8.

Primary venous insufficiency Primary venous insufﬁciency is a degenerative condition of venous walls and valves. It almost always begins as mild reﬂux in the superﬁcial veins of the lower extremity.10 In early stages, veins retain their fundamental elements of valves and intima. The superﬁcial and perforator veins that are affected early are expendable because of their location

Comparison of primary and secondary CVD

43

Table 4.7 Comparative features of primary versus post-thrombotic disease Primary venous insufﬁciency Degenerative Reﬂux only Intima retained Valves stretched, atrophied Primarily superﬁcial veins Widespread occurrence Slow progress to C4–6 = decades Rx: Support, superﬁcial surgery Early surgery for quality of life

Table 4.8 Clinical similarities of primary (primary venous insufﬁciency) and post-thrombotic disease (secondary venous insufﬁciency) Both beneﬁt from external support Rx Similar symptoms of pain and swelling Identical appearance of C4–6 disease Progression from vein disorder to vein/skin disorder

and function; the saphenous veins are also potentially repairable by intervention because their structure is still present. Primary venous insufﬁciency is recognized most often in the lower extremity veins, where its sole pathophysiologic process is reﬂux. The condition is very widespread in the population and is far more prevalent than post-thrombotic disease. The distribution of the affected veins begins in the superﬁcial veins of the lower extremity and progresses to involve perforator and ultimately deep veins in more advanced cases. Deep vein reﬂux is a late development in PVI; it is seen in less than 10% of early C1–C2 cases11 compared with about 70% of advanced (ulcerative) PVI cases.12 Although deﬁnitive studies of the prevalence of primary versus secondary cause of CVI are lacking in the literature, PVI was found in over 80% of a consecutive series of venous insufﬁciency cases in small studies that addressed this subject.13,14 In its milder forms (CEAP C1 and C2 classes), PVI may affect 20% of the adult population and 50% of those 50–70 years of age.15–18 Although objective imaging studies to track the natural history of PVI have yet to be published, PVI is recognized to be a slowly progressive disorder that may advance to C4–C6 manifestations over time in up to 20% of the older population.15–18 In its faradvanced presentation when it affects the deep veins, primary disease can be as devastating as late postthrombotic disease, but the medical and surgical treatment considerations are distinctly different.9,19,20 Medical management of primary disease is limited to external support or limitation of activity. Drug treatment

Secondary venous insufﬁciency Acquired (Inﬂammatory) Obstruction–reﬂux Intima destroyed Valves scarred, destroyed Primarily deep veins Limited occurrence Faster to C4–6 = years Rx: anticoagulant, support Late surgery for C4–6 complications

of symptomatic venous disorders is popular in Europe but not recommended in the USA. Surgical management in primary disease varies from ablation of offending segments of the superﬁcial and perforator veins in the early stages to deﬁnitive repair of deep valve reﬂux in late stages. The results of deﬁnitive surgical treatment have been found to be long-lasting in 70–90% of superﬁcial and perforator21–23 cases and 70% of deep vein valve repairs.19,20,24,25

Secondary venous insufficiency In contrast to primary disease, post-thrombotic secondary disease is an acquired inﬂammatory venous problem that begins as a purely obstructive phenomenon and evolves into a mixture of reﬂux and obstruction in the deep veins. Compared with its occurrence in deep veins, it begins in superﬁcial veins infrequently.26 Its effect is to interrupt the vessel linings and contained valve structures in at least half of the cases of proximal deep vein thrombosis (DVT) in the lower extremity. In the majority of cases the obstructive process undergoes recanalization of obstructed lumina during the ﬁrst 6–12 months,11 and this process leads to a combination of partial obstruction and variable degrees of reﬂux in the diseased lumen due to synechiae, septae, and multichanneled lumina in the deep veins. The ultimate result is variable destruction of venous valves, development of collateral pathways around persistent obstructions, and tendencies to recurrent episodes of venous thrombosis. None of these events are seen in primary disease. The differences in pathologic development between primary and secondary post-thrombotic disease are outlined in Table 4.7. Since a competent saphenous system can provide compensating venous outﬂow in cases where the deep system has a signiﬁcant obstructive element, the pre-existing status of the saphenous veins is of importance in the future course of deep vein thrombosis. When major deep vein thrombosis occurs in an individual with pre-existing primary reﬂux of the

44

Classiﬁcation and etiology of chronic venous disease

saphenous veins, the venous return from the extremity is exposed to double jeopardy and the clinical condition may deteriorate more rapidly. Early thrombus removal of proximal DVT using catheter-directed thrombolysis, percutaneous mechanical/ pharmacologic thrombectomy or surgical thrombectomy (see Chapter 20) is important to secure the venous outﬂow tract and to avoid proximal obstruction that will lead to subsequent incompetence of distal venous valves with reﬂux.27 The combination of proximal outﬂow obstruction and distal reﬂux leads to the most severe postthrombotic syndrome. Continued medical treatment is important to avoid recurrent episodes of DVT; in cases of recurrent DVT, indeﬁnite life-long anticoagulants are usually prescribed. Early and persistent use of support stockings or equivalent is also recommended to minimize chronic swelling in the extremity. For advanced stages of post-thrombotic reﬂux and obstruction, there are highly individualized operations to provide substitute valves28 or to disobliterate the iliac vein or shorter distal segments. Bypass procedures are useful in secondary disease on a highly selective basis, for example, short segment bypass with endophlebectomy,29 but they have no role in primary disease since there is no obstructive component except in the iliac web syndrome where angioplasty and stenting is now the treatment of choice. Various forms of valve substitution20,24 or autogenous valve reconstruction30 have been successful but they require major surgery and are attended by a signiﬁcant rate of recurrent disease. The repair of valves that were not deformed by the thrombotic process can be very successful.19,31 Recent experience with endovenous stenting32 in the iliac veins has been encouraging for both primary (iliac web syndrome) and secondary (postthrombotic webs or obstruction) disease.

Influence of knowledge of etiology on management in chronic venous disease Clinical similarities between primary and secondary disease lead to confusion about the natural history and the proper treatment of the clinical problem. The following are included. 1. Both etiologies affect the veins in the beginning and cause similar complications in the skin in their later stages. 2. Both etiologies are attended by swelling and aching in the legs. 3. The clinical sequelae that cause late suffering and disability in CVI are largely due to similar skin and subcutaneous tissue complications in both entities. This explains why estimation of disease etiology based upon clinical examination of the skin is unreliable. 4. External support leads to clinical improvement in both etiologies since it clearly helps to control swelling and

this is crucial to health of the extremity. The support appears to act by improving the micro-circulation in the superﬁcial tissues but it is yet to be demonstrated that it materially improves venous ﬂow.33,34 Given the great differences in the disease process between primary and post-thrombotic etiologies, important advantages in case management accrue from classiﬁcation systems that differentiate these two entities. 1. The ability to deﬁne the natural history of the disease process in terms of type of complications and in length of time to development of complications, i.e., 2–10 years in secondary disease, 5 years to lifetime in primary disease. 2. The realization that the major involvement is of superﬁcial veins in primary cases versus deep veins in secondary post-thrombotic cases. 3. The appreciation that early proximal thrombus removal and anticoagulation are key to successful prevention of post-thrombotic secondary disease and have no role in primary disease. 4. The usefulness of speciﬁc surgical treatment alternatives: ● saphenous vein ablation is key to management of primary disease and usually not needed or advisable in secondary disease; ● the results of direct deep vein valve repair are superior in primary disease and frequently unfeasible in post-thrombotic disease; ● other forms of deep vein reconstruction are selectively useful in secondary disease and play no or little role in primary disease below the iliac level since it has no obstructive component. These are some of the reasons that determination of etiology is fundamental to management in CVD and needs to be an integral part of classiﬁcation. For progress to occur in the management of CVD, it is essential that clinical diagnosis be complete and accurate and that the many variations of pathologic processes be organized in a manner that allows analysis of variables. The CEAP system is the current best approach to this ideal.

CONCLUSIONS The CEAP classiﬁcation and its scoring systems have been validated and critiqued by an international audience.3,5–7 ●

●

The principal weakness of the CEAP classiﬁcation was identiﬁed to be inadequate differentiation of Clinical Class C-1 (telangiectasias and reticular disease).3 The revised CEAP classiﬁcation retains the basic format and contains important revisions; it replaces the original format.8

References 45

Guidelines 1.3.0 of the American Venous Forum on classiﬁcation and etiology of chronic venous disease No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.3.1 The CEAP (clinical class, etiology, anatomy, pathophysiology) classiﬁcation should be used to describe chronic venous disorders. The system has been validated

1

B

1.3.2 The full CEAP classiﬁcation system should be used for clinical research

1

1.3.3 Primary venous insufﬁciency is a slowly progressive degenerative disorder that results in vein wall weakness producing valvular reﬂux, usually beginning in superﬁcial veins

B

1.3.4 Secondary post-thrombotic venous insufﬁciency is progressive inﬂammatory disease that results in vein valve and wall distortion producing combinations of obstruction and reﬂux; it usually begins in deep veins

B

1.3.5 Primary venous insufﬁciency must be differentiated from secondary post-thrombotic venous insufﬁciency, because the two conditions differ in pathophysiology and management

●

●

●

●

It is necessary that the full CEAP presentation be followed in chronic venous publications to adequately describe the venous state.2,3,8 Primary disease is a slowly progressive degenerative vein disorder that results in vein wall weakness producing pure valve reﬂux, usually beginning in superﬁcial veins.9,10,13,17 Post-thrombotic secondary disease is a more rapidly progressive inﬂammatory disease that results in vein valve and wall distortion producing combinations of obstruction and reﬂux, usually beginning in deep veins.9,11,24 Primary and secondary post-thrombotic diseases require identiﬁcation in classiﬁcation because of the manifold differences in their morphologic and physiologic effects, and their clinical management.9,11,19–21,23

●★2.

◆3.

★4.

◆5.

◆6.

7.

●★8.

REFERENCES ◆★9.

= Key primary paper ◆ = Major review article ★ = First formal publication of a management guideline ●

●1.

Beebe HG, Bergan JJ, Bergqvist D, et al. Classiﬁcation and grading of chronic venous disease in the lower limbs: a consensus statement. Vasc Surg 1996; 30: 5–11.

10.

◆11.

1

B

Porter JM, Moneta GL, International Consensus Committee on Chronic Venous Disease. Reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635–45. Uhl JF, Cornu–Thenard A, Carpentier PH, et al. Reproducibility of the “ C ” classes of the CEAP classiﬁcation. J Phlebology 2001; 1: 39–48. Rutherford RB, Padberg FT, Comerota AJ, et al. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the venous clinical severity score. J Vasc Surg 2002; 36: 889–95. Kakkos SK, Rivera MA, Matsagas M, et al. Validation of the new venous severity scoring system in varicose vein surgery. J Vasc Surg 2003; 38: 224–8. Ricci MA, Emmerich J, Callas PW, et al. Evaluating chronic venous disease with a new venous severity scoring system. J Vasc Surg 2003; 38: 909–15. Eklöf B, Rutherford RR, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: Consensus statement. J Vasc Surg 2004; 40: 1248–52. Bauer G. The etiology of leg ulcers and their treatment by resection of the popliteal vein. J Int Chir 1948; 8: 937–61. Weindorf N, Schultz-Ehrenburg U. The development of varicose veins in children and adolescents [in German]. Phlebologie 1990; 43: 573–7. Markel A, Manzo RA, Bergelin RO, Strandness DE. Valvular reﬂux after deep vein thrombosis: Incidence and time of occurrence. J Vasc Surg 1992; 15: 377–84.

46

Classiﬁcation and etiology of chronic venous disease

12. Danielsson G, Arfvidsson B, Eklöf B, et al. Reﬂux from thigh to calf, the major pathology in chronic venous ulcer disease: surgery indicated in the majority of patients. Vasc Endovasc Surg 2004; 38: 209–19. 13. Labropoulos N, Delis K, Nicolaides AN, et al. The role of the distribution and anatomic extent of reﬂux in the development of signs and symptoms in chronic venous insufﬁciency. J Vasc Surg 1996; 23: 504–10. 14. Kistner RL, Eklöf B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the “CEAP” classiﬁcation. Mayo Clinic Proc 1996; 71: 338–45. ●15. Coon WW, Willis PW, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation 1973; 48: 839–46. 16. Abramson JH, Hopp C, Epstein LM. The epidemiology of varicose veins—a survey of Western Jerusalem. J Epidemiol Community Health 1981; 35: 213–7. ◆17. Kurz N, Kahn SR, Abenhaim L, et al. (eds.) VEINES Task Force Report: The management of chronic venous disorders of the leg (CVDL): An evidence-based report of an international task force. McGill University. Sir Mortimer B. Davis – Jewish General Hospital. Summary reports in Angiology 1997; 48: 59–66 and Int Angiol 1999; 18: 83–102. 18. Giannoukas AD, Tsetis D, Ioannou C, et al. Clinical presentation and anatomic distribution of chronic venous insufﬁciency of the lower limb in a typical Mediterranean population. Int Angiol 2002; 21: 187–92. ◆19. Masuda, EM, Kistner, RL. Long-term results of venous valve reconstruction: A 4- to 21-year follow-up. J Vasc Surg 1994; 19: 391–403. 20. Raju S, Fredericks RK, Neglen PN, Bass JD. Durability of venous valve reconstruction techniques for “primary” and postthrombotic reﬂux. J Vasc Surg 1996; 23: 357–66. 21. Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ. Stripping of the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: ﬁve year results of a randomized trial. J Vasc Surg 1999; 29: 589–92. 22. Jones L, Braithwaite BD, Selwyn D, et al. Neovascularization is the principal cause of varicose vein recurrence: results of a randomized trial of stripping the

23.

24. 25. 26.

27.

28.

29.

30. 31.

32.

33.

34.

long saphenous vein. Eur J Vasc Endovasc Surg 1996; 12: 442–5. Gloviczki P, Bergan JJ, Rhodes JM, et al. Mid-term results of endoscopic perforator vein interruption for chronic venous insufﬁciency: lessons learned from the North American subfascial endoscopic perforator surgery registry. The North American Study Group. J Vasc Surg 1999; 29: 489–502. Perrin M. Reconstructive surgery for deep venous reﬂux: a report on 144 cases. Cardiovasc Surg 2000; 8: 246–55. Sottiurai VS. Results of deep vein reconstruction. Vasc Surg 1997; 31: 276–8. Ioannou CV, Giannoukas AD, Kostas T, et al. Patterns of venous reﬂux in limbs with venous ulcers. Implications for treatment. Int Angiol 2003; 22: 182–7. Caps MT, Manzo RA, Bergelin RO, et al. Venous valvular reﬂux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg 1995; 22: 524–31. Eklöf B, Kistner RL, Masuda EM. Venous bypass and valve reconstruction: long-term efﬁcacy. Vasc Med 1998; 3: 157–64, Puggioni A, Kistner RL, Eklöf B, Lurie F. Surgical disobliteration of postthrombotic deep veins – endophlebectomy is feasible. J Vasc Surg 2004; 39: 1048–52. Maleti O, Lugli M. Neovalve construction in postthrombotic syndrome. J Vasc Surg 2006; 43: 794–9. Raju S, Fredericks RK, Hudson CA, et al. Venous valve station changes in “primary” and postthrombotic reﬂux: an analysis of 149 cases. Ann Vasc Surg 2000; 14: 193–9 Neglen P, Hollis KC, Raju S. Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 2006; 44: 828–33. Mayberry JC, Moneta GL, DeFrang RD, Porter JM. The inﬂuence of elastic compression stockings on deep venous hemodynamics. J Vasc Surg 1991; 13: 91–9; Discussion 99–100. Partsch B, Partsch H. Calf compression pressure required to achieve venous closure from supine to standing positions. J Vasc Surg 2005; 42: 734–8.

5 The physiology and hemodynamics of chronic venous insufficiency of the lower limb KEVIN G. BURNAND AND ASHAR WADOODI Introduction Venous (calf) pump function Superﬁcial venous incompetence The perforating veins of the calf

47 47 48 49

INTRODUCTION Chronic venous insufﬁciency of the lower limb is a poorly deﬁned term and implies a different set of symptoms and signs to different clinicians. To some it encompasses all venous disorders that are not acute venous thromboses, occlusions or injuries.1–5 To others it implies venous disease causing symptoms in the leg, including swelling (venous edema) and the skin changes of lipodermatosclerosis and ulceration.6 The latter deﬁnition excludes uncomplicated varicose veins and has certain advantages, because many patients with varicose veins only seek medical advice for the cosmetic concerns and do not progress to develop skin problems or limb swelling.7 Therefore, the deﬁnition that will be utilized in this chapter is chronic venous disease producing chronic lipodermatosclerosis or ulceration within the limb (clinical classes 3, 4, 5 and 6).

VENOUS (CALF) PUMP FUNCTION The calf muscle pump and to a lesser extent the thigh and foot pumps have a vital role in returning venous blood against gravity from the lower limbs in the erect individual. Abnormalities in the valves or lumen of the superﬁcial, deep and communicating veins can impede or negate the function of these pumps. This causes persistent ambulatory venous hypertension or more correctly an inability to reduce the superﬁcial venous pressure that is achieved by normal calf pump function. The calf pump is the most important of the three venous pumps because it contains the largest venous capacitance (the soleal

The deep veins Mechanism of skin changes Conclusions References

51 52 53 53

sinusoids), and it generates the highest pressures (200 mmHg) during muscular contraction.8 Muscle action drives blood up the stem veins of the limb, where competent valves prevent reﬂux and retrograde ﬂow during relaxation. When muscular relaxation occurs, the veins open up and suck in blood from the superﬁcial system through the competent valves of the communicating veins. This, in turn, reduces the pressure in the superﬁcial veins. This effect is incremental until the arterial inﬂow equals the venous outﬂow capacity of the venous pumps. The efﬁciency of the calf pump in normal subjects is in the region of 70%. The resting venous pressure is approximately 100 mmHg, depending on the patient’s height, reducing to about 30 mmHg after 10 or more repetitive calf contractions. Additional calf contractions fail to reduce the venous pressure further once a steady state has been reached. The normal foot venous pressure during exercise is shown in Fig. 5.1. The thigh pump is not as efﬁcient as the calf pump and the foot pump may well be more important than was originally thought, especially since the perforating veins of the foot have a reversed direction of ﬂow (in to out) under normal circumstances.9 Once exercise ceases, capillary inﬂow from the vis a tergo slowly ﬁlls the superﬁcial veins, which empty during exercise, as the blood is sucked through the communicating veins into the empty deep veins. This causes a slow rise in venous pressure over the next 20–35 seconds as the veins reﬁll back to their original resting pressure (Fig. 5.1). The recovery time is rapid if there is incompetence of the valves in the superﬁcial or communicating veins (Figs 5.2–5.4). When there is deep

48

The physiology and hemodynamics of chronic venous insufﬁciency of the lower limb

Exercise

100

Foot vein pressure (mmHg)

75

50

25

0

0

30

60

Time (s)

Figure 5.1 The changes in foot vein pressure during heel raising exercise in a normal limb. The pressure drops by 80–90% and after exercise, takes 20–35 seconds to return to resting levels. From Browse et al.,6 with kind permission.

venous occlusion, obstruction or agenesis (Figs 5.2 and 5.5) there is little reduction in superﬁcial venous pressure, and the pressure may actually rise above the resting pressure during calf contraction, although persistent venous hypertension is rare. Deep valvular incompetence, with or without associated incompetence of the calf

communicating veins, is responsible for blood “yo-yoing” up and down the deep veins (Fig. 5.6), with accompanying reﬂux through any associated incompetent perforating veins. This produces little venous pressure fall on calf contraction and a rapid return to a high resting pressure (Fig. 5.2). All these mechanisms, described above, can cause persistently elevated ambulatory pressure, which in turn leads to raised pressure at the venous end of the capillary (the venule). This causes increased capillary hydrostatic pressure that encourages both transudation and exudation.10 In 1953, Pappenheimer and Soto-Rivera11,12 described the stretched pore phenomenon to explain the high protein content of interstitial ﬂuid that occurs when the pressure in the venular capillaries is elevated. These authors suggested that raised pressure distended the lumen enlarging the intraendothelial pores, which in turn allowed and encouraged large molecules, especially protein, to enter the interstitial space. These observations conﬁrmed the studies by Landis et al.,13 who had demonstrated that the interstitial protein content increases as the capillary pressure rises. A persistently elevated venous pressure is associated with increased tissue ﬂuid production, which has the composition of an exudate with a high protein content.

SUPERFICIAL VENOUS INCOMPETENCE The mechanism of valvular incompetence in the saphenous systems is still disputed, although the bulk of evidence seems to favor a weakness of the vein wall producing venous dilation that causes secondary valvular incompetence, as the valve ring enlarges and the valve leaﬂets are unable to coapt. Numerous biochemical abnormalities have been reported, including elevated

Typical venous pressure recordings taken on exercise mmHg 120 Normal

LSl

ICPVs

DVT

No cuff 60 0 120 Cuff to thigh

60 0 120

Cuff to 60 calf 0

Figure 5.2 Foot vein pressure measurements. DVT, deep vein thrombosis; ICPVs; incompetent perforating veins; LSI, long saphenous incompetence.

The perforating veins of the calf

P

↓40–70%

P

49

↓10–50%

Figure 5.3 Superﬁcial vein incompetence allows blood to reﬂux down the superﬁcial veins but, providing the communicating veins are competent, the calf pump can usually cope with the additional load and reduce the foot vein pressure during exercise by 40–70%. This is why simple superﬁcial varicose veins are an uncommon cause of venous ulceration. From Browse et al.,6 with kind permission.

Figure 5.4 Communication vein incompetence. Incompetence of the veins within the pump usually following deep vein thrombosis, sometimes in the communicating veins themselves leads to dilatation and incompetence of the communicating veins so allowing reﬂux or blood into the superﬁcial compartment during calf muscle contraction. Communicating vein dilatation and valvular incompetence may also occur as part of the varicose vein diathesis. The arrows indicate the direction of blood ﬂow. During exercise the foot vein pressure falls by 10–50%. From Browse et al.,6 with kind permission.

levels of collagenases, elastases, acid phosphatase, and lactic dehydrogenase, as well as collagen defects and lysosomal abnormalities.14–15 Urokinase-type plasminogen activator,16 free radicals,17 and mast cells have also been shown to be elevated within the vein walls. An important study by Akroyd et al.18 showed that the valve ring and its leaﬂets had far greater tensile strength than the vein wall itself. It has also been pointed out that saphenous veins that have been deliberately denuded of valves for in situ vein bypass hardly ever become varicose.19 These studies and observations all support the theory that valvular incompetence is secondary to a defect in the vein wall. This concept was originally proposed by Cotton,20 after he demonstrated, using anatomical casts, that venous dilation developed below rather than above the valves in patients with varicose veins. This effectively destroyed the

descending valvular incompetence theory21 that had been popular since Trendelenburg had ﬁrst ligated the saphenofemoral junction.22

THE PERFORATING VEINS OF THE CALF The dilating process that affects the saphenous system can also affect the communicating veins including the important posterior tibial perforating veins of the medial calf (Cockett’s veins).23 This may explain the observation of Campbell24 (subsequently conﬁrmed by the Edinburgh Group)25 that in many patients where saphenous and perforator incompetence co-exist, postoperative duplex reexamination shows that perforator valve competence is restored after the saphenous system has been ablated. This

50

The physiology and hemodynamics of chronic venous insufﬁciency of the lower limb

(a)

P ↓50–80%

P

↓10–↑10% (b)

Figure 5.5 Outﬂow tract obstruction. Deep vein obstruction causes upstream dilatation of the veins in the pump chamber and secondary incompetence of the communicating veins because these veins become part of the collateral outﬂow tract. During exercise the foot vein pressure will fall slightly. From Browse et al.,6 with kind permission.

has led to the theory that in many patients the perforating veins simply act as “re-entry” veins allowing blood reﬂuxing down the saphenous system to ﬂow back into the deep system. Incompetent calf perforating veins are also often associated with deep vein obstruction or incompetence, where the primary abnormality is in the deep veins, and under these circumstances the perforating veins act as “safety valves” or “collaterals” allowing blood under high pressure in the calf pump to escape, as it either yo-yos up and down or is unable to pass up the axial limb veins. Under these circumstances, the high pressures developed as the calf muscles attempt to drive blood up the deep veins are directly transmitted via the overlying perforating veins to the superﬁcial venous system of the calf.8 This, in turn, leads to enlargement of the dermal capillary bed26 and the exudation of proteins, including ﬁbrinogen, into the interstitial space.27,28

P

↓10–20%

Figure 5.6 Outﬂow tract incompetence. (a) The calf pump can compensate for pure deep vein (outﬂow tract) incompetence by increasing its output. (b) If the dilatation of the veins within the pump affects the communicating veins the pump begins to fail and foot vein pressure is only reduced by 10–20% during exercise. From Browse et al.,6 with kind permission.

The deep veins 51

THE DEEP VEINS Post-thrombotic damage within the deep veins is the most important cause of chronic venous insufﬁciency. Approximately 50% of venous thrombi resolve completely within 6 months of presentation, when assessed using Doppler ultrasound, through a process of lysis and organization.29,30 This is associated with improved valvular competency at follow up. The anatomical location of the occlusion also predicts outcome: the superﬁcial femoral vein is likely to remain occluded, whereas partial to full recanalization is more commonly found in the external iliac, common femoral and popliteal veins. This may be a result of ﬂow rates at these sites, as well as the presence collateral channels.29 In those in whom thrombus remains, the thrombus organizes by becoming replaced by ﬁbrous tissue and covered by a neoepithelium, which prevents further lysis from occurring. Thrombus ﬁlling the lumen and adhering to the vein wall can cause complete venous obstruction, which becomes permanent after it has been organized (Fig. 5.7), whereas thrombus arising in a valve pocket, or in direct contact with valve cusps, can irreparably damage their function.31 Synechiae, which are permanent endothelialized strands of residual organized thrombus, often develop across the vein wall producing a cribriform meshwork within the venous lumen, which obstructs outﬂow and impedes valve function often binding valve leaﬂets to the vein wall. When the axial veins remain obstructed, collaterals develop. The extent of the obstruction and the collateral pathways developed determine the severity of the hemodynamic changes and the extent of the post-thrombotic symptoms (Fig. 5.8). When the popliteal vein has been obliterated, the calf

Figure 5.7 A venogram showing obstructed iliac veins with collateral ﬂow going up the anterior abdominal wall.

perforating veins become important collaterals. Popliteal obstruction either in isolation or in combination with the calf vein and iliofemoral damage is usually indicative of severe symptoms and subsequent ulceration.32 Deep venous valvular incompetence without coexisting obstruction can be compensated for by the presence of a powerful calf pump and competent perforating veins. When the perforating veins become incompetent, the calf pump can no longer compensate and

Figure 5.8 On the left two panels a normal set of deep veins. On the right two panels post-thrombotic femoral veins with synachiae and collateral pathways.

52

The physiology and hemodynamics of chronic venous insufﬁciency of the lower limb

the superﬁcial venous pressure rises leading to the changes described above. In many patients, the perivenous ﬁbrosis that follows thrombosis prevents venous distension and may also act as a functional obstruction. As is apparent from the data just provided, the lower limb venous system is divided into three segments: deep, superﬁcial, and perforator. Incompetence of one system in isolation is associated with minimal signs of chronic venous insufﬁciency. Incompetence in all three, however, is much more likely to be associated with active ulceration and higher residual calf pump volumes following muscle contraction.33 A small group of patients have primary deep valvular incompetence, with no evidence of a thrombotic etiology. Whether this is a consequence of abnormal valves (the ﬂoppy valves of Kistner)34 or true congenital valvular agenesis remains a matter of conjecture. Both may coexist. It is also possible that valvular incompetence is secondary to dilation of the wall of the deep veins. In some patients, particularly with Klippel–Trenaunay syndrome, the deep veins are completely absent, being replaced by a primitive axial vein.35 This may be a case of true venous agenesis. Deep vein damage and obstruction may also be a consequence of direct or indirect injury, surgical mishap, leiomyomas and leiomyosarcomas. These and a few other unusual causes of deep venous obstruction are, however, very rare causes of chronic venous insufﬁciency.

MECHANISM OF SKIN CHANGES Homans36 was the ﬁrst to suggest that venous stasis was the cause of the skin changes and ulceration that accompany the development of the post-thrombotic limb, although John Gay,37 100 years earlier, had described the presence of “matter” in the deep veins of ulcerated limbs dissected at post-mortem. Gay was also the ﬁrst person to describe perforating vein incompetence in the cadaveric limb. The concept of stasis was later challenged when Blalock38 and subsequently a number of others39–41 demonstrated that the oxygen content of the venous blood was high rather than low in the venous efﬂuent of limbs with venous ulceration. This ﬁnding taken in conjunction with the observation that angiography in these limbs demonstrated rapid passage of contrast material into the veins,42 led to the suggestion that arteriovenous ﬁstulae opened up in response to chronic venous hypertension. There were even claims that arteriovenous ﬁstulae could be demonstrated on histological examination,43 although these claims were subsequently qualiﬁed when the author of the article accepted that he could not differentiate an arteriovenous ﬁstula from a thick-walled capillary or venule. Nevertheless, the consistent ﬁnding of a raised venous oxygen content in ulcerated limbs led Fontaine44 to again propose that arteriovenous shunts situated in the dermis below the ulcer-bearing area were responsible for ulcer development. Schalin45 has continued to champion the

theory that arteriovenous ﬁstulae are the major cause of both varicose veins and venous ulceration. Much of his evidence is, however, speculative and open to debate. Ryan and Copeman46 suggested that the arteriovenous shunts in the dermis, which control temperature regulation, might open up in response to raised venous pressure and shunt blood away from the skin. The whole theory of arteriovenous shunts being responsible for venous ulceration was challenged by the work of Hugo Partsch,47 who as a young researcher in the department of dermatology at Vienna showed that radiolabeled macroaggregates injected into the femoral veins of ulcerated limbs failed to enter the lungs in greater quantities than those injected into the control “normal” limbs. Instead, the macroaggregates were trapped in the capillary bed beneath the ulcer, causing a hot area in the leg. This work was unable to show evidence of excessive shunting in ulcerated limbs, but merely conﬁrmed that the capillary bed had increased in size. Hopkins et al.,48 using positron emission tomography in patients with leg ulcers and lipodermatosclerosis, found that the metabolic and ﬂow measurements suggested excessive blood ﬂow through the local capillary bed with reduced metabolic uptake of oxygen, consistent with a diffusion block. Taken together these two pieces of work provide fairly convincing evidence that physiological arteriovenous shunting is not present in the ulcer bed. The extravasation of red cells also appears to modulate the microenvironment through the elevated levels of ferritin and ferric acid in the affected skin, favoring ulcer formation. The C282Y mutation (iron metabolism), which occurs in hemachromatosis, results in a sevenfold increase in the risk of ulceration in those with chronic venous disease.49 Bollinger et al.50 reported that “halos” were present around the dermal calf capillaries in the ulcer-bearing skin, and Burnand et al.26,27 went on to expand these observations by showing pericapillary ﬁbrin cuffs in the same dermal capillary bed (Fig. 5.9). These were associated with an expanded capillary bed, venous hypertension, and a defective local and systemic ﬁbrinolytic capacity. The presence of pericapillary ﬁbrin cuffs led us to speculate51 that these in combination with other molecules and interstitial ﬁbrin might interfere with the passage of oxygen and other nutrients to the overlying skin. Although evidence was provided that a thick ﬁlm of ﬁbrin did interfere with oxygen diffusion, subsequent theoretical estimations have cast doubt on the idea that pure ﬁbrin would be an effective diffusion block.52 More recently, the ﬁnding of white cell depletion in the venous efﬂuent of dependent limbs led initially to the concept of white cell trapping within the dermal capillaries and plugging of this vascular bed.53,54 Subsequent reﬁnements in this theory have suggested that white cell margination, activation, and even escape into the tissues may cause local damage and eventually lead to ulceration.55 At present, there is no evidence that white cells are activated before skin changes become apparent

References 53

free radicals,60 mast cell activation61 and mechanical damage based upon venous hypertension.62 Speciﬁc MMPs (matrix metalloproteinases) such as MMP-2 are inhibited in patients with varicose veins; this may result in accumulation of more extracellular matrix material. It is unclear at present whether this results from venous hypertension or initiates the process. Falanga and Eaglestein63 have suggested that the ﬁbrin cuff acts as a trap to block or slow down growth factors reaching the skin and Herrick et al.64 have carried out a nice histological study that has demonstrated that the pericapillary halos not only contain ﬁbrinogen but also contain lamisin, and other proteins. The presence of crosslinked ﬁbrin within the cuff has been conﬁrmed by Brakman et al.65

CONCLUSIONS Figure 5.9 The skin of the ulcer bearing area in a patient with lipodermatosclerosis. Immunoﬂuorescent staining with an antiﬁbrin antibody showing bright halos of ﬁbrin around the dermal capillaries. From Professor H. Partsch, with kind permission.

and, therefore, no proof that these changes are the cause rather than the effect of venous hypertension, lipodermatosclerosis, and of course ulceration. A number of studies have shown that changes in white cells are produced by short-term (tourniquet-induced) venous hypertension.56 Certain adhesion molecules expressed by leukocytes such as intercellular adhesion molecule 1, endothelial leukocyte adhesion molecule 1, and vascular cell adhesion molecule 1 are increased in patients with chronic venous disease and rise further in response to venous hypertension.57,58 Induction of venous hypertension also results in the reduction of L-selectin, CD11b integrin on circulating neutrophils and monocytes, whereas circulating plasma L-selectin rises as it is shed from these cells.57 These changes are thought to reﬂect leukocyte trapping.59 Other theories that have recently been put forward for the development of venous ulcers include the release of

The importance of persistent ambulatory venous hypertension in the development of lipodermatosclerosis and ulceration is not disputed. The relative frequency of deep and superﬁcial venous obstruction and reﬂux seems to vary in different studies and the true role of perforator incompetence in the development of venous ulcers remains to be established. The precise mechanisms that cause skin breakdown are not known. A number of theories have been put forward, but these need to be conﬁrmed or refuted by further studies. A better understanding of the mechanisms that cause ulceration should lead to better methods of preventing ulcers from developing and of treating them once they have developed.

REFERENCES ● ◆

= Key primary paper = Major review article 1. Kurz X, Kahn SR, Benhaim EA, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Int Angiol 1999; 18: 83–101. 2. Porter JM, Rutherford RB, Clagett GP, Raju S: Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–9.

Guidelines 1.4.0 of the American Venous Forum on the physiology and hemodynamics of chronic venous insufﬁciency of the lower limb No.

Guideline

1.4.1 Persistent ambulatory venous hypertension is the main cause of chronic venous insufﬁciency

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality) A

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The physiology and hemodynamics of chronic venous insufﬁciency of the lower limb

3. Porter D, Rosen M, Skillman J, et al. Clinical–anamnestic and instrumental data in out patients suffering from venous disease. Int J Angiol 1995; 14: 400–3. 4. Da Silva A, Widmer LK, Martin H, et al. Varicose veins and chronic venous insufﬁciency – prevalence and risk factors in 4376 subjects in the Basle study. Vasa 1974; 3: 118–25. 5. Perrin M. Chronic Venous Insufﬁciency in the Lower Limbs. Paris: McGraw Hill, 1990. 6. Browse N L, Burnand KG, Irvine A. Diseases of the Veins. London: Arnold, 1999. 7. Bradbury A, Evans C, Allan P, et al. What are the symptoms of varicose veins? The Edinburgh vein study cross-sectional population survey. Br Med J 1999; 353–6. ●8. Bjordal RI. Circulation patterns in the saphenous system and the peforating veins of the calf in patients with previous deep vein thrombosis. Vasa 1974; Suppl 3: 3–41. 9. Pegum JM, Fegan WG. Physiology of venous return from the foot. Cardiovasc Res 1967; 1: 249–51. 10. Landis EM. Capillary pressure and capillary permeability. Physiol Rev 1934; 14: 404–81. 11. Pappenheimer JR, Soto-Rivera A. An effective osmotic pressure of plasma proteins and other quantities associated with the capillary circulation in the hind limbs of cats and dogs. Am J Physol 1948; 52: 471–91. ●12. Pappenheimer JR. Passage of molecules through capillary walls. Physiol Rev 1953; 33: 387. 13. Landis EM, Jonas L, Angevine M, Erb W. The passage of ﬂuid and protein through the human capillary wall during venous congestion. J Clin Invest 1932; 11: 717. 14. Urbanova D, Prerovsky I. Enzymes in the wall of normal and varicose veins. Histochemical study. Angiologica 1972; 9: 53–61. 15. Wegmann R, Elsammannoudy FA, Oliver C, Rettori R. Histochemical studies on the walls of human varicose veins: the saphenous varicose vein. Ann Histochem 1974; 19: 285–92. 16. Shireman PR, McCarthy WJ, Pearce WH et al. Plasminogen activator levels are inﬂuenced by location and varicosity in great saphenous vein. J Vasc Surg 1996; 24: 719–24. 17. Farbiszewski R, Glowinski PJ, Makarewicz-Plonska M, et al. Oxygen-derived free radicals as mediators of varicose vein wall damage. Vasc Surg 1996; 30: 47–52. 18. Ackroyd JS, Pattison M, Browse NL. A study on the mechanical properties of fresh and preserved human femoral vein wall and valve cusps. Br J Surg 1985; 72: 117–19. 19. Rose S, Ahmed A. Some thoughts on the aetiology of varicose veins. J Cardiovasc Surg 1986; 27: 534–43. 20. Cotton L. Varicose veins. Gross anatomy and development. Br J Surg 1961; 48: 589–98. 21. Ludbrook J. Valvular defect in primary varicose veins. Cause or effect? Lancet 1963; 2: 1289–92. 22. Trendelenburg F. Uber die Unterbildung der Vena saphena magna bei unterschenkel Varicen. Beitr Klin Chir 1891; 7: 195–210.

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Cockett FB, Jones DE. The ankle blowout syndrome. A new approach to the varicose ulcer problem. Lancet 1953; 1: 17–23. Campbell WA, West, A. duplex ultrasound of operative treatment of varicose veins. In: Negus D, Jantet G, Coleridge Smith P, eds. Phlebology. Berlin: Springer, 1995. Stuart WP, Allan PL, Ruckley CV, Bradbury AW, Saphenous surgery does not correct perforator incompetence in the presence of deep venous reﬂux. J Vasc Surg 1998; 28: 834–8. Burnand KG, Whimster I, Clemenson G, et al. The relationship between the number of capillaries in the skin of the venous ulcer bearing area of the lower leg and the fall in foot vein pressure during exercise. Br J Surg 1981; 68: 297–300. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary ﬁbrin in the ulcer bearing skin of the leg. Br Med J 1982; 285: 1071–2. Burnand KG, Clemenson G, Whimster I, et al. The effect of sustained venous hypertension on the skin capillaries of the canine hind limb. Br J Surg 1982; 69: 41–4. O’shaughnessy AM, Fitzgerald DE. The patterns and distribution of residual abnormalities between the individual proximal venous segments after an acute deep vein thrombosis. J Vasc Surg 2001; 33: 379–84. Killewich LA, Bedford GR, Beach KW, Strandness DE, Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vasc Surg 1989; 9: 89–97. Edwards EA, Edwards JE. The effect of thrombophlebitis on the venous valves. Surg Gynecol Obstet 1937; 65: 310–20. Brittenden J, Bradbury AW, Allan PL, Ruckley CV. Popliteal vein reﬂux reduces the healing of chronic venous ulcer. Br J Surg 1998; 85: 60–2. Ibegbuna V, Delis KT, Nicolaides AN. Haemodynamic and clinical impact of superﬁcial, deep and perforator vein incompetence. Eur J Vasc Endovasc Surg 2006; 31: 535–41. Kistner RL. Primary venous valve incompetence of the leg. Am J Surg 1980; 140: 218–24. Gloviczki P, Stanson AW, Stickler AW, et al. Klippel–Trenaunay Syndrome: the risks and beneﬁts of vascular interventions. Surgery 1991; 110: 469–79. Homans J. The etiology and treatment of varicose ulcer of the leg. Surg Gynaecol Obstet 1917; 24: 300–11. Gay J. Vascular Disease of the Lower Extremities and its Allied Disorders: skin discolouration, Induration and Ulcer. London: Churchill, 1868. Blalock A. Oxygen content of blood in patients with varicose veins. Arch Surg 1929; 19: 898–905. Blumoff RL, Johnson G: Saphenous vein PO2 in patients with varicose veins. J Surg Res 1977; 23: 35–6. Clyne CAC, Ramsden WH, Chant ADR, Webster JH. Oxygen tension in the skin of the gaiter area of limbs with venous disease. Br J Surg 1985; 72: 644–7. Holling HE, Beecher HK, Linton RR. Study of the tendency to oedema formation associated with incompetence of the valves of the communicating veins of the leg. J Clin Invest 1938; 17: 555–61.

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42. Haimovici H. Abnormal arterio-venous shunts associated with chronic venous insufﬁciency. J Cardiovasc Surg 1976; 17: 473–82. 43. Guis JA. Arteriovenous anastomoses and varicose veins. Arch Surg 1960; 81: 299–308. 44. Fontaine R. Remarks concerning venous thrombosis and its sequelae. Surgery 1957; 41: 6–25. 45. Schalin S. Arteriovenous communications localised by thermography and identiﬁed by operative microscopy. Acta Chir Scand 1981; 147: 409–20. 46. Ryan TJ, Copeman PMW. Microvascular patterns and blood stasis in skin diseases. Br J Dermatol 1970; 8: 563–70. 47. Lindemayr W, Loefferer O, Mostbeck A, Partsch H. Arteriovenous shunts in primary varicoses? A critical essay. Vasc Surg 1972; 6: 9–14. 48. Hopkins NFG, Spinks TJ, Rhodes CG, et al. Positron emission tomography in venous ulceration and liposclerosis: a study of regional tissue function. Br Med J 1983; 6: 9–14. 49. Zamboni P Tognazzo S, Izzo M, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 2005; 42: 309–14. 50. Bollinger A, Jager K, Geser A, et al. Transcapillary and interstitial diffusion of Na ﬂuorescein in chronic venous insufﬁciency with white atrophy. Int J Microcirc Clin Exp 1982; 1: 5–17. ●51. Browse NL, Burnand KG: The cause of venous ulceration. Lancet 1982; 2: 243–5. 52. Michel CC. Aetiology of venous ulceration. Br J Surg 1990; 77: 1071. 53. Thomas PRS, Nash GB, Dormandy JA. White cell accummulation in the dependent legs of patients with venous hypertension. Br Med J 1988; 296: 1693–5. ●54. Coleridge-Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296: 1726–7.

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Scott HJ, McMullin GM, Coleridge-Smith PD, Scurr JH. Venous ulceration the role of the white blood cell. Phlebology 1989; 4: 153–9. Shields DA, Andaz S, Abeysinghe RD, et al. Soluble markers of leucocyte adhesion in patients with venous disease. Phlebology 1994; 9 (Suppl): 55–8. Saharay M, Shields DA, Porter JB, et al. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg 1997; 26: 265–73. Saharay M, Shields DA, Georgiannos SN, et al. Endothelial activation in patients with chronic venous disease. Eur J Vasc Endovasc Surg 1998; 15: 342–9. Bergan JJ, Schmid-Schonbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med 2006; 355: 488–98. Edwards AT, Herrick SE, Suarez-Mendez VJ, McCollum CN. Oxidants, antioxidants and venous ulceration. Br J Surg 1992; 79: 443–4. Pappas PJ, Defouw DO, Venezio LM, et al. Morphometric assessment of dermal microcirculation in patients with venous insufﬁciency. J Vasc.Surg 1997; 26: 784–95. Chant A. The biomechanics of leg ulceration. Ann R Coll Eng 1999; 81: 80–5. Falanga V, Eaglestein WH. The ‘trap’ hypothesis of venous ulceration. Lancet 1993; 341: 1006–8. Herrick SE, Sloan P, McGurie M, et al. Sequential changes in histologic patterns and extra cellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 1992; 141: 1085–95. Brakman M, Faber WR, Kerckhaert JA, et al. Immunoﬂuorescence studies of atrophie blanche with antibodies against ﬁbrinogen, ﬁbrin, plasminogen activactor inhibitor, Factor VIII related antigen and collagen type IV. Vasa 1992; 21: 143–8.

6 Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufficiency PETER J. PAPPAS, BRAJESH K. LAL, FRANK T. PADBERG, JR., ROBERT W. ZICKLER AND WALTER N. DURAN Introduction Varicose vein formation (macroscopic alterations) Historical theories Venous stasis theory Arteriovenous ﬁstula theory Diffusion block theory Leukocyte activation Role of leukocyte activation and functional status in CVI The venous microcirculation

56 56 58 59 59 59 59 60 61

INTRODUCTION Ten to 35% of adults in the USA have some form of chronic venous insufﬁciency (CVI) with venous ulcers affecting 4% of people over the age of 65.1,2 Owing to the high prevalence of the disease, the population-based costs to the US government for CVI treatment and venous ulcer care has been estimated at over 1 billion dollars a year. In addition, 4.6 million work days per year are lost to venousrelated illnesses.3,4 The recurrent nature of the disease, the high cost to the healthcare system and the ineffectiveness of current treatment modalities underscore the need for CVI-related research. The past decade has further deﬁned the role of leukocyte-mediated injury and elucidated the role of inﬂammatory cytokines in lower extremity dermal pathology. In addition, several laboratories have performed investigations on pathologic alterations in cellular function and the molecular regulation of these processes observed in patients with CVI. This chapter will discuss the pathogenesis and pathophysiology of varicose vein formation and the molecular regulation of inﬂammatory damage to the lower extremity dermis caused by persistent ambulatory venous hypertension.

Endothelial cell characteristics Types and distribution of leukocytes Extracellular matrix (ECM) alterations Pathophysiology of stasis dermatitis and dermal ﬁbrosis Cytokine regulation and tissue ﬁbrosis Dermal ﬁbroblast function Role of matrix metalloproteinases and their inhibitors in chronic venous insufﬁciency References

61 62 62 63 63 65 66 66

VARICOSE VEIN FORMATION (MACROSCOPIC ALTERATIONS) Genetics and the role of deep venous thrombosis Unlike arteries, veins are thin-walled, low-pressure conduits whose function is to return blood from the periphery to the heart. Muscular contractions in the upper and lower extremities propel blood forward and a series of intraluminal valves prevent retrograde ﬂow or reﬂux. Venous reﬂux is observed when valvular destruction or dysfunction occurs in association with varicose vein formation. Valvular reﬂux causes an increase in ambulatory venous pressure and a cascade of pathologic events that manifest themselves clinically as lower extremity edema, pain, itching, skin discoloration, varicose veins, venous ulceration, and in its severest form limb loss. These clinical symptoms collectively refer to the disorder known as chronic venous insufﬁciency (CVI).5 Age, gender, pregnancy, weight, height, race, diet, bowel habits, occupation, posture, previous deep venous thrombosis, and genetics have all been proposed as

Varicose vein formation (macroscopic alterations) 57

predisposing factors associated with varicose vein formation. Except for previous deep vein thrombosis and genetics, there is poor evidence indicating a causative relationship between these predisposing factors and the formation of varicose veins. The reader is referred to Browse and Burnand’s textbook Diseases of the Vein for further discussion on these predisposing factors.6 There are few reported epidemiologic investigations that suggest a relationship between varicose vein formation and a genetic predisposition.7,8 It was previously thought that axial destruction of venous valves led to transmission of ambulatory venous hypertension causing reﬂux and varix formation.6 However, a publication by Labropoulos et al.9 indicated that the most frequent location for initial varicose vein formation was in the below-knee great saphenous vein (GSV) and its tributaries, followed by the above-knee GSV, and the saphenofemoral junction. This study clearly indicates that vein wall degeneration with subsequent varix formation can occur in any segment of the superﬁcial and deep systems at any time and suggests a genetic component to the disease. In 1969, Gunderson and Hauge7 reported on the epidemiology of varicose veins observed in the vein clinic in Malmo Sweden over a 2 month period. Of 250 patients, 154 female and 24 male patients provided complete survey information on their parents and siblings. Although biased by the predominance of women and dependence on survey data, this report suggested that patients with varicose veins had a higher likelihood of developing varicosities if their father had varicose veins. Furthermore, the risk of developing varicose veins increases if both parents had varicosities. Cornu-Thenard et al.8 prospectively examined 67 patients and their parents. The non-affected spouses and parents of patients were used as controls for a total of 402 subjects. These investigators reported that the risk of developing varicose veins was 90% when both parents were affected, 25% for males and 62% for females if one parent was affected and 20% when neither parent was affected. These data suggest an autosomal dominant with variable penetrance mode of genetic transmission. The decreased incidence in males with an affected parent and the spontaneous development in patients without affected parents suggests that males are more resistant to varix formation and that other multifactorial etiologies in patients with predispositions to the disease must exist. To further elucidate the genetic component of the disease, molecular analyses with gene chip technologies are required. The chromosome associated with the disease and its protein by-products are currently unknown. An injury to the venous endothelium or local procoagulant environmental factors leads to thrombus formation in the venous system. It is currently well accepted that a venous thrombus initiates a cascade of inﬂammatory events that contributes to or causes vein wall ﬁbrosis.10 Thrombus formation at venous conﬂuences and valve pockets leads to activation of neutrophils and

platelets. Activation of these cells leads to formation of inﬂammatory cytokines, pro-coagulants and chemokines leading to thrombin activation and further clot formation. Production of inﬂammatory mediators creates a cytokine/chemokine gradient, leading to leukocyte invasion of the vein wall at the thrombus wall interface and from the surrounding adventitia. Upregulation of adhesion molecules perpetuates this process, eventually leading to vein wall ﬁbrosis, valvular destruction, and alteration of vein wall architecture.10,11 Although the mechanisms associated with vein wall damage secondary to venous thrombosis are beginning to be unraveled, the majority of varicose veins occur in patients with no prior history of deep vein thrombosis (DVT). The etiology of primary varicose veins continues to be a mystery.

Vein wall anatomy, histopathology and functional alterations Whatever the initiating event, several unique anatomic and biochemical abnormalities have been observed in patients with varicose veins. Normal and varicose GSVs are characterized by three distinct muscle layers within their walls. The media contains an inner longitudinal and an outer circular layer, and the adventitia contains a loosely organized outer longitudinal layer.12–14 In normal GSVs, these muscle layers are composed of smooth muscle cells (SMCs) that appear spindle shaped (contractile phenotype) when examined with electron microscopy (Fig. 6.1).15 These cells lie in close proximity to each other, are in parallel arrays, and surrounded by bundles of regularly arranged collagen ﬁbers. In varicose veins, the orderly appearance of the muscle layers of the media is replaced by an intense and disorganized deposition of collagen.15–17 Collagen deposits separate the normally

Figure 6.1 Electron micrograph of normal vein demonstrating contractile smooth muscle phenotype.

58

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency

closely opposed SMCs and are particularly striking in the media. SMCs appear elliptical, rather than spindle shaped and demonstrate numerous collagen-containing vacuoles imparting a secretory phenotype (Fig. 6.2).15 What causes SMCs to dedifferentiate from a contractile to a secretory phenotype is currently unknown. Ascher et al.18,19 theorized that SMC dedifferentiation may be related to dysregulation of apoptosis. These investigators reported a decrease in the pro-apoptotic mediators bax and polyADP-ribose polymerase in the adventitia of varicose veins compared with normal veins. Although no difference in these mediators was observed in the media or intima of varicose veins, a decrease in SMC turnover was postulated as a possible cause for the increase in the secretory phenotype. Increased phosphorylation of the retinoblastoma protein, an intracellular regulator of cellular proliferation and differentiation, has been observed in varicose veins and may similarly contribute to this process.13 Vein wall remodeling has been consistently observed in histologic varicose vein specimens.12,14–17,20 Gandhi et al.20 quantitatively demonstrated an increase in collagen content and a decrease in elastin content compared to normal GSVs. The net increase in the collagen/elastin ratio suggested an imbalance in connective tissue matrix regulation. As a result, several investigators have observed alterations in matrix metalloproteinase and ﬁbrinolytic activity in varicose veins. Tissue inhibitor of metalloproteinase (TIMP-1) and MMP-1 protein levels are increased at the saphenofemoral junction compared with normal controls, whereas MMP-2 levels are decreased.21 No overall differences in MMP-9 protein or activity levels have been identiﬁed; however, the number of cells expressing MMP-9 by immunohistochemistry has been reported to be elevated in varicose veins compared with normal veins.22,23 There are conﬂicting reports regarding the role of plasmin activators and their

inhibitors. Shireman et al.24 reported that uPA (urokinase plasminogen activator) levels are increased three to ﬁve times compared with normal controls in the media of vein specimens cultured in an organ bath system. No differences were noted in tPA (tissue plasminogen activator) or PAI-1 (plasmin activator inhibitor 1) levels. However, other investigations have reported a decrease in uPA and tPA activity by enzyme zymography in varicose veins.22,25 These data suggest that the plasminogen activators may play a role in matrix metalloproteinase activation leading to vein wall ﬁbrosis and varix formation; however, further research into the mechanisms regulating vein wall ﬁbrosis are clearly needed. What effect vein wall ﬁbrosis has on venous function needs further elucidation. The contractile responses of varicose and normal GSV rings to noradrenaline, potassium chloride, endothelin, calcium ionophore A23187, angiotensin II and nitric oxide have been evaluated by several investigators.26,27 These studies have demonstrated decreased contractility of varicose veins when stimulated by noradrenaline, endothelin and potassium chloride. Similarly, endothelium-dependent and -independent relaxations after A23187 or nitric oxide administration, respectively, were diminished compared with normal GSVs. The mechanisms responsible for decreased varicose vein contractility appear to be receptor mediated.27,28 Utilizing sarafotoxin S6c (selective pharmacologic inhibitor of endothelin B) and competitive inhibition receptor assays with [131I]-endothelin-1, a decrease in endothelin B receptors has been observed in varicose veins compared with normal GSVs.28 Feedback inhibition of receptor production secondary to increased endothelin-1 is postulated to mediate the decreased receptor content in varicose vein walls. Other possible mechanisms for decreased contractility appear related to cAMP levels and the ratio of prostacyclin to thromboxaneA2.29 Cyclic-AMP is increased in varicose vein specimens compared with normal GSVs. In addition, the ratio of prostacyclin to throboxane-A2 is increased, even though absolute protein levels do not differ between normal veins and varicosities. Whether venodilation of varicosities is caused by diminished endothelin receptor levels and responsiveness to cAMP or is a secondary effect of varix formation is not known. However, it is clear that with the development of vein wall ﬁbrosis, varicose veins demonstrate decreased contractile properties that probably exacerbate the development of ambulatory venous hypertension.

HISTORICAL THEORIES

Figure 6.2 Electron micrograph of varicose vein wall demonstrating secretory phenotype of smooth muscle cells.

In the twentieth century numerous theories have been postulated regarding the etiology of CVI and the cause of venous ulceration. The venous stasis, arteriovenous ﬁstula and diffusion block theories have been disproven over time and are discussed here for historical interest only. The

Leukocyte activation 59

etiology for dermal skin pathology is primarily a chronic inﬂammatory process and the events regulating these events are discussed below.

evidence. Experiments with radioactively labeled microspheres have never demonstrated shunting and have therefore cast serious doubts on the validity of this theory.

VENOUS STASIS THEORY

DIFFUSION BLOCK THEORY

In 1917, John Homans30 published a manuscript entitled “The etiology and treatment of varicose ulcer of the leg” in Surgery, Gynecology and Obstetrics. This manuscript was a clinical treatise on the diagnosis and management of patients with CVI. In this manuscript Dr Homans coined the term post-phlebitic syndrome and speculated on the cause of venous ulceration. He stated that “Overstretching of the vein walls and destruction of the valves upon which the mechanism principally depends bring about a degree of surface stasis which obviously interferes with the nutrition of the skin and subcutaneous tissues. … It is to be expected, therefore that skin which is bathed under pressure in stagnant venous blood will readily form permanent, open sores or ulcers.”30 This statement resulted in a generation of investigators trying to seek a causal relationship between hypoxia, stagnant blood ﬂow and the development of CVI. The ﬁrst investigator to address the question of hypoxia and CVI scientiﬁcally was Alfred Blalock.31 He obtained venous samples from the femoral, great saphenous and varicose veins in 10 patients with CVI isolated to one limb and compared their oxygen content to samples taken from corresponding veins in the opposite limb. Seven of the patients had active ulcers at the time. All samples were collected in the recumbent and standing positions. He reported that in patients with unilateral CVI the oxygen content was higher in the femoral vein of the affected limb. He speculated that this observation may be reﬂective of increased venous ﬂow rather than stagnation.

Hypoxia and alterations in nutrient blood ﬂow were again proposed as the underlying etiology of CVI in 1982 by Burnand et al.33 These authors performed a study in which skin biopsies were obtained from 109 limbs of patients with CVI and 30 limbs from patients without CVI. Foot vein pressures were measured in the CVI patients at rest and after 5, 10, 15, and 20 heel raises. Vein pressure measurements were then correlated with the number of capillaries observed on histologic section. The authors reported that venous hypertension was associated with increased numbers of capillaries in the dermis of patients with CVI. Whether the histologic sections represented true increases in capillary quantity or an elongation and distension of existing capillaries was not answered by this study. However, in a canine hind limb model, the authors were able to induce enlargement in the number of capillaries with experimentally induced hypertension.34 This important investigation was one of the ﬁrst studies to demonstrate a direct effect of venous hypertension on the venous microcirculation. In a later study, Browse and Burnand35 noted that the enlarged capillaries observed on histologic examination exhibited pericapillary ﬁbrin deposition and coined the term “ﬁbrin cuff.” They speculated that venous hypertension led to widening of endothelial gap junctions with subsequent extravasation of ﬁbrinogen leading to the development of ﬁbrin cuffs. These authors theorized that the cuffs acted as a barrier to oxygen diffusion and nutrient blood ﬂow, resulting in epidermal cell death. Although pericapillary cuffs do exist, it has never been demonstrated that they act as a barrier to nutrient ﬂow or oxygen diffusion.

ARTERIOVENOUS FISTULA THEORY The concept of increased venous ﬂow in the dermal venous plexus was expanded upon by Pratt,32 who reported that increased venous ﬂow in patients with CVI could be clinically observed. He attributed the development of venous ulceration to the presence of arteriovenous connections and coined the term “arterial varices.” He reported that in a series of 272 patients with varicose veins who underwent vein ligation, 24% had arteriovenous connections. Of the 61 patients who developed recurrences, 50% occurred in patients with arteriovenous communications identiﬁed clinically by the presence of arterial pulsations in venous conduits. Pratt hypothesized that increased venous ﬂow shunted nutrientand oxygen-rich blood away from the dermal plexus, leading to areas of ischemia and hypoxia and resulting in venous ulceration. Pratt’s clinical observations, however, have never been conﬁrmed with objective scientiﬁc

LEUKOCYTE ACTIVATION Dissatisfaction with the ﬁbrin cuff theory and subsequent observations of decreased circulating leukocytes in blood samples obtained from the great saphenous veins in patients with CVI led Coleridge Smith and colleagues36 to propose the leukocyte-trapping theory. This theory proposes that circulating neutrophils are trapped in the venous microcirculation secondary to venous hypertension. The subsequent sluggish capillary blood ﬂow leads to hypoxia and neutrophil activation. Neutrophil activation leads to degranulation of toxic metabolites with subsequent endothelial cell damage. The ensuing heterogeneous capillary perfusion causes alterations in skin blood ﬂow and eventual skin damage. The problem with the leukocyte-trapping theory is that neutrophils have never been directly observed to obstruct

60

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency

capillary ﬂow, therefore casting doubt on its validity. However, there is signiﬁcant evidence that leukocyte activation plays a major role in the pathophysiology of CVI.

ROLE OF LEUKOCYTE ACTIVATION AND FUNCTIONAL STATUS IN CVI In 1988, Thomas et al.37 reported that 24% less white cells left the venous circulation after a period of recumbency in patients with CVI compared with normal patients. They studied three groups of 10 patients each. Group 1 consisted of patients with no signs of venous disease. Group 2 were patients with uncomplicated primary varicose veins and group 3 were patients with longstanding CVI as determined by Doppler ultrasonography, strain gauge plethysmography, and foot volumetry. The great saphenous vein was cannulated just above the medial malleolus. Venous samples were obtained at various time points with patients in the sitting and supine position. Samples were then placed in an automated cell counter and the number of leukocytes and erythrocytes determined. The ratios of white cells to red cells at the various time points were then compared. It was reported that with leg dependency, the packed cell volume signiﬁcantly increased in patients with CVI compared with normal control subjects, whereas patients with primary varicose veins showed no difference from control subjects. It was also noted that the relative number of white cells was signiﬁcantly decreased compared with control and primary varicose vein patients (28% vs 5%, p<0.01). It was concluded that the decrease in white cell number was due to leukocyte trapping in the venous microcirculation secondary to venous hypertension. It was further speculated that while trapped, leukocytes may be activated and release toxic metabolites causing damage to the microcirculation and the overlying skin. These important observations were the ﬁrst to implicate abnormal leukocyte activity in the pathophysiology of CVI. The importance of leukocytes in the development of dermal skin alterations was emphasized by Scott et al.38 These authors obtained punch biopsies from patients with primary varicose veins, lipodermatosclerosis, and patients with lipodermatosclerosis and healed ulcers and determined the median number of white blood cells (WBCs) per high-power ﬁeld (40× magniﬁcation) in each group. No patients with active ulcers were included and no attempt to identify the type of leukocytes was made. It was reported that in patients with primary varicose veins, lipodermatosclerosis, and healed ulceration there was a median of 6, 45, and 217 WBCs per mm2 respectively. This study demonstrated that with clinical disease progression and increasing severity of CVI, there was a progressive increase in the number of leukocytes in the dermis of CVI patients.

The types of leukocytes involved in dermal venous stasis skin changes are controversial. In a study performed by Wilkinson et al.,39 skin biopsies were obtained from 23 patients who required surgical ligation, stripping, and/or avulsion for their varicose veins. The condition of the skin was recorded as liposclerotic, eczematous, or normal. Lipodermatosclerosis was deﬁned clinically as palpable induration of the skin and subcutaneous tissues and eczema as visible erythema with scaling of the skin. Using immunohistochemical techniques staining for leukocytespeciﬁc cell surface markers was carried out and it was reported that macrophages and lymphocytes were the predominant leukocytes observed in this patient population. Neutrophils and B-lymphocytes were rarely observed. T-lymphocytes and macrophages were predominantly observed perivascularly and in the epidermis. However, Pappas et al.40 performed a quantitative morphometric assessment of the dermal microcirculation using electron microscopy and reported that macrophages and mast cells were the predominant cells observed in patients with CVI dermal skin changes. Furthermore, lymphocytes were never observed. This discrepancy may reﬂect the types of patients that were studied. Wilkinson et al.39 biopsied patients with erythematous and eczematous skin changes whereas Pappas et al.40 predominantly evaluated older patients with dermal ﬁbrosis. Patients with eczematous skin changes may have an autoimmune component to their CVI, whereas patients with dermal ﬁbrosis may reﬂect changes consistent with chronic inﬂammation and altered tissue remodeling. Given the predominant role of leukocytes in CVI pathology, there has been great interest in the activation state and functional status of leukocytes in CVI patients. Pappas et al.41 explored the hypothesis that circulating leukocytes in CVI patients were in an altered state of activation and therefore may be involved in leukocytemediated injury. They measured the expression of cell surface activation markers of circulating leukocytes using ﬂuorescence ﬂow cytometry.41 Relative to normal individuals, patients with chronic venous stasis ulcers had a decreased expression of the CD3+/DR+ and CD3+/CD38+ markers on T-lymphocytes and an increased expression of CD14+/CD38+ markers on monocytes. Circulating neutrophils demonstrated no evidence of activation. Although Pappas et al.41 identiﬁed a population of circulating cells demonstrating altered activation markers, their results did not test the functional status of these cells. In a follow-up study Pappas et al.42 tested the hypothesis that circulating mononuclear cells in CVI patients were dysfunctional by challenging monocytes with test mitogens. Lymphocyte and monocyte cell function was measured as the degree of proliferation in response to a mitogenic challenge. Fifty patients were separated into four groups: group 1, 14 patients with normal limbs; group 2, 10 patients with class II CVI (stasis dermatitis only); group 3, 15 patients with active venous ulcers; group

Types and distribution of leukocytes 61

4, 11 patients with healed venous ulcers and current evidence of lipodermatosclerosis. Systemically circulating lymphocytes and monocytes were obtained by antecubital venipuncture from groups 1–4. Cells were cultured in the presence of staphylococcal enterotoxins (SEs) A, B, C1, D, E (mitogens), and phytohemagglutinin (PHA), a control mitogen. Proliferative responses to PHA indicated that lymphocytes and monocytes from CVI patients were not globally depressed. However, patients in group 2 did not exhibit the same degree of proliferation to PHA as did groups 1, 3, and 4. Differences in proliferative responses between groups 2 and 1 (44.38 ± 43.9 vs 118.87 ± 27.1, P ≤ 0.05) and groups 2 and 3 (44.38 ± 43.9 vs 105.95 ± 60.99, P ≤ 0.05) were signiﬁcant. Challenges with staphylococcal enterotoxin A and B revealed signiﬁcant diminution of proliferative responses in groups 2 (42.73 ± 11.55, P ≤ 0.05) and 3 (45.57 ± 9.1, P ≤ 0.05) and groups 3 (36.81 ± 6.9, P ≤ 0.05) and 4 (35.04 ± 7.5, P ≤ 0.05) compared with SE A control subjects, (68.68 ± 9.9) and SE B control subjects, (66.25 ± 13.56) respectively. A trend towards diminished cellular function with progression of CVI was observed with staphylococcal enterotoxins B, C1, D, and E, strongly suggesting biologic signiﬁcance. Furthermore, patients with LDS and a history of healed ulcers uniformly exhibited the poorest proliferative responses. This study indicated that deterioration of mononuclear cell function was associated with CVI and suggested that lymphocyte and monocyte function diminished with clinical disease progression. It was speculated that the decreased capacity for mononuclear cell proliferation in response to various challenges may manifest itself clinically as poor and prolonged wound healing.

THE VENOUS MICROCIRCULATION Numerous investigations have attempted to evaluate the microcirculation of patients with CVI.40,43–46 The majority of these investigations were qualitative descriptions of vascular abnormalities, which lacked uniformity of biopsy sites and patient stratiﬁcation. Prior to 1997 it was widely accepted that endothelial cells from the dermal microcirculation appeared abnormal, contained Weibel–Palade bodies, were edematous and demonstrated widened interendothelial gap junctions.45 Based on these descriptive observations it was assumed that the dermal microcirculation of CVI patients have functional derangements related to permeability and ulcer formation. It was not until 1997 that a quantitative morphometric analysis of the dermal microcirculation was reported.40 The objectives of this investigation were to quantify differences in endothelial cell structure and local cell type with emphasis on leukocyte cell type and their relationship to arterioles, capillaries, and postcapillary venules (PCVs). The variables assessed were the number and types of leukocytes, endothelial cell thickness, endothelial vesicle density, interendothelial junctional width, cuff thickness,

and ribosome density. Thirty-ﬁve patients had two 4 mm punch biopsies obtained from the lower calf (gaiter region) and lower thigh. Patients were separated into one of four groups according to the 1995 ISCVS/SVS (International Society for Cardiovascular Surgery/Society for Vascular Surgery) CEAP classiﬁcation.5 Group 1 consisted of ﬁve patients with no evidence of venous disease. Skin biopsies from these patients served as normal controls. Groups 2–4 consisted of patients with CEAP Class 4 (n = 11), Class 5 (n = 9), and Class 6 (n = 10) CVI.

ENDOTHELIAL CELL CHARACTERISTICS No signiﬁcant differences were observed in endothelial cell thickness of arterioles, capillaries and PCVs from either gaiter or thigh biopsies.40 Qualitatively, endothelial cells appeared metabolically active. Many nuclei exhibited a euchromatic appearance, implying active mRNA transcription. In most instances ribosome numbers were so abundant that they exceeded the resolution capacity of the image analysis system and could not be quantiﬁed. The prominence in ribosome content and the euchromatic appearance of the endothelial cell nucleus strongly suggested active protein production. No signiﬁcant differences in vesicle density were observed in gaiter biopsies between groups. Class 6 patients exhibited an increased number of vesicles in arterioles and PCV endothelia from thigh biopsies but did not differ compared to gaiter biopsies. Mean inter-endothelial junctional width varied within a normal range of 20– 50 nm. Signiﬁcantly widened inter-endothelial gap junctions were not observed and thus conﬂicted with the reports of Wenner et al.45 Mean basal lamina thickness differed signiﬁcantly at the capillary level in both gaiter and thigh biopsies. Differences were most pronounced in patients with Class 4 disease. These data indicated that endothelial cells from the dermal microcirculation of CVI patients were far from abnormal. They demonstrated increased metabolic activity suggestive of active cellular transcription and protein production. Most surprising was the observation of uniformly tight gap junctions. Previously these gap junctions were reported to be as wide as 180 nanometers and it was assumed that these widened junctions were responsible for macromolecule extravasation and edema formation.33,45 Pappas et al.40 suggested that alternate methods for tissue edema like increased transendothelial vesicle transport, formation of transendothelial channels and alterations in the glycocalyx lining the junctional cleft may be involved in CVI edema and macromolecule transport.

TYPES AND DISTRIBUTION OF LEUKOCYTES The most striking differences in cell type and distribution were observed with mast cells and macrophages (Fig. 6.3).

62

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency

(a)

Mast cell density: Gaiter PCVs

cells/m3 venule endothelium

7.5

5.0

+ *

2.5

+ *

+

* 0.0

controls

class 4

class 5

class 6

CVI by CEAP class

(b)

Macrophage cell density: gaiter post-capillary venules

cells/m3 venule endothelium

7.5

+ *

enzyme chymase is a potent activator of matrix metalloproteinase-1 and 3 (collagenase and stromelysin).47–49 In an in vitro model using the human mast cell line HMC-1, these cells were reported to spontaneously adhere to ﬁbronectin, laminin, and collagen type I and III, all components of the perivascular cuff (see below).49 Chymase also causes release of latent transforming growth factor beta-1 (TGF-β1) secreted by activated endothelial cells, ﬁbroblasts and platelets from extracellular matrices.50 Release and activation of TGF-β1 initiates a cascade of events in which macrophages and ﬁbroblasts are recruited to wound healing sites and stimulated to produce ﬁbroblast mitogens and connective tissue proteins respectively.51 Mast cell degranulation leading to TGF-β1 activation and macrophage recruitment may explain why decreased mast cell and increased macrophage numbers were observed in class 6 patients. Macrophage migration, as evidenced by the frequent appearance of cytoplasmic tails in perivascular macrophages, further substantiates the concept of inﬂammatory cytokine recruitment (Fig. 6.4).

5.0

EXTRACELLULAR MATRIX (ECM) ALTERATIONS

+ 2.5

Figure 6.3 Histograms demonstrating mast cell and macrophage cell densities according to CEAP disease classiﬁcation and their proximity to post-capillary venules. Class 4: venous dermatitis only; class 5: venous dermatitis and a history of healed ulceration; class 6: active venous stasis ulcer.

Once leukocytes have migrated to the extracellular space they localize around capillaries and post-capillary venules. The perivascular space is surrounded by extracellular matrix (ECM) proteins and forms a perivascular “cuff”. Adjacent to these perivascular cuffs and throughout the dermal interstitium is an intense and disorganized collagen deposition.33,40 Perivascular cuffs and the accompanying collagen deposition are the sine qua non of the dermal microcirculation in CVI patients (Fig. 6.4). The perivascular cuff was originally thought to be the result of ﬁbrinogen extravasation and erroneously referred to as a

In both gaiter and thigh biopsies, mast cell numbers were two to four times greater than control in Class 4 and 5 patients around arterioles and PCVs (P < 0.05). Class 6 patients demonstrated no difference in mast cell number compared to controls. Mast cell numbers around capillaries did not differ across groups in either gaiter or thigh biopsies. Macrophages demonstrated increased numbers in Class 5 and 6 patients around arterioles and PCVs respectively (P < 0.05). Differences in macrophage numbers around capillaries were observed primarily in Class 4 patients in both gaiter and thigh biopsies. Surprisingly, lymphocytes, plasma cells and neutrophils were not present in the immediate perivascular space. Fibroblasts were the most common cells observed in both gaiter and thigh biopsies. It was speculated that mast cells and macrophages may function to regulate tissue remodeling resulting in dermal ﬁbrosis.40 The mast cell

Figure 6.4 Photomicrograph (4300×) of CVI dermal microcirculation demonstrating extracellular matrix changes (pericapillary cuff), migrating macrophages, lymphatic vessel and ﬁbroblast.

++ + * 0.0

controls

class 4

class 5

class 6

CVI by CEAP class

Cytokine regulation and tissue ﬁbrosis

The mechanisms modulating leukocyte activation, ﬁbroblast function and dermal extracellular matrix alterations have been the focus of investigation in the 1990s. CVI is a disease of chronic inﬂammation due to a persistent and sustained injury secondary to venous hypertension. It is hypothesized that the primary injury is extravasation of macromolecules (i.e. ﬁbrinogen and α2-macroglobulin) and red blood cells (RBCs) into the dermal interstitium.33,34,44,45,54 RBC degradation products and interstitial protein extravasation are potent chemoattractants and presumably represent the initial underlying chronic inﬂammatory signal responsible for leukocyte recruitment. It has been assumed that these cytochemical events are responsible for the increased expression of ICAM-1 (intercellular adhesion molecule 1) on endothelial cells of microcirculatory exchange vessels observed in CVI dermal biopsies.39,55 ICAM-1 is the activation dependent adhesion molecule utilized by macrophages, lymphocytes and mast cells for diapedesis. As stated above, all these cells have been observed by immunohistochemistry and electron microscopy in the interstitium of dermal biopsies.39,40

CYTOKINE REGULATION AND TISSUE FIBROSIS

(a)

TGF-β1 gene expression 10–12 moles/g total RNA

PATHOPHYSIOLOGY OF STASIS DERMATITIS AND DERMAL FIBROSIS

dermal biopsies from normal patients and CEAP class 4, 5 and 6 CVI patients were analyzed for TGF-β1 gene expression, protein production and cellular location.56 Quantitative RT-PCR for TGF-β1 gene expression was performed on 24 skin biopsies obtained from 24 patients (Fig. 6.5a). Patients were separated into four groups according to the ISCVS/ SVS classiﬁcation for CVI: normal skin (n = 6), CEAP class 4 (n = 6) and CEAP class 5 (n = 5) CEAP class 6 (n = 7). TGF-β1 gene transcripts for controls, class 4, 5 and 6 patients were 7.02 ± 7.33, 43.33 ± 9.0, 16.13 ± 7.67 and 7.22 ± 0.56 × 10 –14 mol/g total RNA, respectively. The differences in TGF-β1 gene expression in class 4 patients was signiﬁcantly elevated compared to control and class 5 and 6 patients (P < 0.05).56 An additional 38 patients had 54 biopsies from the lower calf (LC) and lower thigh (LT) analyzed for TGF-β1 protein concentration (Fig. 6.5b). The amount of active TGF-β1 in picograms/gram (pg/g) of tissue from LC and LT biopsies compared to normal skin biopsies were as follows: Normal skin (< 1.0 pg/g), Class 4 (LC, 5061 ± 1827, LT 317.3 ± 277), Class 5 (LC, 8327 ± 3690, LT 193 ± 164) and Class 6 (LC, 5392 ± 1800, LT, 117 ± 61) (Fig. 6.5). Differences between normal skin and class 4 and 6 patients were signiﬁcant (P ≤ 0.05 and P ≤ 0.01 respectively). No differences between class 4, 5 and 6 patients were observed. Differences between LC and LT within each CVI group were signiﬁcant (class 4, P ≤ 0.003, class 5, P ≤ 0.008, class 6, P ≤ 0.02). These data demonstrate that in areas of

100

Results: Quantitative RT-PCR for TGF-β1 mRNA from CVI Skin Biopsies

*

50

25

0

Controls

Class 4

Class 5

Class 6

CVI patients * Class 4 compared to controls, class 5 and 6

(b) TGF-β1 levels in pg/gm of tissue

“ﬁbrin cuff”.5 It is now known that the cuff is a ring of ECM proteins consisting of collagens type I and III, ﬁbronectin, vitronectin, laminin, tenascin and ﬁbrin.52 The role of the cuff and its cell of origin is not completely understood. The investigation by Pappas et al. suggested that the endothelial cells of the dermal microcirculation were responsible for cuff formation.40 The cuff was once thought to be a barrier to oxygen and nutrient diffusion however, recent evidence suggests that cuff formation is an attempt to maintain vascular architecture in response to increased mechanical load.53 Although perivascular cuffs may function to preserve microcirculatory architecture, several pathologic processes may be related to cuff formation. Immunohistochemical analyses have demonstrated transforming growth factor-β1 (TGF-β1) and α2-macroglobulin in the interstices of perivascular cuffs.54 It has been suggested that these “trapped” molecules are abnormally distributed in the dermis leading to altered tissue remodeling and ﬁbrosis. Cuffs may also serve as a lattice for capillary angiogenesis explaining the capillary tortuosity and increased capillary density observed in the dermis of CVI patients.

63

Results: Active TGF-β1 Protein Levels from CVI Dermal Skin Biopsies 100 #

LC = Lower calf LT = Lower thigh

50 *,#

*,# 25

0

# # # * CON C4 LC C4 LT C5 LC C5 LT C6 LC C6 LT CVI patient classification * Control vs Class 4 and 6 (p0.05) # LC vs LT biopsies within each class (p0.02)

Leukocyte recruitment, ECM alterations and tissue ﬁbrosis are characteristic of chronic inﬂammatory diseases caused by alterations in TGF-β1 gene expression and protein production. To determine the role of TGF-β1 in CVI,

Figure 6.5 Increased TGF-β1 mRNA transcripts in class 4 patients only (a); active TGF-β1 protein is observed in class 4, 5 and 6 patients in areas of clinically active disease (b).

64

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency

clinically active CVI, increased amounts of active TGF-β1 are present compared with normal skin. Furthermore, active TGF-β1 protein concentrations of biopsies from the LT did not differ from normal skin demonstrating a regionalized repsonse to injury.56 Immunohistochemistry and immunogold labeling experiments were performed to identify the sources of active TGF-β 1 protein production. Immunohistochemistry of normal skin and ipsilateral thigh biopsies of CVI patients demonstrated mild TGF-β1 in the basal layer of the epidermis. The dermis demonstrated few capillaries, ordered collagen architecture, and no interstitial leukocytes. CVI dermal biopsies from areas of clinically active disease demonstrated staining of the basal layer of the epidermis, interstitial leukocytes, and ﬁbroblasts. Many perivascular leukocytes demonstrated positive staining of intracellular granules and appeared morphologically similar to previously reported mast cells (Figs 6.3 and 6.6).56 Numerous capillaries with perivascular cuffs were observed; however, cuffs did not stain positively for TGF-β1.56 This study conﬂicts with the observations reported by Higley et al.54 in which they reported positive TGF-β1 staining in perivascular cuffs and an absence of TGF-β1 in the provisional matrix of the venous ulcer compared with healing donor skin graft sites. They concluded that TGF-β1 was therefore abnormally “trapped” in the perivascular cuff and therefore unavailable for normal granulation tissue development. Differences between the two studies may relate to biopsy site selection. Higley et al.54 biopsied chronic, non-healing venous ulcer edges and ulcer bases, whereas patients with active ulcers in the study by Pappas et al were biopsied 5–10 cm away from an active ulcer. Therefore, the former study reﬂects the biology of chronic wound healing whereas our data suggest active tissue remodeling in response to a chronic injury stimulus. Immunogold labeling conﬁrmed the presence of TGF-β1 in dermal leukocytes. Positive labeling of gold particles was similarly observed in collagen ﬁbrils of the ECM. This observation may explain why the molecular regulation of TGF-β 1 in CVI patients demonstrates

Figure 6.6 Perivascular cuff demonstrating TGF-β1 positive leukocytes. Horizontal arrow indicates a leukocyte morphologically similar to a mast cell. (575×).

differential gene and protein production according to disease classiﬁcation. As stated above, the gene expression of TGF-β1 was increased in class 4 patients only, whereas protein production was essentially increased in classes 4, 5, and 6 patients. These differences may be related to disease severity and the pluripotential responses of TGF-β1. TGF-β1 can have inhibitory and stimulatory effects that are primarily dependent on local concentration, cell source, and surrounding extracellular matrix. In the study by Pappas et al., class 4 patients were younger than the other study groups, never experienced an episode of venous stasis ulceration, and clinically demonstrated less dermal tissue ﬁbrosis. TGF-β1 in these patients may therefore be involved in limiting the response to injury. Indeed, one could speculate that early on in the disease process, a low-grade production of TGF-β1 is a normal wound healing response and may serve to prevent the onset and development of tissue ﬁbrosis. With continued and prolonged exposure an imbalance in tissue remodeling in patients with classes 5 and 6 disease clinically manifests itself as dermatoﬁbrosis. A pathologic effect of increased ECM deposition is an alteration in the storage and release of growth factors.57 The latent form of TGF-β1 is secreted from cells bound to one of three latent TGF-β1 binding proteins (LTBP). Once secreted, LTBPs mediate binding of latent TGF-β1 to matrix proteins. Matrix release of TGF-β1 is mediated by multiple serine proteinases, including plasmin, mast cell chymase, and leukocyte elastase.50,58–60 An increase in the number of mast cells and circulating leukocyte elastase has been previously reported in CVI patients.40,61 The increase in active TGF-β1 observed in class 5 and 6 patients may therefore result from ECM release of latent TGF-β1, resulting in tissue ﬁbrosis. This hypothesis is consistent with the demonstration of immunogold labeling to collagen ﬁbrils in the ECM of CVI patients. The modulation of TGF-β1 release from the ECM may therefore provide a faster means of signal transduction than the simple control of gene expression and therefore explain the sustained increase of TGF-β1 in class 5 and 6 patients in the absence of increased gene expression. This study did not demonstrate increased TGF-β1 staining in the ECM by ICC because the primary antibody used was speciﬁc only for active TGF-β1 and therefore may have missed LAP- (latency-associated peptide) and LTBPassociated TGF-β1. The distribution and location of several other growth factors in the skin of CVI patients has also been investigated. Peschen et al.62 reported on the role of platelet-derived growth factor receptor alpha and beta (PDGFR-α and -β) and vascular endothelial growth factor (VEGF). Skin biopsies from 30 patients were separated into ﬁve groups with a total of six patients in each group: group 1, patients with reticular veins; group 2, venous eczema; group 3, skin pigmentation; group 4, lipodermatosclerosis; and group 5, patients with active leg ulcers. Biopsies were studied with immunohistochemistry

Dermal ﬁbroblast function 65

and the degree of immunoreactivity assessed with a scoring system by two blinded reviewers. Peschen et al.62 reported that PDGFR-α and -β and VEGF expression was strongly increased in the stroma of CVI patients with eczema and active ulcers compared with patients with reticular veins and pigmentation changes only. To a lesser degree, patients with lipodermatosclerosis demonstrated immunoreactivity to PDGFR-α and -β and VEGF as well. PDGFR-α and β expression was considerably elevated in the capillaries and surrounding ﬁbroblasts and inﬂammatory cells of venous eczema patients. In addition, immunoreactivity was increased in dermal ﬁbroblasts, smooth muscle cells and vascular cells of lipodermatosclerosis patients compared with patients with reticular veins only. The greatest expression of PDGFR-α and -β was observed in mesenchymal cells and vascular endothelial cells of patients with active venous ulcers. VEGF immunoreactivity correlated with disease severity. Vascular endothelial growth factor-positive capillary endothelial cells and pericapillary cells increased in patients with venous eczema, lipodermatosclerosis, and active venous ulceration respectively. Based on these observations, the authors speculated that leukocyte recruitment, capillary proliferation, and interstitial edema in CVI patients may be regulated through PDGF and VEGF by upregulation of adhesion molecules leading to leukocyte recruitment, diapedesis, and release of chemical mediators.55 In summary, the above investigations indicate that progression of CVI dermal pathology is mediated by a cascade of inﬂammatory events. Venous hypertension causes extravasation of macromolecules, such as ﬁbrinogen and red blood cells, which act as potent inﬂammatory mediators. These mediators cause an upregulation of adhesion molecules and the expression of growth factors such as PDGF and VEGF, which results in leukocyte recruitment. Monocytes and mast cells travel to the site of injury that activate or release TGF-β1 and probably other undiscovered chemicals as well. What effect growth factor binding has on ﬁbroblast and endothelial cell function was the focus of numerous investigations in the 1990s.

DERMAL FIBROBLAST FUNCTION Several studies have reported aberrant phenotypic behavior of ﬁbroblasts isolated from venous ulcer edges when compared with ﬁbroblasts obtained from ipsilateral thigh biopsies of normal skin in the same patients. Hasan et al.63 compared the ability of venous ulcer ﬁbroblasts to produce αI procollagen mRNA and collagen after stimulation with TGF-β1. These authors were not able to demonstrate differences in αI procollagen mRNA levels after stimulation with TGF-β1 between venous ulcer ﬁbroblasts and normal ﬁbroblasts (control) from ipsilateral thigh biopsies. However, collagen production

was increased by 60% in a dose-dependent manner in control subjects whereas venous ulcer ﬁbroblasts were unresponsive. This unresponsiveness was associated with a fourfold decrease in TGF-β1 type II receptors. In a followup report, Kim et al.64 indicated that the decrease in TGF-β1 type II receptors was associated with a decrease in phosphorylation of the TGF-β1 receptor substrates Smad 2 and 3 as well as p42/44 mitogen-activated protein kinases. A similar investigation reported a decrease in collagen production from venous ulcer ﬁbroblasts and similar amounts of ﬁbronectin production when compared with normal control subjects.65 Fibroblast responsiveness to growth factors was further delineated by Stanley et al.66 These investigators characterized the proliferative responses of venous ulcer ﬁbroblasts when stimulated with basic ﬁbroblastic growth factor (bFGF), epidermal growth factor (EGF) and interleukin 1-β (IL-1β). In their initial study, they reported that venous ulcer ﬁbroblast growth rates were markedly suppressed when stimulated with bFGF, EGF and IL-1β. In a follow-up investigation these authors noted that the previously observed growth inhibition could be reversed with bFGF.67 Lal et al.68 reported that the proliferative responses of CVI ﬁbroblasts to TGF-β1, correlated with disease severity. Fibroblasts from patients with CEAP class 2–3 disease retain their agonist-induced proliferative capacity. Class 4 and 5 ﬁbroblasts demonstrated diminished agonist-induced proliferation whereas class 6 (venous ulcer ﬁbroblasts) did not proliferate after TGF-β1 stimulation, conﬁrming the observations made by the previous investigators. Phenotypically, venous ulcer ﬁbroblasts appeared large, polygonal and exhibited varied nuclear morphologic features whereas normal ﬁbroblasts appeared compact and tapered with well-deﬁned nuclear morphologic features. Venous ulcer ﬁbroblasts appeared morphologically similar to ﬁbroblasts undergoing cellular senescence. Therefore, the blunted growth response of CVI venous ulcer ﬁbroblasts appears related to development of cellular senescence.66,69 Other characteristics of senescent cells are an overexpression of matrix proteins such as ﬁbronectin (cFN) and enhanced activity of β-galactosidase (SA-βGal). In an evaluation of seven patients with venous stasis ulcers, it was noted that there was a higher percentage of SA-β-Gal positive cells in patients with venous ulcers than in normal control subjects (6.3% vs 0.21%, P ≤ 0.006).67 It was also reported that patients with venous ulcer ﬁbroblasts produced one to four times more cFN by western blot analysis than control subjects.69 These data support the hypothesis that venous ulcer ﬁbroblasts phenotypically behave like senescent cells. However, senescence is probably the end manifestation of a wide spectrum of events that leads to proliferative resistance and cellular dysfunction. Telomeres and telomerase activity are the sine qua non of truly senescent cells. To date, there are no reported studies indicating an

66

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency

abnormality in CVI ﬁbroblast telomere or telomerase activity. Despite these investigations, the true role of senescence in CVI remains ill deﬁned.

ROLE OF MATRIX METALLOPROTEINASES (MMPS) AND THEIR INHIBITORS IN CVI The signaling event responsible for the development of a venous ulcer and the mechanisms responsible for prolonged wound healing are poorly understood. Wound healing is an orderly process that involves inﬂammation, re-epithelialization, matrix deposition and tissue remodeling. Tissue remodeling and matrix deposition are processes controlled by MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs). In general, MMPs and TIMPs are not constitutively expressed. They are induced temporarily in response to exogenous signals such as various proteases, cytokines or growth factors, cell–matrix interactions and altered cell–cell contacts. TGF-β1 is a potent inducer of TIMP-1 and collagen production and inhibitor of MMP-1 through regulation of gene expression and protein synthesis. Several studies have demonstrated that prolonged and continuous TGFβ1 production causes tissue ﬁbrosis by stimulating ECM production and inhibiting degradation by affecting MMP and TIMP production. Alterations in MMP and TIMP production may similarly modulate the tissue ﬁbrosis of the lower extremity in CVI patients. Several investigators have reported that the gelatinases MMP-2 and 9 as well as TIMP-1 are increased in the exudates of patients with venous ulcers compared to acute wounds.70–72 However, analyses of biopsy specimens have demonstrated variable results. Herouy et al. reported that MMP-1,2 and TIMP-1

are increased in patients with lipodermatosclerosis compared to normal skin.73 In a subsequent investigation, biopsies from venous ulcer patients were found to have increased levels of the active form of MMP-2 compared to normal skin.74 In addition, increased immunoreactivity to EMMPRIN (Extracellular inducer of MMP), MT1-MMP (Membrane Type 1) and MT2-MMP in the dermis and perivascular regions of venous ulcers.75 Saito et al. were unable to identify differences in overall MMP-1, 2, 9 and TIMP-1 protein levels or activity in CVI patients with CEAP class 2 through 6 disease compared to normal controls or CVI groups.76 However, within a clinical class, MMP-2 levels were elevated compared to MMP-1, 9 and TIMP-1 in patients with class 4 and class 5 disease. These data indicate that active tissue remodeling is occurring in patients with CVI. Which matrix metalloproteinases are involved and how they’re activated and regulated is currently unclear. It appears that MMP-2 may be activated by urokinase plasminogen activator (uPA). Herouy et al. observed increased uPA and uPAR mRNA and protein levels in patients with venous ulcers compared to normal skin.77 The elevated levels of active TGF-β1 in the dermis of CVI patients suggests a regulatory role for TGF-β1 in MMP and TIMP synthesis and activity. However, there is currently no direct evidence indicating such a relationship.

CONCLUSION The mechanisms regulating varicose vein development and the subsequent dermal skin sequelae caused by chronic ambulatory venous hypertension have only recently been investigated. It is clear that varicose vein

Guidelines 1.5.0 of the American Venous Forum on pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.5.1 Genetics and deep venous thrombosis are predisposing factors for varicose veins

A

1.5.2 Age, female gender, pregnancy, weight, height, race, diet, bowel habits, occupation and posture are predisposing factors for varicose veins

C

1.5.3 Vein wall remodeling and ﬁbrosis, affected by hemodynamic factors, matrix metalloproteinases and plasminogen activators, lead to varicose vein formation

C

1.5.4 In chronic venous insufﬁciency the transmission of high venous pressures to the dermal microcirculation causes extravasation of macromolecules and red blood cells that serve as the underlying stimulus for inﬂammatory injury

A

1.5.4 TGF-β1 and matrix metalloproteinases play key roles in the inﬂammatory injury that leads to lipodermatosclerosis and chronic skin changes

B

References 67

formation has a genetic component that is linked to environmental stimuli. Susceptible patients develop vein wall ﬁbrosis and loss of valvular competence that leads to venous hypertension. The transmission of high venous pressures to the dermal microcirculation causes extravasation of macromolecules and red blood cells that serve as the underlying stimulus for inﬂammatory injury. Activation of the microcirculation results in cytokine and growth factor release leading to leukocyte migration into the interstitium. At the site of injury, a host of inﬂammatory events is set into action. TGF-β1 appears to be a primary regulator of CVI induced injury. TGF-β1 secretion from leukocytes with subsequent binding to dermal ﬁbroblasts is associated with intense dermal ﬁbrosis and tissue remodeling. In addition, decreased TGF-β1 type II receptors on venous ulcer ﬁbroblasts, are associated with diminished ﬁbroblast proliferation. Fibroblast proliferation diminishes with disease progression ultimately leading to senescence and poor ulcer healing. In addition, increases in MMP-2 synthesis appear to increase tissue remodeling and further impede ulcer healing. As our understanding of the underlying cellular and molecular mechanisms that regulate CVI and ulcer formation increase, therapeutic interventions for treatment and prevention will ultimately follow.

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11. Takase S, Bergan JJ, Schmid-Schonbein G. Expression of adhesion molecules and cytokines on saphenous veins in chronic venous insufﬁciency. Ann Vasc Surg 2000; 14: 427–35. 12. Rose A. Some new thoughts on the etiology of varicose veins. J Cardiovasc Surg 1986; 27: 534–43. 13. Pappas PJ, Gwertzman GA, DeFouw DO, et al. Retinoblastoma protein: a molecular regulator of chronic venous insufﬁciency. J Surg Res 1998; 76: 149–53. 14. Travers JP, Brookes CE, Evans J, et al. Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content. Eur J Vasc Endovasc Surg 1996; 11: 230–37. 15. Jurukova Z, Milenkov C. Ultrastructural evidence for collagen degradation in the walls of varicose veins. Exp Mol Path 1982; 37: 37–47. 16. Venturi M, Bonavina L, Annoni F, et al. Biochemical assay of collagen and elastin in the normal and varicose vein wall. J Surg Res 1996; 60: 245–8. 17. Maurel E, Azema C, Deloly J, Bouissou H. Collagen of the normal and the varicose human saphenous vein: a biochemical study. Clin Chim Acta 1990; 193: 27–38. 18. Ascher E, Jacob T, Hingorani A, et al. Programmed cell death (apoptosis) and its role in the pathogenesis of lower extremity varicose veins. Ann Vasc Surg 2000; 14: 24–30. 19. Ascher E, Jacob T, Hingorani A, et al. Expression of molecular mediators of apoptosis and their role in the pathogenesis of lower-extremity varicose veins. J Vasc Surg 2001; 33: 1080–6. 20. Gandhi RH, Irizarry E, Nachman GB, et al. Analysis of the connective tissue matrix and proteolytic activity of primary varicose veins. J Vasc Surg 1993; 18: 814–20. 21. Parra JR, Cambria RA, Hower CD, et al. Tissue inhibitor of metalloproteinase-1 is increased in the saphenofemoral junction of patients with varices in the leg. J Vasc Surg 1998; 28: 669–75. 22. Kosugi I, Urayama H, Kasashima F, et al. Matrix metalloproteinase-9 and urokinase-type plasminogen activator in varicose veins. Ann Vasc Surg 2003; 17: 234–8. 23. Woodside KJ, Hu M, Burke A, et al. Morphologic characteristics of varicose veins: possible role of metalloproteinases. J Vasc Surg 2003; 38: 162–9. 24. Shireman PK, McCarthy WJ, Pearce WH, et al. Plasminogen activator levels are inﬂuenced by location and varicosity in greater saphenous vein. J Vasc Surg 1996; 24: 719–24. 25. Badier-Commander C, Verbeuren T, Lebard C, et al. Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathol 2000; 192: 105–12. 26. Lowell RC, Gloviczki P, Miller VM. In vitro evaluation of endothelial and smooth muscle function of primary varicose veins. J Vasc Surg 1992; 16: 679–86. 27. Rizzi A, Quaglio D, Vasquez G, et al. Effects of vasoactive agents in healthy and diseased human saphenous veins. J Vasc Surg 1998; 28: 855–61.

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28. Barber DA, Wang X, Gloviczki P, Miller VM. Characterization of endothelin receptors in human varicose veins. J Vasc Surg 1997; 26: 61–69. 29. Nemcova S, Gloviczki P, Rud KS, Miller VM. Cyclic nucleotides and production of prostanoids in human varicose veins. J Vasc Surg 1999; 30: 876–884. 30. Homans J. The etiology and treatment of varicose ulcer of the leg. Surg Gynecol Obstet 1917; 24: 300–11. 31. Blalock A. Oxygen content of blood in patiens with varicose veins. Arch Surg 1929; 19: 898–905. 32. Pratt GH. Arterial varices; a syndrome. Am J Surg 1949; 77: 456–60. 33. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary ﬁbrin deposition in the ulcer bearing skin of the lower limb: the cause of lipodermatosclerosis and venous ulceration. Br Med J 1982; 285: 1071–2. 34. Burnand KG, Clemenson.G., Gaunt J, Browse NL. The effect of sustained venus hypertension in the skin and capillaries of the canine hind limb. Br J Surg 1981; 69: 41–4. 35. Browse NL, Burnand KG. the cause of venous ulceration. Lancet 1982; 2: 243–5. 36. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296: 1726–7. 37. Thomas P, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988; 296: 1693–5. 38. Scott HJ, Smith PDC, Scurr JH. Histological study of white blood cells and their association with lipodermatosclerosis and venous ulceration. Br J Surg 1991; 78: 210–11. 39. Wilkinson LS, Bunker C, Edward JCW, et al. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg 1993; 17: 669–75. 40. Pappas PJ, DeFouw DO, Venezio LM, et al. Morphometric assessment of the dermal microcirculation in patients with chronic venous insufﬁciency. J Vasc Surg 1997; 26: 784–95. 41. Pappas PJ, Fallek SR, Garcia A, et al. Role of leukocyte activation in patients with venous stasis ulcers. J Surg Res 1995; 59: 553–9. 42. Pappas PJ, Teehan EP, Fallek SR, et al. Diminished mononuclear cell function is associated with chronic venous insufﬁciency. J Vasc Surg 1995; 22: 580–6. 43. Leu AJ, Leu HJ, Franzeck UK, Bollinger A. Microvascular changes in chronic venous insufﬁciency: a review. Cardiovasc Surg 1995; 3: 237–45. 44. Leu HJ. Morphology of chronic venous insufﬁciency-light and electron microscopic examinations. Vasa 1991; 20: 330–42. 45. Wenner A, Leu HJ, Spycher M, Brunner U. Ultrastructural changes of capillaries in chronic venous insufﬁciency. Expl Cell Biol 1980; 48: 1–14. 46. Scelsi R, Scelsi L, Cortinovis R, Poggi P. Morphological changes of dermal blood and lymphatic vessels in chronic venous insufﬁciency of the leg. Int Angiol 1994; 13: 308–11.

47. Saarien J, Lalkkinen N, Welgus HG, Kovannen PT. Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase. J Biol Chem 1994; 269: 18134–40. 48. Lees M, Taylor DJ, Woolley DE. Mast cell proteinases activate precursor forms of collagenase and stromelysin, but not of gelatinases A and B. Eur J Biochem 1994; 223: 171–7. 49. Kruger-Drasagakes S, Grutzkau A, Baghramian R, Henz BM. Interactions of immature human mast cells with extracellular matrix: expression of speciﬁc adhesion receptors and their role in cell binding to matrix proteins. J Invest Dermatol 1996; 106: 538–43. 50. Taipale J, Keski-oja J. Growth factors in the extracellular matrix. FASEB J 1997; 11: 51–9. 51. Roberts AB, Flanders KC, Kondaiah P, et al. Transforming growth factor β: biochemistry and roles in embryogenesis, tissue repair and remodeling, and carcinogenesis. Recent Prog Horm Res 1988; 44: 157–97. 52. Herrick S, Sloan P, McGurk M, et al. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 1992; 141: 1085–95. 53. Bishop JE. Regulation of cardiovascular collagen deposition by mechanical forces. Mol Med Today 1998; 4: 69–75. 54. Higley HR, Kassander GA, Gerhardt CO, Falanga V. Extravasation of macromolecules and possible trapping of transforming growth factor-β1 in venous ulceration. Br J Surg 1995; 132: 79–85. 55. Peschen M, Lahaye T, Gennig B, et al. Expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufﬁciency. Acta Derm Venereol 1999; 79: 27–32. 56. Pappas PJ, You R, Rameshwar P, et al. Dermal tissue ﬁbrosis in patients with chronic venous insufﬁciency is associated with increased transforming growth factorβ1gene expression and protein production. J Vasc Surg 1999; 30: 1129–45. 57. Taipale J, Saharinen J, Hedman K, Keski-oja J. Latent transforming growth factor-β1 and its binding protein are components of extracellular matrix microﬁbirls. J Histochem Cytochem 1996; 44: 875–89. 58. Border WA, Noble NA. Transforming growth factor β in tissue ﬁbrosis. N Eng J Med 1994; 331: 1286–92. 59. O’kane S, Ferguson WJ. Transforming growth factor βs and wound healing. Int J Biochem Cell Biol 1997; 29: 63–78. 60. Grande JP. Role of transforming growth factor-β in tissue injury and repair. PSEBM 1997; 214: 27–40. 61. Shields DA, Sarin AS, Scurr JH, Smith PDC. Plasma elastase in venous disease. Br J Surg 1994; 81: 1496–99. 62. Peschen M, Grenz H, Brand-Saberi B, et al. Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin of patients with chronic venous insufﬁciency. Arch Dermatol Res 1998; 290: 291–7.

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63. Hasan A, Murata H, Falabella A, et al. Dermal ﬁbroblasts from venous ulcers are unresponsive to the action of transforming growth factor-β1. J Dermatol Sci 1997; 16: 59–66. 64. Kim B, Kim HT, Park SH, et al. Fibroblasts from chronic wounds show altered TGF-β signaling and decreased TGF-β type II receptor expression. J Cell Physil 2003; 195: 331–36. 65. Herrick SE, Ireland GW, Simon D, et al. Venous ulcer ﬁbroblasts compared with normal ﬁbroblasts show differences in collagen but not in ﬁbronectin production under both normal and hypoxic conditions. J Invest Dermatol 1996; 106: 187–93. 66. Stanley AC, Park H, Phillips TJ, et al. Reduced growth of dermal ﬁbroblasts from chronic venous ulcers can be stimulated with growth factors. J Vasc Surg 1997; 26: 994–1001. 67. Mendez MV, Stanley A, Park H, et al. Fibroblasts cultured from venous ulcers display cellular characteristics of senescence. J Vasc Surg 1998; 28: 876–83. 68. Lal BK, Saito S, Pappas PJ, et al. Altered proliferative responses of dermal ﬁbroblasts to TGF-β1 may contribute to chronic venous stasis ulcers. J Vasc Surg 2003; 37: 1285–93. 69. Mendez MV, Stanley A, Phillips TJ, et al. Fibroblasts cultured from distal lower extremities in patients with venous reﬂux display cellular characteristics of senescence. J Vasc Surg 1998; 28: 1040–50. 70. Weckroth M, Vaheri A, Lauharanta J, et al. Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996; 106: 1119–24.

71. Wysocki AB, Staiano-Coico L, Grinell F. Wound ﬂuid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993; 101: 64–8. 72. Bullen EC, Longaker MT, Updike DL, et al. Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol 1995; 104: 236–40. 73. Herouy Y, May AE, Pornschlegel G, et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: Implications for venous ulcer formation. J Invest Dermatol 1998; 111: 822–7. 74. Herouy Y, Trefzer D, Zimpfer U, et al. Matrix metalloproteinases and venous leg ulceration. Eur J Dermatol 2000; 9: 173–80. 75. Norgauer J, Hildenbrand T, Idzko M, et al. Elevated expression of extracellular matrix metalloproteinase inducer (CD 147) and membrane-type matrix metalloproteinases in venous leg ulcers. Br J Dermatol 2002; 147: 1180–6. 76. Saito S, Trovato MJ, You R, et al. Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufﬁciency. J Vasc Surg 2001; 34: 930–8. 77. Herouy Y, Trefzer D, Hellstern MO, et al. Plasminogen activation in venous leg ulcers. Br J Dermatol 2000; 143: 930–6.

7 Venous ulcer formation and healing at cellular levels JOSEPH D. RAFFETTO Introduction Theoretical perspectives in venous ulcer formation Leukocytes and chronic venous insufﬁciency Alterations in ﬁbroblast cellular proliferation, motility, senescent phenotype, and regulation

70 70 71 72

INTRODUCTION The basic science literature regarding venous ulcer formation, although very important, cannot be equated with that of large multicenter randomized clinical trials. Therefore, a 1A grade of evidence cannot apply, and at best the work varies from the 1C to the 2C category (observational studies). However, well-performed basic science research can rapidly advance our understanding of the basic mechanisms driving the clinical picture and therefore suggest the best investment for the clinical trials we plan. To be taken seriously, the quality of the basic science research must be driven by sound scientiﬁc methodology, be hypothesis driven, and interpret the results based on ﬁrm statistical analysis backed by the appropriate power level (predetermined number of observations required for a robust analysis). Venous ulcer pathophysiology is a complex process that involves alterations in cellular functions, the overexpression of matrix metalloproteinases, the inhibitory environment of a medium called chronic wound ﬂuid, and changes in tissue microcirculation with resultant hypoxic regions. Collectively these abnormal wound states lead to chronic and recurrent bouts of ulceration. The mechanisms involved in the formation and recurrence of venous ulcer is unknown but the current state of our understanding is the essence of this review. The role of leukocytes cannot be overlooked and its importance in venous ulcer pathogenesis is paramount. For completeness, a summary section on leukocytes and venous ulcers is included. Chronic inﬂammation is a known component of venous ulcer formation and is well presented in Chapter 6.

Wound ﬂuid environment and matrix metalloproteinases Conclusion References

76 79 80

THEORETICAL PERSPECTIVES IN VENOUS ULCER FORMATION Pathologic conditions involving venous disease known as chronic venous insufﬁciency (CVI) results in venous hypertension from either valvular insufﬁciency or obstruction, or both.1 Chronic venous disease has been a challenging problem and was noted by Hippocrates more than 2500 years ago.2 Hippocrates discussed the treatment of venous disorders and observed that “it was better not to stand in the case of an ulcer on the leg.” Despite the passage of many centuries since Hippocrates’ observation, the pathogenesis of venous ulcers remains elusive. The mechanisms for dermal ﬁbrosis and venous ulcer formation are not known. Based upon scientiﬁc observation, a number of investigators have proposed potential etiologies for the advanced forms of dermal pathology and ulceration observed in patients afﬂicted with CVI. In a study consisting of 41 patients with venous ulcers, tissue biopsies were stained for ﬁbrin. Lipodermatosclerotic skin biopsies were found to have layers of ﬁbrin around dermal capillaries but no ﬁbrin was found in the normal skin of control subjects. The pericapillary ﬁbrin cuff observed in skin with lipodermatosclerosis was thought to cause tissue ﬁbrosis and hypoxia that led to ulcer formation.3 A series of investigations conducted in patients with CVI determined that there were 24% fewer leukocytes leaving the dependent lower limb, but this reverted to normal with leg elevation.4 This led to the hypothesis that leukocytes trapped in the microcirculation (dermal capillaries) resulted in tissue ischemia and venous ulceration.5 Growth

Leukocytes and chronic venous insufﬁciency 71

factors are considered important mediators for wound healing. A possible mechanism for venous ulcer formation proposed that growth factors became bound or “trapped” by macromolecules such as α-2 macroglobulin and ﬁbrinogen present in the wound.6 These proposed theories drove the current research aimed at deﬁning the role of pericapillary changes, leukocyte function, cytokines and growth factor effects, and the effects of soluble compounds in the tissue ﬁbrosis and venous ulcer formation connected with CVI.

LEUKOCYTES AND CHRONIC VENOUS INSUFFICIENCY Leukocytes in the chronic venous insufficiency limb In patients with CVI, biopsies of dermal tissue demonstrate an increased presence of leukocytes in lipodermatosclerotic and healed ulcerated skin.4 Further work in this area focused on deﬁning the cell type and function responsible for the formation of skin ﬁbrosis and ulceration. In a study evaluating the number of white blood cells in tissue biopsies of patients with CVI, it was determined that the number of leukocytes was highest in the dermis of patients with a history of ulceration followed by tissues with lipodermatosclerosis, and lowest in CVI patients with no evidence of skin changes.7 In a careful histological study using immunohistochemistry in patients with severe lipodermatosclerotic skin changes, the predominant cell types were found to be T lymphocytes and macrophages but rarely were neutrophils observed. The expression of intercellular adhesion molecule 1 (activation of leukocytes to adhere to the endothelium) was elevated, but not endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule. The authors concluded that the accumulation and adhesion of macrophages and T lymphocytes in the perivascular and dermal matrix was associated with CVI skin changes and ulceration.8

Activity and location of leukocytes in chronic venous insufficiency To further evaluate the activity of these leukocytes and conﬁrm the observed dermal histological ﬁndings, an elegant study evaluated surface activation markers on leukocytes comparing blood from normal control subjects with that of patients with CVI. Patients with CVI had decreased CD3+/CD38+ expression on T-lymhocytes, and increased expression of CD14+/CD38+ markers on monocytes, but no evidence of neutrophil activation was observed, consistent with the histologic leukocyte ﬁndings noted above.9 The function of the mononuclear cells was evaluated by proliferation response assays in the presence of a staphylococcal enterotoxin antigen challenge. The

study concluded that mononuclear cell function deteriorated with CVI, and that diminished proliferative responses were observed with greater severity of the disease (lipodermatosclerosis and venous ulcers), suggesting that decreased mononuclear cell proliferation may be involved in poor wound healing.10 The role of leukocytes was studied by morphometric analysis in a quantitative study utilizing electron microscopy. Differences in endothelial cell structure, leukocyte cell type, and their relationship to the microcirculation were investigated in dermal biopsies of patients with advanced CVI. The authors determined that tissues with severe lipodermatosclerosis and healed ulcers contained signiﬁcant numbers of mast cells around arterioles and postcapillary venules, and in active ulcers macrophages were predominantly located in the postcapillary venules. As might be expected in scarred tissue, ﬁbroblasts were the most abundant cell type in all biopsies evaluated, but there was no association with the severity of disease, and no differences in interendothelial junction widths were observed.11 The signiﬁcance of this study lies in its deﬁning the location of the inﬂammatory cells with respect to the microcirculation and its demonstration of the predominance of macrophages in active ulcers.

Leukocytes and signaling markers The involvement of leukocytes in CVI pathology requires some interaction with endothelial cells (leukocyte/ endothelial signaling) to allow the leukocytes to reach the dermal tissue. An immunohistochemistry study of biopsies obtained adjacent to ulcerated skin evaluated changes in adhesion molecules in patients with severe lipodermatosclerosis and active ulceration, and demonstrated that increased expression of intracellular adhesion molecule 1 (CD54, expressed on macrophages, endothelial and dendritic cells, cell surface marker antigen that activates T cells via LFA-1) and vascular cell adhesion molecule 1 was present. In addition, the expression of lymphocyte function-associated antigen 1 (LFA-1) and very late-activated antigen 4 was dramatically increased on perivascular leukocytes compared with healthy skin, indicating that the upregulation of adhesion molecules in CVI patients is an important mediator that can facilitate leukocyte endothelial adhesion, activation, and transendothelial migration.12

The role of neutrophils in chronic venous insufficiency Although current evidence suggests that neutrophils are rarely found in the dermis of patients with severe CVI and that activation has not been detected, several studies have identiﬁed a role for neutrophils in this disease process. Investigators evaluating patients with varicose veins with

72

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and without skin changes took blood samples from the foot in dependent legs and then again while in the supine position. Leukocyte surface marker CD11b and L-selectin expression were analyzed by ﬂow cytometry and plasmasoluble L-selectin was measured by ELISA. In dependent legs with skin changes, both the median neutrophil and monocyte CD11b and the L-selectin levels decreased and remained low even after venous hypertension was reversed (supine position). This was also noted in patients with uncomplicated varicose veins. The soluble L-selectin increased in the plasma in both patient groups with varicose veins during dependence, indicating that leukocytes were adhering to the endothelium. The authors concluded that venous hypertension resulted in a sequestration of activated neutrophils and monocytes in the microcirculation that persists despite the removal of venous hypertension.13 The systemic activation of leukocytes has been studied in patients with lipodermatosclerosis and venous ulcers as well. Blood samples were analyzed for granulocyte activation with nitroblue tetrazolium reduction. Neutrophil activation was observed in the patient’s plasma, but not the whole blood. This ﬁnding was more pronounced in patients with lipodermatosclerosis and ulcers than in those with varicose veins and edema. They concluded that CVI patient plasma may contain activating factors for granulocytes. Since neutrophils were fewer in CVI patient whole blood than in healthy control subjects, it was suggested that activated neutrophils in CVI patients become trapped in the peripheral circulation and that this lack of available neutrophils may be important in the development of CVI and dermal skin changes.14

ALTERATIONS IN FIBROBLAST CELLULAR PROLIFERATION, MOTILITY, SENESCENT PHENOTYPE, AND REGULATION Venous ulcer fibroblasts and reduced proliferation Fibroblasts are important in the healing of acute and chronic wounds, and in microscopic analysis they have been determined to be a major cell type in dermal biopsies from venous ulcer and lipodermatosclerotic skin.11 Interest in alterations in ﬁbroblasts growth and growth factor response from patients with venous ulcers was evaluated by biopsies taken from the ulcer margin and compared with normal ipsilateral thigh biopsy ﬁbroblasts from the same patient. The authors found a signiﬁcant reduction in proliferation and the ﬁbroblasts were morphologically larger and polygonal in shape with less uniform nuclear features. However, the response to growth factors (basic ﬁbroblast growth factor, bFGF; epidermal growth factor, EGF) was maintained in venous ulcer ﬁbroblasts, albeit not to the same magnitude as that observed for control ﬁbroblasts. These results indicated

the presence of a functional abnormality in dermal ﬁbroblasts obtained from venous ulcers and suggests that cellular senescence may be a factor in the pathophysiology of venous ulcer formation.15

Venous ulcer fibroblasts and senescence The sine qua non of cellular senescence is an irreversible arrest of DNA synthesis otherwise required for replication (multiple transcription nuclear factors that are inactive and or blocked) and such cells cannot initiate cellular proliferation by normal physiologic means, including growth factor stimulation; however, the cell maintains normal biologic functions and remains viable. An interesting observation is that ﬁbroblasts cultured from venous ulcers have senescent-like characteristics, yet have an ability to respond to growth factor (FGF and EGF) stimulation, although not to the same magnitude of that of normal control ﬁbroblasts.15,16 Other studies have determined that venous ulcer ﬁbroblasts show a signiﬁcant decrease in proliferative response to platelet-derived growth factor (PDGF).17 The ﬁbroblasts from patients with ulcers unhealed for more than 3 years grew signiﬁcantly slower than those ulcers of a less chronic duration.18 This could help to explain why chronic venous ulcers of long duration are so difﬁcult to heal. The environment of these ulcers may represent a state of exhausted cellular replication and arrested growth leading to the inability of the ulcer wound to heal. This idea is supported by a study that evaluated patients with active venous ulcers of various durations. Biopsies were obtained from the ulcer border and the ipsilateral thigh, and ﬁbroblasts from each site were cultured. The percentage of senescent cells was quantiﬁed in vitro by evaluating the number of ﬁbroblasts expressing senescent-associated β-galactosidase, a speciﬁc senescent marker. The authors determined that there was a direct clinical relationship in time to ulcer healing in patients with greater than 15% of ﬁbroblast staining for the senescent marker.19 Although this study is important in identifying an in vitro marker associated with prolonged ulcer healing, these ﬁndings should be interpreted with caution since in vitro results may not reﬂect what is occurring in vivo. There are many uncontrolled factors in an active venous ulcer bed (bandaging, infection, the continuous bathing of wound ﬂuid, postural changes, medical comorbidities) when compared with the controlled setting of a tissue culture dish; in addition, other cells such as keratinocytes are important in ulcer healing.

Senescent phenotype in venous ulcer fibroblasts Certain characteristics of cellular senescence were elucidated in subsequent experiments. Venous ulcer

Alterations in ﬁbroblast cellular proliferation, motility, senescent phenotype, and regulation

ﬁbroblasts contain more cells that stain positive for senescent-associated β-galactosidase (a speciﬁc marker for the senescent state) and have an increased expression of protein and mRNA product for cellular ﬁbronectin. The authors speculated that the increased accumulation of senescent cells in venous ulcers led to the impaired healing noted.16 Furthermore, when these investigators subjected the ulcer ﬁbroblasts to progressive cell culture passage, the cells reacted much differently from normal ﬁbroblast or ﬁbroblasts cultured from patients with varicose veins only. Not only did the ulcer ﬁbroblasts versus control ﬁbroblasts have an increased mean number of senescent-associated β-galactosidase-expressing cells averaged over six passages (63.8 ± 8.9% vs 11.2 ± 3.1%, P < 0.05), but after six passages nearly all the ulcer ﬁbroblasts were senescent (> 95%). These data indicate that ulcer ﬁbroblasts were signiﬁcantly advanced in cellular age and closer to replicative exhaustion, another indication that the accumulation of such senescent cells in venous ulcer wounds may lead to recalcitrant healing.20 Although demonstrated in vitro, deﬁnitive proof of ﬁbroblast cellular senescence in venous ulcer or lipodermatosclerotic skin in vivo has yet to be proven. Fibroblasts from venous ulcer and CVI patients, when compared with normal control subjects, were found to have an increased expression of ﬁbronectin and MMP-2 expression (matrix metalloproteinase-2) when stimulated by bFGF. That ulcer ﬁbroblasts at baseline have higher levels of ﬁbronectin may not signify that they possess more of a senescent-like phenotype, although it could, but rather that they have been subjected to more mitogenic stimuli as a result of their slow growth or location in the ulcer environment.21 The upregulation of ﬁbronectin and MMP-2 may be a normal, transient, and inducible response of these cells to bFGF.

Venous ulcer fibroblasts: cell motility, myofibroblast differentiation, receptors, and collagen synthesis Functional studies evaluating ﬁbroblast motility by time lapse digital photoimaging were performed for both venous ulcer ﬁbroblasts and ﬁbroblasts cultured from the medial malleolar skin of patients with varicose veins. The ﬁndings demonstrated a signiﬁcant reduction in venous ulcer ﬁbroblast motility compared with the ipsilateral normal thigh ﬁbroblasts, and in ﬁbroblasts from control subjects without any CVI. Interestingly, ﬁbroblasts from varicose vein patients also had signiﬁcant lower motility. The decreased ﬁbroblast motility was associated with the expression of α-sma, a marker for myoﬁbroblast differentiation. Myoﬁbroblast differentiation is a normal process that occurs during wound healing, but in conditions of chronic inﬂammation persistent myoﬁbroblast expression has been known to lead to tissue ﬁbrosis.22,23 In the same study, it was demonstrated that chronic wound ﬂuid collected from venous ulcers

73

dramatically decreased the motility of neonatal ﬁbroblasts and led to myoﬁbroblast differentiation when compared with neonatal ﬁbroblasts treated with bovine serum albumin (control).24 These data showing altered motility in CVI ﬁbroblast and myoﬁbroblast differentiation provide further evidence to support the concept that ﬁbroblast dysfunction is an important fact in impaired venous ulcer wound healing. In addition, the wound ﬂuid from the ulcer environment causes signiﬁcant alternations in the function and structure of ﬁbroblasts. The response to PDGF by venous ulcer ﬁbroblast has previously been demonstrated to be attenuated.18 Although the authors were unable to demonstrate any differences in PDGF receptors, a recent report has demonstrated that venous ulcer ﬁbroblasts had no growth response to PDGF AB, and the basal levels of PDGF-α and PDGF-β receptors were decreased.17 A possible explanation for these differences is that in the latter study, ﬁbroblasts were cultured from biopsies taken from the ulcer margin,17 whereas in the former, biopsies were taken from the central portion of granulation tissue and from lipodermatosclerotic skin.18 This clearly illustrates that in the venous ulcer wound, there is variability in cellular function inﬂuenced by local environmental stimuli, cytokines, growth factors, and inhibitors. This variability can account for the differing results noted in tissue culture studies. In addition to PDGF receptors, the transforming growth factor-β (TGF-β) type II receptors have been studied. The growth factor TGF-β is very important in ﬁbroblast regulation of extracellular proteins, proliferation, and differentiation during wound healing.25 In a study evaluating venous ulcer ﬁbroblasts versus control ﬁbroblasts, the investigators found that there was no difference in incorporation of proline into procollagen, synthesis of total TGF, or mRNA levels of procollagen or TGF-β. However, when the ﬁbroblasts were stimulated with exogenous TGF-β and collagen synthesis was measured, the venous ulcer ﬁbroblasts failed to respond whereas the normal ﬁbroblasts had a more that 60% increase in collagen production (P = 0.0001). When the TGF-β type II receptors were examined, venous ulcer ﬁbroblasts had a fourfold reduction. The unresponsiveness by venous ulcer ﬁbroblasts to synthesize collagen in the presence of TGF-β is in part due to a signiﬁcant reduction in the receptor. This ﬁnding could explain the lack of appropriate extracellular matrix deposition needed for reepithelialization and wound healing in the venous ulcer.26

Alterations in venous ulcer fibroblast regulation The regulatory mechanisms to explain why ﬁbroblasts from venous ulcer have reduced growth and an attenuated response to growth factors remain unknown. Cell proliferation and the senescent state is regulated by

74

Venous ulcer formation and healing at cellular levels

activation or deactivation of key regulatory proteins and transcriptional factors,27,28 and in addition to cell growth and differentiation, metabolic functions requiring activation of nuclear transcription and subsequent protein synthesis are tightly regulated by the mitogen-activated protein kinase (MAPK) cascade.29 Two very important regulatory proteins are p21 (also known as senescent cellderived inhibitors, sdi1, cip1, waf1, or p21), which inhibits the cyclin-dependent protein kinases as well as the E2F transcription factor (E2F is a key regulatory gene product that activates necessary enzymes to allow the cell to proceed from the G1 to the S phase of cell-cycle progression) and hence blocks DNA replication, and tumor suppression protein retinoblastoma (pRb), which when phosphorylated (ppRb) allows activation of E2F transcriptional regulator and DNA synthesis. In senescent ﬁbroblasts, there is an overexpression of p21 and a constitutively underphosphorylation of pRb leading to growth arrest.30–32 In venous ulcer cultured ﬁbroblast, compared with control ﬁbroblast at basal levels, there is a signiﬁcant overexpression of p21 (P = 0.016) and underphosphorylation of pRb (P = 0.069). Importantly, treatment of the ulcer ﬁbroblasts with bFGF growth factor caused a signiﬁcant downregulation of p21 (P = 0.008) and increased ppRb (P = 0.03) compared with basal (untreated) ulcer ﬁbroblasts.33 This study indicated the importance of alterations in cell cycle regulatory proteins in venous ulcer ﬁbroblasts consistent with a senescent phenotype, but unlike senescent cells, ulcer ﬁbroblasts responded to growth factor with reversal of the inhibitory effects of p21 and positive inﬂuence of ppRb. These alterations in cellular regulation could explain some of the ﬁndings of decreased proliferation and recalcitrant healing rates observed clinically. As mentioned earlier, MAPK functions as an important signaling pathway for regulating cell proliferation, migration, and differentiation in all eukaryotic cells. The MAPK family is composed of three signaling pathways, ERK 1/2 (p44/p42), p38, and JNK/SAPK, which all have upstream kinases (MKKK, MKK) that require phosphorylation for activation. The ERK 1/2 (p44/p42) is stimulated by mitogens (PDGF, FGF) and is responsible for transducing the signals to the cell nucleus leading to proliferation and cell growth. The two other MAPKs (p38 and JNK/SAPK) are stimulated by stress states (ultraviolet light, oxidation, inﬂammation) and cytokines, and are responsible for transducing signals to the nucleus, causing cell differentiation, growth arrest, and apoptosis.29,34 The p38 pathway has been found to cause cell cycle arrest at the G1/S transition and it is thought that this may force cells out of the cell cycle toward a post-mitotic differentiated phenotype.35 In a recent report, the MAPKs ERK1 and -2 were studied in venous ulcer ﬁbroblasts treated with PDGF AB. The ulcer ﬁbroblasts were found to activate MAPK. Inhibition (PD 98059) of the upstream kinase MEK1 (MKK) signiﬁcantly reduced ﬁbroblast proliferation, which was reversible with the addition of PDGF. In

addition, venous ulcer wound ﬂuid inhibited MAPK ERK1 and -2 directly. These data provide evidence that the MAPK ERK pathway is important in regulating venous ulcer ﬁbroblast proliferation and conﬁrm the inhibitory effects of wound ﬂuid on the MAPK ERK pathway.36 The MAPK pathway involving p38 is activated by stress responses (venous ulcer microenvironment, cytokines, inﬂammation), and is responsible for regulating cell proliferation by inducing growth arrest at the G1/S phase of the cell cycle. In unpublished data, our group has demonstrated that venous ulcer ﬁbroblasts have increased expression of p38 when compared with normal ﬁbroblasts. When venous ulcer ﬁbroblasts were treated with bFGF 10 ng/mL, there was a temporal reduction in the expression of p38 over 48 hours (i.e., bFGF can reverse p38, thereby leading to cell proliferation). Alternatively, treatment with the cytokines, TNF-α and IL-1, upregulated p38. The kinase p38 appears as a key kinase in growth attenuation of venous ulcer ﬁbroblasts, but the effects of p38 are reversed with a potent mitogen such as FGF. Fig. 7.1 summarizes the regulation and alterations of venous ulcer ﬁbroblasts and senescent cells in general.

Keratinocytes and epithelialization in venous ulcers The importance of wound coverage by keratinocytes leading eventually to re-epithelialization, and the impact of the granulating wound bed are emphasized in the following studies. Important cell cycle regulatory proteins for proliferation and apoptosis speciﬁcally involved with epithelialization have been studied. In biopsies of venous ulcers, diabetic ulcers, and control subjects no major differences in keratinocyte immunohistochemical staining was observed for cell-cycle regulatory proteins or apoptosis-related proteins.37 In a follow-up study, these investigators compared the edge of venous ulcer to that of the central granulation tissue for growth factors and cytokines expression of keratinocytes and endothelial cells by immunohistochemistry and phenotype characterization. Keratinocytes and endothelial cells on the ulcer margin retained their secretory potential for growth factors and cytokines. In the ulcer bed, very few ﬁbroblasts were noted and the bed was composed mainly of macrophages.38 The authors speculated that the wound bed was altered by chronic infections and that the impaired nutrition inhibited keratinocyte migration. It is well known that ﬁbronectin is an important protein of the extracellular matrix involved in keratinocyte reepithelialization. A study evaluating biopsies from venous ulcer wound margins, acute wounds, and normal skin, determined that the transcription product for ﬁbronectin was signiﬁcantly increased in the venous ulcer. However, immunostaining for α5β1 integrin, the cell surface receptor for ﬁbronectin, was undetectable in venous ulcer biopsies. The authors concluded that although ﬁbronectin

Alterations in ﬁbroblast cellular proliferation, motility, senescent phenotype, and regulation

Hormone, EGF, PDGF

FGF, EGF, PDGF Fas L, TNF, IL Hormones stress, inflammation R1

Tyr Kin

Death R TGF

GF R

GP

AC

TGF-R Ser Thr Kin GP coupled R

Ras

PI3K

GP

PIP2 cAMP

MEKK

PMA, TMA

PLC

Cell membrane

Raf 1

Rac Ask 1 Tak 1

PL

GF R2

p44/p42 Kinase activation Signal transduction

IP3 DAG p44/p42

75

XR UV H2O2 Drugs Toxins Disease

PKC Raf 1

Map2k6 Smad 2/3 Smad 4 AA

PGE2

p38 JNK/SAPK

Blocked attenuated response

PLA2

p21 pRb pRb-PO4 Bcl-2 p53

p16 Arrest of DNA transcription Repression of genes E2F, Id, c-fos

CDK

Nucleus

Genes not expressed Cyclin A, Cdc2, DHFR, TK, DNA poly-, PCNA

Figure 7.1 Signaling pathways leading to inhibition of DNA transcription and cell proliferation: senescence phenotype in venous ulcer ﬁbroblasts. Schematic of the venous ulcer ﬁbroblast signaling pathways for regulation of cell proliferation and pathways leading to growth attenuation and DNA inhibition rendering these cells with a senescent phenotype. Growth factors, hormones, and cytokines bind to cell surface receptors (transforming growth factor, death, hormone R1, growth factor) and various noxious stimuli (inﬂammation, radiation, stress) and phorbol esters (PMA, phorbol-12-myristate 13-acetate; TPA, 12-tetradecanoate phorbol 13-acetate) have direct or indirect effects on receptors. Following receptor activation, the signal pathway leading to protein phosphoryaltion and production of secondary messengers involves various membrane-associated proteins: tyrosine kinase (Tyr Kin), serine threonine kinase (Ser Thr Kin), G protein (GP), adenylyl cyclase (AC), Ras, Rac, phosphatidyl inositol 3-kinase (PI3K), phospholipase C (PLC), and protein kinase C (PKC). The Ras (a GDP/GTP activated protein) dependent pathway activates the kinase cascade activating Raf, MEK, and MAPK (ERK 1/2, p44/p42), and the Ras-independent pathway leads to activation of PKC and Raf and the MAPK for activation of transcription factors (Elk-1, c-Myc, CREB, Sap-1), and DNA transcription and proliferation. Phosphoinositol 4,5-biphosphate (PIP2) is the substrate for PLC to form the secondary messengers inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). In turn, DAG is important in activating PKC by membrane translocation. Ligand-stimulated TGF-βR receptor complex causes phosphorylation of the Smad complex (Smad 2/3–Smad 4) and translocates to the nucleus binding to transcription factors and gene activation. Stimuli to the death receptors by cytokines and stress activates the Rac, Ask, and Tak pathways leading to kinase activity (MEKK, Map2k6) and phosphorylation of the p38 and JNK/SAPK kinase leading to transcription factor activation (c-Jun, ATF-2, Elk-1, Sap-1, CHOP), which confer growth arrest and apoptosis. Note that active Ras can also activate p38 and JNK (not shown in the diagram). Senescent cells and venous ulcer ﬁbroblasts (senescent-like phenotype) have an attenuated response to signal transduction (=) leading to inhibition of DNA synthesis. Arrest of DNA synthesis is also a result of increased metabolites of phospholipids (PL) by the action of phospholipase A2 (PLA2) to produce elevated levels of arachidonic acid (AA) and prostaglandin E2 (PGE2), and by the inhibition of cyclin-dependent protein kinases (CDK) by the overexpression of p21 and p16 causing underphosphorylation of pRb (i.e., decreased pRb-PO4) and consequently inhibition of gene expression necessary for DNA replication. Unlike senescent cells, venous ulcer ﬁbroblasts although having decreased mitogenic receptors utilize the MAPK pathway (elevated ERK 1/2 p44/p42), and are able to respond to growth factors (bFGF) and downregulate negative proliferative proteins and kinases (p21, p38) to increase proliferation. Dihydrofolate reductase (DHFR), thymidine kinase (TK), DNA polymerase alpha (DNA poly-α), and the cofactor proliferating cell nuclear antigen (PCNA). Dashed arrows indicate pathway, solid up or down arrow indicates if that compound is overexpressed or underexpressed, respectively, double solid bar indicates a blocked-attenuated response.

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Venous ulcer formation and healing at cellular levels

mRNA was expressed, the lack of an integrin receptor may have prevented keratinocyte migration and wound closure.39

transcriptional and pre- and post-translational alternations, as well as phenotypic alterations and will advance our understanding of how to better treat venous ulcers.

WOUND FLUID ENVIRONMENT AND MATRIX METALLOPROTEINASES

The extracellular matrix and matrix metalloproteinases

Venous ulcer wound fluid

The ECM is an important structural and functional scaffolding made up of proteins that are necessary for cell function, wound repair, epithelialization, blood vessel support, cell differentiation and signaling, and cellular migration. The ECM is composed of proteins and glycoproteins including collagen, elastin, ﬁbronectin, vitronectin, aggrecan, entactin, proteoglycans, growth factors, tenascin, ﬁbrin, and laminin.46,47 The ECM is particularly important in providing a substrate for keratinocytes to migrate upon to ultimately establish skin coverage in both acute and chronic wounds.39 Abnormalities in ECM metabolism in wounds has been an area of active investigation. The MMPs are important proteases involved in both health and disease states involving ECM turnover. MMPs are highly homologous zinc-dependent endopeptidases that belong to a large group of proteases called the metzincins, and are able to cleave most of the constituents of the ECM. There are at least 26 identiﬁed and characterized MMPs. MMPs are classiﬁed according to their substrate speciﬁcity and structural similarities. The four major subgroups of MMPs are interstitial collagenases, gelatinases, stromelysins, and membrane-type matrix metalloproteinases (MT-MMPs). Other MMPs are in subgroups, such as the matrilysins.48 The naturally occurring inhibitors of MMPs are the tissue inhibitors of matrix metalloproteinase (TIMP). Other molecules such as trocade (Ro 32-3555), marimastat (BB25160, BB-94, and Ro 28-2653 are also known to inhibit MMPs and are useful in studying the kinetics and mechanisms of MMPs in biologic systems. In an early report evaluating venous ulcer wound ﬂuid compared with ﬂuid from acute wounds, it was found that the chronic wound ﬂuid contained up to a 10-fold increase in the levels of MMP-2 and MMP-9 (gelatinases) as well as an increased activity of the enzymes, suggesting a high tissue turnover.49 Increased levels of MMP-1 and gelatinase activity from the exudates of chronic venous leg ulcers has been conﬁrmed by other investigators, and doxycycline inhibition studies suggested that the protease activity was such that the cell source was from ﬁbroblasts, mononuclear cells, keratinocytes, or endothelial cells and not neutrophils.50 It was important to determine the source of collagenase activity since bacteria also produce collagenase and are abundant in venous ulcer wounds. An important distinguishing feature of human collagenase is that it degrades collagen in speciﬁc 3/4 and 1/4 fragments, whereas bacterial collagenase degrades collagen randomly in a non-speciﬁc manner. It was determined that the

The venous ulcer microenvironment consists of dermal ﬁbroblasts, keratinocytes, inﬂammatory cells, extracellular matrix (ECM), growth factors, cytokines, bacteria, and a microcirculation. An interesting aspect of the venous ulcer milieu is the presence of chronic wound ﬂuid. The wound ﬂuid is known to have properties consistent with excess protease activity. The collagenase activity of venous ulcer wound ﬂuid is 116-fold more than that found in normal acute wound ﬂuid. The collagenase activity of venous ulcers demonstrating healing at 2 weeks is decreased.40,41 The venous ulcer wound ﬂuid causes inhibition of ﬁbroblast proliferation and induces changes in cellular senescence.24,42 The venous ulcer wound ﬂuid inhibits the growth of neonatal ﬁbroblasts causing the majority of cells to remain in the G1 or G2 phase of the cell cycle (i.e., unable to enter S phase, blocking DNA synthesis). When compared with ﬁbroblasts treated with bovine serum albumin, the wound ﬂuid demonstrated a dose-dependent inhibition at a concentration of 500 μg/plate and was not toxic (by trypan blue exclusion assay). Normal proliferation of the neonatal ﬁbroblasts treated with venous ulcer wound ﬂuid can be reversed by heat inactivation of the wound ﬂuid or by removal and placement of the cells in 10% serum.43 In addition to ﬁbroblasts, venous ulcer wound ﬂuid inhibits the proliferation of endothelial cells and keratinocytes. Although the speciﬁc inhibitory component(s) are not known, there is evidence to suggest that the active inhibitory substance from venous ulcer wound ﬂuid resides in the less than 30 kD fraction and is two to three times more inhibitory to cells than the fraction greater than 30 kD.44 The inhibitory effect of wound ﬂuid can be reversed by heating to 100°C. At concentrations of 2% and 4%, wound ﬂuid causes cell death. Venous ulcer wound ﬂuid was demonstrated to inhibit the expression of MAPK, speciﬁcally ERK 1 and ERK 2, with a simultaneous decrease in the proliferation of neonatal ﬁbroblasts.36 In addition, the mechanism of cell inhibition by wound ﬂuid in part, involves downregulation of the phosphorylated retinoblastoma tumor suppression gene and cyclin D1, via inhibition of the Ras-dependent MAPK pathway.45 The compound(s) in venous ulcer wound ﬂuid that cause changes in cellular function will be a focus of future investigations. Identifying the inhibitory substances in wound ﬂuid will be important in understanding its molecular effects on cell behavior, regulation,

Wound ﬂuid environment and matrix metalloproteinases

collagenase from venous ulcer wound ﬂuid degraded collagen in the speciﬁc 3/4 and 1/4 fragments indicative of human collagenase.50 It is important to note that the changes noted in the MMP levels and activity in venous ulcers is not speciﬁc to just venous disease and similar alterations are found in other inﬂammatory wounds, including burn and pressure ulcers.51 The production of TIMP can have a signiﬁcant inﬂuence on MMP expression. In an in vitro study ﬁbroblasts cultured from venous ulcers demonstrated a marked reduction in MMP-1 and MMP-2 level and activity, and a signiﬁcant increase in TIMP-1 and TIMP-2 production. The authors of this study concluded that the inhibition of ﬁbroblast proteinase activity by TIMP causes an impaired reorganization of the ECM in chronic wounds leading to delays in healing.52 This study indicated that although there is elevated proteinase activity in the venous ulcer wound and wound ﬂuid, cellular components studied in vitro (in this case ﬁbroblasts) are compensating by altering their expression of MMP and TIMP. The abnormalities in the structure and the healing process seen in lipodermatosclerotic skin have also been attributed to MMP pathophysiology. In a study where dermal biopsies were obtained from lipodermatosclerotic skin and compared with healthy skin and analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction, immunoblot, and zymography analysis found that lipodermatosclerotic skin had an increased expression of mRNA and protein for MMP-1, MMP-2, and TIMP-1, and increased levels of active MMP-2. In addition, there was an increase in the proMMP-1–TIMP1 complex, indicating the overexpression of proteinase was bound to TIMP.53 By immunohistochemistry, both MMP-1 and MMP-2 were predominantly localized in the basal and suprabasal layers of the epidermis, perivascular region, and reticular dermis and signiﬁcantly reduced expression of TIMP-2 was found in the basement membrane of the diseased skin.53 This study demonstrates that in lipodermatosclerotic skin, a precursor to venous ulcer formation, excessive and unrestrained MMP activity and ECM turnover is occurring. A consistent ﬁnding is the presence of MMPs in the perivacular region (see below in the section Modulation and activation of matrix metalloproteinases). A consideration is that MMPs may cause abnormalities in tissue perfusion or affect angiogenesis and the microvasculature. In an elegant study, investigators took venous ulcer wound ﬂuid compared with control acute wound ﬂuid (donor skin graft sites) and tested the wound ﬂuids in an in vitro angiogenesis model by measuring tubule length. The venous ulcer wound ﬂuid caused a signiﬁcant reduction in the formation of tubules and length (490 ± 130 μm) compared with the control ﬂuid (1740 ± 320 μm, P < 0.05). When a synthetic inhibitor for MMP-2 and MMP-9 was added to chronic venous ulcer wound ﬂuid, angiogenesis increased signiﬁcantly (870 ± 220 μm, P < 0.05).54 These data raise the possibility that MMPs in venous ulcer

77

wound ﬂuid may have signiﬁcant antiangiogenic effects and disrupt the microcirculation in the perivascular regions, thereby inhibiting wound healing

Modulation and activation of matrix metalloproteinases Matrix metalloproteinases are synthesized in a proenzyme form. The pro-enzyme have a cysteine domain called the cysteine switch that interacts with the zinc active binding site preventing activation and substrate degradation. The cysteine switch is cleaved prior to the pro-enzyme becoming active.48 The excess proteolytic activity in venous leg ulcers has been found to degrade essential plasminogen, which is important in activating proMMP to MMP necessary for ﬁbrinolysis and cell migration, and MMPs inhibit plasmin production by keratinocytes, which may lead to reduced cell migration.55 Important to the healing wound is factor XIII (FXIII), which impacts collagen cross-linking. FXIII has the ability to modulate the detrimental effects of MMPs. In an in vitro study, investigators evaluated the effects of increasing concentrations of collagenase and FXIII on ﬁbroblast survival assayed by the MTT colorimetric test. At high concentrations of collagenase (2 mg/mL), 95% of ﬁbroblasts were killed and FXIII (5 U/mL) was unable to mitigate the effect. However, at lower collagenase concentrations (0.5–1 mg/mL), the addition of FXIII was able to abrogate the effects of collagenase and increase ﬁbroblast survival. These data were consistent with clinical ﬁndings that the topical application of FXIII has the ability to improve venous ulcer healing.56 In addition to FXIII, iron overload has been found in the serum and dermis of limbs of patients with venous ulcer compared with control subjects. A concomitant elevation in MMP-9 activity was also present in patients with venous ulcers. The importance of iron overload in venous ulcer tissue is that it can cause oxidative stress and production of free radicals or reactive oxygen species. The authors of this study suggest that elevated iron deposits in the limbs are released into the serum with activation of MMPs and reactive oxygen species, and impaired ulcer healing.57 As mentioned previously, plasminogen is important in MMP regulation.55 Urokinase-type plasminogen activator (uPA) functions as a ﬁbrin-independent PA in a cellbound fashion, and when uPA is bound to its receptor uPAR the activity of uPA is potentiated. Comparing venous ulcers with normal dermis, one study found that both the transcriptional product and the protein of uPA and uPAR were overexpressed in venous ulcers. Localization of uPA and uPAR by immunohistochemistry determined that these proteins were present in the dermis and in the pericapillary regions.58 One could hypothesize that uPA is crucial in maintaining proteolytic activity and likely has a role in the activation of MMPs in the pathogenesis of venous ulcers.

78

Venous ulcer formation and healing at cellular levels

Two important molecules in the activation of MMPs are MT1-MMP and the extracellular MMP inducer (EMMPRIN; CD147).48,59 Utilizing an immunohistochemistry assay, MMP-2, MT1-MMP, MT2-MMP, and EMMPRIN were found to be signiﬁcantly elevated in venous ulcer dermis and only EMMPRIN and MMP-2 were found overexpressed in the perivascular regions in venous ulcer biopsies. These data indicate the presence of MMP activators in venous ulcer tissue that favor extracellular turnover and unrestrained MMP activation.59 In another study evaluating healing versus non-healing venous ulcers, investigators determined that in healing ulcer tissue there was increased levels of PDGF AA but no difference in MMP or EMMPRIN levels. In the same study, the venous ulcer wound ﬂuid of healing ulcers versus non-healing ulcer demonstrated elevated levels of PDGF AA and TIMP-2 and low levels of MMP-2. These ﬁndings are important as they help to deﬁne factors important for ulcer healing, and support the theory that elevated proteinase activity favors a non-healing environment. In addition, the growth factor PDGF AA appears to be essential in promoting healing.60 The activation of MMPs and their potential involvement in ulcer formation is summarized in Fig. 7.2.

Regulation of matrix metalloproteinases The regulation of MMP production in venous ulcers and lipodermatosclerotic tissue is complex. Post-translational modiﬁcations of MMPs are essential to activity and are likely regulated by TGF-β1. Dermal ﬁbroblasts and leukocytes are major sources for MMPs, especially MMP-2.61 The interplay of MAPK with MMP activation has also been investigated in ﬁbroblasts. The cytokine tumor necrosis factor alpha has been demonstrated to induce MMP-19 expression, which is inhibited by blocking MAPK pathways ERK1 and ERK2 with PD98059 and p38 with SB203580. In addition, adenovirus-mediated induction of ERK1 and ERK2 in combination with p38 resulted in potent MMP-19 expression in ﬁbroblasts, and the activation of c-JNK also produced abundant proMMP-19. These data and ﬁndings of MAPK alterations in venous ulcer ﬁbroblasts and by the effects of wound ﬂuid36,45 indicate the important regulatory functions of MAPK and proteolytic activity in dermal ﬁbroblasts and its implications in venous ulcer pathogenesis.62

Cells: Kt, Fb, Et Cells: Mc Fe, ROS

EMMPRIN

Factors Growth factors PDGF AA TIMPs FXIII

MMP transcription translation pro-MMP-1, -2, -9 pro-MT1–MMP pro-MT2–MMP

MT–MMP Ulcer Pro-MMPs

Active MMPs

Plasminogen uPA

uPAR

TGF-1

Cells: Et, Kt

Plasmin uPA

pro-uPA

Factors Wound fluid Active MMPs Hypoxia Antiangiogenesis

Figure 7.2 Matrix metalloproteinase (MMP) activation and unbalanced proteinase activity leading to venous ulcer formation. Schematic diagram of activation of MMP. EMMPRIN activation leads to synthesis of proMMPs. In addition, iron overload and reactive oxygen species lead to expression of MMPs. In addition pro-uPA is synthesized and converted to uPA by transforming growth factor (TGF) and binds to its receptor uPAR, which potentiates the conversion of plasminogen to plasmin. The proMMPs are secreted in their inactive form and are activated by both plasmin and membrane-type MMPs (MT1–MMP, MT2–MMP). Active MMPs in the wound ﬂuid cause tissue degradation, antiangiogenesis, and ﬁbroblasts and keratinocyte inhibition promoting non-healing of the venous ulcer (negative factors). Factors promoting healing of venous ulcers are the presence of tissue inhibitors of MMP (TIMP), growth factors as platelet-derived growth factor AA (PDGF AA), and factor XIII (FXIII) (positive factors). Cells involved: Kt keratinocytes; Fb ﬁbroblasts; Et endothelial; Mc macrophages and leukocytes.

Conclusion 79

CONCLUSION Venous ulcer pathophysiology is a complex process that involves many changes involving the inﬂammatory response by leukocytes acting on the venous endothelium and microcirculation, alterations in cellular functions with dysregulation of important cellular elements (ﬁbroblasts, keratinocystes), the overexpression of MMPs and their inﬂuence on the ECM, and the inhibitory environment of chronic wound ﬂuid causing a signiﬁcant negative inﬂuence towards cellular growth and healing. From this review and the research examined, several observations and conclusions can be summarized. 1. Leukocyte activity in the microcirculation and the interaction with the endothelial cells initiates a cascade of inﬂammatory events. The advanced stages of CVI have dysfunctional leukocytes that may be involved in the chronic and protracted healing seen with venous ulceration. 2. The postcapillary venules have a predominant macrophage population and indicate that this resident cell has an important function in the formation of venous ulcers. 3. In patients with advanced CVI there may be circulating “venous” factors that activate circulating neutrophils and lead to macrophage sequestration in the lower limbs and resultant inﬂammation. 4. In ﬁbroblasts cultured from venous ulcers there are alterations in cellular functions resulting in decreased proliferation, overexpression of extracellular matrix proteins, motility and cytoskeletal elements expression, and markers of cellular senescence resulting in a senescent-like phenotype. These characteristics may be a factor in delayed ulcer healing. 5. Venous ulcer ﬁbroblasts have an attenuated response to several growth factors, and the decreased expression/function of important mitogenic receptors may explain the observed reduction in cell proliferation and extracellular matrix production. 6. There are key regulatory cell cycle proteins (p21, pRb) that are altered in venous ulcer ﬁbroblasts. The expression of these proteins has important implications on ﬁbroblast proliferation and likely is involved in the delayed effects of wound healing in venous ulcers. 7. The MAPK pathway in venous ulcer ﬁbroblast is an important regulatory system that has been demonstrated to have expression of ERK1 and ERK2 despite decrease proliferation. In addition, when upstream kinases that regulate ERK are inhibited this has a profound effect on decreasing ﬁbroblast proliferation. 8. Chronic venous ulcer wound ﬂuid has a direct impact on downregulating the expression of ERK. 9. Keratinocytes are an important cell component in venous ulcer pathology. The wound bed may contain

inhibitory factors, and integrin receptor downregulation in venous ulcers contributes to a decrease in re-epithelialization. 10. Chronic venous ulcer wound ﬂuid is present in the venous ulcer environment. The exact components leading to the inhibitory effects are unknown. However, it is well established that the wound ﬂuid has elevated inhibitory cytokines and MMPs that are active. It is unknown exactly which cells in the ulcer are producing these important compounds and the temporal relation that is involved with the progression from lipodermatosclerosis to active ulcer. However, macrophages and ﬁbroblasts are likely involved in wound ﬂuid production. 11. MMPs have an integral role in the pathogenesis for venous ulcer formation. The degradative properties are one aspect to delayed healing and likely MMPs have other important biologic functions in venous ulcer development. 12. Multiple cell types including ﬁbroblasts, mononuclear cells, keratinocytes, or endothelial cells can produces collagenase and gelatinase. These cell types are all present in the developing venous ulcer. 13. In lipodermatosclerosis, a precursor of venous ulcer formation, there is a signiﬁcant amount of MMP activity. In addition MMPs are found in the perivascular regions and have antiangiogenic effects (in vitro). This would implicate MMPs in negatively affecting the microcirculation inhibiting tissue perfusion and metabolism. 14. Factor XIII has an important role in venous ulcer wound healing. 15. Iron overload is a consistent ﬁnding in patients with advanced CVI, and iron-laden macrophages present in the dermal tissue may be involved in oxygen radical formation leading to venous ulcer pathology. 16. Plasminogen is an important protein in the regulation of MMPs. uPA bound to its receptor uPAR activates plasminogen to form plasmin, which in turn activates proMMPs to MMPs. Venous ulcer tissue is know to overexpress uPA and uPAR and are signiﬁcant activators of MMPs with resultant imbalance of tissue turnover and poor wound healing. 17. Activation of venous ulcer MMPs is regulated by EMMPRIN and MT1-MMP activator of proMMP to active MMP. In addition, EMMPRIN is expressed in the perivascular region of the venous ulcer, which is an area vulnerable to activation by leukocytes and its relation to changes in venous pressure. 18. MMP expression appears to be in part regulated by the MAPK pathway. From these conclusions it is apparent that venous ulcer pathophysiology is a complex disease that involves systemic and local processes. It is likely that targeting only one system may or may not cause a clinical change in ulcer healing, and probably several systems need to be

80

Venous ulcer formation and healing at cellular levels

Guidelines 1.6.0 of the American Venous Forum on venous ulcer formation and healing at cellular levels No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.6.1 Leukocyte activity and interaction with endothelial cells initiates a cascade of inﬂammatory events (in chronic venous insufﬁciency) that lead to venous ulcer formation

A

1.6.2 Macrophages have a major role in ulcer formation

B

1.6.3 Dysfunctional leukocytes and senescent ﬁbroblasts contribute to delayed ulcer healing

B

1.6.4 Altered regulatory cell cycle proteins (p21, pRb) affect ﬁbroblast proliferation and delay wound healing

B

1.6.5 Venous ulcer ﬂuid has elevated inhibitory cytokines and matrix metalloproteinases

A

1.6.6 Matrix metalloproteinases have an integral role in the pathogenesis of venous ulcers

A

1.6.7 Factor XIII, plasminogen, and extracellular matrix metalloproteinases inducer (EMMPRIN) modulate matrix metalloproteinases activity and contribute to venous ulcers

B

intercepted to achieve a signiﬁcant clinical response and decrease the chances for recurrence. To date our research in the understanding of venous ulcer development can be equated to that of just seeing the tip of an iceberg. However monumental it may seem, the task to gain knowledge through careful research must progress. As specialists in venous diseases who are caring for patients suffering from the devastation of a venous ulcer, we must now focus our resources on issues involving regulation of leukocytes in the microcirculation, regulation of cells involved in healing, the wound ﬂuid and its effect on the ulcer environment, and the effect and regulation of MMPs in order to gain a better understanding of the complexities of venous ulcer pathology.

●5.

●6.

●7.

8.

9.

REFERENCES ●10.

= Key primary paper ◆ = Major review article ●

●11.

1. Flanigan DP, Goodreau JJ, Burnham SJ, et al. Vascular laboratory diagnosis of clinically suspected acute deep vein thrombosis. Lancet 1978; 2: 331–4. 2. Flye MW. Venous disorders. In: Sabiston DC Jr. ed. Textbook of Surgery: The Biological Basis of Modern Surgical Practice, 14th edn. Philadelphia PA: W.B. Saunders Company, 1991: 1490–1501. ●3. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary ﬁbrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. Br Med J 1982; 285: 1071–2. ●4. Thomas PR, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous

12.

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hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988; 296: 1693–5. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296: 1726–7. Falanga V, Eaglstein WH. The “trap” hypothesis of venous ulceration. Lancet 1993; 341: 1006–8. Scott HJ, Coleridge Smith PD, Scurr JH. Histological study of white blood cells and their association with lipodermatosclerosis and venous ulceration. Br J Surg 1991; 78: 210–1. Wilkinson LS, Bunker C, Edwards JC, et al. Leukocytes: their role in the etiopathogensis of skin damage in venous disease. J Vasc Surg 1993; 17: 669–75. Pappas PJ, Fallek SR, Garcia A, et al. Role of leukocyte activation in patients with venous stasis ulcers. J Surg Res 1995; 59: 553–9. Pappas PJ, Teehan EP, Fallek SR, et al. Diminished mononuclear cell function is associated with chronic venous insufﬁciency. J Vasc Surg 1995; 22: 580–6. Pappas PJ, DeFouw DO, Venezio LM, et al. Morphometric assessment of the dermal microcirculation in patients with chronic venous insufﬁciency. J Vasc Surg 1997; 26: 784–95. Weyl A, Vanscheidt W, Weiss JM, et al. Expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectins and their ligands VLA-4 and LFA-1 in chronic venous leg ulcers. J Am Acad Dermatol 1996; 34: 418–23. Saharay M, Shields DA, Porter JB, et al. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg 1997; 26: 265–73. Takase S, Schmid-Schonbein G, Bergan JJ. Leukocyte activation in patients with venous insufﬁciency. J Vasc Surg 1999; 30: 148–56.

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Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: 827–39. Wysocki AB, Staiano-Coico L, and Grinnell F. Wound ﬂuid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993; 101, 64–8. Weckroth M, Vaheri A, Lauharanta J, et al. Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996; 106: 1119–24. Yager DR, Zhang LY, Liang HX, et al. Wound ﬂuid from human pressure ulcers contain elevated matrix metalloproteinase levels and activity to surgical wound ﬂuids. J Invest Dermatol 1996; 107: 743–8. Cook H, Stephens P, Davies KJ, et al. Defective extracellular matrix reorganization by chronic wound ﬁbroblasts is associated with alterations in TIMP-1, TIMP-2, and MMP-2 activity. J Invest Dermatol 2000: 115, 225–33. Herouy Y, May AE, Pornschlegel G, et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol 1998; 111, 822–7. Ulrich D, Lichtenegger F, Unglaub F, et al. Effects of chronic wound exudates and MMP-2/-9 inhibitor on angiogenesis in vitro. Plast Reconstr Surg 2005; 116: 539–45. Hoffman R, Starkey S, Coad J. Wound ﬂuid from venous leg ulcers degrades plasminogen and reduces plasmin generation by keratinocytes. J Invest Dermatol 1998; 111: 1140–4.

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Zamboni P, De Mattei M, Ongaro A, et al. Factor XIII contrasts the effects of metalloproteinases in human dermal ﬁbroblasts cultured cells. Vasc Endovascular Surg 2004; 38: 431–8. Zamboni P, Scapoli G, Lanzara V, et al. Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg 2005; 31: 644–9. Herouy Y, Trefzer D, Hellstern MO, et al. Plasminogen activation in venous ulcers. Br J Dermatol 2000; 143: 930–6. Norgauer J, Hildenbrand T, Idzko M, et al. Elevated expression of extracellular matrix metalloproteinase inducer (CD147) and membrane-type matrix metalloproteinases in venous leg ulcers. Br J Dermatol 2002; 147: 1180–6. Mwaura B, Mahendran B, Hynes N, et al. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGFAA on the chronicity of venous leg ulcers. Eur J Vasc Endovasc Surg 2006; 31: 306–10. Saito S, Trovato MJ, You R, et al. Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufﬁciency. J Vasc Surg 2001; 34: 930–8. Hieta N, Impola U, Lopez-Otin C, et al. Matrix metalloproteinase-19 expression in dermal wounds and by ﬁbroblasts in culture. J Vasc Surg 2003; 121: 997–1004.

8 Acute venous thrombosis: pathogenesis and evolution THOMAS W. WAKEFIELD AND PETER K. HENKE Introduction Inﬂammation and thrombosis P-selectin, microparticles, and thrombosis Clinical translation: P-selectin, microparticles, and patients with DVT

83 83 85 86

INTRODUCTION Deep vein thrombosis (DVT) remains a serious healthcare problem in this country, with over 250 000 patients affected yearly and at least 200 000 diagnosed yearly with pulmonary embolism (PE), although some suggest these ﬁgures are conservative.1–3 In fact, Heit has recently demonstrated over 900 000 cases of venous thromboembolism (VTE) and close to 300 000 deaths from PE in the Rochester, MN, population that he has been following (J Heit, unpublished data). This is more than breast cancer and AIDS combined. The incidence of total cases of VTE exceeds the number of myocardial infarctions and total strokes in this country yearly, whereas the incidence of VTE-related deaths exceeds the number of myocardial infarction-related deaths or stroke-related deaths. The incidence of DVT has been increasing with the aging of the population. In those 85–89 years old, the incidence is reported to be as high as 310/100 000 population.4 Additionally, treatment costs are in billions of dollars per year.5 The late DVT consequence, post-thrombotic syndrome (PTS), affects between 400 000 and 500 000 patients with skin ulcerations and 6 to 7 million patients with severe manifestations including stasis pigmentation and stasis dermatitis. It has been reported that up to 28% of the patients evaluated after having an iliofemoral DVT develop marked edema and skin changes, and 28% of cases develop venous stasis syndrome within a period of 20 years.4 Even asymptomatic DVT has been associated with PTS.6 Treatment for DVT is not perfect – even with the best therapies, there remains a signiﬁcant risk of recurrence and extension. A recurrence rate of 29–47% is observed

Inﬂammation and vein wall damage Conclusion References

87 91 91

with iliofemoral DVT without anticoagulation, 5–7% with full heparin anticoagulation, 4–5% with low-molecularweight heparin (LMWH) anticoagulation, and 3–9% with direct thrombin inhibitors.7–9 Bleeding complications include minor bleeding and major bleeding episodes, which can lead to death. The incidence of chronic venous insufﬁciency (CVI) was approximately 29% after 8 years in treated patients, with the development of ipsilateral recurrent DVT strongly associated with an increased risk of this syndrome.10 Thus, anticoagulant treatment for venous thrombosis, although effective in preventing fatal PE after venous thrombosis,11 often does not result in optimal outcomes. Even thrombolytic therapy, designed to remove the thrombus, although demonstrating promise in early studies, is not the therapy that is chosen by most clinicians because of the bleeding risk associated with its use and the inability to predict who will beneﬁt most from this aggressive therapy.12

INFLAMMATION AND THROMBOSIS After venous thrombosis, an acute to chronic inﬂammatory response occurs in the vein wall and thrombus. This response leads to thrombus ampliﬁcation, organization, and recanalization, and occurs at the expense of the vein wall and vein valve damage. Leukocytes, cytokines, chemokines, and inﬂammatory factors such as tumor necrosis factor alpha (TNF-α) facilitate the inﬂammatory response. Both proinﬂammatory and anti-inﬂammatory mediators are

Acute venous thrombosis: pathogenesis and evolution

Control

iliofemoral DVT formation. Two days after thrombus development, baboons were treated with rPSGL-Ig, 4 mg/kg, LMWH, or saline and treatment continued once weekly (rPSGL-Ig) or daily (LMWH, saline) based on drug half-life assessment.18 The animals were examined and killed 14 or 90 days after treatment initiation. The percent spontaneous vein reopening was increased signiﬁcantly in the proximal iliac vein in rPSGL-Ig- and LMWH-treated animals compared with controls (Fig. 8.1). There were no differences in inﬂammation between groups. At 90 days after thrombosis, recanalization with iliac vein valve competence was found in the rPSGL-Ig- and LMWHtreated animals. Thus, rPSGL-Ig successfully treated established DVT as did LMWH; however, in this case, it enhanced spontaneous vein reopening without anticoagulation. How can these results related to P-selectin inhibition be explained? P-selectin is the key adhesion molecule involved in the interactions between inﬂammatory cells and vessels and has been linked with cardiovascular events in both the arterial and the venous circulations.19 This molecule is present in the alpha-granules of platelets and

r-PSGL-Ig

involved in the ultimate vein wall and thrombus response. We have also found selectins (P- and E-selectin) to be integrally involved in this process. These are cell adhesion molecules that modulate leukocyte–endothelial cell interactions. Other interactions between inﬂammation and coagulation exist. For example, inﬂammation increases tissue factor (TF), membrane phospholipids, platelet reactivity, and ﬁbrinogen, whereas it decreases thrombomodulin, the receptor for protein C, the half-life of activated protein C, protein S, vascular heparins, and ﬁbrinolysis (by increasing plasminogen activator inhibitor-1, PAI-1).13 In a rodent model of stasis DVT, P-selectin is upregulated as early as 6 hours after thrombus induction, whereas E-selectin is upregulated at day 6 after thrombosis, with increases in gene expression preceding the protein elevations. The anti-inﬂammatory cytokine interleukin (IL)-10 gene expression is upregulated at day 2, and remains so to day 9 after thrombosis, suggesting a counterbalance to the inﬂammatory response. Additionally, IL-10 protein levels are elevated before mRNA upregulation, suggesting an initial increase from preformed IL-10 followed by IL-10 synthesis.14 In order to further deﬁne the importance of the selectins to the thrombo-inﬂammatory response, genetically modiﬁed knock-out (KO) mice have been studied in which either P-selectin or E-selectin, or both P and E-selectin have been gene deleted. In these studies, deletion of E-selectin and combined P-selectin/E-selectin deletion was associated with decreased thrombosis, whereas the vein wall inﬂammatory response was most inhibited in the combined P-selectin/E-selectin and Pselectin KO groups.14 We have also conﬁrmed the importance of P-selectin and its receptor P-selectin glycoprotein ligand (PSGL-1) in venous thrombosis using a primate model of stasisinduced inferior vena cava (IVC) thrombosis, induced by a temporary 6-hour balloon occlusion. In this model, we have found that an antibody to P-selectin or a receptor antagonist (termed rPSGL-Ig) inhibits inﬂammation and thrombosis when given prophylactically.15,16 Further study has demonstrated a signiﬁcant dose–response relationship between rPSGL-Ig and thrombosis and rPSGL-Ig and spontaneous recanalization.17 The peri-thrombotic vein wall had decreased gadolinium enhancement (marker of inﬂammation) in all rPSGL-Ig groups compared with control, despite no signiﬁcant differences in inﬂammatory cell extravasation being observed. In fact, the highest dosage produced the best inhibition of thrombosis, but was associated with the greatest inﬂammatory cell inﬂux, suggesting that the prevention of thrombosis does not depend on inhibiting vein wall leukocyte inﬂux. Importantly, these effects were observed with rPSGL-Ig with no systemic anticoagulation, bleeding time prolongation, thrombocytopenia, or wound-healing complications. Direct selectin inhibition also effectively treats established venous thrombosis in a primate model of

LMWH

84

Figure 8.1 Venographic examples at baseline, day 2, day 9, and day 16 for a representative saline control (top panel), rPSGL-Igtreated (middle panel), and low-molecular weight heparin (LMWH)-treated animals (bottom panel). Note the improvement in recanalization in the rPSGL-Ig-treated animal compared with the saline control and even the LMWH-treated animal. The shaded area indicates the evaluated area between balloons. Reproduced with permission from Myers, et al.18

P-selectin, microparticles, and thrombosis 85

the Weibel–Palade bodies of endothelial cells. It is ﬁrst translocated to the plasma membrane of these cells, mediating the initial inﬂammatory response.20 rPSGL-Ig binds and inhibits cell-associated P-selectin. Thrombinactivated platelets expressing P-selectin bind to neutrophils, and rPSGL-Ig effectively blocks this effect approximately 90%.21 Recently, a synergism between leukocytes and platelets has been identiﬁed,22 such that TF can be transferred from leukocytes to platelets in a Pselectin-mediated fashion, and even platelets have been demonstrated to express functional PSGL-1, allowing for a P-selectin mechanism for platelet rolling.23,24 Thus, P-selectin blockade inhibits leukocyte–platelet, leukocyte–endothelial cell, leukocyte–leukocyte, and even platelet–endothelial cell interactions; all actions that potentially would decrease thrombus ampliﬁcation after its initiation. The ﬁndings of an improvement in spontaneous thrombolysis in animals in which P-selectin is inhibited by rPSGL-Ig is similar to results found in primate, porcine, and rat models of arterial and venous thrombolysis using P-selectin inhibition.18,24–26 This ﬁnding is likely due to reductions in leukocyte–platelet interactions that lead to TF release and ﬁbrin deposition, as these are P-selectin dependent.27 Thrombi in P-selectinnull mice have decreased TF and ﬁbrin accumulation compared with thrombi generated in wild-type mice, suggesting a decrease in ﬁbrin formation.28

thrombosis, and a decreased level of MPs derived from leukocyte origin (Fig. 8.2). We hypothesize that with a thrombogenic stimulus, P- and E-selectin becomes expressed on endothelial cells and platelets, facilitating leukocyte–endothelial cell, leukocyte–leukocyte, and leukocyte–platelet interactions through PSGL-1. Such interactions stimulate ﬁbrin formation.34 Additionally, through P-selectin interactions with its receptor PSGL-1, MPs are derived from platelets, leukocytes, and endothelial cells. These MPs are procoagulant and are recruited back to the developing thrombi, where they amplify coagulation23,35 (Fig. 8.3). The PSGL-1 present on the surface of MPs can bind to P-selectin on activated platelets and endothelial cells, allowing the MPs to interact directly at the point of thrombus initiation, accumulation, and propagation. Fluorescent-labeled MPs have been shown to be taken up into thrombi within 1 minute of ferric chloride-induced venule thrombosis in a mouse cremaster muscle model.36 The co-localization of ﬁbrin, platelets, and leukocytes in the developing thrombus supports this hypothesis, as do

Thrombus mass day 2

(a) 400

*ΔCT vs WT, PKO, EPKO, P⬍ 0. 01

350

When P-selectin binds to its receptor PSGL-1, microparticles (MPs) are produced. Micro-particles are fragments of phospholipid cell membranes that promote coagulation and modulate a number of inﬂammatory cell–vessel wall interactions. Platelet-derived MPs are involved in heparin-induced thrombocytopenia.29 Platelet MPs rich in P-selectin have been found to allow ﬂowing neutrophils to aggregate irrespective of L-selectin.30 Less is known regarding leukocyte-derived MPs, although they are associated with endothelial cell activation and cytokine gene induction.31 Additionally, MPs derived from endothelial cells induce monocyte TF antigen release and increased expression.32 The thrombogenic potential of MPs is dependent on TF expression and their anionic, prothrombotic surface capable of assembling prothrombinase and tenase.25 We have studied the inﬂuence of elevated levels of soluble P-selectin on thrombogenesis and MPs using a mouse termed the delta CT mouse (ΔCT). This mouse demonstrates fourfold elevations in circulating soluble P-selectin. A 50–60% increase in thrombus mass was found at days 2 and 6 after thrombosis, and this increase was associated with the occurrence of procoagulant MPs in the circulation, most prominent from leukocyte origin.33 Animals deﬁcient in P- and E-selectin had decreased

250 200 150 100 50 0

Shams (n 95)

(b)

WT (n 35)

ΔCT (n 22)

PKO (n 26)

EPKO (n 14)

Thrombus mass day 6 ⫹57% * *ΔCT vs WT, EPKO, P ⬍ 0. 01

400 350 300 g/cm ⫻10⫺4

P-SELECTIN, MICROPARTICLES, AND THROMBOSIS

g/cm ⫻ 10⫺4

300

250 200 150 100 50 0

Shams (n 65)

WT (n 24)

ΔCT (n 35)

PKO (n 21)

EPKO (n 20)

Figure 8.2 Thrombus mass measurements (weight/length); signiﬁcant differences were noted for ΔCT versus all other groups at day 2 and between ΔCT and WT/EPKO at day 6. A remarkable 50% and 57% increase in thrombus mass was noted for ΔCT animals. Sham, operated but no ligature tied; WT, wild type; ΔCT, mice with high circulating P-selectin; PKO, P-selectin gene deleted; EPKO, combined P-selectin and E-selectin gene deleted. Reproduced with permission from Myers, et al.33

86

Acute venous thrombosis: pathogenesis and evolution

Injury

P-/E-selection expressed on surface

Stasis Procoagulant syndromes

↑Microparticles (procoagulant) Monocytes

Activation of TF:FVII complex Fibrin deposition Thrombus amplification

Figure 8.3 Proposed mechanism of the ampliﬁcation of thrombus formation by the elaboration of microparticles and the thrombogenic nature of inﬂammatory cells. Reproduced and modiﬁed with permission from Myers DD, Wakeﬁeld, TWW. Inﬂammation-dependent thrombosis. Front Biosci 2005; 10: 2750–7, on-line.

the recent observations of the importance of P-selectinmediated monocyte–platelet interactions to the generation of TF.37,38 Although complex, numerous investigators conclude that P-selectin, MPs and thrombosis are interdependent.38–45 Wagner39 suggests that P-selectin expressed on activated endothelial cells mediates initial platelet rolling, which might initially allow platelets to participate in a growing platelet plug. Then “P-selectin shed from activated platelets or endothelial cells, either in soluble form or from activated MPs, binds to PSGL-1 on leukocytes and induces procoagulant MP generation. Some of these MPs contain TF.” Following this, P-selectin expressed by the activated platelet in the developing thrombus helps to recruit the procoagulant MPs to the thrombus by binding to PSGL-1 expressed on MPs, leading to increased thrombin generation and ﬁbrin deposition at the site of the developing thrombus.39 Similarly, Furie and Furie41 suggest that “P-selectin and PSGL-1-dependent delivery of circulating MPs to thrombi appears to be important for normal TF accumulation and ﬁbrin generation in thrombus.” McEver46 states that “the interaction of leukocytes with both activated platelets and endothelial cells adds to the growing evidence that the hemostatic and inﬂammatory responses to tissue injury are linked. Interactions of P-selectin with PSGL-1 and GPIbα with Mac-1 may concentrate leukocytes or leukocyte MPs at sites of vascular injury and signal expression of TF, cytokines, growth factors, and oxygenderived free radicals that augment coagulation and promote wound repair. Conversely, excessive adhesion interactions may contribute to atheromas, thrombosis, and neointimal formation in the vascular system.” Finally, Lopez emphasizes the role of endothelial P-selectin and Eselectin in DVT formation, with endothelial cell activation from stasis and hypoxia and the interaction of TF bearing MPs with activated endothelium.43

CLINICAL TRANSLATION: P-SELECTIN, MICROPARTICLES, AND PATIENTS WITH DVT Endothelium- and platelet-derived MPs are elevated in patients with DVT with higher leukocyte CD11b expression in those patients with PE,47 and a recent study has demonstrated marked elevations in endotheliumderived MPs alone and conjugated with monocytes along with platelet–leukocyte conjugates in patients with VTE.48 Importantly, MPs have been found to be present in healthy individuals, and may have an anticoagulant function by promoting the generation of low amounts of thrombin that activates protein C, supporting protein C’s anticoagulant function.49 Elevated levels of soluble Pselectin have also been associated with the presence of DVT.27,50–52 Most recently, a study of soluble P-selectin levels in patients with many different thromboembolic conditions found that the level of soluble P-selectin in patients with DVT before beginning heparin treatment was 88.7 ± 41 ng/mL, 7 days after heparin therapy 54.5 ± 28.9 ng/mL, and in 30 control patients 22.1 ± 8.0 ng/mL.52 Such data support the association of both MPs and soluble P-selectin in DVT. We have also investigated the ability to use a combination of biomarkers to rule in DVT. Currently, the serum marker D-dimer can reliably exclude DVT in the presence of a low clinical probability.44,53 However, no marker or combinations of markers exist that improve upon the speciﬁcity of D-dimer (approximately 50%) in order to rule in the diagnosis of DVT or PE. Thus, diagnostic Duplex imaging is the only practical means to make the diagnosis today. Unfortunately, such imaging is not always available and is labor intensive. A prospective study was performed measuring plasma assays for D-dimer, soluble P-selectin, and total MPs in patients with documented DVT by duplex ultrasound scanning (DUS).45 Three groups of individuals were examined: group 1, 30 normal volunteers; group 2, 22 patients positive for DVT on DUS; and group 3, 21 patients with symptoms of leg pain but negative for DVT (SMP) by ultrasound. D-dimer and MPs were assayed at the time of diagnosis. No differences in age, weight, body mass index (BMI), use of oral contraceptives/hormone replacement therapies, smoking, family history of DVT, or trauma history were noted between DVT and SMP patients. Patients with DVT were more likely to have traveled recently or to have a malignancy present. Clinical stratiﬁcation showed 100% of patients with DVT were at highest risk (score ≥ 5) for thrombosis by clinical risk assessment, whereas only 62% of patients with SMP were at highest risk. Using a logistic regression model using dichotomous variables, we determined a sensitivity of 73%, speciﬁcity of 81%, and accuracy of 77% when combining d-dimer, soluble serum P-selectin, and total MPs to differentiate patients with DVT from patients with SMP (Table 8.1). Similar values were noted when using continuous variables, with a sensitivity of 81%, speciﬁcity

Inﬂammation and vein wall damage 87

Table 8.1 Logistic regression analysis using dichotomous variables Variables

D-dimer Soluble P-selectin Total microparticles

Threshold value

Sensitivity (%)

Speciﬁcity (%)

Accuracy (%)

≥ 3 mg/L ≥ 0.68 ng/mg TP 125% (compared with FACS controls)

64 68 50

76 81 67

70 74 58

73

81

77

Combined variables FACS, ﬂuorescence-activated cell sorter; TP, total protein

of 62%, and accuracy of 71% (Table 8.2). Of interest, the single variable most predictive for thrombosis was soluble P-selectin. This study, which demonstrated that combining markers for venous thrombosis improved sensitivity and speciﬁcity, will be repeated on a larger scale in the near future.

matrix metalloproteinase (MMP) expression and activation.56–59 In the rodent models of IVC stasis-induced DVT, we have found an acute to chronic inﬂammatory response in the vein wall and thrombus in response to IVC ligation and thrombosis induction.18–20,60,61 In the vein wall, polymorphonuclear neutrophils (PMNs) are signiﬁcantly elevated above sham control animals at day 2 after thrombosis, and monocytes are signiﬁcantly elevated above sham controls at day 6 after thrombosis. Total inﬂammatory cell counts are signiﬁcantly elevated at both time points (Fig. 8.4). Although PMNs may cause vein wall injury, they are essential for early thrombus resolution by promoting both ﬁbrinolysis as well as collagenolysis.61–63 We have found that neutropenia in a rat model of stasis DVT is associated with larger thrombi at 2 and 7 days, increased thrombus ﬁbrosis (larger and less cellular thrombi), and signiﬁcantly lower thrombus levels of both uPA and MMP-9.61,62 Counterintuitvely, PMNs are not entirely detrimental for early vein wall remodeling via some of these same mechanisms.61 It seems a lack of intrathrombus PMNs when the thrombus forms may directly impair thrombus resolution, rather than by secondary cellular signaling. As a clinical correlate, patients with malignancy and neutropenia are signiﬁcantly more likely to have a VTE recurrence than those that are not neutropenic when other risk factors are controlled.64 An important unanswered question is whether patients with transient neutropenia have impaired thrombus resolution, and whether this manifests clinically as a higher long-term risk of PTS.

INFLAMMATION AND VEIN WALL DAMAGE Thrombus resolution For many years the endothelial lining of the vasculature was assumed to play little or no role in homeostasis, a tenet ultimately proven very wrong. In an analogous fashion, the in vivo thrombus is not inert, but biologically active, with speciﬁc cellular types and matrix components orchestrated in a temporal fashion. Thus, therapies to manipulate and accelerate its resolution are possible. The normal thrombus (even without anticoagulation treatment) does lyse over time, presumably through the plasmin system, activated by urokinase plasminogen activator (uPA).54,55 It is likely that the uPA is produced from leukocytes that have inﬂuxed into the thrombus as well as resident vein wall cells. At the current time, it is not known what speciﬁc cellular signals modulate this process, but probably includes the natural anticoagulant factors of antithrombin III, proteins C and S, and thrombin. DVT resolution resembles wound healing and involves both proﬁbrotic growth factors, collagen deposition, and

Table 8.2 Results of logistic regression analysis using continuous variables Variables

D-dimer Soluble P-selectin Total microparticles

Threshold value

Sensitivity (%)

Speciﬁcity (%)

Accuracy (%)

≥ 3 mg/L ≥ 0.68 ng/mg TP 125% (compared with FACS controls)

59 71 59

81 81 62

70 76 61

81

62

71

Combined variables FACS, ﬂuorescence-activated cell sorter; TP, total protein

88

Acute venous thrombosis: pathogenesis and evolution

(a) 80

Cells 5HPFs

70 60 50 40 30 20 10 0 Control 6 hours

2

6

9

12

9

12

9

12

Time (days) (b) 35

Cells 5HPFs

30 25 20 15 10 5 0 Control 6 hours

2

6

Time (days) (c) 100

Cells 5HPFs

80 60 40 20 0 Control 6 hours

2

6

Time (days)

Figure 8.4 (a) Neutrophils are the ﬁrst leukocyte to invade the mouse vein wall after thrombosis, and peak at day 2 is compared with shams. (b) Monocytes are signiﬁcantly greater at day 6. (c) Total inﬂammatory cells in the vein wall are similarly increased at days 2 and 6, trending toward sham levels at days 9 and 12. *P < 0.05; **P < 0.01. Reproduced with permission from Myers, et al.14

macrophage-inﬂammatory protein-2 (MIP-2), analogs of human IL-8.60 The CXCR2 KO mice had larger, less organized early thrombi, fewer intrathrombus PMNs, and fewer monocytes (over the ﬁrst 8 days). Decreased late (day 12 and 21) thrombus neovascularization was also observed as well as impaired ﬁbrinolysis. Taken together, PMNs play a role in early thrombus resolution, whereas monocytes predominate later; both are mediated by CXC chemokine activity. The monocyte is probably the most important cell for DVT resolution as it is multifunctional and directs resident cell activation through multiple signals. Monocyte inﬂux into the thrombus peaks at 8 days after thrombogenesis, and correlates with elevated MCP-1 levels. This is one of the primary CC chemokines that directs monocyte chemotaxis and activation59,66 and has also been associated with DVT resolution.67 Targeted deletion of CC receptor-2 (CCR-2 KO) in the mouse model of stasis thrombosis was associated with early and late impairment of thrombus resolution, probably via impaired early interferon gamma (IFN-γ)-mediated MMP-2 and -9 activity. Indeed, CCR-2 KO mice with stasis thrombosis supplemented with exogenous IFN-γ had full restoration of thrombus resolution, in part due to recovery of MMP-2 and -9 activities, without an increase in thrombus monocytes or ﬁbrinolytic activity.68 These experiments suggest a broader and intriguing role for early Th1 lymphokine activity (e.g., IFN-γ) in thrombus resolution, probably mediated by CCR2 (+) monocytes. Others have also shown similar dependence of DVT resolution on CCR2 cellular signaling activity.69 Healing tissue depends on physiologic neovascularization, and a thrombus is similar to a wound-healing milieu. The aforementioned experiments with chemokine receptor-deleted mice have also conﬁrmed a strong association between thrombus resolution and neovascularization (Table 8.3). However, neovascularization may reﬂect thrombus organization and not impact thrombolysis. For example, we have administered exogenous pro-angiogenic agents in the rat model of stasis DVT and despite documenting increased thrombus microvascular blood ﬂow, no signiﬁcant decrease in thrombus size was found.70 However, other investigators have found a potential role for VEGF in accelerating thrombus resolution when administered exogenously.71

Thrombus resolution and vein wall damage Stimulating the proinﬂammatory PMN response with exogenous administration of the chemotactic peptide interleukin 8 (IL-8) can accelerate experimental DVT resolution.65 It is speculated that IL-8 increases intrathrombus PMN activation and release of plasminogen activators. To further investigate the role of chemokines involved with PMN inﬂux into the resolving DVT, we utilized mice with targeted gene deletion of the CXC receptor (CXCR2 KO) whose ligands include KC and

As the thrombus resolves, numerous proinﬂammatory factors are released in the local thrombovenous environment. These include IL-1b, TNF-α and transforming growth factor beta (TGF-β), which are present in the thrombus at differing times and may have direct effects on the vein wall.60,72 Often, the thrombus is intimately attached to the vein wall and direct cellular communication results. Although our experimental

Inﬂammation and vein wall damage 89

Table 8.3 Chemokine receptor effect on deep vein thrombosis resolution Chemokine receptor (genetic deletion)

CXCR2 CCR2 CCR7

Thrombus size Early

Late

Monocyte inﬂux (thrombus)

↑ ↑ ↓

↔ ↑ UK

↓ ↓ ↓

Neovasc. (thrombus)

Proﬁbrotic factors (vein wall)

MMP-2/9 (vein wall)

uPA Thrombus wall

↓ ↓ ↔

↓ ↓ ↓

↑↓ ↓↓ ↓↓

↑↓ ↔ ↑

Thrombus size is measured in mg/cm length of thrombosed inferior vena cava. Monocyte inﬂux was determined by ED-1 immunopositive staining in ﬁve high-powered ﬁelds. Neovascularization was determined by a combination of vWF-postitive immunostaining in the thrombus, and laser Doppler measures (CCR2 only). Proﬁbrotic growth factors were assayed by enzyme-linked immunosorbent assay and included bFGF and TGF-β. MMP-2 and -9 activity was assessed by zymography. uPA levels were determined by thrombus western immunoblot assay.

models often separate the thrombus from the vein wall speciﬁcally to analyze these tissues, this is likely somewhat artiﬁcial compared with the in vivo environment. The cellular sources of these different mediators have not been speciﬁcally deﬁned, but likely include leukocytes and ﬁbroblast-like cells within the resolving thrombus. The cellular leukocyte kinetics in the vein wall after DVT is similar to what is observed in the thrombus, with an early inﬂux of PMNs followed by monocytes. Based on the rat model of stasis DVT, vein wall elastinolysis seems to occur early, with partial recovery by 28 days, and correlates with a marked increase in vein wall stiffness (the inverse of compliance, a property of normal veins) (Fig. 8.5). Persistent increased stiffness continues for 14 days and is accompanied by elevated MMP-2 and -9 activities. Gene expression of MMP-2 and -9 has also been documented in a similar stasis mouse model of DVT resolution.73 Whether these proteinases are the major mechanism of the early elastinolysis and collagenolysis and the affect these have on later vein wall ﬁbrosis is not clear. To extrapolate (a)

this to the clinical situation, normal vein walls are very compliant to accommodate large changes in blood volume and positional changes. We believe the DVT causes vein wall damage via elastin and collagen breakdown that renders normal veins stiff and non-compliant, and promotes the symptoms observed in patients with PTS. This generalized vein wall damage may be more important than isolated valve destruction. Associated with this biomechanical injury from the DVT is an elevation of proﬁbrotic mediators including TGF-β, RANTES, and MCP-1. Late ﬁbrosis has been observed in the mouse model of DVT, with a signiﬁcant increase in total vein wall collagen after stasis thrombosis.73 Correlating with this increase in ﬁbrosis is an increase in vein wall collagen I and III gene expression as well as an increase in MMP-2 and -9 gene expression and activity. The proﬁbrotic growth factor TGF-β is also present in the thrombus and is released with normal thrombolysis.74 This factor may be one local mechanism promoting vein wall ﬁbrosis. However, early vein wall (b) 50

1.6 *

1.4

40

*

OD/mg protein

1.2

N /cm

1.0 *

0.8 0.6 0.4

30 * 20 10

0.2 0.0

0 Sham

2

14

Thrombus age (days)

Sham

2

14

Thrombus age (days)

Figure 8.5 (a) Inferior vena cava (IVC) stiffness increases signiﬁcantly over time after stasis deep vein thrombosis (P < 0.05, n = 3–5). (b) Inferior vena cava MMP-9 zymography activity was signiﬁcantly elevated at 2 and 14 days after thrombogenesis (P < 0.05, n = 3). Reproduced with permission from Wakeﬁeld TW, Henke PK, The role of inﬂammation in early and late venous thrombosis: are there clinical implications? Semin Vasc Surg 2005; 18: 126.

90

Acute venous thrombosis: pathogenesis and evolution

collagenolysis (rather than collagen production) seems to occur within the ﬁrst 7 days in stasis DVT in the rat model, representing an acute response to injury. Interestingly, Pselectin inhibition has been found to be associated with a decrease in thrombus collagen content and vein wall ﬁbrotic injury in our mice and rat models,75,76 suggesting that such inhibition may be protective of late vein wall damage. Clinically, it has been documented by Duplex ultrasonographic studies that the faster and more completely a DVT lyses, the less likely that PTS will develop.77,78 This has also been observed in experimental histological studies.79 To investigate the role of the thrombogenic mechanism and the contribution of the thrombus itself on the vein wall, the rat IVC ligation model was modiﬁed to allow a silicone plug insertion into the IVC to displace the thrombus (and functionally remove its contribution) yet maintain the stretch and stasis component. To eliminate the role of stasis but assess the contribution of the thrombus to the injury, a transvenous chemical injury was induced with a 3 minute application of 10% FeCL3 on the exposed IVC.58 This consistently produces a thrombus in the IVC for ≥ 24 hours. Preliminary studies with these models suggest that nonstasis thrombosis causes lesser injury than stasis DVT (e.g., decreased vein wall stiffness, no alteration in collagen levels, with less activation of MMP-9), and it seems the longer a stasis thrombus is in contact with the vein wall, the greater the injury. Experiments are ongoing to better solidify the mechanisms involved. However, our preliminary ﬁndings are consistent with the clinical supposition that rapid and complete thrombus removal will lessen vein wall damage (Fig. 8.6).

Overall hypothesis Proximal vain

Area of stasis

Clot

Area of flow

Clot

Clot factors Stretch No flow

Less clot Less stretch Flow MMP 2/9 Collagen: elastin Stiffness

MMP 2/9 Collagen: elastin Stiffness

Peripheral systemic MMP 2/9 gene upregulation

Figure 8.6 Proposed hypothesis of segmental venous injury, based on acute thrombosis models in the rat and mouse. Areas of relative stasis thrombosis have greatest long-term damage because of thrombus released proinﬂammatory factors. Thus, increased matrix metalloproteinase (MMP) activation, decreased endothelialization, and stretch causes greater collagenolysis and elastinolysis. The area where the thrombus is lysing with prograde ﬂow has less activation of MMPs, less collagen turnover, and less injury. Reproduced with permission from Wakeﬁeld TW, Henke PK, Semin Vasc Surg 2005; 18: 126.

Guidelines 1.7.0 of the American Venous Forum on pathogenesis and evolution of acute venous thrombosis No.

Guideline

1.7.1 Acute venous thrombosis causes an acute to chronic inﬂammatory response in both the vein wall and the thrombus. This leads to thrombus ampliﬁcation, organization, and recanalization, and damage to the vein wall and the valves 1.7.2

D-dimer,

endothelium- and platelet-derived microparticles and soluble P-selectin are markers of thrombosis and they are increased in patients with acute venous thromboembolism

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality) A

A

1.7.3 Resolution of acute thrombus is modulated by natural anticoagulants such as antithrombin III, protein C and S, and thrombin

B

1.7.4 Polymorphonuclear cells promote both ﬁbrinolysis and collagenolysis and they play key role in early thrombus resolution. Monocytes are essential in the late phase of thrombus resolution

A

References 91

Over the last several years, in human and experimental studies, circulating bone marrow endothelial progenitor cells have been shown to be important in repair of arterial injury. Intriguing work from Modarai and colleagues80 has shown these cells also play a signiﬁcant role in DVT resolution. We have found evidence of these circulating cells in the resolving thrombus, and also expression of CCR7. This chemokine receptor is involved in lymphocyte hemostasis and also confers ﬁbrogenesis in models of pulmonary inﬂammation.81 Interestingly, antibody blockade of CCR7 was associated with less vein wall ﬁbrotic injury but also signiﬁcantly smaller thrombi (PK Henke, unpublished data). Further investigation is ongoing into this potentially exciting area of cellular-based therapy to accelerate vein wall healing after DVT.

◆6.

◆7.

8. ◆9.

●10.

11.

CONCLUSION It is an exciting time to study venous thrombogenesis and the pathophysiology of the resulting vein wall damage, in part because it has been relatively neglected (particularly by vascular surgeons) compared with arterial disease. Fortunately, the National Institutes of Health has put forth two requests for funding applications in the last several years to better study the clinical and basic pathobiology of venous disease and the Surgeon General has approved a call-to-action against VTE. Adjuncts to or replacement therapies for anticoagulants hold tremendous promise and will hopefully decrease the early risk of PE and the late complications of PTS for the beneﬁt of the patient.

◆12.

◆13.

14.

15.

16.

●17.

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24. Toombs CF, DeGraaf GL, Martin JP, et al. Pretreatment with a blocking monoclonal antibody to P-selectin accelerates pharmacological thrombolysis in a primate model of arterial thrombosis. J Pharmacol Exp Ther 1995; 275: 941–9. 25. Myers DD, Jr., Rectenwald JE, Bedard PW, et al. Decreased venous thrombosis with an oral inhibitor of P selectin. J Vasc Surg 2005; 42: 329–36. ●26. Falati S, Liu Q, Gross P, et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585–98. ●27. Palabrica T, Lobb R, Furie BC, et al. Leukocyte accumulation promoting ﬁbrin deposition is mediated in vivo by Pselectin on adherent platelets. Nature 1992; 359: 848–51. 28. Sullivan VV, Hawley AE, Farris DM, et al. Decrease in ﬁbrin content of venous thrombi in selectin-deﬁcient mice. J Surg Res 2003; 109: 1–7. 29. Walenga JM, Jeske WP, Messmore HL. Mechanisms of venous and arterial thrombosis in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2000; 10 (Suppl 1): 13–20. 30. Kumar A, Villani MP, Patel UK, et al. Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model. Circulation 1999; 99: 1363–9. 31. Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem 1999; 274: 23111–8. 32. Sabatier F, Roux V, Anfosso F, et al. Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 2002; 99: 3962–70. ●33. Myers DD, Hawley AE, Farris DM, et al. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075–89. 34. Swords NA, Tracy PB, Mann KG. Intact platelet membranes, not platelet-released microvesicles, support the procoagulant activity of adherent platelets. Arterioscler Thromb 1993; 13: 1613–22. 35. Kirchhofer D, Tschopp TB, Steiner B, Baumgartner HR. Role of collagen-adherent platelets in mediating ﬁbrin formation in ﬂowing whole blood. Blood 1995; 86: 3815–22. 36. Breimo ES, Osterud B. Generation of tissue factor-rich microparticles in an ex vivo whole blood model. Blood Coagul Fibrinolysis 2005; 16: 399–405. ●37. Hrachovinova I, Cambien B, Hafezi-Moghadam A, et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 2003; 9: 1020–5. 38. Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92: 459–66. ◆39. Wagner DD. New links between inﬂammation and thrombosis. Arterioscler Thromb Vasc Biol 2005; 25: 1321–4.

40. Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 2005; 3: 1590–6. ◆41. Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10: 171–8. ◆42. Prescott SM, Weyrich AS, Zimmerman GA. Classiﬁcation of venous thromboembolism (VTE). The clot is hot: inﬂammation, myeloid leukocytes, and venous thromboembolism. J Thromb Haemost 2005; 3: 2571–3. 43. Lopez JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology Am Soc Hematol Educ Program 2004: 439–56. ●44. Wells PS, Anderson DR, Rodger M, et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–35. 45. Rectenwald JE, Myers DD, Jr., Hawley AE, et al. D-dimer, Pselectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005; 94: 1312–7. ◆46. McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inﬂammation. Thromb Haemost 2001; 86: 746–56. 47. Biro E, Sturk-Maquelin KN, Vogel GM, et al. Human cellderived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 2003; 1: 2561–8. 48. Berckmans RJ, Neiuwland R, Boing AN, et al. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85: 639–46. 49. Blann AD, Noteboom WM, Rosendaal FR. Increased soluble P-selectin levels following deep venous thrombosis: cause or effect? Br J Haematol 2000; 108: 191–3. 50. Yang LC, Wang CJ, Lee TH, et al. Early diagnosis of deep vein thrombosis in female patients who undergo total knee arthroplasty with measurement of P-selectin activation. J Vasc Surg 2002; 35: 707–12. 51. Bucek RA, Reiter M, Quehenberger P, et al. The role of soluble cell adhesion molecules in patients with suspected deep vein thrombosis. Blood Coagul Fibrinolysis 2003; 14: 653–7. 52. Papalambros E, Sigala F, Travlou A, et al. P-selectin and antibodies against heparin-platelet factor 4 in patients with venous or arterial diseases after a 7-day heparin treatment. J Am Coll Surg 2004; 199: 69–77. 53. Motykie GD, Zebala LP, Caprini JA, et al. A guide to venous thromboembolism risk factor assessment. J Thromb Thrombolysis 2000; 9: 253–62. 54. Singh I, Burnand KG, Collins M, et al. Failure of thrombus to resolve in urokinase-type plasminogen activator geneknockout mice: rescue by normal bone marrow-derived cells. Circulation 2003; 107: 869–75. 55. Moir E, Booth NA, Bennett B, Robbie LA. Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u-PA-dependent mechanism. Br J Haematol 2001; 113: 72–80.

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56. Madlener M, Parks WC, Werner S. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res 1998; 242: 201–10. 57. Grinnell F. Fibronectin and wound healing. J Cell Biochem. 1984; 26: 107–16. 58. Zhu YK, Liu X, Wang H, et al. Interactions between monocytes and smooth-muscle cells can lead to extracellular matrix degradation. J Allergy Clin Immunol 2001; 108: 989–996. 59. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69: 513–21. 60. Henke PK, Varga A, De S, et al. Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model. Arterioscler Thromb Vasc Biol 2004; 24: 1130–7. ●61. Henke PK, Varma MR, Deatrick KB, et al. Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization. Thromb Haemost 2006; 95: 272–81. 62. Varma MR, Varga AJ, Knipp BS, et al. Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 2003; 38: 1090–8. ◆63. Stewart GJ. Neutrophils and deep venous thrombosis. Haemostasis 1993; 23 (Suppl 1): 127–40. 64. Lin J, Proctor MC, Varma M, et al. Factors associated with recurrent venous thromboembolism in patients with malignant disease. J Vasc Surg 2003; 37: 976–83. 65. Henke PK, Wakeﬁeld TW, Kadell AM, et al. Interleukin-8 administration enhances venous thrombosis resolution in a rat model. J Surg Res 2001; 99: 84–91. 66. Hogaboam CM, Steinhauser ML, Chensue SW, Kunkel SL. Novel roles for chemokines and ﬁbroblasts in interstitial ﬁbrosis. Kidney Int 1998; 54: 2152–9. ●67. Humphries J, McGuinness CL, Smith A, et al. Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. J Vasc Surg 1999; 30: 894–9. 68. Henke PK, Pearce CG, Moaveni DM, et al. Targeted deletion of CCR2 impairs deep vein thrombosis resolution in a mouse model. J Immunol 2006; 177: 3388–97. 69. Ali T, Humphries J, Burnand K, et al. Monocyte recruitment in venous thrombus resolution. J Vasc Surg 2006; 43: 601–8.

70. Varma MR, Moaveni DM, Dewyer NA, et al. Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 2004; 40: 536–42. ●71. Waltham M, Burnand KG, Collins M, et al. Vascular endothelial growth factor enhances venous thrombus recanalisation and organisation. Thromb Haemost 2003; 89: 169–76. ●72. Wakeﬁeld TW, Strieter RM, Wilke CA, et al. Venous thrombosis-associated inﬂammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 1995; 15: 258–68. 73. Deatrick KB, Eliason JL, Lynch EM, et al. Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late ﬁbrosis in a mouse model. J Vasc Surg 2005; 42: 140–8. 74. Grainger DJ, Wakeﬁeld L, Bethell HW, et al. Release and activation of platelet latent TGFb in blood clots during dissolution with plasmin. Nature Med 1995; 1: 932–937. 75. Myers DD, Jr., Henke PK, Wrobleski SK, et al. P-selectin inhibition enhances thrombus resolution and decreases vein wall ﬁbrosis in a rat model. J Vasc Surg 2002; 36: 928–38. 76. Thanaporn P, Myers DD, Wrobleski SK, et al. P-selectin inhibition decreases post-thrombotic vein wall ﬁbrosis in a rat model. Surgery 2003; 134: 365–71. ●77. Delis KT, Bountouroglou D, Mansﬁeld AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004; 239: 118–126. 78. Prandoni P. Toward the simpliﬁcation of antithrombotic treatment of venous thromboembolism. Ann Intern Med 2004; 140: 925–6. 79. See-Tho K, Harris EJ, Jr. Thrombosis with outﬂow obstruction delays thrombolysis and results in chronic wall thickening of rat veins. J Vasc Surg 1998; 28: 115–22; discussion 123. ●80. Modarai B, Burnand KG, Sawyer B, Smith A. Endothelial progenitor cells are recruited into resolving venous thrombi. Circulation 2005; 111: 2645–53. 81. Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary ﬁbrosis. J Clin Invest 2004; 113: 243–52.

9 The epidemiology of and risk factors for acute deep venous thrombosis MARK H. MEISSNER Introduction The epidemiology of lower extremity deep vein thrombosis Risk factors for deep vein thrombosis Primary hypercoagulable states Oral contraceptives and hormonal therapy

94 94 95 98 99

INTRODUCTION Venous thromboembolism (VTE) is the third most common cardiovascular disorder in Western populations, following only myocardial infarction and stroke.1 Among patients presenting with thromboembolic events, approximately one-third manifest pulmonary embolism (PE) whereas two-thirds manifest deep venous thrombosis (DVT). The deep veins of the lower extremity are most commonly involved, although with more frequent instrumentation and improved diagnostic testing, thrombosis of the upper extremity veins is increasingly recognized. Thrombosis only rarely involves unusual sites such as the cerebral sinuses, retina, and mesenteric veins. The prevention and management of VTE requires some understanding of the epidemiology and associated risk factors, particularly in recognizing populations warranting prophylaxis; counseling patients regarding high-risk situations such as pregnancy and contraception; and deterring the duration of anticoagulation required to minimize recurrent thrombosis.

THE EPIDEMIOLOGY OF LOWER EXTREMITY DEEP VEIN THROMBOSIS The incidence of lower extremity DVT is highly dependent on the population studied, their underlying risk factors, and the means by which DVT is documented. Autopsy studies are biased by inclusion of the very sick and very

Pregnancy Antiphospholipid antibodies Other risk factors Conclusions References

100 100 100 101 102

old, whereas clinical trials are often directed towards speciﬁc inpatient groups, such as postoperative patients. True estimates of the incidence of DVT are limited by the few population-based studies, the clinically silent nature of most thromboses, and the need for objective documentation of the diagnosis. Even the interpretation of methodologically sound studies is complicated by inconsistent inclusion of DVT and/or PE, differing exclusion or inclusion of recurrent DVT, and variable age ranges. It is generally believed that incidence rates from autopsy studies are overestimates, whereas those from epidemiological studies are underestimates.2 Community-based studies of hospitalized patients have suggested ﬁrst episodes of acute DVT to have a crude annual incidence of 56 per 100 000.3 In contrast, studies of venographically conﬁrmed DVT in Sweden have suggested a somewhat higher crude incidence of 160 cases of new or recurrent DVT per 100 000 population per year.4 However, incidence rates are strongly inﬂuenced by age and, not surprisingly, a higher age-adjusted incidence of 192 per 100 000 population has been reported for persons ≥ 45 in the USA.5 A systematic review of nine methodologically sound epidemiological studies suggests a weighted mean age adjusted incidence of a ﬁrst episode of DVT alone of 50.4 per 100 000 person–years.6 Most sources suggest an age- and sex-adjusted incidence of ﬁrst time symptomatic VTE (DVT + PE) in the USA of between 71 and 117 cases per 100 000 population.2 The higher incidence ﬁgure corresponds to approximately 275 000 new VTE cases annually in the United States, a ﬁgure that has not substantially changed over the last 10 years.7

Risk factors for deep vein thrombosis 95

Deep venous thrombosis is a multicausal disease resulting from the interaction of genetic and environmental risk factors. Thrombosis occurring in the absence of recognized thrombotic risk factors is designated primary or idiopathic DVT whereas that developing in their presence is designated secondary DVT. Such risk factors may be either transient or permanent and may be either genetic or acquired (environmental). Permanent risk factors may be considered as those that raise an individual’s baseline thrombotic potential, whereas transient risk factors are often those that trigger an acute thrombotic event. Among 2119 patient enrolled in a prospective, multicenter registry, 57% were associated with one or more thrombotic risk factors, whereas 43% were considered to have idiopathic DVT.8 The proportion of patients with idiopathic DVT in a number of other studies ranges between 26% and 49%.1,2,5 Temporary, reversible risk factors are present in 42.4% of patients, most commonly immobility (15%), surgery (14.4%), and severe medical illness (8.2%).8 Most risk factors for DVT can be related to the components of Virchow’s triad and many are associated with some component of hypercoagulability on a genetic, acquired, or situational basis. (Table 9.1) Well-established risk factors for thrombosis are shown in Table 9.2. There are substantial differences between the risk factors associated with inpatient and outpatient DVT. Although malignancy, surgery, and trauma within the previous 3 months remain signiﬁcant risk factors for outpatient thrombosis, the frequency of surgery and malignancy are higher among inpatients with DVT.9,10 The degree of risk associated with each of these factors has been established to a variable extent (Table 9.2), but the importance of any individual factor is a function of both its relative risk in comparison to normal control subjects as well as its prevalence in the population. For example, although deﬁciencies of the natural anticoagulants (antithrombin, proteins C and S) are associated with an approximately 10-fold increased risk of thrombosis, they are rare defects. In contrast, the factor V

Leiden mutation is associated with a much lower relative risk, but with a prevalence of 5% in Caucasians, it is far more important from a population-based perspective. Perhaps most importantly, the development of clinically manifest thrombosis most often occurs with the convergence of multiple genetic and acquired risk factors. The simultaneous presence of multiple risk factors is a prerequisite for thrombosis, with synergistic gene–gene and gene–environment interactions often increasing the risk above the sum of individual risk factors.11 Not surprisingly, the risk of venous thromboembolism increases with the number of risk factors. In symptomatic outpatients, the odds ratio for an objectively documented DVT increases from 1.26 for one risk factor to 3.88 for three or more risk factors.9 Three or more risk factors are present in 80% of inpatients with VTE3 and 30% of outpatients with conﬁrmed DVT9.

RISK FACTORS FOR DEEP VEIN THROMBOSIS Demographic risk factors Age, gender, and race may potentially inﬂuence the incidence of DVT. Among these, age has been most consistently associated with an increased risk of DVT. The incidence of DVT increases exponentially with age,1 rising by a factor of 200 between 20 and 80 years of age with a relative risk of 1.9 for each 10 year increase in age.3 Rosendaal12 similarly noted an incidence of 0.006 per 1000 children under age 14 increasing to 0.7 among adults 40–54 years of age, whereas Hansson et al.13 found the prevalence of objectively documented thromboembolic events among men to increase from 0.5% at age 50 to 3.8% at age 80. This increased risk appears related to several ageassociated factors, including decreased mobility, an increased number of major thrombotic risk factors, agerelated hypercoagulability, and changes in the venous system. Three or more risk factors are present in 30% of hospitalized patients over age 40 compared with only 3%

Table 9.1 Congenital, acquired, and situational thrombophilias Congenital Factor V Leiden Prothrombin G20210A Antithrombin deﬁciency Protein C deﬁciency Protein S deﬁciency Factor VII excess

Acquired

Situational

Congenital or acquired

Age Malignancy Antiphospholipid antibodies HIV infection Polycythemia vera Paroxysmal nocturnal hemoglobinuria Heparin-induced thrombocytopenia Behçet disease Nephrotic syndrome Inﬂammatory bowel disease

Surgery Trauma Pregnancy Oral contraceptives Hormone replacement therapy

Hyperhomocysteinemia Factor VIII, IX, XI excess

96

The epidemiology of and risk factors for acute deep venous thrombosis

Table 9.2 Thromboembolic risk factors Risk factor

Prevalence (%)*

Age Surgery

18–39

Trauma Malignancy

3–12 18–51

Hospital/nursing home History of venous thromboembolism Primary hypercoagulable states Antithrombin, proteins C and S deﬁciency Factor V Leiden Heterozygous Homozygous Prothrombin 20210A Increased Factor VIII Hyperhomocysteinemia Family history Oral contraceptives Estrogen replacement Immobilization Long distance travel Pregnancy and puerperium Central venous catheter Antiphospholipid antibodies Inﬂammatory bowel disease Obesity Varicose veins Myocardial infarction/CHF

5.5–9.5 20

4–7 25 10 16†

10-17 13.3 25–30† 3.1

11

Risk

References

1.9× per 10 year increase 4–5.9× (General surgery 25%; retropubic prostatectomy 32%; gynecology (benign disease) 14%; neurosurgery 22%; hip/knee arthroplasty 51%/47%) 20.5 × Without chemotherapy 4.4–6.9× With chemotherapy 6.5–9.9× 18.4× 15.6×

3 26, 41

35 35, 43 35 36

10× 3−8× 50−80× 2−4× 6× 2−4× 2.9× 2.9× (30–50× with Factor V Leiden) 2–4× 2× (preoperative) – 5.6× (medical patients) 2.4× – 3× 4.3 × 11.8× Lupus anticoagulant 6× Anticardiolipin antibody 2× 1.2–7.1% of patients Variable Variable Variable

11, 41, 43

93 72 74 36, 90 36, 41, 48 76 35 80 94

*Prevalence of risk factor among patients with deep vein thrombosis or venous thromboembolism (population attributable risk). †Among women < 45 years of age. CHF, congestive heart failure.

of those less than age 40.14 Increased levels of thrombin activation markers suggest an acquired prothrombotic state whereas anatomic changes in the soleal veins, as well as increased stasis in the valve pockets, have also been noted with advanced age.15,16 Gender differences in the incidence of DVT have been variable, and may be related to other risk factors. Although Coon and associates17 found a higher frequency of DVT in young women, one-half of thromboembolic events in women less than 40 years old were associated with pregnancy. Some have noted no signiﬁcant differences in incidence between men and women,4,9 while others have noted a slightly increased risk (relative risk 1.4) in males3. The absence of consistent data makes it unlikely that there are signiﬁcant overall gender differences in the incidence of VTE.2,18 However, incidence rates in young populations

are higher in women during the childbearing years and may be higher in men over 45–60 years of age.1,5,7 Geographic differences in the incidence of DVT do exist. In the United States, the incidence of venous thromboembolism is higher in the interior than on either coast.19 However, regional variations in medical and surgical diseases, prophylactic measures, and methods of diagnosis make conclusions regarding ethnic differences difﬁcult. Among elderly Medicare patients, the incidence of PE is higher among African Americans, whereas the incidence of DVT is lower.19 However, both autopsy series20 and coded hospital discharge data18,21 suggest an identical prevalence of thromboembolism among African Americans and white patients. Although there is suggestive evidence that the incidence of postoperative DVT may be lower in Asian, Arab, and African populations than among

Risk factors for deep vein thrombosis 97

Europeans,22 the incidence of postoperative DVT is similar among South African European and non-European patients.23 Data from several sources does, however, suggest a lower risk of VTE among Hispanics and Asians. The incidence of VTE in Asian populations is particularly low, the rate ratio being only 0.21 compared with white people in the United States.18 A variety of observations suggest that such differences are more likely due to genetic factors than to acquired thrombotic risk factors.24 Racial and ethnic differences in genetic determinants such as blood group and the factor V Leiden mutation are well recognized. The prevalence of the factor V Leiden mutation in Asians (0.5%) is only one-tenth that in Caucasian populations (5%).2

Surgery The thromboembolic risk associated with surgery is multifactorially related to perioperative immobilization, activated coagulation, and transient depression of ﬁbrinolysis. Increases in thrombin activation as well as elevated levels of plasminogen activator inhibitor 1 (PAI1) have been well documented perioperatively. The degree of risk further varies with the age of the patient, length and type of procedure, and the presence of other thrombotic risk factors.25 Without appropriate prophylaxis, the incidence of deep venous thrombosis is approximately 25% in patients undergoing general surgical operations; 32% for retropubic prostatectomy; 22% and 14% for gynecological procedures with and without malignancy; 22% for elective neurosurgical procedures; and 45%, 51%, and 47% among those undergoing surgery for hip fracture, hip arthroplasty, and knee arthroplasty respectively.26 Based upon these data, patients can be classiﬁed as being at low, moderate, high, or highest risk for thromboembolic complications (Table 9.3). Of 7.7 million patients older than age 18 and hospitalized for longer than 2 days in the United States, only 40% were at low risk for VTE, whereas 41% were at high or very high risk.27

Approximately half of postoperative DVTs develop in the operating room, most of the remainder occurring during the ﬁrst 3–5 postoperative days.28 However, the risk of developing a DVT does not uniformly end at the time of hospital discharge. Among gynecology patients, 51% of thromboembolic events occurred after initial discharge.29 Similarly, up to 25% of patients undergoing abdominal surgery have been noted to develop DVT within 6 weeks of discharge.30

Trauma The trauma patient perhaps best represents the convergence of all components of Virchow’s triad. Direct venous injury; multiple coagulation and ﬁbrinolytic derangements; and immobilization by skeletal injuries, paralysis and critical illness may all contribute to the high incidence of DVT in the injured patient. The prevalence of DVT among autopsied trauma casualties has been reported to be 62–65%,31,32 similar to the 58% incidence among injured patients in modern venographic series.33 The incidence in series employing only Duplex ultrasonography has generally been substantially lower. Factors identiﬁed as important determinants of DVT in this population have included advanced age; blood transfusion; surgery; fractures of the pelvis, femur or tibia; spinal cord injury; Injury Severity Score (ISS); Trauma Injury Severity Score (TRISS); major venous injury; and femoral venous catheters.34

Medical illness Approximately 60% of VTE events are related to conﬁnement in a hospital or nursing home and coded discharge data suggest that approximately 1% of hospitalized patients are diagnosed with DVT.18 Medical (22%) and surgical (24%) illness account for approximately equal proportions of these events.7 As in surgical patients, assess-

Table 9.3 Risk of postoperative deep vein thrombosis (DVT) Category

Calf vein DVT (%)

Proximal DVT (%)

Characteristics

Low Moderate

2 10–20

0.4 2–4

High

20–40

4–8

Highest

40–80

10–20

Minor surgery in patients < 40 without other risk factors Minor surgery in patients with additional risk factors Surgery in patients 40–60 with no additional risk factors Surgery in patients > 60 Surgery in patients 40–60 with additional risk factors Surgery in patients with multiple risk factors Hip or knee arthroplasty/hip fracture Major trauma, spinal cord injury

Adapted from Geerts WH, et al.38

98

The epidemiology of and risk factors for acute deep venous thrombosis

ment of associated risk factors is important in deﬁning the thromboembolic risk in medical populations. Among medical patients with DVT, 85% have at least one risk factor and over 50% have at least two risk factors.36 Data from clinical trials suggest that age greater than 75 years, cancer, previous VTE, and acute infectious disease are independent predictors of VTE.37 The American College of Chest Physicians currently considers high-risk medical patients to be those hospitalized with congestive heart failure, severe respiratory illness, or having risk factors including previous VTE, cancer, acute neurological disease, sepsis, and inﬂammatory bowel disease.38

Malignancy Deep venous thrombosis may complicate 19–30% of malignancies, may be present at the time of diagnosis in 3–23% of patients with idiopathic thrombosis, and may develop 1–2 years after presentation in another 5–11% of patients. The incidence of occult malignancy diagnosed within 6–12 months of an idiopathic DVT is 2.2–5.3 times higher than that expected in the general population.39,40 Preclinical malignancy may be even more common among those presenting with upper extremity thrombosis. Thrombosis may accompany a wide variety of cancers, the highest risk being associated with hematological malignancies followed by lung and gastrointestinal cancers.41,42 The frequency of any individual malignancy likely depends on referral patterns, treatment, and intensity of screening. Active cancer is associated with a 4.1–6.9-fold increased risk of VTE, rising to 6.5–9.9-fold with chemotherapy, and accounts for approximately 20% of thromboembolic events.7,41,43 Thromboembolic risk is highest early after the diagnosis of malignancy. A 54-fold increased risk of VTE within the ﬁrst 3 months after diagnosis decreases to a 13.4-fold increase over the ﬁrst year.42 The risk of cancerassociated VTE is further increased by distant metastases as well as the presence of the factor V Leiden or prothrombin 20210A mutations. Abnormalities of the coagulation system are present in up to 90% of patients with cancer. Tissue factor and cancer procoagulant, a cysteine protease activator of factor X, are the primary tumor cell procoagulants.44,45 Associated macrophages may also produce procoagulants and inﬂammatory cytokines. In addition to the risks of surgery and central venous catheters, the treatment of some malignancies may also be associated with thrombosis through mechanisms including direct endothelial toxicity, induction of a hypercoagulable state, reduction in ﬁbrinolytic activity, and tumor cell lysis.46,47

Immobilization A relationship between bed rest and DVT has long been recognized. Prior to the use of DVT prophylaxis, the

autopsy incidence of lower extremity thrombosis was noted to rapidly rise from 15% to 77% and 94% after 1, 2, and 4 weeks of conﬁnement respectively.16 The importance of immobilization is further emphasized by observations that thrombosis following bed rest is frequently bilateral whereas that associated with stroke is often conﬁned to the paralyzed limb. Pulmonary embolism is estimated to have an incidence of 0.39 per 1 million passengers arriving after long-haul air ﬂights,48 and is the second leading cause of travel-related mortality.49 Although termed the “economy class syndrome,” at least some data suggest that travel-related thrombosis can occur with modes other than air travel.41 Putative mechanisms of travel-related thrombosis include hypobaric hypoxia-induced activation of coagulation, stasis, and dehydration.50 Four case–control studies have demonstrated a recent travel history in 13.3% of VTE patients compared with 6.9% of controls.48 Prospective trials have further demonstrated ultrasound-documented DVT to have an overall incidence of 3.9% after longdistance air travel. Such thrombi are usually asymptomatic, conﬁned to the calf veins, and largely prevented by the use of knee-high elastic compression stockings.51 Older age, obesity, a previous history of VTE, the use of oral contraceptives, and underlying thrombophilia signiﬁcantly increase the risk of travel-related thrombosis.41,48

History of venous thromboembolism As many as 15–26% of DVT patients will have a history of a previous thromboembolic event. The incidence of recurrent DVT is higher among those having irreversible thrombotic risk factors and those with idiopathic DVT. Some52 have also noted a signiﬁcantly higher incidence in patients less than 65 years of age. Although other factors may also play a role, many recurrences do appear associated with primary hypercoagulability. The cumulative incidence of recurrent thrombosis among patients heterozygous for the factor V Leiden mutation is 40% at 8 years of follow-up, 2.4-fold higher than in those without the mutation.53 Others54 have estimated that 17% of recurrent thromboembolic events may be due to hyperhomocysteinemia. A relationship between impaired ﬁbrinolysis and recurrent DVT has been suggested, although the methodological validity of these ﬁndings has been questioned.55

PRIMARY HYPERCOAGULABLE STATES The primary hypercoagulable states constitute those thrombophilic conditions that have a genetic basis. Primary thrombophilia accounts for approximately 25% of conﬁrmed thromboses occurring outside the setting of surgery or malignancy.43 Although occasionally associated with thrombosis in unusual sites, hypercoagulable states

Oral contraceptives and hormonal therapy

appear to be less important as a risk factor for upper extremity thrombosis.56 Those thrombophilias leading to a loss of function (antithrombin, proteins C and S) tend to be more severe than those causing a gain of function (factor V Leiden, prothrombin 20210A). In general, the more common thrombophilias are associated with less risk, although because of their frequency, are responsible for more thrombotic events. (Table 9.2) The phenotypic expression of these abnormalities varies both within and between families, but the risk is higher and the age at ﬁrst thrombosis earlier among those with a family history of thrombosis. Thrombophilic families appear to have a signiﬁcant incidence of combined, multigenic defects. Guidelines for thrombophilia screening are shown in Box 9.1. The evaluation of hypercoagulable states is further discussed in Chapter 11. Classical deﬁciencies of the naturally occurring anticoagulants – antithrombin, protein C, and protein S – are present in approximately 0.5% of healthy subjects57 and 5–10% of patients with DVT. A variety of nonsense (type I deﬁciencies characterized by absence of a protective protein) and missense (type II deﬁciencies characterized by the presence of an abnormal protein) mutations have been described in association with these congenital deﬁciencies. Heterozygous deﬁciencies are associated with an approximately 10-fold increased risk of thrombosis.41 Resistance to activated protein C, characterized by the failure of exogenous activated protein C to prolong the activated partial thromboplastin time, was initially described in 1993. A single point mutation in the factor V

BOX 9.1 Guidelines for thrombophilia screening A ﬁrst episode of idiopathic VTE VTE occurring at < 50 years of age, even in the presence of transient risk factors VTE occurring during pregnancy or oral contraceptive/ hormone replacement therapy Children with VTE Recurrent VTE Recurrent superﬁcial thrombophlebitis in the absence of cancer or varicose veins VTE at unusual sites (cerebral sinus, mesenteric/hepatic veins) Warfarin-induced skin necrosis and infants with purpura fulminans in the absence of sepsis Females of child-bearing age with documented symptomatic thrombophilia in a ﬁrst-degree relative Two consecutive/three non-consecutive abortions at any gestational age; one fetal death after the 20th week Severe pre-eclampsia VTE, venous thromboembolism. Adapted from Nicolaides et al.43

99

gene, resulting in replacement of arginine 506 with glutamine (factor V Leiden; FV:R506Q), is present in 94% of individuals with activated protein C resistance58–60 and renders factor V less sensitive to degradation by activated protein C. The factor V Leiden mutation is inherited in an autosomal dominant pattern and is the most common heritable thrombophilic disorder. The mutation shows signiﬁcant geographic variability, but, depending on ethnicity, may be present in 0–15% of the normal population and up to 20% of patients with DVT. Limited data suggest that the mutation is also present in up to 37% of patients with post-thrombotic syndrome.43 Allele frequency is highest in Scandinavian, Northern European, and Eastern Mediterranean populations, less in Asians and South Americans, and almost non-existent in Oriental populations.43 A mutation in the 3′ region of the prothrombin gene, prothrombin 20210A, is associated with increased plasma levels of prothrombin and is present in approximately 6% of those with venous thrombosis. Although there is signiﬁcant regional variation, the mutation is present in 2–3% of Caucasians. Increased levels of plasma coagulation proteins, including factors II, VIII, IX, and XI, have also been associated with a two- to threefold increased risk of VTE.41,43 Increased plasma concentrations of factor VIII may be present in as many as 25% of those with VTE and likely at least partially account for the association between VTE and non-type O blood group. There is also evidence that hyperhomocysteinemia may be associated with an increased risk of VTE.54,61 Finally, several disorders of plasmin generation including dysplasminogenemia, hypoplasmingenemia, decreased synthesis or release of tPA, and increased PAI-1 have been associated with recurrent familial thromboembolism.62,63

ORAL CONTRACEPTIVES AND HORMONAL THERAPY Pharmacologic doses of estrogen are associated with alterations in the coagulation system including decreases in PAI-164 and increases in blood viscosity, ﬁbrinogen, plasma levels of factors VII and X, and platelet adhesion and aggregation.65–67 Approximately one-quarter of thromboembolic events among women of childbearing age have been attributed to oral contraceptives.68 Thrombotic risk is correlated with estrogen dose, preparations containing more than 50 micrograms of estrogen being associated with the highest risk. Although cautious interpretation has been advised and there is some potential for bias,69 the progestin components in thirdgeneration contraceptive formulations have also been associated with a twofold increased thrombotic risk compared with other formulations.41 The risk of hospital admission for a thromboembolic event, including cerebral thrombosis, has been estimated to be 0.4–0.6 per 1000 for oral contraceptive users

100

The epidemiology of and risk factors for acute deep venous thrombosis

compared with 0.05–0.06 for non-users.67,70,71 The overall summary relative risk from eight case–control, six followup, and one randomized study in the literature is 2.9, corresponding to a calculated absolute risk of approximately 3.3 per 10 000 users.72 However, some populations, particularly those with congenital thrombophilias, are at substantially higher risk and resistance to activated protein C is present in 30% of patients with contraceptive-associated VTE.73 Factor V heterozygotes using combined oral contraceptives are at 25- to 35-fold increased risk of VTE, whereas those heterozygous for the prothrombin 20210A mutation and with elevated factor VIII levels are at 16-fold and 10-fold increased risk respectively.43 Pharmacologic doses of estrogen, such as those used for suppression of lactation have similarly been associated with an increased risk of thromboembolism. Although estrogen doses used for postmenopausal replacement therapy are approximately one-sixth those in oral contraceptives, there is a two- to fourfold increased risk of thromboembolism. However, the risk of replacement therapy must be kept in perspective, as it contributes only approximately two new cases of VTE per 10 000 women per year.74 As in the case of oral contraceptives, the presence of congenital thrombophilic defects, particularly the factor V Leiden mutation, protein S deﬁciency, and high factor XI levels increase the thrombotic risk associated with estrogen replacement. The estrogen receptor antagonist tamoxifen, used in the treatment of estrogen receptor-positive breast cancer, also signiﬁcantly increases thrombotic risk.43

PREGNANCY Venous thromboembolism is second only to abortion as a cause of pregnancy-associated death. The increased thrombotic risk during pregnancy has been attributed to an acquired prethrombotic state in combination with impaired venous outﬂow due to uterine compression. Pregnancy is associated with a variety of changes in the coagulation system, including increases in ﬁbrinogen and factors II, VII, VIII, and X; decreases in protein S levels; and diminished ﬁbrinolytic activity. Population-based studies performed since the introduction of venous ultrasound suggest an incidence of 75 per 100 000 deliveries.75 Data regarding the timing of DVT during pregnancy are conﬂicting. Although some data suggest that risk is equally distributed over all trimesters, more recent data76 suggest a lower incidence of DVT during the ﬁrst trimester. In contrast, the risk of post-partum DVT is two- to fourfold higher than that during pregnancy. The overall incidence is 351.4 per 100 000 women–years for DVT occurring within 3 months of delivery compared with 85.2 per 100 000 women–years during pregnancy.76 Recurrent thromboembolism many complicate 4–15% of subsequent pregnancies.77

Other concurrent risk factors, notably documented hypercoagulable states, suppression of lactation, increased maternal age, and assisted delivery, are associated with an increased thrombotic risk. Among women with thrombophilia, those with antithrombin deﬁciency are at very high risk for pregnancy-associated thrombosis; those with proteins C or S deﬁciency or homozygous or combined factor V and prothrombin mutations are at high risk; and those with heterozygous factor V or prothrombin mutations are at moderate risk.43 The factor V Leiden mutation has been associated with up to 59% of cases of pregnancy-associated thromboembolism.73,78

ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies may be present in 4–20% of patients with VTE. Lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) may be seen in association with systemic lupus erythematosis; other autoimmune disorders; non-autoimmune disorders such as syphilis and acute infection; drugs including chlorpromazine, procainamide, and hydralazine; and in elderly people.79 They are present in 34% and 44% of patients with systemic lupus erythematosis compared with 2% and 0–7.5% of the general population.79 Among patients with systemic lupus erythematosis, those with LA are at a sixfold increased risk for VTE while those with ACA are at a twofold greater risk.80 Lupus anticoagulant activity is also associated with a 3.6-fold increased risk of thrombosis in otherwise healthy patients, a risk further increased by the presence of anti-β2-glycoprotein I or antiprothrombin antibodies.81 Although the data are conﬂicting, there are at least suggestions that VTE and ACA may be unassociated in patients without autoimmune disorders.82 The antiphospholipid antibody syndrome is characterized by at least one episode of arterial or venous thrombosis and/or a history of at least three spontaneous abortions prior to the 10th week, one fetal death after 10 weeks, or one premature delivery before 24 weeks. Laboratory conﬁrmation requires the presence of LA or moderate to high titers of immunoglobulin (Ig) G or IgM ACA on at least two occasions at least 6 weeks apart.43 Approximately 80% of those with antiphospholipid antibody syndrome are women.81

OTHER RISK FACTORS Although lacking the strong epidemiologic support discussed above, a number of other circumstances have been consistently associated with an increased incidence of DVT. These include central venous instrumentation and inﬂammatory bowel disease. Other risk factors such as obesity, varicose veins, myocardial infarction, and

Conclusions 101

congestive heart failure have been inconsistently identiﬁed as independent risk factors for acute DVT. Obesity has been associated with an increased thrombotic risk by some,28,74,83 but not others.84 It has been associated with an increased incidence of DVT in trauma patients,85 but not in medically ill patients.37 Varicose veins have also been included as a risk factor for acute DVT, presumably as a marker of either previous DVT or venous stasis. The evidence supporting such an association has been equivocal and has often been complicated by the presence of other risk factors. The few studies evaluating outpatients have suggested that varicose veins are either not a risk factor for DVT10 or are an independent risk factor only among women and those greater than age 65.9 The importance of varicose veins in the general population is questionable, although their role in some high-risk groups cannot be entirely excluded. Systemic hypercoagulability, congestive heart failure, and enforced bed rest could theoretically predispose patients hospitalized for acute myocardial infarction to DVT. The incidence of DVT in this population has been reported to be 20–40% with an overall average of 24%.86–88 Although Kotilainen et al.86 found the incidence of DVT to be similar among those in whom myocardial infarction was conﬁrmed (21%) and excluded (25%), a substantially higher incidence was noted among those over age 60 with congestive heart failure (54%). This ﬁnding has been conﬁrmed by some89 but not others90. Heit et al.35 found that congestive heart failure was not a risk factor for VTE manifest either before death or as a cause of death, although it was a risk factor for post-mortem VTE as an incidental ﬁnding. The balance of evidence suggests that severely ill medical patients are at signiﬁcant risk for

VTE,91 although it is difﬁcult to precisely deﬁne the additional risk associated with cardiac disease in these patients.

CONCLUSIONS The appropriate management of VTE requires a thorough knowledge of diagnostic and treatment modalities. However, an understanding of the underlying epidemiology and associated risk factors is equally essential. Risk stratiﬁcation is obviously important in determining which patients require prophylaxis in highrisk situations. Schemes for risk stratiﬁcation in these situations,92 such as patients undergoing surgery or hospitalized for medical illness, as well as appropriate evidence-based prophylactic measures, have been well described.38 However, an understanding of the risk factors leading to VTE is also important in counseling patients regarding their risk associated with contraception, pregnancy, and hormone replacement; understanding who requires further consideration of an underlying malignancy or hypercoagulable state; determining the risk of recurrent VTE; and deﬁning the duration of therapy after an episode of VTE. These considerations require knowledge of thrombotic risk factors, their relative importance in thrombogenesis, and their synergistic interaction. The last one is particularly important as VTE almost always develops in the setting of multiple genetic and environmental risk factors. The synergistic effects of gene–gene and gene–environment interactions are the basis for venous thrombosis and the relative risks of these interactions are becoming better understood.

Guidelines 1.8.0 of the American Venous Forum on the epidemiology of and risk factors for acute deep venous thrombosis No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.8.1 In the USA each year 275 000 new cases of venous thromboembolism are observed. The incidence of a ﬁrst episode of venous thromboembolism is 50.4 per 100 000 person years

A

1.8.2 The most important risk factors for acute venous thromboembolism include age, major surgery, trauma, hypercoagulable states, malignancy, hospital/nursing home care, history or family history of venous thromboembolism, immobilization, central venous catheters, pregnancy, estrogen replacement, oral contraceptives, hormonal treatment and long distance travels

A

1.8.3 Heterozygous factor V Leiden mutation increases the risk of venous thromboembolism three- to eightfold, while the risk with homozygous mutation is increased by 50- to 80-fold

A

1.8.4 The highest risk for postoperative venous thromboembolism include patients with multiple risk factors, those after hip or knee arthroplasty or operations for hip fracture and patients with major trauma or spinal cord injury

A

102

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10 Epidemiology of chronic venous disorders EBERHARD RABE AND FELIZITAS PANNIER Introduction Early epidemiologic studies Epidemiologic studies based on the CEAP classiﬁcation Risk factors for varicose veins and chronic venous insufﬁciency

105 105 105 108

INTRODUCTION In the last decades, epidemiologic studies of chronic venous disorders (CVDs) were performed in many countries worldwide. Most of these were focused on varicose veins.1–8 By reviewing these data some principal problems were noted. Different deﬁnitions for CVDs or for chronic venous insufﬁciency (CVI) and different age groups were used in the various studies. In only a very few instances was the investigated population based on a random sample of the general population.9 In many studies, only information gathered from questionnaires was used. Clinical and duplex evaluation were incorporated into the studies only rarely and a few recent studies incorporated the CEAP classiﬁcation into the study design.9–14

EARLY EPIDEMIOLOGIC STUDIES In early studies, the reported prevalence for varicose veins differs from 1% to 73% in females and from 2% to 56% in males, and for CVI from 1% to 40% in females and from 1% to 17% in males.1 The results varied by geographic region and also by the methods used for evaluation. In Western countries, varicose veins are reported to be present in 25–33% of female adults and 10–20% of male adults.1,2,5,8 The incidence of varicose veins per year in the Framingham study was 2.6% in women and 1.9% in men.15 The prevalence of skin changes varied between 3% and 13%, and of active and healed ulcers between 1% and 2.7% in the investigated populations. Established risk factors for varicose veins were older age, a positive family history, female gender, multiple pregnancies, a standing occupation, and obesity in females.1,2,5,15

Summary Clinical recommendations References

109 109 109

EPIDEMIOLOGIC STUDIES BASED ON THE CEAP CLASSIFICATION In recent years, ﬁve studies have been published that are based on the CEAP classiﬁcation (Table 10.1).9–14 In the revised CEAP classiﬁcation precise venous deﬁnitions have been given. Telangiectasia, conﬂuence of dilated intradermal venules less than 1 mm in caliber. Reticular vein, dilated bluish subdermal vein, usually 1 mm to less than 3 mm in diameter. Varicose vein, subcutaneous dilated vein 3 mm in diameter or larger, measured in upright position. Edema, perceptible increase in volume of ﬂuid in skin and subcutaneous tissue, characteristically indented with pressure. The term “chronic venous insufﬁciency” implies a functional abnormality of the venous system, and is usually reserved for more advanced disease, including edema (C3), skin changes (C4), or venous ulcers (C5–6).16 Unfortunately, the CEAP-based studies still differ concerning the mode of recruitment of the study population, the deﬁnition of CVI, age, and mode of investigation.

The San Diego Population Study13 Between 1994 and 1996, 2211 men and women between 40 and 79 years of age in San Diego, CA, were evaluated for major manifestations of CVD: telangiectases, varicose veins, trophic changes, and edema by visual inspection and Duplex ultrasound using a modiﬁed CEAP classiﬁcation using the most severe clinical ﬁndings and excluding C3. Nineteen percent were classiﬁed C0, 51.6% C1, 23.3% C2, and 6.2% C4–6. Out of the whole population, 5.8% presented with edema, 7.4% among men and 4.9% among women. Venous disease increased with age and non-

Table 10.1 Prevalence of C0–C6 (CEAP) in recent studies from Western countries Reference Country M/F Age Year proportion (years) (%) Criqui (2003)13* Jawien (2003)14* Rabe (2003)9* Carpentier (2004)10‡ Chiesa (2005)12‡

Sample size

CO C1 All M F All (%) (%) (%) (%)

M F (%) (%)

C2 C3 All M F All (%) (%) (%) (%)

M F (%) (%)

43.6 55.9

23.3

15.0 27.7 5.8

7.4

21.8

4.5

USA

35.3/64.7

40–79

2211

19.0 33.6 11.0 51.6

Poland

16.0/84.0

16–97

40095

51.5

Germany 43.9/56.1

18–79

3072

9.6

France

67.7/32.3

Over 18

409

48.7 (including C0 + C1)

Italy

14.1/85.9

18–90

5187

22.7 36.0 20.6 64.8

16.5 13.6 6.4

59.1

58.4 59.5

33.4 69.9

14.3

4.9†

12.4 15.8 13.4

11.6 14.9

23.7 46.3

1.1

29.4 29.3 29.4¶ 13.6 13.6 11.4 13.9§

C4 All M (%) (%)

6.2 7.8 5.3 (Including C4-C6) 4.6

1.0

2.9

0.6

2.2

11.4 13.9

C5 F All M (%) (%) (%)

3.1

2.7

4.0

2.1

C6 F All M (%) (%) (%)

0.5 0.6

0.6

1.4

0.7

3.4 5.2 3.1 8.6 11.6 8.1 (Including C4a only) (Including C4b-C6)

*Highest assigned clinical category; †edema in the whole population; ‡all clinical categories listed; ¶non-saphenous varicose veins; §saphenous varicose veins m, male; f, female.

F (%)

0.1

0.1

0.1

0.0

0.0

Epidemiologic studies based on the CEAP classiﬁcation 107

Hispanic white people had more occurrences of disease than the other ethnic groups. C1 and C2 were more common in women than in men, but C4–C6 were more common in men.

24-Cities Cohort Study, Italy11,12 In this cross-sectional population study, 5247 participants in 24 cities in the north, center, and south of Italy were recruited during the spring and summer of 2003 by advertising on television, in newspapers, and by leaﬂets. The majority of the participants were women (85.9%). All answered a standardized questionnaire and were investigated clinically and by Duplex sonography. All clinical ﬁndings were classiﬁed: 22.7% of the population was in class C0, 64.8% C1, 43.0% C2, 13.6% C3, 3.4% C4a, and 8.6% C4b–C6. Chronic venous insufﬁciency was deﬁned as C1–C6. Risk factors for varicose veins were older age, living in southern Italy, number of pregnancies, and positive family history.

Bonn Vein Study, Germany9 Between November 2000 and March 2002 the German Society of Phlebology performed the Bonn Vein Study in the city of Bonn and two rural townships. The participants were chosen from a simple random sample of the population registers. A total of 3072 (1722 women, 1350 men) participants between 18 and 79 years of age were investigated. All participants answered a standardized questionnaire and were investigated clinically and by Duplex sonography by four physicians trained in phlebology. The complete CEAP classiﬁcation was used for classiﬁcation. In the clinical stages, the participants were classiﬁed according to the most severe clinical ﬁndings. Leg complaints consistent with symptoms of venous diseases, such as heaviness and a feeling of swelling, etc., were present in 49.1% of the male and 62.1% of the female population. The prevalence increased with age. In the previous 4 weeks, 14.8% of the population experienced leg swelling: 7.9% of the men and 20.2% of the women. Concerning the CEAP classiﬁcation only 9.6% of the population (13.6% men, 6.4% women) lacked signs of venous disorders (C0), 59.1% (58.4 men, 59.5% women) demonstrated only teleangiectases or reticular veins (C1) (Table 10.1). Varicose veins were present without edema or skin changes (C2) in 14.3% (12.4% men, 15.8% women) of the population. At the time of investigation 13.4% (11.6% men, 14.9% women) had pretibial pitting edema (C3). Only 2.9% (3.1% men, 2.7% women) showed a C4 classiﬁcation with skin changes such as eczema, pigmentation or lipodermatosclerosis. Only 0.6% had healed venous ulceration (C5), and 0.1% were afﬂicted with active venous ulcers (C6). Only participants with

stages C2 and C3 had a prevalence that was signiﬁcantly higher in the female population. The urban population showed a higher frequency of chronic venous insufﬁciency (C3–C6). The prevalence of stages C2–C6 increased with age. In a multivariate analysis adjusted for age and region of living, risk factors for varicose veins were older age, female gender, and number of pregnancies. Risk factors for CVI were older age, obesity, and urban inhabitance.

The Polish study14 A total of 40 095 Polish adults between 16 and 97 years of age (mean age 44.8 years) were interviewed and clinically investigated by 803 participating primary care physicians (general practitioners, internists, gynecologists) in this cross-sectional multicenter study. Fifty consecutive patients were chosen from their outpatient clinics. The majority were women (84%). The clinical classiﬁcation of CEAP (highest clinical level) was used to classify the patients. CVI was diagnosed when any of the stages C1–C6 was present. Leg complaints were reported in up to 81% in the varicose vein group and up to 35% in the varicose-free participants. Ten percent of the population presented with edema, 34.3% had varicose veins and 1.5% had active or healed venous ulcers. C0 was found in 51.1% of the population, C1 in 16.5%, C2 in 21.8%, C3 in 4.5%, C4 in 4.6%, C5 in 1.0%, and C6 in 0.5%. Risk factors for varicose veins were older age, number of pregnancies, positive family history, and obesity. Female gender was not shown to be a risk factor for varicose veins.

The French study10 In this cross-sectional study, a sub-population of a survey concerning Raynaud’s phenomenon was used. A total of 409 participants, 277 males and 132 females, were investigated using a standardized questionnaire and clinically by trained vascular medicine professionals; 48.7% were classiﬁed as C0 or C1. C2 was present in 23.7% of the males and 46.3% of the females. C3 was found in 1.1% and 2.2% respectively. Four percent of the men and 2.1% of the women had skin changes (C4). Healed ulcers were found in 1.4% of the males and in 0.7% of the females. No active ulcers occurred in this study. Positive family history, advanced age, pregnancies and height in women, and exercise less than once a week in men were the main risk factors for varicose veins.

Prevalence of varicose veins and chronic venous insufficiency The results from many studies1,2,5have shown that there is a high prevalence of CVD in the general population. The

108

Epidemiology of chronic venous disorders

comparability of results from recent studies, in which the participants had been properly investigated by clinical investigation and by Duplex ultrasound, with older studies, in which only questionnaires and photographs have been used, is questionable. Because the prevalence of CVD is increasing with age and is higher for the female gender in most of the studies, all the data have to be adjusted at least for age and gender. Even in the recent CEAP-based studies, there are still differences concerning recruitment of the study population, age and sex distribution, and the deﬁnition of CVI (Table 10.1). Only in three studies were the participants investigated by Duplex ultrasonography.9,12,13 The method by which pitting edema was veriﬁed was only mentioned in the Bonn Vein Study. This may somewhat explain the differences in the reported prevalence of C3, which varied between 1.1% and 14.9% (Table 10.1). In the CEAP-based epidemiological studies, the reported prevalence is similar for most of the items (Table 10.1). C0 and C1 together are prevalent in more than 60% of the population (48.7–70.6%). Varicose veins are present in more than 20% (21.8–29.4%) with a higher prevalence in women. Skin changes due to venous diseases, including venous ulcers, are present in less than 10% of those investigated (3.6–8.6%). The prevalence ranges from 0.6% to 1.4% for healed ulcers and from 0 to 0.5% for active ulcers.9,10,12,13,14

RISK FACTORS FOR VARICOSE VEINS AND CHRONIC VENOUS INSUFFICIENCY The main risk factors for varicose veins are advanced age, female gender, pregnancies, and positive family history (Table 10.2).

Age Older age was the most important risk factor for varicose veins and CVI in all studies.1,5,8–11,13–15 The mean 2 year

Table 10.2 Association of risk factors with varicose veins (VV) and chronic venous insufﬁciency (CVI)

Older age Family history Female gender Pregnancies Obesity Oral contraceptives or hormone replacement therapy +, established; ±, uncertain; –, no association.

VV

CVI

+ + + + ± –

+ + ± ± + –

incidence rate for varicose veins in the Framingham study was 5.2% for women and 3.9% for men, resulting in a steady increase in prevalence for varicose veins with increasing age.15 In the San Diego study, older age as a risk factor showed a signiﬁcant odds ratio up to 2.42 for varicose veins and up to 4.85 for CVI.13 In the Bonn Vein Study, older age was the most important risk factor for varicose veins and CVI (OR age 70–79 years: varicose veins 15.9, CVI 23.3).9

Positive family history A positive family history for varicose veins or venous diseases is associated with a higher risk for varicose veins in several studies.1,8–10,14 In the Bonn Vein Study, the OR for varicose veins was 2.1 in men and 2.3 in women, and for CVI 1.4 (CI 1.01–2.02) in men and 1.3 (CI 0.92–1.74) in women. This effect diminishes with age.17 Although heredity seems to be a risk factor for varicose veins, no responsible genetic defects have been identiﬁed to date.

Gender, pregnancies, and hormones The prevalence of varicose veins is higher in women than in men.1 In the San Diego Study, the OR for female gender as risk factor for varicose veins was 2.18, and in the Bonn Vein Study, 1.5.9,13 Similar results could be shown in many studies.2,5,8 In contrast, there is no obvious gender difference for the prevalence of CVI. Chiesa et al.12 found a higher prevalence of edema (13.9% vs 11.4%) but a lower prevalence of C4a (3.1% vs 5.2%) and C4b–C6 (8.1% vs 11.6%) in women than in men. Similar results were found in the Bonn Vein Study.9 In the San Diego Study, the OR for female gender and trophic changes was 0.65.13 The main cause for the gender differences in varicose veins could be the number of pregnancies. Chiesa et al.12 found a higher OR for women with previous pregnancies (OR 1.11) than that noted in the never pregnant women (OR 0.75) for non-saphenous varicose veins. Jukkola et al.18 conﬁrmed parity as an independent risk factor for varicose veins (OR 2.0). In the Bonn Vein Study, the OR increased with the number of pregnancies from 1.3 to 2.2. Neverpregnant women and men had similar prevalences for varicose veins.19 Hormone replacement therapy or oral contraceptives seem not to be a risk for varicose veins or CVI. In the Bonn Vein Study, we did not see a consistent effect of intake of hormones on varicose veins (OR 0.9), but a negative association with CVI (OR 0.6).19 In a 5 year follow-up study, Jukkola et al.18 also demonstrated that hormone replacement therapy and oral contraceptives did not increase the risk of varicose veins. Bérard20 found a protective effect of hormone replacement therapy for the development of venous ulcers.

References 109

Obesity The role of obesity in varicose veins is controversial. In the Framingham study, obesity with a BMI greater than 27 increased the risk of varicose veins in women but not in men.15 In the Bonn Vein Study, a BMI greater than 30 increased the risk of varicose veins for women (OR 1.9) but not signiﬁcantly so. In contrast, the risk for CVI was increased signiﬁcantly for men and women (OR 6.5 and 3.1).9 Iannuzzi and colleagues21 demonstrated a positive association of BMI greater than 30 with varicose veins in postmenopausal women (OR 5.8). Carpentier et al.10 did not ﬁnd an elevated risk for varicose veins with obesity but did so with height in women. In the Polish study, obesity was a risk factor for venous disease compared with venoushealthy participants.14

Other risk factors For other risk factors, such as smoking, hypertension, physical activity or constipation, the data are inconsistent. If positive, the risk seems to be low.1,2,4,5,22,23

can be found in more than 20% of the general population. Established risk factors for varicose veins are older age, family history, female gender, and pregnancies. In CVI obesity plays an important additional role.

CLINICAL RECOMMENDATIONS 1 The prevalence of C0/C1 together is over 60% (48.7–70.6%), with varicose veins (C2) present in more than 20% (21.8–29.4%). Skin changes resulting from venous disease, including venous ulcers, are present in less than 10% of the population (3.6–8.6%) with a prevalence of between 0.6% and 1.4% for healed ulcers and between 0 and 0.5% for active ulcers.9,10,12–14 2 Relevant risk factors for varicose veins are ● advanced age9,13,15 ● positive family history9,10,14 ● female gender9,13 ● multiparity12,18 ● obesity.15 3 Relevant risk factors for CVI are ● advanced age9,13 ● positive family history9 ● obesity.9,14

SUMMARY Chronic venous disorders are among the most prevalent conditions in the Western population. As a result, venous symptoms such as heaviness of the legs, feeling of swelling and pain during standing are frequent complaints in the general population. The frequency of more severe chronic venous signs such as eczema, pigmentation, and lipodermatosclerosis or venous ulceration reaches a prevalence of about 5% in men and women. Varicose veins

REFERENCES 1. Beebe-Dimmer JL, Pfeifer J, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufﬁciency and varicose veins. Ann Epidemiol 2005; 15: 175–84. 2. Evans CJ, Fowkes FGR, Hajivassiliou CA, Harper DR, Ruckley C. Epidemiology of varicose veins – a review. Int Angiol 1994; 13: 263–70.

Guidelines 1.9.0 of the American Venous Forum on epidemiology of chronic venous disorders No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.9.1 The prevalence of varicose veins in the adult Western population is more than 20% (21.8–29.4%)

A

1.9.2 About 5% (3.6–8.6%) of the adult Western population has skin changes or ulcers due to chronic venous insufﬁciency

B

1.9.3 Active venous ulcers are present in 0–0.5% of the adult Western population; 0.6–1.4% have healed ulcer

B

1.9.4 Advanced age is a risk factor for varicose veins and chronic venous insufﬁciency

A

1.9.5 Positive family history, female gender and multiparity are risk factors for varicose veins

B

1.9.6 Positive family history and obesity are risk factors for chronic venous insufﬁciency

B

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Epidemiology of chronic venous disorders

3. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ: Prevalence of varicose veins and chronic venous insufﬁciency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 1999; 53: 149–53. 4. Fischer H. (ed.) Venenleiden – Eine repräsentative Untersuchung in der Bundesrepublik Deutschland (Tübinger Studie). Munich: Urban und Schwarzenberg, 1981. 5. Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufﬁciency. Angiology 2001; 52 (1): S5–S15. 6. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc Surg 2001; 33: 1022–7. 7. Ruckley CV, Evans CJ, Allan PL, et al. Chronic venous insufﬁciency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg 2002; 36: 520–5. 8. Widmer LK, Stählin HB, Nissen C, Da Silva A. (eds). Venen-, Arterien-Krankheiten, koronare Herzkrankheit bei Berufstätigen, Prospektiv-epidemiologische Untersuchung Baseler Studie I–III 1958–1978. Bern: Hans Huber, 2002. 9. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen Gesellschaft für Phlebologie – epidemiologische Untersuchung zur Frage der Häuﬁgkeit und Ausprägung von chronischen Venenkrankheiten in der städtischen und ländlichen Wohnbevölkerung. Phlebologie 2003; 32: 1–14. 10. Carpentier PH, Maricq HR, Biro C, et al. Prevalence, risk factors and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. J Vasc Surg 2004; 40: 650–59. 11. Chiesa R, Marone EM, Limoni C, et al. Demographic factors and their relationship with the presence of CVI sigs in Italy. The 24-Cities Cohort Study. Eur J Vasc Endovasc Surg 2005; 30: 674–80. 12. Chiesa R, Marone EM, Limoni C, et al. Chronic venous insufﬁciency in Italy: the 24-Cities-Cohort study. Eur J Vasc Endovasc Surg 2005; 30: 422–9.

13. Criqui MH, Jamosmos JM, Fronek AT, et al. Chronic venous disease in an ethnically diverse population. The San Diego Population Study. Am J Epidemiol 2003; 158: 448–56. 14. Jawien A, Grzela T, Ochwat A. Prevalence of chronic venous insufﬁciency in men and women in Poland: multicenter cross-sectional study in 40095 patients. Phlebology 2003; 18: 110–21. 15. Brand FN, Dannenberg AL, Abbott RD, Kannel WB: The epidemiology of varicose veins: the Framingham Study. Am J Prev Med 1988; 4: 96–101. 16. Eklöf B, Rutherford RB., Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. 17. Hirai M, Naiki K, Nakayama R. Prevalence and risk factors of varicose veins in Japanese women. Angiology 1990; 41: 228–32. 18. Jukkola TM, Mäkivaara LA, Luukkaala T, et al. The effects of parity, oral contraceptiva use and hormone replacement therapy on the incidence of varicose veins. J Obstet Gynaecol 2006; 26: 448–51. 19. Bromen K, Pannier-Fischer F, Stang et al. Lassen sich geschlechtspeziﬁsche Unterschiede bei Venenerkrankungen durch Schwangerschaften und Hormoneinnahme erklären? Gesundheitswesen 2004; 66: 170–4. 20. Bérard A, Kahn SR, Abenheim L. Is hormone replacement therapy protective for venous ulcer of the limbs? Pharmacoepidemiol Drug Saf 2001; 10: 24–51. 21. Iannuzzi A, Panico S, Ciardullo AV, et al. Varicose veins of the lower limbs and venous capacitance in postmeopausal women: Relationship with obesity. J Vasc Surg 2002; 36: 965–8. 22. Fowkes FGR, Lee AJ, Evans CJ, et al. Lifestyle risk factors for lower limb venous reﬂux in the general population: Edinburgh Vein Study. Int J Epidemiol 2001; 30: 846–52. 23. Lee AJ, Evans CJ, Hau CH, Fowkes GR. Fiber intake, constipation and risk of varicose veins in the general population: Edinburgh Vein Study. J Clin Epidemiol 2001; 54: 423–9.

PART

2

DIAGNOSTIC EVALUATIONS AND VENOUS IMAGING STUDIES Edited by Gregory L. Moneta

11 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis Edith A. Nutescu, Jessica B. Michaud, Joseph A. Caprini 12 Duplex ultrasound scanning for acute venous disease Sergio X. Salles-Cunha 13 Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence Babak Abai and Nicos Labropoulos 14 Evaluation of venous function by indirect non-invasive testing (plethysmography) Fedor Lurie and Thomas W. Rooke 15 Lower extremity ascending and descending phlebography Curtis B. Kamida, Robert L. Kistner, Bo Eklöf and Elna M. Masuda 16 Computed tomography and magnetic resonance imaging in venous disease Terri J. Vrtiska and James F. Glockner

113 129 142 156 160 169

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11 Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis EDITH A. NUTESCU, JESSICA B. MICHAUD, JOSEPH A. CAPRINI Introduction D-dimer assay Thrombophilias Heparin-induced thrombocytopenia Cancer

113 113 114 121 122

INTRODUCTION The normal physiologic balance between clot formation and dissolution can be damaged by the presence of certain genetic or acquired defects leading to abnormal thrombosis. Reasons that the hemostasis and thrombosis process may be unbalanced toward coagulation include vessel injury, venous stasis, and hereditary and acquired thrombophilias. These three facets of coagulation are represented by Virchow’s triad. All risk factors for venous thromboembolism (VTE) are mediated by one of these three pathophysiologic processes. Venous thrombosis occurs because of the presence and the interaction of various inherited and environmental risk factors. The risk of VTE increases in proportion with the presence of these predisposing risk factors.1–2 (See Chapter 9 for a more detailed discussion on the epidemiology and risk factors for VTE.) Thrombophilia is more common than usually appreciated, with as high as 50–80% of patients with thrombosis having an underlying hereditary or acquired defect.2 A typical clinical scenario of patients with thrombophilia is spontaneous onset VTE at an early age. Healthcare providers are now confronted with a vast array of new diagnostic tests in the area of inherited and/or acquired thrombophilia. Despite the rapid development of the various laboratory assays for thrombophilia, controversy exists in the clinical setting regarding which patients should be tested, what tests to use, the appropriate timing of the various tests, and the relevance of the detected thrombophilias. This chapter reviews the most commonly encountered thrombophilic conditions and

Patient care considerations Surgical considerations Clinical practice guidelines General recommendations References

122 124 125 125 127

discusses their clinical relevance, diagnostic and patient management considerations.

D-DIMER ASSAY Elevated D-dimer is not necessarily a risk factor causing VTE, but it should be used and interpreted as a marker of hypercoagulability. D-dimer is formed when ﬁbrin is proteolysed by plasmin.3 The presence of elevated levels of D-dimer in the circulation signiﬁes that endogenous ﬁbrinolysis of a venous thrombus has yielded cross-linked ﬁbrin.4 The degree of D-dimer elevation with VTE may depend on the extent of disease, the duration of symptoms, and the use of anticoagulants, with lower D-dimer levels associated with less extensive disease, longer duration of symptoms, and anticoagulant use.3 Elevated D-dimer levels can also result from recent major surgery, hemorrhage, trauma, pregnancy, cancer, or acute arterial thrombosis.5 Different assays vary with respect to sensitivity and speciﬁcity, speed of testing, and the labor involved in performing the assay.3 Moderately and highly sensitive assays range from about 85% to at least 95%, respectively, but speciﬁcity can be as low at 40% depending on the assay used.5 Other issues with the D-dimer assays include differences in the speciﬁcity of the antibody to the various binding sites on the D-dimer molecule, lack of a deﬁnitive cut-off value between abnormal and normal results, lack of a reference standard assay, and lack of a standard unit of measurement.3 One ﬁbrinogen equivalent unit (FEU) is approximately onehalf of a D-dimer unit. Because the D-dimer assay has a

114

Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis

high negative predictive value and is generally sensitive, but not speciﬁc, it is used to help “rule out” VTE.5 The test can be used to rule out VTE without ultrasound when the clinical probability is low based on a prediction rule, and potentially when the probability is moderate.4–5 D-dimer should not be tested for if the clinical suspicion is high for VTE, because imaging is indicated and the D-dimer assay is less speciﬁc and thus has a higher rate of false positives at this level of suspicion. Therefore, the D-dimer test should be used in combination with clinical evaluation or an assessment tool such as the Wells clinical prediction rule.4–5 The role of D-dimer in determining an appropriate duration of anticoagulation for VTE is evolving. Patients with elevated D-dimer 1 month after discontinuing anticoagulation after at least a 3 month course are more likely to have VTE recurrence, and resuming anticoagulation after an abnormal D-dimer test decreases the rate of recurrent VTE in the subsequent 9–18 months.6 In addition to VTE recurrence, elevated D-dimer levels have been associated with decreased survival, the extent of pulmonary embolism (PE), development of postthrombotic syndrome, and the presence of malignancy.7

THROMBOPHILIAS

2 disorders, although likely risk factors for initial thrombosis, may not be strong risk factors for subsequent thrombosis.11 Patients with group 1 disorders usually present at a younger age with idiopathic or recurrent VTE, have a higher likelihood of recurrent VTE, and are more likely to have a family history of VTE.10

ANTITHROMBIN DEFICIENCY

Background Antithrombin (formerly termed “antithrombin III”) is a natural anticoagulant. It binds and inactivates factors IIa (thrombin), Xa, IXa, XIa, and XIIa to reduce clot formation.11 More than 100 mutations may result in antithrombin deﬁciency, which is inherited as an autosomal dominant trait.12 Antithrombin deﬁciency is classiﬁed into two types: type I, which indicates reduced levels of both functional (activity) and antigenic antithrombin, and type II, which indicates reduced functional but preserved antigenic levels.11–13 Prevalence A deﬁciency in antithrombin is present in 0.07–0.2% of the general population and 0.5–8% of patients presenting with venous thromboembolism.11–13 Diagnostic considerations

Hypercoagulable states can be categorized as hereditary, acquired, or mixed.8 Thrombophilic patients most commonly present with characteristic features such as thrombosis at a young age, recurrent thrombosis, resistance to heparin, warfarin-induced skin necrosis, purpura fulminans, family history of thrombosis, and thrombosis that develops at an unusual site. The identiﬁcation of a congenital or acquired thrombophilic defect is most important when the information obtained would affect clinical management of the patient or of a family member.9 Thrombophilia testing leads to a diagnosis in approximately 50% of patients who present with idiopathic VTE.10

Hereditary thrombophilia The hereditary thrombophilias may be classiﬁed into two or more types. Group 1 disorders, deﬁned as deﬁciencies of coagulation factor inhibitors, include antithrombin deﬁciency, protein C deﬁciency, and protein S deﬁciency. Group 2 disorders, deﬁned as an increased level or function of coagulation factors, include activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, and elevated levels of factors VIII, IX, and XI. Other hereditary thrombophilias include disorders of the ﬁbrinolytic system and hyperhomocysteinemia.11 In general, the group 1 disorders are less common, but more thrombogenic than the group 2 disorders. The group

Antithrombin levels are inﬂuenced by many competing factors. Levels can be decreased during an acute thrombotic event, so laboratory diagnosis should occur at least 3 months after the event. Diagnosis should also be deferred until at least 5 days after the cessation of heparin therapy, as antithrombin levels may be low during therapy.12–13 Levels can also be decreased in late pregnancy and by acquired conditions that impair antithrombin synthesis (e.g., liver disease, malnutrition, premature infancy, inﬂammatory bowel disease, extensive burns) or those that result in loss of protein, e.g., disseminated intravascular coagulation (DIC), acute hemolytic transfusion reaction, thrombotic microangiopathy, L-asparaginase therapy, acute thrombotic episodes, malignancy, and nephrotic syndrome. In addition, antithrombin levels have been demonstrated to drop after major vascular surgery with lowest levels noted the third postoperative day. Levels can be increased during menopause, with high-dose oral contraceptive therapy, or during warfarin use; thus the laboratory evaluation should occur when the patient is not taking warfarin.12–13 To test for antithrombin deﬁciency, a functional antithrombin level should be drawn at an appropriate time and checked a second time to conﬁrm the diagnosis. If the test was inadvertently drawn during an acute event and was normal, antithrombin deﬁciency can be excluded; if it was abnormal, the test needs to be performed again. Antithrombin antigenic levels do not need to be routinely tested.12–13

Thrombophilias 115

Risk of venous thromboembolism or arterial thromboembolism

type I deﬁciency. Heterozygous deﬁciency is present in 1.5–11.5% (mean 4%) of patients with VTE.11–13

Antithrombin deﬁciency is a strong risk factor for VTE. The risk in patients with heterozygous antithrombin deﬁciency is increased by 5–50 times. Most (> 50%) patients with heterozygous mutations will develop VTE by age 30. Severe deﬁciency from a homozygous mutation is incompatible with life, except for the homozygous type IIb deﬁciency, which involves mutations of the heparinbinding site on antithrombin and confers a lower thrombotic risk.11–13 Arterial thrombosis has been reported, but is uncommon, and its association with antithrombin deﬁciency is unclear.13

Diagnostic considerations

Treatment considerations Although, heparin resistance and thrombus progression are cause of concern in patients with antithrombin deﬁciency, it appears that these are not frequently encountered issues in clinical practice.8 A common clinical presentation in patients with antithrombin deﬁciency and thrombosis is the inability to reach adequate anticoagulation despite massive doses of heparin therapy. If heparin resistance is suspected, use of a non-antithrombin dependent anticoagulant (i.e., a direct thrombin inhibitor) is suggested for the acute treatment of VTE. Antithrombin concentrates may also be considered in cases of acute thrombosis, until appropriate anticoagulation with an alternate non-heparin anticoagulant is attained. Warfarin therapy is recommended for the chronic treatment phase, and in general long-term anticoagulation therapy is recommended.14–15

PROTEIN C DEFICIENCY

Background Protein C is a natural anticoagulant produced primarily in the liver that is activated during the coagulation process on the surface of the endothelial cell. To be activated, protein C binds to endothelial cell protein C receptor (EPCR) and is converted by thrombin, which is bound to the membrane protein thrombomodulin adjacent to the EPCR, to activated protein C (APC). APC, along with its cofactor protein S, is then able to inactivate factors Va and VIIIa to block thrombin generation.11–13 Similar to antithrombin deﬁciency, protein C deﬁciency is classiﬁed into two types. Type I implies a reduction in both functional and antigenic levels, usually due to low protein C production, and type II implies a reduced functional level but a normal antigenic level. More than 160 mutations result in protein C deﬁciency.11–13 Prevalence Protein C deﬁciency is present in approximately 0.17–0.4% of the general population, the majority being

Protein C deﬁciency should be diagnosed with a functional protein C level.12–13 Like antithrombin deﬁciency, the high number of possible mutations makes genetic testing impracticable.13 Testing antigenic levels is generally unnecessary since the results would not affect treatment decisions. Conﬁrmation with a second test may also be prudent.13 Warfarin and other vitamin K antagonists (VKAs) are the most common reason for low protein C functional or antigenic levels; thus, waiting to test until 2–4 weeks after warfarin is discontinued is prudent.12–13 Other potential circumstances that may decrease protein C levels include acute thrombosis (in which protein C may be consumed), vitamin K deﬁciency, liver disease, DIC, sepsis, renal insufﬁciency, postoperative state, adult respiratory distress syndrome, after plasma exchange, in breast cancer patients with some types of chemotherapy, and after massive hemorrhage and dilution with crystalloid solutions. A ﬁnding of normal protein C level during an acute event would rule out deﬁciency.13 The protein C functional level can be falsely low in the presence of high levels of factor VIII or lupus anticoagulant.12 Protein C levels in normal newborns are lower than in adults and increase with age.13 Protein C levels may be increased in diabetes, ischemic heart disease, pregnancy, postmenopausal period, hormone replacement therapy, and oral contraceptive therapy. Protein C functional levels may be low or high with the nephrotic syndrome, depending on the test used.13 Risk of venous thromboembolism or arterial thromboembolism The odds ratio of VTE in patients with protein C deﬁciency is 3.1. By age 40, about 50% of patients with heterozygous protein C deﬁciency will have an episode of VTE, and the risk is increased by an additional concurrent hereditary or acquired thrombophilia.13 The association between arterial thrombosis and protein C deﬁciency is weak. Patients with homozygous or multiple heterozygous mutations generally have levels of less than 20%. A homozygous mutation resulting in severe deﬁciency causes an often fatal neonatal purpura fulminans characterized by diffuse venous thrombosis.12–13 Treatment considerations When testing is carried out for protein C deﬁciency, the timing of the test is important as patients need to have stopped warfarin therapy for at least 2–4 weeks. In addition, the presence of other confounding factors needs to be ruled out before a deﬁnite diagnosis can be made. Intravascular coagulation, in the form of skin necrosis, can be precipitated by VKA initiation since protein C is a vitamin K-dependent protein. The short half-life of

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protein C (approximately 5–10 hours) results in a signiﬁcant drop in protein C level after warfarin initiation, which can be thrombogenic in the presence of underlying protein C deﬁciency. Thus, use of a fast-acting anticoagulant such as unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) is recommended in conjunction with warfarin therapy, until the international normalized ratio (INR) is therapeutic and stable. In addition, to minimize the risk of skin necrosis, when initiating warfarin therapy lower doses should be used and higher “loading” doses should be avoided. In cases of warfarin-related skin necrosis, proteins C or S deﬁciency should be ruled out. In the preoperative period, when the use of heparin may be contraindicated, fresh–frozen plasma can be considered to supply the necessary protein C.12–14

PROTEIN S DEFICIENCY

Background

this difference). The effect of oral contraceptives on protein S levels is dependent on the product and type of progestin used. As with protein C and antithrombin, work-up should be avoided during an acute event, but a normal test during this time rules out the diagnosis.12,16 As in protein C deﬁciency testing, wait 2–4 weeks after VKA discontinuation before testing for protein S deﬁciency. As an acute-phase reactant, C4b-BP levels can ﬂuctuate, affecting the proportion of free versus bound protein S.16 Levels can be falsely low with high factor VIII levels and lupus anticoagulant.12 Available tests for diagnosis of protein S deﬁciency are free antigen level, total antigen level, and functional (APC cofactor activity) level. Routine testing of antigenic total protein S is not usually necessary. The functional test is inﬂuenced by factors other than protein S activity and should be interpreted with caution. Fluctuations in protein S levels have been noted over time. Thus, the diagnosis should be conﬁrmed with a second test.12,16

Like protein C, protein S is a vitamin K-dependent endogenous anticoagulant primarily produced in the liver.12,16 Protein S is a cofactor for APC’s inactivation of factors Va and VIIIa; therefore, protein S deﬁciency is phenotypically similar to protein C deﬁciency. Protein S deﬁciency differs from the other two deﬁciencies of natural anticoagulants in that 60–70% of the total protein S is bound to the transport protein C4b-binding protein (C4bBP) and is not available as a cofactor for APC. More than 131 mutations are associated with protein S deﬁciency.11–12,16 Protein S deﬁciency is classiﬁed into three types based on free, total, and functional tests. Type I deﬁciency denotes low levels of both free and total antigen, type II denotes low activity but normal free and total levels, and type III denotes low free but normal total levels. Type III deﬁciency usually results from abnormal binding of protein S to C4b-BP.12,16

Risk of venous thromboembolism or arterial thromboembolism

Prevalence

As in the case of protein C deﬁciency, timing of the test for protein S deﬁciency should be carried out after patients have stopped warfarin therapy at least for 2–4 weeks. In addition, because of an initial heightened risk of skin necrosis due to a rapid drop in the protein S level when warfarin is initiated, the use of large initiation doses is not recommended and the use of a quick onset anticoagulant such as UFH or LMWH is recommended in conjunction with warfarin therapy, until the INR is therapeutic and stable.14–16

Approximately 0.03–0.2% of the general population has protein S deﬁciency, but the true prevalence is unknown due to the difﬁculty in making an accurate diagnosis. About two-thirds of protein S deﬁciency is type I, onethird is type III, and type II is rare. In patients with VTE, 1.3–5% have protein S deﬁciency.11–12,16 Diagnostic considerations Diagnosing protein S deﬁciency is challenging due to multiple factors affecting the free protein S level. Conditions associated with reduced protein S include vitamin K antagonist use, oral contraceptive use, pregnancy, liver disease, nephrotic syndrome, disseminated intravascular coagulation, premenopause compared with postmenopause, men compared with women, newborns compared with adults, and decreasing age in women (although hormonal status may account for

Varying rates of VTE associated with protein S deﬁciency have been reported, ranging from no association to 2.4- to 11.5-fold.12 A familial study showed that 50% of patients with protein S deﬁciency develop VTE by 45 years of age, but population-based studies show a weaker or no association, possibly due to the difﬁculty in reaching statistical signiﬁcance with the low incidence of protein S deﬁciency.16 A recent study of patients with a history of VTE found a rate of 7.4 recurrent events per 100 patient–years in patients with protein S deﬁciency compared with 4.6 for patients without a thrombophilia.17 Homozygous or severe deﬁciency, like that for protein C deﬁciency, causes neonatal purpura fulminans and often death. A deﬁnite association between arterial thrombosis and protein S deﬁciency has not been demonstrated.11–12,16 Treatment considerations

ACTIVATED PROTEIN C RESISTANCE/FACTOR V LEIDEN MUTATION

Background Activated protein C resistance refers to the resistance of factor V to cleavage by APC, slowing down factor V

Thrombophilias 117

cleavage by about 10-fold, thus increasing thrombin production. Approximately 90% of APC resistance is caused by the factor V Leiden mutation (FVL), which is a point mutation in the factor V gene at position 506, where APC cleaves factor V. Other mutations may result in APC resistance, such as those at position 306, a second APC cleavage site.11–12,18

is associated with poorer outcomes in renal transplantation recipients. Whether FVL is associated with arterial thrombosis is unknown.12,18 Despite its relatively high prevalence and association with VTE in oral contraception use, screening for FVL is not cost-effective and would deny many eligible patients oral contraception.18 Testing is important for those with a personal or family history of thrombosis.4

Prevalence The FVL is the most common inherited thrombophilia, with particularly high prevalence in Caucasian people of European descent. The mutation occurs in approximately 5% of Caucasians, 1.2% of African Americans, 2.2% of Hispanic Americans, 1.2% of Native Americans, and 0.45% of Asian Americans. In patients with VTE, 10–20% have FVL. Homozygous mutation is present in about 1% of Caucasians.11–12,18 Diagnostic considerations The APC resistance assay and/or the genetic test for FVL are appropriate tests to diagnose APC resistance.12,18 The APC resistance assay could be performed ﬁrst, and a positive result conﬁrmed with or explained by the FVL genetic test; a negative result does not need to be conﬁrmed. Patients with lupus anticoagulant or a markedly prolonged baseline activated partial thromboplastin time (aPTT), which may affect the APC resistance assay, or those with a family history of FVL should have an FVL genetic test initially.12,18 Risk of venous thromboembolism or arterial thromboembolism Compared with group 1 disorders (deﬁciencies of antithrombin, protein C, and protein S), APC resistance is a relatively weak risk factor for thrombosis.11 Heterozygotes for FVL are at three to seven times the risk of VTE, and homozygotes are at 50–100 times the risk.12,18 The risk of recurrent VTE is less clear, but is likely higher in patients who also have the prothrombin G20210A mutation.12,18 A recent meta-analysis found that the odds ratio of a recurrent DVT after a ﬁrst event in patients with heterozygous FVL was 1.41 (95% CI 1.14–1.75), which is statistically signiﬁcantly higher than patients without the mutation, but lower than the risk of a ﬁrst DVT.19 APC resistance not caused by FVL also confers an increased risk of thrombosis.11,18 The lifetime probability of symptomatic VTE in patients with heterozygous FVL mutation is approximately 10%, thus the vast majority of patients will not develop complications of the mutation.18 Although the VTE risk with FVL is relatively low, an increased risk occurs with some concurrent thrombophilic conditions, such as oral contraceptive use, hormone replacement therapy, and pregnancy, but possibly not with others, such as cancer or postoperative status. The FVL may increase the risk of recurrent pregnancy loss and obstetric complications and

PROTHROMBIN DEFECTS: PROTHROMBIN GENE 20210A MUTATION

Background The prothrombin G20210A mutation is a G to A point mutation on the factor II gene at position 20210, which results in higher circulating levels of functionally normal prothrombin.11–12,20 Why higher levels of normal prothrombin increase the thrombotic risk has not yet been elucidated, but APC-mediated factor V inactivation may be inhibited by the higher prothrombin level.11,20 Prevalence Prothrombin G20210A mutation is the second most common inherited thrombophilia. It is present in 2% of Caucasians, 3% in people of southern European descent, 1.7% in people of northern European descent, rare in Native Americans, and rare in Asian or African descent with 0.2–0.3% of African Americans having the heterozygous mutation.12,20 The prevalence in the USA is 1–2%. About 5–10% of patients with VTE have the mutation.11,20 Diagnostic considerations Since this thrombophilia is a mutation, it is diagnosed with a genetic test and can be tested without regard to patients’ current conditions.12,20 Risk of VTE or arterial thromboembolism The risk of thrombosis is relatively low and similar to that of FVL, with a reported two to three times increased risk.11–12,20 Also similar to FVL, the risk of recurrent VTE is less signiﬁcant, demonstrated by a recent meta-analysis which showed an odds ratio of 1.72 (95% CI 1.27–2.31) for recurrence after a ﬁrst event in patients heterozygous for prothrombin G20210A, which is lower than the risk for ﬁrst VTE but higher than the risk in non-carriers.19 Although most patients with the mutation will not have had an episode of VTE by the age of 50 years, the risk of ﬁrst VTE, and possibly the risk of recurrence, is increased with co-inheritance of FVL. The thrombotic risk may also be increased by pregnancy or oral contraceptive use – half of VTE episodes occur around surgery, trauma, prolonged immobilization, pregnancy, or estrogen therapy. As with FVL, the association of prothrombin G20210A mutation with arterial thrombosis is not clear.11–12,20

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FACTOR ELEVATIONS

Background The elevation of levels of coagulation factors V, VII, VIII, IX, X, and XI is potentially induced by regulatory proteins or by unidentiﬁed mutations in the factor genes themselves. Whether the elevated levels are thrombophilic themselves, or at all, or a reﬂection of another thrombophilic process is not known; however, persistent factor level elevations are more common in patients with a history of VTE.11,21 Prevalence The prevalence of elevated factor levels is unknown and complicated by the lack of deﬁnition of “elevated,” but ranges from 10% to 20% for factors VIII and IX.21 Diagnostic considerations Factor levels can be measured using functional or antigenic tests. A value of 100% is equivalent to 100 international units per dL. Levels of factors VII, IX, and X may be reduced in conditions associated with vitamin K deﬁciency, such as VKAs, malnutrition, and hepatic or biliary disease. Other conditions associated with changes in factor levels include oral contraceptive use, pregnancy, dyslipidemia, obesity, aging, acute stress, chronic inﬂammation, recent aerobic exercise, and blood type.21 Testing elevated factor levels is challenging, since interlaboratory tests results are not consistent, the conditions or medications that may affect the laboratory results are unclear, and diagnostic criteria and reference ranges for elevated factor levels are not deﬁned.21 For example, a recent article suggested an increase in the upper limit of the factor VIII reference range.22 Risk of venous thromboembolism or arterial thromboembolism Elevation of factors V and VII has not been clearly associated with VTE, but may be associated with arterial thrombosis. In contrast, the elevation of factors VIII, IX, and XI likely imparts an increased risk of VTE, albeit a relatively weak risk.11,21 The relative risk for elevated factors IX and XI are in the range of 2–3.11,21,23 Factor VIII elevation has the strongest evidence of an association, with each 10 international units per dL increment increasing the ﬁrst and recurrent VTE risk by 10% (95% CI 0.9–21%) and 24% (95% CI 11–38%), respectively.11 Although the relative risk for thrombosis in elevated factor VIII is generally considered modest, it has ranged up to 4.8 in some reports.21 HYPERHOMOCYSTEINEMIA

Background Hyperhomocysteinemia refers to the acquired or hereditary elevation of the plasma level of the amino acid homo-

cysteine.11,24 Acquired hyperhomocysteinemia may occur in certain medical conditions, such as renal insufﬁciency, hypothyroidism, or deﬁciencies in folate, vitamin B6, or vitamin B12 since these vitamins are important in the metabolism of homocysteine. Inherited hyperhomocysteinemia can result from mutations in the genes coding enzymes involved in homocysteine metabolism: methylene-tetrahydrofolate reductase (MTHFR), cystathione β synthase (CBS), or methionine synthase.11,24 These mutations may or may not lead to hyperhomocysteinemia, depending on the homozygosity or heterozygosity of the mutations, co-inheritance with another mutation, or the presence of concurrent B vitamin deﬁciency.12 The most common known mutations resulting in hyperhomocysteinemia are the MTHFR C677T (“thermolabile”) and the MTHFR A1298C mutations. Although these mutations may result in hyperhomocysteinemia, they are not directly associated with thrombosis.11,24 Hyperhomocysteinemia, unlike other thrombophilias except for antiphospholipid antibody syndrome, is associated with both arterial and venous thrombosis. The mechanism of hyperhomocysteinemia-associated thrombosis is not fully elucidated, but may involve effects on the endothelium, factor V, thrombomodulin, and tissue factor.11,24 Prevalence The prevalence of the heterozygous MTHFR C677T mutation is 34–50% and of the homozygous mutation is 12–15%, depending on the population. The MTHFR A1298C mutation is less common.11–12,24 Diagnostic considerations Since an elevated homocysteine level, not the underlying mutation, is associated with thrombosis, measuring the total plasma homocysteine level (tHcy) is more useful than testing for genetic mutations.4,24 Not clearly deﬁned are the classiﬁcation for the degrees of elevation, whether patients should be fasting, and whether methionine loading is helpful, making testing for tHcy challenging. Reasonable deﬁnitions for moderate, intermediate, and severe elevations are tHcy 15–30 μmol/L, 31–100 μmol/L, and more than 100 μmol/L, respectively. Also, tHcy may be elevated for several months after an acute thrombotic event. Acquired causes of hyperhomocysteinemia should be ruled out if homocysteine-lowering treatment is being considered.24 Risk of venous thromboembolism or arterial thromboembolism Hyperhomocysteinemia is associated with arterial and venous thrombosis, although it is not clear whether hyperhomocysteinemia is a marker or a cause of the thrombosis.12,24 The relative risk for arterial thrombosis according to a meta-analysis was 1.3 (95% CI 1.1–1.5); data showing an increased risk of recurrent VTE are more substantial than that for ﬁrst VTE.24

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The importance of testing for hyperhomocysteinemia and of its risk of thrombosis is tempered by the recent data indicating that medical lowering of the homocysteine level does not reduce events. For venous thrombosis, the randomized, placebo-controlled VITRO (Vitamins and Thrombosis) trial showed that lowering homocysteine with B vitamin supplementation does not reduce the risk of recurrent VTE in 701 patients with ﬁrst VTE and hyperhomocysteinemia.25 For arterial thrombosis, the authors of the randomized, double-blind VISP (Vitamin Intervention for Stroke Prevention) trial found that despite homocysteine lowering, high-dose vitamin therapy had no effect on stroke, coronary heart disease events, or death.26 In addition, the NORVIT (Norwegian Vitamin) trial also demonstrated that folate plus vitamin B12 with or without vitamin B6 does not lower cardiovascular disease or death after acute myocardial infarction, and actually had a nonstatistically signiﬁcant increase in events, despite a reduction in homocysteine.27 HOPE (Heart Outcomes Prevention Evaluation) 2 also found that folic acid and vitamins B6 and B12 did not reduce cardiovascular events in 5522 patients.28 Of note, the NORVIT and HOPE trials included patients without regard to baseline homocysteine level. Treatment considerations Elevated homocysteine levels can be decreased with folic acid, vitamin B6, and vitamin B12 therapy or a combination of these treatments. However, the beneﬁts of lowering homocysteine levels have been questioned by recent studies as highlighted in the above section.

either hemorrhagic or thrombotic complications. Testing for any of the ﬁbrinolytic system defects is not routine, as the tests are not standardized, the thrombotic risk is either not signiﬁcant or not established, and it is unclear how treatment would change because of a positive result.32,34 The major action of heparin cofactor II is the inhibition of thrombin, the rate of which is ampliﬁed 1000-fold in the presence of heparin. Present in approximately 1% of the population, a deﬁciency of heparin cofactor II may predispose to thrombosis, especially with other concurrent thrombophilia.11,29 The contact system includes factor XII, prekallikrein, and high-molecular-weight kininogen. Rare deﬁciencies in these proteins do not cause bleeding even though they may result in a signiﬁcantly prolonged aPTT, but instead have been postulated to increase thrombotic risk33

Acquired thrombophilia Acquired thrombophilic risk factors include certain disease states (malignancy, nephrotic syndrome, heparininduced thrombocytopenia, etc.), conditions (surgery, pregnancy, oral contraceptive use, postmenopausal hormone replacement, prolonged immobility, etc.), or laboratory abnormalities (lupus anticoagulant, antiphospolipid antibodies, etc.) that predispose patients to thrombosis.8–10 This section will focus on the discussion of the antiphospholipid antibody syndrome APS, heparininduced thrombocytopenia, and cancer.

Antiphospholipid antibody syndrome Other hereditary thrombophilias Background Emerging laboratory markers include defects in the ﬁbrinolytic system, heparin cofactor II deﬁciency, and deﬁciencies of contact factors.29–34 In addition, it is possible that there are yet unidentiﬁed prothrombotic markers or defects associated with a high thrombosis risk. The ﬁbrinolytic system is essential for dissolution of clots, and defects in this process may increase the risk of thrombosis. To review, thrombin converts ﬁbrinogen to ﬁbrin, whose ﬁbers are cross-linked to form the clot. When the clot is to be dissolved, tissue plasminogen activator (tPA) converts plasminogen to plasmin to break up the clot. This process is regulated by plasminogen activator inhibitor-1 (PAI-1), which inactivates tPA.30–31,34 Intuitively, elevated ﬁbrinogen, changes in ﬁbrinogen structure, plasminogen deﬁciency, elevated PAI-1, and tPA deﬁciency could all increase the thrombotic risk.11,30–32,34 Besides increasing ﬁbrin levels, an elevated ﬁbrinogen level may enhance platelet binding to the glycoprotein IIb/IIIa receptor and increase plasma viscosity. An acquired or inherited change in ﬁbrinogen structure, dysﬁbrinogenemia, may result in abnormal ﬁbrinogen function and

Antiphospholipid antibodies are a heterogeneous family of autoantibodies, including the lupus anticoagulants and anticardiolipin antibodies, directed against the phospholipid binding proteins important for coagulation. The APS is an antibody-mediated hypercoagulable state, deﬁned as the presence of antiphospholipid antibodies in individuals with arterial or venous thrombosis or pregnancy-related thrombosis or morbidity.35 Primary APS includes patients with the syndrome but without lupus or other autoimmune conditions, whereas secondary APS includes patients who also have systemic lupus erythematosus.36 Antiphospholipid antibodies can also develop during treatment with certain medications and also during periods of infection, but their clinical signiﬁcance in these scenarios is not known.35 Prevalence Antiphospholipid antibodies are reported in up to 10% of healthy subjects and in 30–50% of patients with systemic lupus erythematosus.35 Antiphospholipid antibodies that are positive on a persistent basis are reported in less than

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2% of healthy individuals. The prevalence of antiphospholipid antibodies in the pregnant population appears to be similar to non-pregnant individuals.35 In patients with thrombotic events the prevalence is higher in the range of 4% to 21%, suggesting a potential association between antiphospholipid antibodies and thrombosis. This association appears to be stronger with the lupus anticoagulants than with the anticardiolipin antibodies.35,37 Diagnostic considerations The deﬁnition and diagnosis of APS is based on the Sapporo criteria, which speciﬁes that patients who have at least one clinical and one laboratory criteria present have APS.35,38 Patients who have medium or high-titer IgG or IgM anticardiolipin antibodies or lupus anticoagulant present on two or more occasions at least 12 weeks apart meet the laboratory criteria. Antibody levels have been reported to change over time, and the clinical relevance of transient or low-titer antiphospholipid antibodies is unknown at this time. Patients who present with objectively conﬁrmed venous, arterial, or small vessel thrombosis, or pregnancy-related adverse outcomes and morbidity meet the clinical criteria.35 When screening for lupus anticoagulants, current guidelines recommend using two or more phospholipiddependent coagulation tests such as the aPTT, dilute Russell viper venom time, dilute prothrombin time, kaolin clotting time, textarin time, or taipan time.35 In patients taking anticoagulant therapy, particularly heparin, the accuracy of the test may be affected. Anticardiolipin antibodies, immunoglobulin (Ig) isotypes IgG, IgM, IgA, are detected by using enzyme-linked immunosorbent assays and are usually reported as a titer speciﬁc to each isotype. It is believed that the IgG immunoglobulin isotype is most strongly linked with the development of thrombosis. The anti-B2-glycoprotein I antibodies appear to be more speciﬁc for APS, although their clinical relevance is not clearly established. At this time, the antiB2-glycoprotein I antibodies are not included in the Sapporo criteria.35 RISK OF VENOUS THROMBOEMBOLISM OR ARTERIAL THROMBOEMBOLISM

Thromboembolic events are reported in approximately one-third of APS patients. Venous thromboembolism is the most frequent clinical manifestation in patients with APS. Patients with increased antiphospholipid antibody levels, and without systemic lupus erythematosus (SLE), are at an 11-fold higher risk of VTE than patients without these antibodies. The incidence of arterial thrombosis is also higher in patients with elevated antiphospholipid antibody levels. Patients with SLE have a high prevalence of thrombosis even in the absence of antiphospholipid antibodies.36 The incidence of recurrent VTE in patients with APS has been reported in the range of 52% to 69%,

and it is higher than in patients without APS. The risk of recurrent thrombosis in patients with APS appears to be highest in the ﬁrst few months of stopping anticoagulation.36 Treatment considerations In patients with APS and a ﬁrst VTE, the initial treatment consists of a short-acting anticoagulant such as heparin, low-molecular-weight heparin or fondaparinux for a minimum of 5 days, and overlapped with an oral vitamin K antagonist such as warfarin. Long-term therapy is accomplished by using an oral vitamin K antagonist at a target INR of 2.5 (range 2.0–3.0).35 Two randomized trials have demonstrated that higher INR intensity (> 3.0) was not better then moderate intensity INR at 2.0–3.0.39–40 Because of the high recurrent VTE rates, patients with APS and VTE should receive long-term (minimum of 12 months) to indeﬁnite anticoagulation therapy with warfarin.14,35 In patients with APS and arterial thrombosis, such as ischemic stroke, warfarin (INR 1.4–2.8) and acetylsalicylic acid (325 mg) appear to have similar efﬁcacy; however, because of some limitations in the current data some experts recommend warfarin therapy over acetylsalicylic acid.36 Owing to lack of data, the role of primary thromboprophylaxis in patients with APS and no history of thrombosis is controversial. Aspirin 81 mg is recommended in such cases; however, in cases of additional risk factors or high-risk surgical procedures prophylaxis with an anticoagulant agent such as heparin or LMWH should be considered.35 Patients with APS may have difﬁculty in monitoring anticoagulant therapies. The aPTT can be prolonged, which can interfere with heparin therapy, and in these cases, an anti-factor Xa assay can be used for monitoring. In addition, the lupus anticoagulant can interfere with the PT/INR determination causing a prolonged value in some patients. In these cases a chromogenic factor X assay, or a clot-based factor II or X activity is recommended for monitoring of warfarin therapy.36 International normalized ratio determinations by point of care instruments are often inaccurate in these patients, leading to overestimating the level of anticoagulation.12 It is suggested that APS patients receiving warfarin therapy should have the validity of their INR checked with one of the other methods of monitoring (i.e., chromogenic factor X assay) at least once during the course of therapy when the anticoagulant levels are stable.12

HEPARIN-INDUCED THROMBOCYTOPENIA BACKGROUND

Heparin-induced thrombocytopenia (HIT) is a severe pathologic adverse effect of heparin with a signiﬁcant potential to cause thrombotic complications. The pathogenesis of HIT involves an immunoglobulin-

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mediated response to the heparin molecule leading to platelet activation and thrombin generation. Although heparin-induced antibody formation occurs in 10–20% of patients treated with heparin, the vast majority of these patients never develop HIT. Antibodies to the heparin/PF4 complex are transient, and they have been reported to disappear from the circulation within a median of 85 days.41,42

functional assays and ELISAs may reduce false-negative results. When results of one test are negative or indeterminate in patients suspected of HIT, another test should be considered.41–43 If the disease is suspected, one should never wait for test conﬁrmation before stopping heparin and switching to an approved thrombin inhibitor for anticoagulation since HIT-mediated thrombosis can be catastrophic.

PREVALENCE

RISK OF VENOUS THROMBOEMBOLISM OR ARTERIAL THROMBOEMBOLISM

The estimated overall incidence of HIT after 5 days of UFH use is 1–3% but the cumulative incidence may be as high as 6% after 14 days of continuous intravenous use. Low-molecular-weight heparins are associated with a signiﬁcantly lower risk of HIT than UFH (< 1%).41 DIAGNOSTIC CONSIDERATIONS

The diagnosis of HIT is based on clinical and laboratory ﬁndings that conﬁrm heparin antibody formation and platelet activation. A new thrombosis shortly after the development of thrombocytopenia is a distinguishing feature in approximately 50% of patients with HIT. Acute thrombosis and skin lesions may also occur prior to the development of overt thrombocytopenia. Heparininduced thrombocytopenia should immediately be suspected when these events occur in any patient on UFH or LMWH therapy.41–42 Platelet counts that begin to fall on days 5–10 following initiation of heparin and reach a threshold by days 7–14 are known as typical-onset HIT. The development of thrombocytopenia can be delayed (delayed-onset HIT) up to 20 days, and begin several days after heparin has been stopped in patients naive to heparin therapy. Conversely, so-called “rapid-onset” HIT can occur rapidly and abruptly (within 24 hours following heparin initiation) in patients with a recent exposure to heparin (i.e., previous 3 months). In some cases overt thrombocytopenia may not occur, but a drop in the platelet count greater than 50% from the baseline is considered indicative of HIT.41,42 In some cases the resulting platelet count will still be in excess of 100 000 mm3. Laboratory testing needs to be performed to conﬁrm the diagnosis of HIT.41–43 Two types of assays are available to detect the presence of heparin antibodies. Platelet activation assays, also known as functional assays, conﬁrm in vitro platelet activation in the presence of therapeutic heparin levels. Functional assays include the heparininduced platelet activation assay (HIPAA), the serotonin release assay (SRA), and the platelet-aggregation assay (PAA). The HIPAA and SRA tests have higher sensitivity and speciﬁcity than the PAA assay but are technically more difﬁcult to perform. Antigen assays that detect the presence of speciﬁc antibodies against the heparin/PF-4 complex using enzyme-linked immunosorbent assays (ELISAs) are also available. These tests have reasonably high sensitivity and speciﬁcity. The combined use of

Thrombotic complications are the most common clinical sequelae of HIT. Approximately 50% of patients who develop the disorder will suffer a thrombotic complication or die within 30 days in the absence of appropriate treatment.41–43 The thrombotic risk is 30 times higher in patients with HIT than in control populations. Venous thrombosis is the most common thrombotic complication associated with HIT and the majority of patients develop proximal DVT. PE occurs in 25% of patient with thrombotic complications and contributes signiﬁcantly to mortality. Arterial thrombosis occurs less commonly. Limb artery occlusion, stroke, and myocardial infarction are the most commonly reported arterial events. Heparininduced thrombocytopenia has also been linked with atypical manifestations such as skin necrosis, venous limb gangrene, and anaphylactic-type reactions after IV bolus of UFH. Heparin-induced skin lesions occur in 10–20% of patients with HIT. Lesions range from painful, localized erythematous plaques to widespread dermal necrosis. Amputation in such cases is frequently required. Thrombosis may also occur in patients with seemingly mild thrombocytopenia, but platelet counts invariably have dropped more than 50% from baseline.41–43 TREATMENT CONSIDERATIONS

Once the diagnosis of HIT is established or strongly suspected, all sources of heparin and LMWH, including heparin ﬂushes, should be discontinued and an alternative anticoagulant agent should be initiated.41–43 It is crucial that alternate anticoagulant agents be initiated in a timely fashion to prevent new thrombosis, as the time required for diagnostic laboratory results can be prolonged. Anticoagulant agents, such as the direct thrombin inhibitors, that rapidly inhibit thrombin activity and are devoid of signiﬁcant cross-reactivity with heparin/PF-4 antibodies are the drugs of choice for the management of HIT. Three DTIs are currently available in the USA for the treatment of patients with HIT, lepirudin, argatroban, and bivalirudin, but only the ﬁrst two are FDA approved for this indication. Fondaparinux, an indirect factor-Xa inhibitor that lacks in vitro cross-reactivity to HIT antibodies, has shown promise in a few case reports for the management of HIT, although as of this date the FDA has not approved the drug for HIT.44 The LMWHs are not

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recommended for use in HIT because they have nearly 100% cross-reactivity with heparin antibodies by in vitro testing. Warfarin can be reinitiated once platelet counts have been recovered (> 150 000 mm3) but it should be overlapped with a direct thrombin inhibitor for a minimum of 5 days and until the full anticoagulant effect of warfarin has been achieved (i.e., INR within the therapeutic range for at least 2 consecutive days). Initial doses of warfarin greater than 5 mg should be strictly avoided in these patients, as the risk of inducing further thrombosis secondary to protein C and S inhibition is possible.41–43 Future use of UFH, particularly in the next 3–6 months, should be strictly avoided. As PF4-heparin antibodies are transient and usually cleared within 3 months, patients with a history of HIT should be tested for HIT antibodies prior to any future use of UFH. Although there are few data regarding the use if UFH in patients with a remote history of HIT, these patients should receive alternative anticoagulant agents for most indications until more rigorous data are available.41–43

PATIENT CARE CONSIDERATIONS The initial evaluation of patients presenting with a strong clinical case suggesting thrombophilia must include a detailed family and personal history. Depending on the initial assessment and on the speciﬁc treatment considerations, laboratory testing for thrombophilia may be considered in certain patients. A negative test only rules out the presence of the thrombophilic defects for which the patient has been tested, and it is not necessarily proof that an unidentiﬁable defect does not exist. Thus, in each case evaluating and documenting a detailed initial clinical history is crucial.8 Currently, there are no consistent guidelines in the literature for which patients should be considered for thrombophilia work-up and what speciﬁc tests should be included if patients are tested. Boxes 11.1–11.2 give some practical recommendations regarding these issues. Many of the function and antigen assays for thrombophilias can be affected by a variety of external factors such as medications, acute thrombosis, and other acquired

CANCER Venous thromboembolism is a major cause of morbidity and mortality in cancer patients. Pulmonary embolism is the cause of death in one of every seven hospitalized cancer patients who dies.45–46 The frequency of new and recurrent VTE is much higher in cancer patients then in non-cancer patients, and the majority of the events occur spontaneously without the presence of other triggering risk factors as in the case of non-cancer patients. The reverse association is also true, as evidenced by the high rate of cancer development in patients with VTE, especially idiopathic thrombosis.45 Some common risk factors that further heighten the risk of VTE in cancer patients include surgery, chemotherapy, the insertion of central venous catheters, and immobility. Treatment of VTE should be continued indeﬁnitely until the cancer is in remission and the patient is no longer receiving chemotherapy. Treatment with LMWH is more effective then warfarin, and it is the preferred treatment approach for the ﬁrst 3–6 months after an acute event.14,45

Combination of thrombophilic defects In cases where a combination of thrombophilic defects is present, the risk of thrombosis can be extremely high. Thus, in cases where a known hereditary thrombophilia is present, consideration should be given to test for other potential defects or risk factors.47 In addition, the combination of a genetic thrombophilic defect and one or more acquired risk factors, such as surgery or oral contraceptive use, lead to a higher risk of VTE then the separate effects of these single factors.10

BOX 11.1 Patients who may be considered for thrombophilia work-up10,12 Unexplained or “idiopathic” thromboembolism (ﬁrst event) Secondary, non-cancer-related ﬁrst event and age < 50 (includes thrombosis on oral contraceptives and hormone replacement therapy) Recurrent “idiopathic”, or secondary non-cancer-related events Thrombosis at unusual sites (portal vein, sinus veins, etc.) Extensive thrombosis Strong family history of venous thromboembolism

BOX 11.2 Commonly ordered tests for thrombophilia work-up of patients with venous thromboembolism12 Factor V Leiden Prothrombin 20210 mutation Protein C activity Protein S acitivity, free and total protein S antigen Antithrombin activity Anticardiolipin IgG and IgM antibodies Lupus anticoagulant Anti-β-2-glycoprotein I IgG and IgM antibodies Homocysteine Factor VIII, Factor IX, Factor XI Prothrombin time, activated partial thromboplastin time

Surgical considerations

conditions (Table 11.1). Thus, these assays should be repeated after ruling out any external factors and before a ﬁnal diagnosis of an hereditary thrombophilia is made.47 As the notion and implications of thrombophilia can often be controversial and confusing to patients, it is recommended that prior to laboratory testing for thrombophilia informed consent is obtained and documented in the patient’s medical record. This is especially important to document in the cases of testing asymptomatic relatives of a patient with a documented defect as this can have a ﬁnancial and health insurance impact.47 Identiﬁcation of high-risk patients with underlying genetic or acquired thrombophilic disorders may be especially important in cases of elective surgery and prior to prescribing birth control or hormone replacement therapy.4 In addition, thrombophilia testing should be considered in all patients in which the results would affect their medical management or where useful information is derived for family members. In addition to the presence of one or more thrombophilic defects, the presence of risk

123

factors such as pregnancy, estrogen-containing oral contraceptives, hormone replacement therapy, surgery, cancer, advanced age, medical illness, further compound and markedly increase the risk of thrombosis, and should be considered as part of the patients overall thromboticrisk evaluation.4 As laboratory testing for inherited or acquired thrombophilia can be associated with beneﬁts but also with potential harm for the patients or family members involved, both the pros and cons of thrombophilia testing should be considered before a ﬁnal clinical decision is made (Table 11.2).

SURGICAL CONSIDERATIONS It is most important that patients with known thrombophilic defects or related positive family members be carefully screened and counseled preoperatively.48 Complete thrombophilic work-ups should be done since the presence of multiple positive markers may

Table 11.1 Practical considerations in thrombophilia testing12,13,16,18,20,23,24 Thrombophilia

Available

Recommended

Warfarin

UFH or LMWH

Disease–laboratory interaction Acute thrombosis

Antithrombin deﬁciency

Functional Antigenic

May be increased12,13

May be decreased12, 13

May be decreased12,13

Protein C deﬁciency

Functional Antigenic Functional Total antigenic Free antigenic Clotting assay, with or without addition of factor V-deﬁcient plasma Factor V Leiden genetic test

Functional amidolytic assay13,23 ± antigenic assay12 Functional12,23

May be decreased12,13 May be decreased12,16

Reliable12

May be decreased13

Reliable12

May be decreased12

APC resistance assay: reliable if factor V deﬁcient plasma used12 Genetic test: reliable12

APC resistance assay: depends on the way the assay is performed in each lab12 Genetic test: reliable12

APC resistance assay: reliable if factor V deﬁcient plasma used12 Genetic test: reliable12

Reliable12 20

Reliable12,20

Reliable12,20

May be decreased in IX, otherwise reliable12 tHcy: reliable12 MTHFR genetic test: reliable12

Reliable12

May be increased in VIII, otherwise possibly reliable12 tHcy: May be increased24 MTHFR genetic test: reliable12

Protein S deﬁciency

APC resistance

Prothrombin G20210A mutation Elevated factors VIII, IX, and XI

Laboratory tests

Genetic test Functional Antigenic

Hyperhomocysteinemia Total plasma homocysteine levels (tHcy)24 MTHFR genetic test

Drug–laboratory interactions

Free antigenic and/or functional16 ± total antigenic12 APC resistance assay with factor V-deﬁcient plasma or FVL genetic test (or use FVL genetic test as conﬁrmatory test for + APC resistance assay)12, 18, 23 Genetic test20, 23 Either

tHcy

tHcy: reliable12 MTHFR genetic test: reliable12

LMWH, low-molecular-weight heparin; MTHFR, methylenetetrahydrofolate reductase; UFH, unfractionated heparin.

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Table 11.2 Pros and cons of thrombophilia testing8,12 Thrombophilia testing Pros

Cons

Results aid in explaining the cause of thrombosis Identify individuals with single or multiple thrombophilic defects at high risk of thrombosis Test results can aid the decision to initiate prophylactic anticoagulant therapy in high risk patients (i.e., undergoing surgery, extended travel, etc.) Test results can aid the decision to determine the length of anticoagulant therapy after the ﬁrst thrombotic episode Aid in counseling patients about their future risk of thrombosis Aid in counseling asymptomatic family members regarding testing for thrombophilia and their risk of thrombosis

No impact on course of therapy even if thrombophilia testing is positive Only applies to selected single defects such as heterozygous Leiden or prothrombin defects Patients with proteins C or S deﬁciency, antithrombin defects, and antiphospholipid syndrome may need indeﬁnite anticoagulation after the ﬁrst episode Patients with a ﬁrst episode of VTE that are found to have multiple defects may be at such high risk for recurrence that indeﬁnite anticoagulation may be advised Risk of being denied health insurance coverage or of higher premium payments High cost of testing Laboratory analytical error Over- and underdiagnosis of thrombophilia due to laboratory accuracy issues can lead to potentially harmful clinical decisions and misleading patient advice False reassurance to those testing negative

dramatically increase the chance of thrombosis. This knowledge will allow proper selection, onset, dosage, and duration of thromboprophylaxis as well as justify the addition of physical methods of prophylaxis despite added cost. These decisions we feel should be based on randomized prospective clinical trials employing venographic endpoints and autopsy proven fatal pulmonary emboli when available. These types of studies indicate which approach has produced the absolute lowest incidence of all clots (small, large, fatal, and non-fatal). We are aware of the fact that many excellent surgeons protect patients who are at average thrombosis risk with antithrombotic regimes that show acceptable clinical results but often inferior venographic results. The bleeding rates with these agents are lower, which pleases the surgeons and patients, and the rate of VTE including fatal events are low in the average-risk patients. A good example of this approach is the multicenter trial of Colwell et al.49 in 3000 patients undergoing total hip replacement and randomized to receive LMWH or warfarin prophylaxis. The endpoint was clinical and the 1.0% clinical incidence of DVT was reduced to 0.3%. Based on these data, many surgeons concluded that warfarin prophylaxis that prevents 99% of thrombi and tends to have a slightly lower incidence of bleeding complications and no injections is adequate for prophylaxis in these patients. A different scenario exists in patients with past thrombosis, or thrombophilic defects where the chance of recurrent thrombosis postoperatively may be well over 50%.4 We feel that these very high risk situations need the maximum protection against thrombosis. A prophylactic

regimen should be selected that has been demonstrated by randomized prospective clinical trials to result in the fewest venographic thrombi. Until we can predict which postoperative thrombi will present as sudden death we need to follow this aggressive approach realizing that bleeding complications may be 1% greater. We wish to highlight a recent analysis by Heit et al.50 that documented the incidence of VTE in over 37 million patients in 2002. Pulmonary emboli were found in 296 000 patients and 34% of these individuals presented as sudden death. Obviously, the clinician has no warning and no opportunity to treat these individuals. Aggressive anticoagulant prophylaxis never causes sudden death and complications can be treated almost always in some fashion without the patient losing their life. The philosophy expressed by the authors is certainly not for everyone but we feel that the patient needs to be fully informed about these data and they along with the surgeon can make the ﬁnal decision. Finally, as a result of these discussions there may be certain quality of life operations that may be deferred because the risk of thrombosis is too great.

CLINICAL PRACTICE GUIDELINES Who to Test Universal testing for thrombophilia is inappropriate and not recommended. Testing in select patient cases may be considered but only with the full understanding of assay

General recommendations 125

limitations and pitfalls (see Box 11.1) In most cases, the value of testing will relate to preventing a ﬁrst VTE in affected relatives.8,10,12

When to test The acute thrombotic state, the use of various anticoagulant agents, and other acquired conditions interfere with the accuracy of certain tests for thrombophilia such as antithrombin, protein C, and protein S levels. Thus, testing should be timed appropriately to avoid false positives and negatives due to these interfering factors. As, the management of an acute thrombotic event is almost never inﬂuenced by the presence or absence of a thrombophilic defect, testing should not be done during an acute thrombotic event. Typically, testing can be performed 2–4 weeks after completing the typical course (usually 6 months) of anticoagulant therapy. In addition, testing should be avoided during pregnancy, use of OCPs (oral contraceptive pills), or hormone replacement therapy8,10 (see Table 11.1).

What to test When testing is indicated, assays for the most common hereditary and acquired thrombophilias should be included as highlighted in Box 11.2.8,10,12

Prophylaxis and treatment considerations PROPHYLAXIS OF VENOUS THROMBOEMBOLISM

TREATMENT OF VENOUS THROMBOEMBOLISM

The initial treatment of an acute VTE (deep vein thrombosis and/or pulmonary embolism) in patients with thrombophilia is similar to the treatment approach used in all other patients presenting with VTE. The acute treatment phase of VTE is typically accomplished by administering a fast acting parenteral anticoagulant such as UFH, LMWH, or fondaparinux. The sub-acute and chronic treatment phase of VTE is usually accomplished using oral anticoagulant agents, such as warfarin. In certain populations, such as patients with cancer and women who are pregnant, the LMWHs are the preferred agents. The injectable agent should be overlapped with warfarin therapy for a minimum of ﬁve days. Warfarin should be dosed to achieve a goal INR of 2.5 (range 2.0–3.0). Once the INR is stable and above 2.0, the injectable anticoagulant is discontinued.14

DURATION OF THERAPY

Anticoagulation therapy is usually given for 6 months but should be given longer depending on the underlying etiology of the VTE and patient’s risk factors.14 In cases of persistent risk factors such as cancer or other thrombophilic defects, the duration of therapy should be extended beyond the usual period of anticoagulation. Patients with more than one thrombophilic defect, APS, deﬁciency of protein C, protein S, or antithrombin, thrombosis at unusual site, strong family history of thrombosis should be considered for long-term anticoagulation therapy.10 Table 11.3 summarizes the current American College of Chest Physicians Recommendations for duration of therapy in patients with VTE.14

Asymptomatic patients without a prior venous thromboembolism Long-term, primary pharmacologic thromboprophylaxis of asymptomatic thrombophilic patients is not recommended, as the risk of major and fatal bleeding outweighs the risk of fatal VTE even in patients with most severe types of thrombophilia. However, these patients should be considered candidates for prophylaxis at times of high thrombotic risk such as surgery, trauma, prolonged immobility, pregnancy, acute illness, etc.8,10 Patients with prior venous thromboembolism Patients with documented thrombophilia and history of a prior VTE, are candidates for short-term thromboprophylaxis during times of heightened thrombotic risk such as surgery, trauma, prolonged immobility, pregnancy, acute illness, etc. There is no evidence to suggest that patients with thrombophilia would beneﬁt from more intense anticoagulant regimens or longer duration of prophylaxis.8

GENERAL RECOMMENDATIONS8,10,12,47 Informed consent should be obtained from patients and especially asymptomatic family members before thrombophilia testing is performed. Counseling should be provided to patients who test positive for one or more thrombophilias regarding their risk of thrombosis, signs and symptoms of VTE, and the beneﬁts of antithrombotic prophylaxis in high-risk situations such as elective surgery or pregnancy. Since more then one thrombophilic defect can be present in a given patient, testing for additional hereditary or acquired thrombophilias should be considered even after identiﬁcation of a single thrombophilic defect. Consider repeating function or antigen diagnostic assays after ruling out interfering factors such as medications and acquired conditions, before a deﬁnite diagnosis of a hereditary thrombophilia is made.

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Table 11.3 Duration of anticoagulation therapy for the treatment of venous thromboembolism (VTE)14 Patient characteristics

First episode of VTE secondary to a transient (reversible) risk factor First episode of VTE and cancer

Drug

Duration of therapy

Comments

Warfarin

3 months

Low-molecularweight heparin

6 months: indeﬁnite therapy or until cancer is resolves should be considered At least 6–12 months; indeﬁnite therapy may be considered. 12 months to indeﬁnite

Recommendation applies to both proximal and calf vein thrombosis Low-molecular-weight heparin is recommended over warfarin

First episode of idiopathic VTE with or without a documented hypercoagulable abnormality

Warfarin

First episode of VTE with documented antiphospholipid antibodies or two or more thrombophilic abnormalities First episode of VTE with documented deﬁciency of antithrombin, protein C, protein S, factor V Leiden or prothrombin 20210 gene mutation, homocysteinemia, elevated factor VIII Second episode or recurrent VTE

Warfarin

Warfarin

6–12 months: indeﬁnite for idiopathic thrombosis

Warfarin

Indeﬁnite

Continue warfarin therapy after 12 months if patient is low risk for bleeding

The risk-beneﬁt of indeﬁnite therapy should be reassessed at periodic intervals

The risk–beneﬁt of indeﬁnite therapy should be reassessed at periodic intervals

Guidelines 2.1.0 of the American Venous Forum on evaluation of hypercoagulable states and molecular markers of acute venous thrombosis No.

Guideline

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest)

2.1.1 We recommend evaluation for thrombophilia for patients with the following conditions: 1 unexplained or “idiopathic” thromboembolism (ﬁrst event) 2 secondary, non-cancer-related ﬁrst event and age < 50 (includes thrombosis on oral contraceptives and hormone replacement therapy) 3 recurrent “idiopathic”, or secondary non-cancer-related events 4 thrombosis at unusual sites (portal vein, sinus veins, etc.) 5 extensive thrombosis 6 strong family history of venous thromboembolism

1

C

2.1.2 Testing for thrombophilia is recommended to most patients 2–4 weeks after completing the typical course (usually 6 months) of anticoagulant therapy

1

C

2.1.3 We suggest long-term, primary pharmacologic thromboprophylaxis of asymptomatic thrombophilic patients

2

B

2.1.4 We recommend that patients with thrombophilia receive thromboprophylaxis at times of high thrombotic risk such as surgery, trauma, prolonged immobility, pregnancy, or acute illness

1

A

2.1.5 We recommend prolonged anticoagulation following acute deep vein thrombosis in patients with thrombophilia

1

B

References 127

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12 Duplex ultrasound scanning for acute venous disease SERGIO X. SALLES-CUNHA Introduction Indications for testing Examination techniques Interpretation Venous coaptability or compressibility Venous echogenicity

129 130 130 131 134 135

INTRODUCTION The specter of pulmonary embolism and its link to venous thromboembolism of the extremities1 has led to the practice of non-invasive examination of patients with relevant symptoms or at risk of developing deep vein thrombosis (DVT). Virchow’s classic triad remains important today and identiﬁes patients at risk of venous thrombosis as having increased blood coagulability, decreased blood ﬂow, and venous wall abnormality or injury. Signs and symptoms of DVT are a consequence of venous obstruction causing swelling from edema, and pain from muscle compartment pressure, or perivenous inﬂammation. The reliability of clinical diagnosis, however, is so poor that objective conﬁrmation is required. Duplex ultrasonography (US) has become the most common procedure to test for venous thrombosis of the lower and upper extremities. Recent examples of patients evaluated with duplex US, adults or children,2,3 include those in emergency departments,4,5 in the medical intensive care unit,6 in rehabilitation programs,7 having hormonal therapy,8 women during pregnancy,9 patients who had superﬁcial femoral artery angioplasty,10 or ablation of the saphenous vein to treat reﬂux11,12 patients with pulmonary embolism13,14 trauma,8 traumatic brain injury,15,16 acute spinal cord injury,17 malignancies,8,18 thrombophilia,8 stroke,19 stroke caused by paradoxical embolism,20 catheter insertion in central or peripheral veins,21 or patients suspected of having upper extremity,

Venous ﬂow Continuous-wave Doppler Laboratory quality assurance Accuracy Research References

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combined or not with lower extremity, venous thrombosis.22–26 Furthermore, the patient with superﬁcial thrombophlebitis deserves a full evaluation of the deep veins.27 This chapter addresses diagnosis of DVT of the lower and upper extremities by use of direct US testing. When indicated, examination of the lower extremities is extended to the iliac veins and inferior vena cava. Upper extremity evaluation also includes the jugular, subclavian, axillary, and innominate veins. Catheterization and implantation of other devices has contributed to an increase in thrombosis in these veins. Advantages of non-invasive US of the extremities over phlebography and other techniques include absent or extremely rare morbidity, portability, particularly with lap-top US scanners, patient follow-up with repeat examination, simultaneous anatomic and hemodynamic information, appropriate identiﬁcation of veins based on adjacent structures, differential diagnosis of non-venous pathologies, often described as incidental ﬁndings, and cost effectiveness.28–33 Often, the cause of calf pain and swelling is not acute venous disease, particularly in the outpatient, ambulatory population. Gender differences may dictate type of testing with interpretation focusing on valvular insufﬁciency besides DVT.34 A complete vascular laboratory evaluation should focus not only on DVT but also on venous valvular incompetence, extravascular masses, arteriovenous ﬁstulas, arterial aneurysms and evidence for lymphedema.33,35–37

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These beneﬁts of the US technique have caused a substantial increase in the number of venous examinations, and, as a consequence, the percentage of positive tests for DVT has dropped below 10–20% in many centers. A high frequency of negative tests has resulted in suggestions of limited protocols.38 In contrast, several investigators have emphasized the importance of complete examination with inclusion of calf vein scanning.39–43 Unilateral examinations have been proposed to optimize timing and effort.44 Occult DVT in the asymptomatic leg is low, and, if the scan is being done to support diagnosis of pulmonary embolism, a positive scan in the ﬁrst leg might obviate the need for studying the other. Deﬁning the extent of DVT in both legs, however, is useful in subsequent evaluations for treatment follow-up,45 recurrent acute thrombosis,46 or chronic venous insufﬁciency.47 New protocols for stat and emergency-room late-hour testing may evolve with integration of risk factors, symptoms and signs, and treatment/diagnostic alternatives.4,5,35 Ultrasound of the extremities may be complementary to magnetic resonance or computed tomography for evaluation of patients with pulmonary embolism or thoracic or abdominal DVT.48 Alternative treatments and diagnostic methods such as lowmolecular-weight heparin and D-dimer tests, and extent of proximal or calf DVT49 may alter protocols for diagnostic and follow-up US testing. Conversely, results of US followup may inﬂuence changes in treatment.45

INDICATIONS FOR TESTING Patients examined for acute venous disease in the vascular laboratory can be grouped into the following categories: ●

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patients with signs and symptoms of pulmonary embolism who may have the extremities examined seeking the most probable embolic source; patients with extremity pain and/or swelling as common indications for performing a bilateral or unilateral examination of upper or lower extremities; patients at increased risk of developing DVT because of known factors such as trauma, joint replacement surgery, other major surgery, prolonged mobility limitation, or hypercoagulability, often associated with cancer; patients with superﬁcial thrombophlebitis, who should be tested for progression of disease and DVT; patients who had their saphenous vein thermally or chemically ablated for treatment of reﬂux; patients who have or had catheters inserted in veins or even concomitant arteries for diagnosis or therapy;

The deep veins of patients who are candidates for dialysis access or superﬁcial vein treatment should also be evaluated for acute thrombosis or chronic obstruction.

EXAMINATION TECHNIQUES In a comfortable warm room, the patient is positioned supine in a slightly reversed Trendelenburg position with the legs or arms dependent, to take advantage of the venous dilation caused by temperature and gravity. Positioning should be altered accordingly for the study of the axillary, subclavian, innominate, and jugular veins. A warm blanket wrapped around the limb aids venodilation. This detail is particularly useful in demonstrating patency of constricted or compressed calf veins. Slight external rotation of the hip together with slight knee ﬂexion avoids venous compression by normal anatomic structures of the lower extremity. A linear transducer with broadband frequencies in the 5–10 MHz range is usually employed. Lower frequencies are selected for evaluation of the vena cava and iliac or innominate veins. A cardiac-type transducer facilitates insonation of the innominate veins. A lower frequency, sector probe can facilitate visualization of calf and thigh veins in large extremities, or the axillary and subclavian veins. Higher frequencies may improve imaging of the superﬁcial veins either in the lower or in the upper extremity. There are three essential phases to the venous examination, applied successively in each venous segment: thrombus visualization, venous coaptability or compressibility, and detection of venous ﬂow.29,32,50 The examination can start proximally in the thigh, following the veins distally as needed. Calf examination does not need to be performed if venous thrombi are detected within the femoropopliteal segments. Similarly, upper extremity evaluation may be interrupted if thrombus is found in the proximal veins. Thrombus visualization is sought with B-mode imaging. On occasion, acute, hypoechoic thrombus may not be detectable with standard settings stored in the instrument. Color ﬂow imaging is supplemental but can greatly facilitate detection of non-occluding thrombus. The coaptation or compressibility maneuver is performed by application of topical pressure using the US transducer while observing the vein with B-mode. This maneuver should be performed in cross-section because a longitudinal scan intersects the vein in only one plane and usually misses most of the lumen. Longitudinally, the plane of insonation may be displaced away from the vein, giving the misleading impression that the vein is compressed or coapted when in reality the vein is in another plane not being insonated. Coaptation of the vena cava, iliac, innominate, and subclavian veins is difﬁcult or practically impossible because of limited access to apply pressure with the US probe. Full coaptation testing is also impaired by the inguinal ligament, structures of the adductor canal, tendons in the popliteal fossa, and bones of the lower leg. Velocity quantiﬁcation is not important in this venous examination. Therefore, venous ﬂow assessment can be

Interpretation 131

performed with either cross-sectional or longitudinal insonation. The latter optimizes US beam angulation, increasing the sensibility to slow-ﬂow velocity or low-ﬂow volume. Doppler spectrum analysis and/or color ﬂow can be used. A large sampling volume facilitates detection of the ﬂow waveform. Color sensitivity should be set for low ﬂow. High persistence of the color signal improves detection of low ﬂow but gives a false impression of longer than real duration of ﬂow. Flow study comprises observation of respiratory ﬂow ﬂuctuations or phasicity and response to external extremity compression proximal and distal to the segment being insonated. During leg studies, manual abdominal compression is often faster and more effective than instructing the patient to perform a Valsalva maneuver. Venous ﬂow should stop with proximal compression, augment with release of proximal compression, and also augment with distal compression. Scanning for thrombus visualization and venous coaptability should encompass as much vein length as possible, while ﬂow study may be restricted to a few anatomic locations. In the lower extremity, ﬂow signals are detected at the common femoral, mid-thigh femoral, popliteal, posterior tibial, and peroneal veins. The anterior tibial veins are small and their study is often omitted unless the patient has localized signs or symptoms. The superﬁcial veins, commonly the saphenous veins, are examined by direct observation and palpation or by US in a similar manner as the deep veins. Flow waveforms are detected in the great saphenous vein in the thigh and calf and at the small saphenous vein. In the upper extremity, ﬂow signals are detected at selected locations, often in the mid-segment of the veins being examined: subclavian,

(a)

axillary, brachial, ulnar, and radial. The cephalic and basilic veins are important contributors to the venous drainage and are evaluated at the upper arm and forearm. The examiner must recognize the variant anatomies of these veins.29 Normally, venous ﬂow increases with pressure applied distally to the foot, calf, hand, or forearm, facilitating identiﬁcation of a patent vein by Doppler waveform or color ﬂow. Because we have yet to ﬁnd a person with “three hands,” one to press the buttons of the instrument, a second to hold the US transducer, and a third to compress the extremities, an automatic pressure pump connected to a cuff wrapped around the limb has been used for the ﬂow augmentation maneuvers. An automatic, rhythmic, pulsatile pump may deplete the blood reservoir in the extremity and may produce the false impression that venous ﬂow is decreased. It is preferred to perform the proximal compression maneuver ﬁrst, followed by the distal compression maneuver. Two interconnected, loosely inﬂated cuffs can be used for the compression maneuvers. One is wrapped around the limb while the other is compressed with the foot when the ﬂow augmentation testing is performed.

INTERPRETATION Normal findings Figure 12.1 shows a series of images of patent lower extremity veins, the most commonly studied. Figure 12.2 shows how the appearance of normal veins change as the gain setting of the instrument is increased. Figure 12.3 is a

(b)

Figure 12.1 Cross sections of blood vessels. (a) Iliac vessels: the common iliac artery (A) is the smaller vessel on top; the common iliac vein (V) is the larger vessel at the bottom. A branch can be seen entering the vein (arrow). (b) Vessels at the saphenofemoral junction: the larger vessel on the right is the common femoral vein (arrow) receiving blood from the greater saphenous vein on top (gsv) and a deep branch from the bottom (db); the two vessels on the left are the superﬁcial femoral artery (sfa) on top and the deep femoral artery below.

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(d)

(c)

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Figure 12.1 (contd) Cross sections of blood vessels. (c) Femoral vessels at mid thigh: in the middle, the superﬁcial femoral artery (A) has low ﬂow near the wall and high ﬂow in the center, as shown in this picture taken during late systole. The other two vessels are femoral veins (V); this duplicate variant occurs in about one-third of patients. Use of the phrase/term “superﬁcial” femoral vein should be discouraged because it has been misinterpreted as superﬁcial rather than deep venous thrombosis. (d) Vessels in the popliteal fossa: the larger vein (V) is on the top (superﬁcial) with the smaller artery (A) below. The shadow on the right is caused by probe placement over tendon, which may impair the probe compressibility maneuver. (Picture taken using a posterior approach). (e) Posterior tibial vessels underneath muscular fascia: the smaller vessel in the center is the artery (A), surrounded by the larger veins (V). (Picture taken using a medial approach, the tibia being on the left). (f) Peroneal vessels by the ﬁbula: the smaller vessel in the center is the artery (A), surrounded by the larger veins (V). (Picture taken using a lateral approach). (g) Anterior tibial vessels: the vessel in the center is the artery (arrow) surrounded by two veins (V). The anterior tibial veins are often small or undetectable. (Picture taken using an anterior-lateral approach with the tibia on the left).

Interpretation 133

(a)

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sequence of changes during compression of a normal coaptable vein. Figure 12.4 shows normal Doppler spectral ﬂow ﬁndings: phasicity with respiration, interruption of ﬂow with proximal compression and ﬂow augmentation with release of proximal compression, followed by ﬂow augmentation with distal compression. Phasicity with respiration in the upper extremities is reversed from that of the lower extremities. Inspiration lowers intrathoracic pressure, resulting in venous return in the upper extremities.

(b)

Figure 12.2 Appearance of the intraluminal image changes as the gain of the instrument is increased progressively from (a) to (c). Fresh thrombus may be missed at low gains. If excessive gain is used, even the lumen of a normal vein may become hyperechoic, giving the false impression of thrombosis. (Uncommon conﬁguration at mid-thigh with the superﬁcial femoral artery (a) surrounded by three veins).

duplex is not separable from continuous interpretation as the examination proceeds. Knowledge of conditions associated with similar signs or symptoms as DVT along with certain speciﬁc ultrasound ﬁndings greatly aids this examination. Lower extremity pain and edema may be caused by a variety of pathologies including: ● ● ● ●

Abnormal findings and differential diagnosis

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All characteristics of veins, as observed by US, should be taken into account. Contradictions or inconsistencies should alert the observer to the possibility of a false impression. Thus, the process of performing venous

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incompetent superﬁcial system incompetent perforator veins incompetent deep system arteriovenous ﬁstulas arteriovenous malformations popliteal or femoral aneurysms enlarged lymph nodes compressing veins lymphatic obstruction obstruction by tumors synovial cyst (Baker’s cyst)

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(a)

(b)

(c)

(d)

Figure 12.3 Coaptability or compressibility of four femoral vessels at mid-thigh: (a) Minimal pressure applied to the transducer: the two vessels on the left are veins; on the right, a valve leaﬂet can be seen within a large vein (arrow); the superﬁcial femoral artery (a), is the most circular of these vessels. (b) As pressure applied to the transducer increases, the cross-section of veins diminishes. The most signiﬁcant change occurred ﬁrst in the vein on the right (arrow); only the origin of the valve leaﬂet is now noted. (c) With additional pressure applied to the transducer, the vein on the right coapts (arrow), while the other veins change in shape and diminish in size. (d) As applied pressure increases, the veins coapt while the smallest vein is almost closed. Note that the artery (a) is only minimally compressed. (Uncommon conﬁguration at mid-thigh with the superﬁcial femoral artery surrounded by three veins).

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hematoma bony abnormalities and exostoses nerve compression or inﬂammatory process.

VENOUS COAPTABILITY OR COMPRESSIBILITY The primary criterion of a positive duplex US scan DVT is an incompressible vein, clearly visualized in cross-section and subjected to adequate pressure forces from the US probe. Even fresh thrombi, barely detected during B-mode

imaging, impede the complete collapse of a vein under compression. The innominate and subclavian veins, segments of the iliac veins, and inferior vena cava usually cannot be compressed because of their anatomic location. Therefore, diagnosis of these segments is based on thrombus visualization and study of ﬂow patterns. If the only abnormal ﬁnding is incompressibility of a very localized segment of the common femoral vein near the inguinal ligament, femoral vein at the adductor canal, popliteal vein, or tibial and peroneal veins near the calf bones, false-positive venous incompressibility should be

Venous echogenicity

135

(a)

(a)

(b) Figure 12.4 Normal venous ﬂow in the femoral vein at midthigh: (a) At rest, venous ﬂow is phasic with respiration; the respiratory cycle lasts about 3 seconds. (b) Valsalva maneuver (V) interrupts venous ﬂow during the respiratory wave. When this is relieved, venous ﬂow increases suddenly. The following respiratory wave also has increased ﬂow. At the end of this respiratory wave, compression of calf muscles (C) causes another increase in venous ﬂow.

suspected. The compression maneuver should be repeated with the patient in a different position or the angle of compression should be changed.

VENOUS ECHOGENICITY Thrombus echogenicity generally increases with age of the thrombus.51,52 The appearance of the ultrasonic image progresses from “black” blood due to lack of ultrasound reﬂection to densely speckled hyperechoic old thrombi (Fig. 12.5). At an intermediary level, a new thrombus has a spongy appearance with noticeable echo reﬂection at the blood–thrombus interfaces. Such fresh thrombi may appear to “ﬂoat” inside the vein (Fig. 12.6). When

(b) Figure 12.5 (a) Fresh, barely detected hypoechoic and apparently unattached thrombus (arrow head) at the saphenofemoral junction. This classical “Mickey Mouse” appearance is formed by the common femoral vein (face), common femoral artery (right ear) and greater saphenous vein (left ear). (b) Old, hyperechoic and apparently attached thrombus in an enlarged saphenous vein (arrow head).

relatively acute and not attached to the wall, such thrombi may occasionally be seen to change position within the vein in response to compression or hemodynamic forces. As the thrombus ages, the ratio of black-to-gray echoes decreases. If a catheter is present inside a vein, it acts as a catalyst for thrombus formation, and a layer of mildly echogenic thrombus is observed alongside the catheter (Fig. 12.7). Once fresh thrombus ﬁlls the vein, the venous diameter enlarges and a diameter difference between the

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Figure 12.7 Experimental laboratory study showing catheter coated with thrombus. The catheter is in the center of the vein, pictured in longitudinal section. Flow is present between the catheter and the venous wall (arrows).

(a)

thrombosed vein and the corresponding contralateral vein may be observed. If recanalization occurs, the open lumen is usually surrounded by a thickened venous wall with an irregularly contoured ﬂow lumen (Fig. 12.8). Venous thrombosis stimulates development of collateral veins, and superﬁcial venous enlargement can occur as soon as the deep system becomes occluded. Small deep veins dilate and are noted by their tortuosity and irregular pathway through muscle. Thrombosis and thrombolysis may be occurring simultaneously. The inﬂammatory process dilates both arteries and veins adjacent to the thrombus. Fistula-like arterial ﬂow signals may be detected adjacent to the thrombosed vein or even inside the thrombolysing vein. Extended segments of thrombi may look hypoechoic in certain regions and hyperechoic in others. The research section below brieﬂy describes tissue characterization applied to thrombus analysis by computer. A note of caution is warranted regarding modern scans with the ability to depict blood cells while moving, or even stationary. A fuzzy, uniform, grainy image throughout the vein or localized in the central ﬂow channel is not indicative of thrombosis. Gain settings, color ﬂow conﬁrmation of ﬂow, and awareness of instrument characteristics may avoid false-positive results based on blood cell echogenicity.

(b) Figure 12.6 Unattached thrombi. (a) An apparently unattached thrombus (T) is seen at the saphenofemoral junction. Note that it is surrounded on both sides by nonechoic channels. (b) Floating tip of a thrombus (T) in the common femoral vein distal to the saphenous vein oriﬁce (S).

VENOUS FLOW Most Doppler spectra and color ﬂow ﬁndings are similar. A persistent lack of ﬂow signal indicates total obstruction. Lack of phasicity with respiration is indicative of venous

Laboratory quality assurance

Figure 12.8 Recanalization with wall thickening (W) and irregularities in a post-thrombotic deep vein. The diameter measured between markers is only 3.5 mm in a femoral vein that originally was 7 mm in diameter.

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The unreliability of ﬂow signal information in ruling out DVT and the difﬁculty of proving that ﬂow signals are being obtained from named, deep veins create an unacceptably high possibility of error in diagnosis. Furthermore, the ready availability of duplex scanning equipment capable of removing these variables makes the use of continuous-wave Doppler generally unwise. An exception might be the simple conﬁrmation of common femoral vein occlusion in a patient with clinical syndrome, suggesting the diagnosis of iliofemoral DVT or vena cava thrombosis, in a setting or time when vascular laboratory examinations are not available. This might be a useful test if applied either by a physician or by a technologist completely familiar with groin vascular anatomy, since the likelihood of anatomic variance producing false information in that speciﬁc anatomic locus is exceedingly small. Even so, subsequent examination and documentation by more reliable duplex scanning, also yielding formal recording of images, should be obtained.

LABORATORY QUALITY ASSURANCE

ﬂow obstruction. Decreased ﬂow augmentation after the release of proximal compression suggests venous obstruction proximal to the site of US observation. Decreased ﬂow augmentation following distal compression suggests either proximal obstruction or lack of blood distally, with the venous lumen taken up by the thrombus. Before an abnormal ﬁnding leads to a positive interpretation, the ﬂow test should be conﬁrmed by repeating with the knee and hip slightly ﬂexed at a different angle. Of the various signs observable by duplex scan for diagnosis of acute venous disease, ﬂow changes are the least reliable. Any presumed abnormal Doppler ﬁnding, either spontaneous or induced, should be conﬁrmed by additional observations before being heavily weighted. This is especially true when ruling out thrombosis. The reason for this is that even though the vein under observation may be 90% occluded by acute thrombus, even this small remaining patent portion of the lumen may allow sufﬁcient ﬂow to produce readily observable Doppler signals.

CONTINUOUS-WAVE DOPPLER Venous ﬂow signals may be detected by the use of simple, hand-held, continuous-wave Doppler ultrasound instruments readily available in many settings throughout most hospitals. In the author’s opinion, the use of such instrument for diagnosis of deep venous thrombosis has extremely limited value.

Duplex ultrasonography with B-mode imaging and Doppler, aided or not by color ﬂow, has become the standard of practice to evaluate the extremity veins. If the hospital or clinic has a vascular laboratory performing at the level required for Intersocietal Commission for Accreditation of Vascular Laboratories certiﬁcation, phlebography is probably being performed in far less than 10% of the patients. Thus, quality control issues are important for continuing validation of a test that is so necessarily dependent upon operator skills. There should also be formal comparison with phlebography whenever it may be obtained, realizing, however, that the patient set having contrast phlebograms represents a highly selected “problem” group. Blinded duplicate scanning programs by different technologists for a percentage of routine examinations also offers a method of documenting quality control of this important diagnostic test. Comparison of results obtained in serial examinations of the same patient has been reported as a means to discover conditions of higher or lower consistency of results.53 Systematic review by interpreting physicians is only a part of maintaining excellent results of scanning for DVT. Although complete physician review of negative examinations is probably not of practical value, all positive ﬁndings should be submitted for formal conﬁrmation by physician interpretation. Physicians who are responsible for interpretation of ﬁndings and vascular laboratory oversights should be knowledgeable in the techniques of venous duplex scanning and the equipment used. Eventually, technologists and physicians should obtain the certiﬁcations offered by the American Registry of Diagnostics Medical Sonographers.

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ACCURACY In the past, the results of venous ultrasonography for the detection of DVT have been extensively compared with phlebography. Accuracy greater than 90% has been consistently reported for detection of femoropopliteal thrombosis.32 A modern trend is to use duplex US to investigate various aspects of DVT in a variety of patient populations.2–27 Lower accuracies, in a widespread range from 50% to 90%, have been reported for calf vein thrombosis, and, in particular, in asymptomatic patients in the immediate postoperative period. These results are affected by several factors: ●

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technologists not as well trained in calf vein scanning, and often lacking experience; the use of scanners with insufﬁcient resolution; venous scanning below the knee avoided because it is time-consuming and uneconomical; existence of a mental attitude minimizing the importance of calf thrombosis, created by the myth that thrombus below the knee is not relevant; physical hindrances to the performance of the test, for example, orthopedic patients with casts, or patients with an awkward bed position; lack of regular serial tests in patients at risk, with thrombus developing after a negative study.

determine the grayscale. Additional data from different centers using distinct equipment is necessary to conﬁrm the utility of a GSM simple measurement as a means of calculating the age of a thrombus. Another research application would be to determine the degree of thrombus attachment to the wall. Figure 12.9 shows a thrombus that is apparently ﬂoating in the middle of the vein. An analysis similar to Lal’s55 pixel distribution analysis, however, suggested that the thrombus may already be connected to the wall on one side while still unattached on the other. A reason for the discrepancy between the human eye impression and the computer analysis is based on the great differences in the shades of grey: the human eye perceives far fewer shades of grey than the ultrasound scanner and the computer. A computer analysis may also emphasize that extended thrombi may have different ages at different segments. The age of the thrombus as a whole may not be as signiﬁcant as the age of the most dangerous segment of the thrombus. This research on grayscale analysis may inﬂuence not only diagnosis but also redirect treatment and development of more efﬁcacious medications.

Duplex ultrasound for detection of upper limb deep vein thrombosis yielded sensitivities in the 78–100% range and speciﬁcities in the 82–100% range, according to a recent literature review.26 The sample populations examined had different extents and locations of thrombosis, including axillary-subclavian DVT and complications of central venous catheters.

RESEARCH This section mentions brieﬂy ongoing research to characterize the B-mode imaging of venous thrombi. Clinical practice and computer analysis of animal experimental data have demonstrated that echogenicity increases with thrombus age.51,52 The same computer program used for carotid plaque characterization54 is being applied to grade venous thrombi (M. F. Cassou, personal communication). Based on clinical history and expert opinion of duplex venous examinations, the average grayscale median (GSM) of fresh, acute thrombi averages 25; however, the GSM increases as the thrombus ages. This GSM value is quite similar to that of carotid plaques posing a higher risk of embolization during endovascular procedures.54 Grayscale median values, however, are dependent on the selection of low (e.g., blood as zero) and high (e.g., arterial wall as 200) echo values to

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(b) Figure 12.9 Thrombus in the common femoral vein. (a) Grey scale suggesting that the thrombus is not attached to the wall. (b) Pixel analysis suggests that thrombus is attached to the wall with exception of the lower proximal tip. The computer analysis of a broader grey scale suggests that the thrombus is more attached to the wall than indicated by the human-eye impression.

References 139

Guidelines 2.2.0 of the American Venous Forum on duplex ultrasound scanning for acute venous disease No.

Guideline

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest)

2.2.1 Duplex ultrasound scanning is the standard of care to diagnose acute deep vein thrombosis of the limbs

1

A

2.2.2 Duplex examination for deep vein thrombosis should include three phases in each vein segment studied: thrombus visualization, venous coaptability or compressibility, and detection of venous ﬂow

1

A

2.2.3 Duplex scanning has an accuracy of ≥ 90% for detection of femoropopliteal thrombosis and a range of 50% to 90% for calf vein thrombosis

A

2.2.4 Duplex scanning for upper extremity DVT has a sensitivity between 78 and 100% and speciﬁcity between 82 and 100%

A

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19. De Silva DA, Pey HB, Wong MC, et al. Deep vein thrombosis following ischemic stroke among Asians. Cerebrovasc Dis 2006; 22: 245–50. 20. Igushi Y, Kimura K, Kobayashi K, et al. Ischaemic stroke with malignancy may often be caused by paradoxical embolism. Neurol Neurosurg Psychiatry 2006; 77: 1336–9. 21. Kulkarni S, Naidu R. Vascular ultrasound imaging to study immediate postcatheterization vascular complications in children. Catheter Cardiovasc Interv 2006; 68: 450–5. 22. Meissner MH. Axillary-subclavian venous thrombosis. Rev Cardiovasc Med 2002; 3 (Suppl 2): S76–33. 23. Hingorani AP, Ascher E, Markevich N, et al. Prospective evaluation of combined upper and lower extremity DVT. Vasc Endovasc Surg 2006; 40: 131–4. 24. Bernardi E, Pesavento R, Prandoni P. Upper extremity deep venous thrombosis. Semin Thromb Hemost 2006; 32: 729–36. 25. Ong B, Gibbs H, Catchpole I, et al. Peripherally inserted central catheters and upper extremity deep vein thrombosis. Australas Radiol 2006; 50: 451–4. 26. Sajid MS, Ahmed N, Desai M, et al. Upper limb deep vein thrombosis: a literature review to streamline the protocol for management. Acta Haematol 2007; 118: 10–8. 27. Hanson JN, Ascher E, Depippo P, et al. Saphenous vein thrombophlebitis (SVT): a deceptively benign disease. J Vasc Surg 1988; 27: 677–80. 28. Talbot SR. Use of real-time imaging in identifying deep venous obstruction. Bruit 1982; 6: 41–2. 29. Salles-Cunha S, Andros G. Atlas of Duplex Ultrasonography: Essential Images of the Vascular System. Pasadena, CA: Appleton Davies, 1988. 30. Barnes RW, Nix ML, Barnes CL, et al. Perioperative asymptomatic venous thrombosis: role of duplex scanning versus venography. J Vasc Surg 1989; 9: 251–60. 31. Killewich LA, Bedford GR, Beach KW, et al. Diagnosis of deep venous thrombosis. A prospective study comparing duplex scanning to contrast venography. Circulation 1989; 79: 810–14. 32. Talbot SR, Oliver MA. Techniques of Venous Imaging. Pasadena, CA: Appleton Davies 1991. 33. Muller C, Muller R, Andros G, et al. Pitfalls in the comparison of phlebographic and ultrasonic-based diagnosis in the evaluation of the lower extremity. J Vasc Tech 1992; 16: 136–9. 34. Beebe HG, Scissons RP, Salles-Cunha SX, et al. Gender bias in use of venous ultrasonography for diagnosis of deep venous thrombosis. J Vasc Surg 1995; 22: 538–42. 35. Lohr JM, James KV, Hasselfeld KA, et al. Vascular laboratory personnel on-call: effect on patient management. J Vasc Surg 1995; 22: 548–52. 36. Langsfeld M, Matteson B, Johnson W, et al. Baker’s cysts mimicking the symptoms of deep vein thrombosis: diagnosis with venous duplex scanning. J Vasc Surg 1997; 25: 658–62. 37. Drinan KJ, Wolfson PM, Steinitz D, et al. Duplex imaging in lymphedema. J Vasc Tech 1993;17: 26–8. 38. Gottlieb RH, Widjaja H. Clinical outcomes of untreated

39.

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45.

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48.

49.

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53.

symptomatic patients with negative ﬁndings on sonography of the thigh for deep vein thrombosis: our experience and a review of the literature. AJR Am J Rooentgenol 1999; 172: 1601–4. Mattos MA, Melendres G, Sumner DS, et al. Prevalence and distribution of calf vein thrombosis in patients with symptomatic deep venous thrombosis: a color-ﬂow duplex study. J Vasc Surg 1996; 24: 738–44. Passman MA, Moneta GL, Taylor LM Jr, et al. Pulmonary embolism is associated with combination of isolated calf vein thrombosis and respiratory symptoms. J Vasc Surg 1997; 25: 39–45. Cornuz J, Pearson SD, Polak JF. Deep venous thrombosis: complete lower extremity venous US evaluation in patients without known risk factors – outcome study. Radiology 1999; 211: 637–41. Labropoulos N, Webb K, Kang SS, et al. Patterns and distribution of isolated deep calf vein thrombosis. J Vasc Surg 1999; 30: 787–93. Gillet JL, Perrin MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007; 46: 513–9. Blebea J, Kihara TK, Neumyer MM, et al. A national survey of practice patterns in the noninvasive diagnosis of deep venous thrombosis. J Vasc Surg 1999; 29: 799–804. Ascher E, Depippo PS, Hingorani A, et al. Does repeat duplex ultrasound for lower extremity deep vein thrombosis inﬂuence patient management? Vasc Endovasc Surg 2004; 38: 525–31. Young L, Ockelford P, Milne D, et al. Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. J Thromb Haemost 2006: 4: 1919–24. Meissner MH, Caps MT, Zierler BK, et al. Deep venous thrombosis and superﬁcial venous reﬂux. J Vasc Surg 2000; 32: 48–56. Salles-Cunha, Wakeﬁeld T. Deep vein thrombosis: imaging modality options. In: Greenhalgh RM, ed., 27th Charing Cross International Symposium Towards Vascular and Endovascular Consensus. London: BIBA Publishing, 2005: 573–86. Ferrara F, Meli F, Amato C, et al. Optimal duration of treatment in surgical patients with calf venous thrombosis involving one or more veins. Angiology 2006; 57: 418–23. Lohr J. Upper extremity venous duplex imaging. In: Mansour MA, Labropoulos N, eds., Vascular Diagnosis. Philadelphia: Elsevier Saunders, 2005; 469–77. Salles-Cunha SX, Fowlkes JB, Wakeﬁeld TW. B-mode ultrasonographic quantiﬁcation of deep vein thrombi. J Vasc Technol 1994; 18: 207–9. Fowlkes JB, Strieter RM, Downing LJ, et al. Ultrasound echogenicity in experimental venous thrombosis. Ultrasound Med Biol 1998; 24: 1175–82. Salles-Cunha SX, Ascher E, Hingorani A, et al. Lower extremity deep venous thrombosis: vascular laboratory quality assurance without correlation between ultrasound and venography. Vasc Endovasc Surg 2004; 38: 443–7.

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54. Biasi GM, Froio A, Dietrich EB, et al. Carotid plaque echolucency increases the risk of stroke in carotid stenting: the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004; 110: 756–62.

55. Lal BK, Hobson RW 2nd, Pappas PJ, et al. Pixel distribution analysis of B-mode ultrasound scan images predicts histologic features of atherosclerotic carotid plaques. J Vasc Surg 2002; 35: 1210–7.

13 Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence BABAK ABAI AND NICOS LABROPOULOS Introduction Duplex ultrasound Obstruction Reﬂux Technique Role of duplex ultrasound in understanding the pathophysiology of chronic venous disease

142 142 143 144 148 149

INTRODUCTION Venous obstruction and reﬂux are the two pathologies that lead to venous hypertension, which causes the sequellae of chronic venous disease (CVD). Despite the high prevalence of CVD and the number of studies performed, the etiology of CVD is poorly understood. The challenge to the clinician is to ﬁnd a method to reliably evaluate a patient for CVD. The physical examination is useful. Many of the signs and symptoms of CVD can be detected by physical examination, but physical examination alone is not adequate. Phlebography, plethysmography and duplex ultrasound (DUS) are the main methods for evaluation of the venous system. Plethysmography is used in the assessment of the amount of reﬂux, the efﬁciency of the calf muscle pump, and obstruction. Phlebography is used when there is a need for endovenous therapy and deep vein reconstruction. Duplex ultrasound has become the test of choice for the evaluation of CVD in most patients as it is safe, non-invasive, cost-effective, and reliable. Although the evaluation of acute venous pathology has been discussed in Chapter 12, it must be mentioned that such pathology can recur in new or previously affected vein segments and can worsen the clinical severity of CVD. The CEAP classiﬁcation was developed by the American Venous Forum in 1994 and revised in 2004 to delineate the severity of CVD, improve standards for reporting, and develop treatment plans for various stages of the disease.1,2 It relies on the four components of clinical

Progression of chronic venous disease Recurrent varicose veins Use of duplex ultrasound before, during, and after treatment References

151 152 152 153

signs (C), etiology (E), anatomy (A), and pathophysiology (P). This classiﬁcation system is described in detail in Chapter 4. Both the physical examination and diagnostic tests are employed to report the patient’s condition before and after treatment.

DUPLEX ULTRASOUND The choice of the ultrasound probe is important. The pulse-wave Doppler of a 4–7 MHz linear array transducer is ideal for examination of most veins. Other multifrequency arrays can be used as well. The more superﬁcial veins can be evaluated using higher frequency probes that give better resolution. The deep veins and veins in obese patients are evaluated using a 3 MHz curvilinear probe that provides better depth of penetration. Lower frequency probes are also used to evaluate the venous system in the pelvis and abdomen. During imaging, low ﬂow settings are most commonly used. The pulse repetition frequency (PRF) is set at 1500 Hz or lower. In cases of vein stenosis or arteriovenous ﬁstulae the PRF is set higher since the ﬂow velocity is signiﬁcantly elevated in such situations. The focus is set with the posterior wall (far wall in relation to the skin) to allow better lateral resolution in the ﬁeld of imaging. The vein lumen should be set to appear dark in the absence of stasis and thrombosis. The time gain compensation (TGC) is set according to the echogenicity and depth of the relevant tissues to perfect the imaging of the pertinent

Obstruction

pathology. When obtaining velocity waveforms the gain is set to have a dark background to avoid overestimation. If the signal is weak because of depth the gain is increased accordingly. The angle of insonation in the venous system is often set at 0o. However, because most veins run parallel to the skin, if a precise velocity is needed then the angle has to be corrected to be parallel to the ﬂow channel. The examination room conditions should also be conducive to obtain optimal results. The room should be warm and comfortable in order to ensure there is no spasm of veins at the time of examination and the veins are at the natural size.

OBSTRUCTION Obstruction in the venous system can occur from extrinsic and intrinsic pathologies. Tumors, hematomas, cysts, aneurysms and musculoskeletal structures can cause extrinsic vein compression. However, the most common cause of obstruction is venous thrombosis. Its diagnosis is critical, as deep vein thrombosis (DVT) is obviously a signiﬁcant cause of long-term morbidity and premature mortality in those afﬂicted with the disease. The long-term consequences of DVT are devastating in terms of numbers and cost of care. Post-thrombotic syndrome (PTS) is a term used to describe the sequellae of CVD. The typical ﬁndings are pain, a burning sensation, itching, varicose veins, chronic limb swelling, skin discoloration and ulceration. After a single episode of DVT, the incidence of PTS has been reported to be from 23% to 79%. A large prospective study showed an incidence of about 25% at 5 years.3 Ipsilateral recurrent DVT has shown to increase the odds for developing PTS by six times.3 Duplex ultrasound evaluation of the veins can determine the presence of anatomic obstruction with a sensitivity and speciﬁcity of over 90%.4 The evaluation of functional obstruction cannot be achieved with DUS as it assesses a single vein segment at a time. Unfortunately, it is difﬁcult to measure functional obstruction since there are no validated tests to quantify functional obstruction. Duplex techniques for evaluation of chronic venous disease are similar to those used in the evaluation of acute venous thrombosis. In chronic disease states the major veins might be chronically obstructed. Collateralization and recanalization may also occur. The major veins are seen in immediate proximity to the corresponding artery. If a vein is seen more than 1 cm away from the artery, one must consider the possibility of a dilated collateral vein. Normal venous Doppler signals are obtained in cases where full recanalization has occurred or in the presence of duplicated veins that were unaffected by the thrombotic process. The popliteal vein is duplicated in 35–40% and occasionally is triplicated. The femoral vein in the thigh is duplicated in about 25–30% of people, and this duplication may have different patterns along the course of the vein. The veins in the calf are often paired around

143

the corresponding artery. A single calf vein or a triplication may also be found. Aplasia of the posterior tibial veins has also been reported. In cases of venous duplication or aplasia, direct visualization, attention to detail, and experience with the ultrasound techniques are invaluable to reduce erroneous results. Venous ultrasound studies are reasonably well standardized. In brief, the patient is placed on the examination table in the reverse Trendelenburg position. The knee is bent and externally rotated. The examination is started below the inguinal ligament at the common femoral vein and saphenofemoral junction (SFJ). The probe is placed in transverse direction to the vein and compression is applied. The probe is then turned longitudinally to evaluate for ﬂow and augmentation. The veins are examined in 3–5 cm intervals. In a similar manner, all the deep veins of the leg including the femoral, deep femoral, popliteal, peroneal, soleal, gastrocnemial, anterior and posterior tibial veins are examined for obstruction. The superﬁcial veins including the great saphenous vein (GSV) and small saphenous (SSV) are then evaluated. Finally, in cases of obstruction, it is important to check the iliac veins and the inferior vena cava. In abdominal and pelvic veins mainly ﬂow is evaluated since compression can be difﬁcult and uncomfortable for the patient. Asymmetry in ﬂow velocity, waveform patterns at rest and during ﬂow augmentation in the common femoral veins indicate proximal obstruction. However, the absence of the asymmetry does not exclude obstruction. Therefore, when iliocaval obstruction is suspected the full extent of these veins must be imaged. The presence of stenosis, usually from extrinsic compression, is recognized by a mosaic color pattern that denotes post-stenotic turbulence, abnormal Doppler waveform at the area of stenosis, slow ﬂow, spontaneous contrast, and vein dilatation prior to the stenosis.5 The vein diameter reduction can be measured by planimetry, comparing the smallest lumen to the normal lumen. Peak vein velocity (PVV) ratios comparing intrastenotic to prestenotic peak velocities, or comparing poststenotic to prestenotic peak velocities can be calculated. In patients with a pressure gradient across the stenosis ≥ 3 mmHg, the PVV ratio has shown to be > 2.5.5 The four components that should be examined in all venous duplex examinations are visualization, compressibility, ﬂow, and augmentation. There are ways to potentially distinguish acute obstruction from chronic obstruction (Table 13.1). The veins with acute thrombosis are echolucent, distended, and have smooth walls. In chronic thrombosis the veins are echogenic, contracted, and have thick irregular walls (Fig. 13.1). Acute thrombus is “spongy” on compression examination but it will still keep the walls of the vein from coapting with probe compression. Chronic thrombus is more ﬁrm. On the color ﬂow examination, acute thrombus will have conﬂuent ﬂow channels. Chronic thrombus will either have multiple channels or collateralization. Intraluminal

144

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence

Table 13.1 Duplex ultrasound (DUS) criteria used to differentiate acute versus chronic obstruction Acute (days to weeks)

Subacute (weeks to months)

Chronic (months to years)

Size

Distended

No longer distended due to lysis

Echogenicity

Echolucent: acute thrombi do not contain dense material

Moderate echogenecity: increased cellular components

Lumen characteristics

Recanalization with adherence of residual thrombus to vein wall

Wall characteristics

The lumen is non- or partially compressible and often has spongy feel on compression Thin and smooth

Flow characteristics

Absence of ﬂow/ﬁllings defects

Partial recanalization

Reduced; sometimes unable to be traced by DUS Echogenic: as the clot ages ﬁbroblasts and collagen deposits form Partial recanalization with ﬁlling defects and reﬂux may be present Thickening with luminal reduction due to inﬂammatory response from the thrombus Partial recanalization with reﬂux. Enhanced ﬂow in dilated collateral veins

Thrombus characteristic

Presence of tail

Collateral veins

Absent

Decreased linear extension of thrombus May be present

Thickened

Often found around the obstructed segments

webs and wall thickening with or without reﬂux indicate a previous thrombosis in the absence of visible thrombus. The presence of dilated collateral veins indicates the presence of obstruction but, unfortunately, their absence cannot exclude it. It is also possible for the veins to be fully recanalized without any evidence of anatomic obstruction. However, the thickening and increased stiffness of the vein wall can still result in functional obstruction. Signs and symptoms in both lower extremities are present when there is bilateral iliac vein obstruction or when the inferior vena cava (IVC) is involved. The iliac

veins and IVC may have extrinsic compression from masses (Fig. 13.2). The extrinsic compression can lead to signs and symptoms of CVD. In such patients, thrombosis of the compressed vein is a common event.

(a)

(b)

REFLUX Venous reﬂux is the reversal of ﬂow in the veins of the lower extremity. The reversal of ﬂow in the vein can be subdivided into physiologic and pathologic. Physiologic

Figure 13.1 (a) Acute thrombosis in the common femoral vein. There is absence of color, the vein is dilated (twice the size of the adjacent common femoral artery in red) with a homogeneous echolucent texture. (b) Acute on chronic thrombosis in the soleal vein in a patient with recent calf pain. The vein is dilated and has echogenic material (old thrombus), and echolucent material (fresh thrombus).

Reﬂux 145

(c)

(d)

(e)

(f)

(g)

(h)

Figure 13.1 (contd) (c) Chronic thrombus with partial recanalization in the great saphenous vein. Flow channels with reﬂux are seen over the old thrombus that appears as an echogenic band in the lumen. (d) Complete recanalization with prolonged reﬂux in the popliteal vein. Thickening is seen in the far wall. (e) Chronic iliofemoral occlusion with collaterals from the inferior epigastric and internal iliac veins. (f) Chronic IVC obstruction with partial recanalization. The lumen of the IVC is smaller than the adjacent aorta. The azygos vein is dilated and larger than the aorta. (g) Non-phasic ﬂow in a groin collateral in a patient with iliofemoral occlusion. (h) Chronic occlusion of the external iliac vein in a female patient who underwent stenting for previous thrombosis. Flow is seen in the adjacent artery. The vein has a small diameter and echogenic material in the lumen. The stent is seen in both the near and the far wall as an echogenic rim between the wall and the thrombus.

146

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence

(a)

(b)

Figure 13.2 (a) Bilateral swelling in a patient with inferior vena cava (IVC) compression. Notice the pitting edema in both limbs after digital compression over the tibia. (b) Compression of the IVC by a tumor at the level of the liver. The lumen of the IVC at the site of compression measured 0.4 mm whereas the normal distal segment measured 1.4 mm. The color changes from blue in the normal portion of the IVC to white at the area of compression indicating signiﬁcant vein stenosis.

reversal of ﬂow accounts for the fraction of the second it takes for the valve leaﬂets to appose. A prospective study has demonstrated that the acceptable physiologic reversal of ﬂow is different for various venous systems in the lower limb.6 The cut-off value for reﬂux in the author’s experience in the common femoral, femoral, and popliteal veins is > 1000 ms. For the superﬁcial veins, deep femoral, deep calf axial, and muscular veins the value is 500 ms and in the perforating veins it is 350 ms. It is postulated that in the larger veins with fewer valves, the time it takes for the

valve leaﬂets to come together is longer in comparison to smaller, shorter veins. As an international consensus, a reﬂux of ≥ 0.5 second is accepted as abnormal. Different patterns of reﬂux are displayed in Fig. 13.3. It is important to differentiate between primary, secondary, and congenital reﬂux. This classiﬁcation is based on the pathophysiology of the reﬂux. Congenital reﬂux exists since birth but is rarely recognized early since there is a lag in the presenting signs and symptoms. Secondary reﬂux is most often the result of thrombosis.

(a)

(b)

Figure 13.3 (a) Normal saphenofemoral junction. During distal augmentation there is ﬂow towards the heart (negative deﬂection as blood traveling away from the transducer). After release of the compression there is a short duration of retrograde ﬂow until the valve is closed. (b) Prolonged reﬂux in the great saphenous vein (GSV) below the knee. The vein has a normal diameter indicating that a vein does not have to be dilated when it is incompetent. This patient was class 2 according to CEAP and she was asymptomatic.

Reﬂux 147

(c)

(d)

(e)

(g)

(f) Figure 13.3 (contd) (c) Reﬂux in the popliteal, medial gastrocnemial, and small saphenous vein (SSV). This patient had a chronic thrombosis that was fully recanalized. He presented with CEAP class 4 and had pain and itching. (d) Reﬂux in a lower calf medial perforator in a patient with a healed ulcer (C5). The vein was dilated (> 6 mm) and had prolonged outward ﬂow. (e) Crosssectional view of a focal dilation in the lower thigh GSV with a frozen valve seen at the 4 o’clock position. (f) Dilation of the SSV in the upper calf with wall thickening in a patient with skin changes, edema, and varicose veins in the posterior calf. The diameter of the SSV measured 8 mm and the reﬂux duration was longer than 5 seconds. (g) Prolonged reﬂux from the medial gastrocnemial vein to the SSV. The SSV was incompetent from its union with the gastrocnemial vein at mid-calf to the lateral malleolus. The proximal SSV was normal.

148

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence

The most common type of reﬂux is primary where the cause has not been determined. Two studies that have used the CEAP classiﬁcation to investigate the causes of CVD, showed that congenital accounts for 1–3% of CVD, secondary reﬂux 18–28% of CVD, and primary reﬂux 64–79% of CVD.7,8

TECHNIQUE Reﬂux can be elicited in two ways. During the Valsalva maneuver the intra-abdominal pressure is increased and this can lead to reversal of ﬂow if there is valvular incompetence. This technique is mainly useful in the evaluation of valves in the groin, as competent valves proximally will limit its usefulness. Compression and release distal to the point of examination on the limb is a reliable method of evaluating reﬂux and is referred to as augmentation. With compression there is an initial increase ﬂow in the vein as the blood is pushed in the normal direction of ﬂow from distal to proximal. Once the pressure is released, the blood ﬂow reverses momentarily. If there are competent valves there is minimal to no back ﬂow. However, with incompetent valves the blood continues to ﬂow in the reverse direction. For the purposes of more precise measurement and stan-

dardization, the technique used by van Bemmelen and associates is necessary.9 The use of automated pneumatic cuffs with rapid inﬂation and deﬂation is also essential. The cuff is placed around the leg 5 cm below the probe site. A 24 cm cuff is used around the thigh, a 12 cm cuff around the calf, and a 7 cm cuff around the foot. The inﬂation lasts for 3 seconds followed by rapid deﬂation in 0.3 seconds. To ensure complete venous emptying and overcome the hydrostatic pressures from above, thigh cuffs are inﬂated to 80 mmHg, those on the calf to 100 mmHg, with 120 mmHg required for foot cuffs. Occasionally in patients with signiﬁcant edema, the above techniques are inadequate and dorsi/plantar ﬂexion is also used. To obtain the best results, the examination should start with the patient in the standing position, with the weight of the patient on the contralateral limb. The limb of interest should be slightly ﬂexed and externally rotated. If a patient is unable to stand for the time required the veins from the mid-thigh and below can be assessed in the sitting position. If the test is performed on a bed the torso should be elevated > 45 degrees. A tilt-table with a leg rest to keep weight on the contralateral limb and reﬂected backwards into a 60 degree position is another technique that can be used for reﬂux measurements. The routine examination of the veins of the lower extremity starts at the common femoral vein above the

C1–4S EP AS+P+D PR+O

C1–3A EP AS+P PR Right

Left

R R

N R R

R R

R

N R

N

R

R

R R

LT: POPV + MGV partial recanalization with reflux

N R

Figure 13.4 Report of a duplex ultrasound examination in a patient with bilateral chronic venous disease (CVD). She was a 53-year-old female with two pregnancies and a positive family history of CVD in both parents. She noticed signs and symptoms of CVD after her second pregnancy, ﬁrst in the left lower extremity and 2 years later in the right lower extremity. She had also developed thrombosis in the left lower extremity 7 years previously. POPV, popliteal vein; MGV, medial gastrocnemial vein.

Role of duplex ultrasound in understanding the pathophysiology of chronic venous disease 149

junction of the femoral and deep femoral veins. The SFJ at the terminal and preterminal valve and the associated tributaries are examined next. This is followed by the popliteal and the deep calf veins. The GSV, SSV their tributaries, and non-saphenous veins are examined in detail as these are the most common sites of reﬂux. The GSV can be identiﬁed and differentiated from other superﬁcial veins because it is surrounded by two layers of fascia in the saphenous eye.10,11 The SSV is found in the triangular fascia and is surrounded by the crural fascia and the medial and lateral heads of the gastrocnemius muscle.12 The tributaries of the superﬁcial veins that are often incompetent in the thigh are the anterior and medial accessory veins and, in the calf, the posterior and anterior arch veins. These veins should be examined along their full length if they are incompetent. Duplication of the saphenous veins is rare: < 3% of patients with CVD.13 The most common anatomic variations of the saphenous veins are segmental hypoplasia and aplasia.14 Accessory veins to assure good venous drainage are frequently found close to such segments.15 Perforating veins (PVs) are the last to be examined. They can be distinguished from the superﬁcial and deep veins since they course perpendicular to these veins and pierce the deep fascia. The deep fascia is dense and echogenic and can be easily visualized on the ultrasound scan. There are approximately 150 PVs in the lower extremity, of which only 20 are of clinically signiﬁcant in terms of reﬂux possibly leading to clinical pathology.16 The normal direction of ﬂow is from superﬁcial to the deep veins through the PVs. These veins are examined using transverse and oblique scanning since their long axis is seen in these planes. They are found by following the course of the GSV, the SSV, and the tributaries. Outward ﬂow in these veins is seen only in the presence of superﬁcial and deep vein reﬂux. The results of the ultrasound examination in patients with CVD are often depicted in drawings. An example of this is given in Fig. 13.4. The left and right lower extremities have been drawn to scale and have skin, muscular, and bony landmarks such as the popliteal skin crease, sartorious muscle, knee, and medial malleolus, etc. Such drawings allow better understanding and interpretation of the ﬁndings and therefore facilitate the planning of treatment in each limb.

ROLE OF DUPLEX ULTRASOUND IN UNDERSTANDING THE PATHOPHYSIOLOGY OF CHRONIC VENOUS DISEASE The majority (70–80%) of patients presenting with CVD are symptomatic. These symptoms include itching, ache, restless limb, heaviness, burning, and ulceration. Varicose veins and telangiectasias are present in 80% of patients. Skin changes of some sort are seen in 20–25% and active or healed ulcerations in 12–14% of patients with CVD

Class 0 Class 1 Class 2 Class 3 Class 4 Class 5 Class 6

1.3 5.9 38.3 20.4 21.6 4.3 8.2

Primary Secondary Primary secondary Congenital

68.3 24.7 6.1 0.9

Superficial Perforating Deep

90.7 24.2 28.8

Reflux Obstruction Reflux obstruction

81.6 1.8 16.7

0

10

20

30

40

50

60

70

80

90

100

Figure 13.5 Presentation of 1000 consecutive limbs with chronic venous disease according to the CEAP classiﬁcation.

(Fig. 13.5). Patients with C1 and C2 disease have reﬂux conﬁned to the superﬁcial system. As the clinical severity worsens (C3–6), the prevalence of incompetence in the perforator and deep veins increases. In limbs with CVD, reﬂux alone exists in 80% of patients, reﬂux and obstruction are present in 17% of patients and only 2% of patients have obstruction alone.7,8 In addition, the combination of reﬂux and obstruction has the worse prognosis for development of skin lesions.17 The most common location of reﬂux in patients with CVD is the superﬁcial veins irrespective of clinical class. These veins are affected in 90% of patients. Of the superﬁcial veins, the GSV is involved in 70–80% of cases, the SSV is involved in 15–20%, and non-saphenous veins in about 10%. The deep system in only affected in 30% of patients with CVD, and the PVs in 20%.7,8 Complex patterns of reﬂux are present in patients with skin damage.18 Several studies have demonstrated that reﬂux in the superﬁcial system alone is the cause of venous ulcerations in 17–54%. Of all limbs with venous ulceration, 74–93% have reﬂux in the superﬁcial system.19–23 Superﬁcial reﬂux, with or without perforator reﬂux, is present in more than 50% of patients with ulceration. This subclass of patients will beneﬁt from intervention directed towards the superﬁcial venous system.24 Isolated deep vein reﬂux occurs in < 10% of patients.22–25 Among the deep veins, popliteal vein reﬂux has the strongest association with the severity of CVD. Two vein systems are involved in ulcerated limbs in 52–70% of patients, and all three systems are involved in 16–50% of patients.22–25 The veins that are in the ulcer bed or within 2 cm of the ulcer have reﬂux in 86% of cases. However, perforator vein reﬂux is found only in a third of cases in this area.22 Saphenous reﬂux can occur without SFJ and SPJ (saphenopopliteal junction) incompetence, and therefore ligation of these junctions may not be appropriate in such patients.26–28 In 2.6–4% of patients no reﬂux or obstruction is found in any of the systems. In these patients, other causes of ulceration should be evaluated.23,29 It has been shown that saphenous hypoplasia occurs in varicose limbs more frequently than in healthy ones

150

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence

(P > 0.001). It greatly inﬂuences the path of the reﬂux and the anatomy of the varicose veins. Great saphenous vein segmental hypoplasia can be detected preoperatively by duplex ultrasonography. Its occurrence may inﬂuence surgical management for two main reasons: in about 68% of varicose limbs with segmental hypoplasia, the distal GSV is competent; if the distal GSV is incompetent, its size and ﬂow direction is normalized by treating the accessory vein that bypasses the hypoplastic segment.15 Several patterns of reﬂux in the superﬁcial veins are worthy of discussion as treatment of the saphenous trunks may be avoided. In fact, there are occasions where both the GSV and SSV should be spared. An incompetent anterior accessory vein with or without involvement of the SFJ in

(a)

(c)

the absence of GSV reﬂux is found in 9% of patients.30 After treating the anterior accessory vein, at 1 year followup no patients had reﬂux in the GSV and 95% were satisﬁed with the treatment. In a large series of patients with reﬂux in the SSV system, 3.1% had incompetence in the thigh extension of the SSV only.13 In another series where the thigh extension was studied, great saphenous vein and SSV system, reﬂux was found in 4.7%.31 Reﬂux in tributaries alone was detected in 9.7% of limbs with CVD. The most common site was the posterior arch vein.32 Reﬂux in non-saphenous veins, such as the vulvar, gluteal, posterolateral thigh, and other locations, is found in 10% of limbs with CVD.33 These are mostly multiparous female patients with a mean of three

(b)

(d)

Figure 13.6 Examples of reﬂux in non-saphenous veins. (a) Varicose tributaries are seen in the right popliteal fossa of a male patient who presented with pain and itching. The varicosities disappear above the popliteal skin crease as they dive deeper to join the popliteal vein. (b) Signiﬁcant reﬂux in the vein of the popliteal fossa of the same patient. The vein is dilated and varicose and pierces the deep fascia just above the popliteal skin crease. It unites with the lateral aspect of the popliteal vein above the saphenopopliteal junction. (c) Reﬂux in the dilated and tortuous veins of vastus medialis muscle. These veins were connected with a perforating vein at the lower thigh that was in continuity with posteromedial varicose tributaries. (d) Left ovarian vein reﬂux in a 24-year-old woman with three pregnancies. She presented with left vulvar veins that were extending from the groin medial to the GSV to the posterolateral calf. The ovarian vein measured 8.8 mm in diameter.

Progression of chronic venous disease 151

pregnancies. On all of these occasions, treatment can be targeted by ultrasound and the saphenous veins spared. Reﬂux in non-saphenous veins is seen in Fig. 13.6. It has been suggested that in patients with primary reﬂux in the superﬁcial and deep system, deep venous reﬂux may be directly linked to superﬁcial reﬂux. The reﬂux circuit theory of venous overload states that reﬂux in the superﬁcial system at the level of the perforators and major superﬁcial to deep vein junctions will ﬂow into the deep system and overload the deep system. This leads to dilatation and development of reﬂux in the deep system. Two studies have demonstrated that by surgically correcting the reﬂux in the superﬁcial system, the deep system reﬂux is also eliminated in more than 90% of the patients.34,35 In a prospective study, deep reﬂux in patients with primary CVD was shown to occur near the SFJ, SPJ, and gastropopliteal junction.36 It was more likely to occur when the reﬂux at these junctions had high peak velocity and long duration. The reﬂux in the deep veins was usually segmental and of shorter duration than post-thrombotic reﬂux. Most PVs have at least one subfascial bicuspid valve that prevents reﬂux from the deep system to the superﬁcial system. The role of PV incompetence in development of signs and symptoms of CVD remains unclear. However, there is evidence to suggest that the number of incompetent PVs and the size of competent and incompetent PVs increase with worsening CVD.37,38,39 It has also been reported that patients with increasing numbers of incompetent PVs have a higher venous ﬁlling index. The venous ﬁlling index is known to correlate well with the severity of CVD.39 Perforating vein incompetence occurs more in the calf than in the thigh.19,37–39 There are more incompetent PVs found in the lower and middle thirds of the medial calf. Most PVs that are > 3.5 mm in diameter will be incompetent.37,40 The sensitivity of the size alone to determine incompetence is, however, low as about a third of the reﬂuxing PV have a diameter < 3.5 mm. The duration of outward ﬂow and local hemodynamics worsen in PVs when both the superﬁcial and deep veins connected to those PVs are incompetent.37,41 The development of new PV reﬂux is closely related to reﬂux in the superﬁcial system.42 In primary CVD, reﬂux in PVs develops in an ascending manner through the adjoining incompetent superﬁcial vein, in a descending manner from the reentry ﬂow of a reﬂuxing superﬁcial vein, and in new locations where the superﬁcial veins are also involved. The correction of reﬂux in the superﬁcial system has been shown to eliminate reﬂux in the PV. This is not the case when the deep system is incompetent.43 In a prospective study where PVs were treated with surgical ligation using DUS guidance, it was shown that recurrence of PV at 3 years was very common (76%).44 The recurrent PVs were due to neovascularization or the development of incompetence in new sites and not because of poor surgery. Duplex ultrasound can also identify other uncommon pathologies in the veins such as aneurysms, tumors and

phlebosclerosis (Fig. 13.7). These pathologies are not usually associated with signs and symptoms of CVD unless there is concomitant reﬂux or obstruction. However, their diagnosis is important and can alter management.

PROGRESSION OF CHRONIC VENOUS DISEASE It was previously hypothesized that because of hydrostatic pressure, reﬂux must start at the level of the iliac or common femoral valves and develop in a retrograde

(a)

(b) Figure 13.7 (a) Cross-sectional view of an anterior accessory saphenous vein aneurysm in the upper thigh measuring 23 mm. The adjacent vein segment that is partially seen at the 7 o’clock position measured 3.4 mm. The aneurysm is free of thrombus as seen from the echolucent lumen. This was also documented by its full compressibility. (b) Dense calciﬁcation of the great saphenous vein (GSV) near wall in the lower thigh. Acoustic shadowing is seen throughout the calciﬁcation. Phlebosclerosis occasionally is seen in the lower extremity veins and has no signiﬁcant implications in contrast to calciﬁcation in intestinal veins that may lead to signiﬁcant morbidity.

152

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence

manner. However, studies on the morphology, biochemistry, and function of the venous wall have demonstrated that changes can occur in any vein segment irrespective of the site and function of the valves.45–50 With the use of DUS it has been clearly shown that in the early stages of CVD reﬂux develops in most people in the lower thigh, knee, and calf without having a connection to the groin area.26 Reﬂux therefore may have an ascending or descending progression or both, or it can be multifocal. These ﬁndings are further supported by a recent study that examined patients below the age of 30 years with varicose veins and compared them with another group of patients over the age of 60 years.51 It was shown that most often the saphenous and non-saphenous tributaries are diseased and this was more common in younger patients. Junctional involvement was signiﬁcantly less prevalent in the younger group (38 vs 59%, P = 0.0005). The progression of reﬂux in CVD and its relation to physical ﬁndings have been examined in a study that followed 116 limbs in 90 patients.52 These patients had two or more DUS examinations prior to operation since the procedure was delayed for various reasons. It was demonstrated that in 73.3% of patients there was no change in the DUS examination and extent of reﬂux. In 13 limbs there was advancement of CEAP staging, of which seven also had progression on DUS as well. Progression of reﬂux was seen in 26.7% of patients. These results indicated that physical examination or DUS alone were not reliable in predicting the progression of disease. Progression of reﬂux occurred mostly with anatomic extension in an ascending or descending manner, and in both directions. Few patients developed reﬂux in a different area.

RECURRENT VARICOSE VEINS In 1998 an international committee met in Paris to establish guidelines for recurrent varices after surgery (REVAS). Their ﬁndings and classiﬁcation was to supplement the CEAP system taking into account intervention. This system accounts for true recurrence, residual disease, and progression of existing disease. The prevalence of REVAS has been reported to be 20–80%.53 Perrin and colleges54 performed a multicenter study to evaluate the etiology, pathophysiology, and progression of disease in REVAS. They enrolled 170 patients with 199 affected limbs in 14 different institutions during the period of 1 year. The areas most involved by recurrent reﬂux in these patients were the SFJ in 47% of patients and the perforators in 55% of the limbs. Recurrent reﬂux resulted from technical failure to ligate the SFJ, neovascularization in cases of SFJ disease, and failure to recognize signiﬁcant diseased perforators in the preoperative evaluation. In addition, more patients tended to have below-knee reﬂux after their procedures than thigh reﬂux. This is because the

entire GSV is often obliterated or removed above the knee, and the veins below the knee are simply ligated or stripped. Technical failure occurred in 19% of patients, and neovascularization occurred in 20%. A combination of the two was seen in 17% of the patients. In 35% of the recurrences, the cause was unknown. Recurrence developed in a new site in 32% of the limbs. Family history had the highest prevalence of recurrence (68%). This is not a surprising ﬁnding since the strong relationship between hereditary and venous disease has been established.55 Women tended to have more procedures to correct recurrence than men, even though the severity of recurrence was greater in men.

USE OF DUPLEX ULTRASOUND BEFORE, DURING, AND AFTER TREATMENT The role of DUS in diagnosis and evaluation of venous obstruction and reﬂux has been described. Duplex ultrasound also can be used as an adjunctive tool during therapy and for follow up. The type of treatment is based on the baseline DUS. In the ﬁrst examination a map is made of the distribution and extent of reﬂux and obstruction. Based on the ﬁndings and the type of disease, other tests may be necessary to further delineate the treatment plan. This will occur in a deep vein reconstruction, endovenous or bypass operations to relieve obstruction, and in the treatment of pelvic vein reﬂux.56 The effect of the procedure at a local level, i.e., improvement, elimination, or worsening of the reﬂux and obstruction can be documented. Also, the effect of the procedure in veins proximal and distal to the site of the treatment can be assessed. However, DUS evaluates a short venous segment at the time. The overall effect of the treatment in the limb can be assessed better with physiologic testing such as plethysmography and pressure measurements. Endovenous treatment of the superﬁcial veins and PVs by ablation or sclerotherapy is now performed with DUS guidance. The vein diameter, proximity to the skin, tortuosity, obstruction, and areas with hypoplasia and aplasia are important to document in order to have a good treatment plan.57 During the procedure, DUS is used to obtain percutaneous venous access and guides the wire and catheters. Accurate positioning for the treatment area of interest is easily achieved as the tip of the catheter is placed in the correct location safely. Before the ablation takes place, the tumescence ﬂuid is injected around the vein. The goal is to create a halo sign over the entire length of the treated segment with the vein being collapsed around the catheter. Enough ﬂuid is injected around the vein to protect the surrounding structures and the skin from thermal damage. During the catheter pull back the immediate effect on the vein can be observed. The vein is reexamined at the end of the procedure to ensure complete

References 153

Guidelines 2.3.0 of the American Venous Forum on duplex ultrasound scanning for chronic venous obstruction and valvular incompetence No.

Guideline

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest)

2.3.1 Duplex scanning is recommended as the ﬁrst diagnostic test for all patients with suspected chronic venous obstruction or valvular incompetence. The test is safe, non-invasive, cost-effective, and reliable

1

A

2.3.2 The four components that should be included in duplex scanning examinations for chronic venous disease are visualization, compressibility, venous ﬂow, and augmentation

1

A

2.3.3 Duplex scanning is suggested to distinguish acute from chronic venous occlusion

2

B

2.3.4 Reﬂux can be elicited in two ways: increased intra-abdominal pressure using a Valsalva maneuver or manual or cuff compression and release of the limb distal to the point of examination

2

B

2.3.5 We recommend that the cut-off value for abnormally reversed venous ﬂow (reﬂux) is 500 ms

1

B

ablation and that the saphenous junctions and deep veins are free of thrombus. If adjunct procedures are performed, such as phlebectomies or sclerotherapy, DUS can also be used to guide that treatment as well. In many centers various forms of sclerotherapy are being performed as a sole treatment and this is also carried out under DUS guidance.58,59 Follow-up of endovenous therapy is important to monitor its success, identify complications, and also to treat recurrent or new sites when deemed appropriate by the patient and the specialist. It has been demonstrated that to alleviate the symptoms of CVD, it is essential to diagnose obstruction and reﬂux. Early treatment should aim to improve the patient’s condition and prevent recurrence.60 Duplex ultrasound has an important role in diagnosis, treatment, and followup of patients with CVD.

●3.

●4.

5.

●6.

7.

8.

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chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep vein thrombosis. Ann Intern Med 1996; 125: 1–7. Kearon C, Julian JA, Math M, et al. Noninvasive diagnosis of deep venous thrombosis. McMaster diagnostic imaging practice guidelines initiative. Ann Intern Med 1998; 128: 663–677. Labropoulos N, Borge M, Pierce K, Pappas PJ. Criteria for deﬁning signiﬁcant central vein stenosis with duplex ultrasound. J Vasc Surg 2007; 46: 101–7 Labropoulos N. Tiongson J. Pryor L, et al. Deﬁnition of venous reﬂux in lower-extremity veins. J Vasc Surg 2003; 38: 793–8. Kistner RL, Eklöf B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the “CEAP” classiﬁcation. Mayo Clin Proc 1996; 7: 338–45. Labropoulos N. CEAP in clinical practice. Vasc Surg 1997; 31: 224–225. Van Bemmelen PS, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reﬂux with duplex ultrasound scanning. J Vasc Surg 1989: 10: 425–31. Caggiati A. Fascial relationships of the long saphenous vein. Circulation 1999; 100: 2547–9. Caggiati A, Bergan JJ, Gloviczki P. International Iterdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement. J Vasc Surg 2002; 36: 416–622.

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12. Caggiati A. Fascial relationships of the short saphenous vein. J Vasc Surg 2001; 34: 241–6. 13. Labropoulos N, Giannoukas AD, Delis K, et al. The impact of isolated lesser saphenous vein system incompetence on clinical signs and symptoms of chronic venous disease. J Vasc Surg 2000; 32: 954–60. 14. Caggiati A, Ricci S. The caliber of the human long saphenous vein and its congenital variations. Anat Anz 2000; 182: 195–201. 15. Caggiati A. Mendoza E. Segmental hypoplasia of the great saphenous vein and varicose disease. Eur J Vasc Endovasc Surg 2004; 28: 257–61. 16. van Limborgh J. L’anatomie du système veineux de l’extremite inférieure en relation avec la pathologie variqueuse. Folia Angiol 1961; 8: 240–57. 17. Johnson BF, Manzo RA, Bergelin RO, Strandness DE Jr. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995; 21: 307–12. 18. Labropoulos N, Patel PJ, Tiongson JE, et al. Patterns of venous reﬂux and obstruction in patients with skin damage due to chronic venous disease. Vasc Endovasc Surg 2007; 41: 33–40. 19. Labropoulos N, Delis K, Nicolaides AN, et al. The role of the distribution and anatomic extent of reﬂux in the development of signs and symptoms in chronic venous insufﬁciency. J Vasc Surg. 1996; 23: 504–10. 20. Labropoulos N, Giannoukas AD, Nicolaides AN, et al. The role of venous reﬂux and calf muscle pump function in non-thrombotic chronic venous insufﬁciency: correlation with severity of signs and symptoms. Arch Surg 1996; 131: 403–6. 21. Labropoulos N, Leon M, Geroulakos G, et al. Venous haemodynamic abnormalities in patients with leg ulceration. Am J Surg 1995; 169: 572–4. 22. Labropoulos N, Giannnoukas AD, Nicolaides AN, et al. New insights into the pathophysiologic condition of venous ulceration with color-ﬂow duplex imaging: Implications for treatment? J Vasc Surg. 1995; 22: 45–50. 23. Hanrahan LM, Araki CT, Rodriguez AA, et al. Distribution of valvular incompetence in patients with venous stasis ulceration. J Vasc Surg. 1991; 3: 805–12. 24. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004; 363: 1854–9. 25. Yamaki T, Nozaki M, Sasaki K. Color duplex ultrasound in the assessment of primary venous leg ulceration. Dermatol Surg 1998; 24: 1124–1128. 26. Labropoulos N, Giannoukas AD, Delis K, et al. Where does venous reﬂux start? J Vasc Surg. 1997; 26: 736–742. 27. Abu-Own A, Scurr JH, Coleridge Smith PD. Saphenous vein reﬂux without incompetence at the saphenofemoral junction. Br J Surg 1994; 81: 1452–4. 28. Labropoulos N, Leon M, Nicolaides AN, et al. Superﬁcial

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46. Clarke H, Smith SRG, Vasdelds SN, et al. Role of venous elasticity in the development of varicose veins. Br J Surg 1989; 76: 577–80. 47. Maurel E, Azema C, Deloy J, Bouissou H. Collagen of the normal and varicose human saphenous vein: a biochemical study. Clin Claim Acta 1990; 193: 27–38. 48. Porto LC, da Silveira PRM, de Carvalho JJ, Panico MDB. Connective tissue accumulation in the muscle layer in normal and varicose saphenous veins. Angiology 1995; 46: 243–9. 49. Gandhi Rift, Irizarry E, Nackman GB, et al. Analysis of the connective tissue matrix and proteolytic activity of primary varicose veins. J Vasc Surg 1993; 18: 814–20. 50. Labropoulos N, Giannoukas A, Stavridis G, et al. The role of venous wall changes in the pathogenesis of primary varicose veins. Vasc Surg 1999; 33: 191–6. ●51. Caggiati A, Rosi C, Heyn R, et al. Age-related variations of varicose veins anatomy. J Vasc Surg 2006; 44: 1291–5. ●52. Labropoulos N, Leon L, Kwon S, et al. Study of the venous reﬂux progression. J Vasc Surg 2005: 41: 291–5. 53. Perrin M, Guex JJ, Ruckley CV, et al. Recurrent varices after surgery (REVAS) a consensus document. Cardiovasc Surg 2000; 8: 233–45.

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14 Evaluation of venous function by indirect noninvasive testing (plethysmography) FEDOR LURIE AND THOM W. ROOKE Introduction Technical principles Practical applications

156 156 157

INTRODUCTION Management of chronic venous disease has made signiﬁcant advances in the past three decades. New treatment modalities ranging from surgical reconstruction of venous valves to ofﬁce-based minimally invasive treatment of superﬁcial veins to endovascular treatment of acute and chronic venous obstruction are now available for the management of patients with venous disease. In this environment, the demand for reliable diagnostic techniques capable of answering key clinical questions is growing. In cases of acute venous thrombosis, location of the thrombus, its age and recent dynamics (propagation, organization, recanalization) are as important as identiﬁcation of the thrombus. Duplex ultrasound has become a standard test addressing these diagnostic needs. The CEAP classiﬁcation1 provides a framework for investigating patients with chronic venous disease. The diagnosis of the disease and deﬁnition of clinical class are based on clinical examination. The role of non-invasive testing is to identify pathophysiological changes (reﬂux or obstruction) in individual anatomical segments of the venous system, and, in some cases, to deﬁne etiology. Other than clinical class, CEAP does not estimate the severity of disease, and its ability to measure changes in a patients’ condition is limited. Venous severity scores (clinical, segmental, and disability)2 address this by grading the same variables that are used in CEAP. Thus, the combination of clinical examination with duplex ultrasound is sufﬁcient for classiﬁcation (CEAP) and for estimation of the severity of chronic venous disease. Limitations of this approach to evaluation of patients with chronic venous disease are few. The pathophysiologic

Summary References

158 159

part of the classiﬁcation – “P” of CEAP – is descriptive. It includes identiﬁcation of reﬂux and obstruction, but does not quantify severity of either reﬂux or obstruction. This is partially justiﬁed by technological limitations. Imaging modalities such as ultrasound and venography cannot assess the severity of reﬂux or obstruction in individual segments. A “segmental” approach to the pathophysiology of chronic venous disease (CVD) makes it difﬁcult to assess the impact of the changes in an individual segment on the overall function of the venous system of the lower extremity. It also makes it difﬁcult to understand the dynamics of the physiologic changes as they can occur in different segments at different times. Assessment of physiologic outcomes of treatment and changes in CVD severity over time and after surgery are especially challenging because the responsiveness of CEAP and the severity scores may not be sufﬁcient and has not been tested. These limitations dictate the need for an examination that can assess the global function of the venous system of the lower extremity. Venous pressure measurements can serve this purpose, but are invasive and unpractical. Indirect non-invasive tests, such as the various forms of plethysmography, are alternatives.

TECHNICAL PRINCIPLES Indirect non-invasive tests most often used in evaluation of patients with chronic venous disease are air plethysmography (APG) and strain-gauge plethysmography (SGP). Both of these techniques assess venous function by measuring changes in the size of the extremity in respond to exercise, postural change, and

Practical applications

ml 150 125 100 75 50 25 0 25

VC A MVO B MVO

1 second

Figure 14.1 Air plethysmography tracings of a patient 3 years after femoropopliteal deep venous thrombosis. (a) Unaffected extremity; (b) extremity with venous obstruction has decreased venous capacitance (VC), and decreased maximum venous outﬂow (MVO). Assuming that the central venous pressure is close to 0, venous resistance can be estimated as R = Pc/MVO, where Pc is the pressure in the occlusion cuff.

application and release of a venous tourniquet. The main assumption of these examinations is that the arterial blood supply to the extremity and transcapillary ﬂuid exchange do not change signiﬁcantly in response to the utilized maneuvers. Changes in the extremity’s volume are therefore attributed to ﬁlling and emptying of the veins (Fig 14.1). Air plethysmography and SGP use different models for the calculation of volume changes. Air plethysmography measures changes in pressure in a measurement cuff calibrated to reﬂect volume changes. Strain-gauge plethysmography calculates volume changes from changes in circumference. It assumes the extremity to have a cylindrical shape with an even distribution of volume changes in response to the testing maneuvers. The two methods give quantitatively different, but qualitatively identical, information [1B].3 Both APG and SGP require considerable patient cooperation. Consistency in performing exercise, maintaining position, and distributing weight between the legs can contribute signiﬁcantly to variability of the results. External mechanical, thermal, and chemical (pharmacological) stimuli may also cause signiﬁcant changes in size of the venous lumen and in venous capacitance. All these factors, along with changes in central venous hemodynamics and arterial supply, should be considered when results of these indirect tests are analyzed. Photoplethysmography (PPG) and light reﬂection rheography calculate changes in tissue blood density by measuring the intensity of reﬂected light. Because of the inability of the light to penetrate deeper through the skin, difﬁculties in calibration, and poor speciﬁcity, these techniques currently have found little application in the evaluation of chronic venous disease [1C].4

PRACTICAL APPLICATIONS Although plethysmography studies can identify both obstruction and reﬂux, they are unable to allocate these changes to speciﬁc venous segments. Duplex ultrasound is

157

the preferable and standard technique for the identiﬁcation of reﬂux and, when feasible, obstruction. When venous obstruction is suspected, but not identiﬁed by duplex scan, plethysmography can help to overcome low sensitivity of the ultrasound for detection of venous obstruction. An advantage of these indirect tests over ultrasound is their ability to provide a quantitative measure of impact of obstruction and valvular insufﬁciency on the overall function of the venous system of the lower extremity. In addition, plethysmography can provide a quantitative assessment of muscle pump function (Fig 14.2). This information also can be used in assessment of treatment outcomes, and for follow-up [1B] [1C].5–6

Identification and assessment of obstruction The physiological roles of the venous system of the lower extremities include adjustments to changes in circulating blood volume and central hemodynamics by accumulation and release of additional volumes of blood. To serve this need, under normal conditions, veins maintain a signiﬁcant reserve capacity. Venous obstruction can measurably decrease this reserve. Increased resistance to outﬂow decreases the rate of emptying of more distal veins. Identiﬁcation and assessment of venous obstruction by plethysmography is based on the estimation of these two parameters: venous capacitance and venous resistance. Measurements of the calf volume increase in response to venous occlusion by tourniquet and the calf volume decreases after its rapid release; this constitutes the basis of venous occlusion plethysmography. Although venous pressure rises to equal the pressure of the tourniquet, blood accumulates in the veins of the studied extremity. Because veins easily increase their size under low pressure and become inextensible after the pressure exceeds 50– 80 mmHg, they reach the level of maximal capacity, which reﬂects in maximally increased size of the calf.

ml 250 225 200 175 150 125 100 75 50 25 0

EV VV RV

Figure 14.2 Assessment of muscle pump function by air plethysmography. VV, functional venous volume; EV, ejected volume (single tiptoe exercise); RV, residual volume after 10 consecutive tiptoe exercises). The ejection fraction is calculated by dividing the EV by the VV and is expressed as a percentage by multiplying by 100. The residual volume fraction is calculated by dividing RV by the VV, and is also expressed as a percentage.

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Evaluation of venous function by indirect non-invasive testing (plethysmography)

Rapid release of the tourniquet creates a pressure gradient between extremity veins, where the pressure is equal to the pressure of the tourniquet and the central venous pressure, which is close to zero. Deﬁning the pressure gradient makes possible the calculation of venous resistance by measuring the rate of decrease in the calf volume after the tourniquet is released. In extremities with venous obstruction this resistance can exceed normal values by threefold or more [1B]7 unless developed collateral ﬂow offsets the effects of axial vein obstruction.

Assessment of reflux severity Leg elevation or exercise can be used to decrease the blood volume accumulated in the veins of an extremity. When an extremity is positioned vertically, reﬁll of the veins can occur from relatively slow arterial inﬂow, or, in the case of valvular incompetence, by rapid reﬂuxing from a larger proximal segment. Measuring the rate of venous reﬁll, usually indexed to 90% of the total volume, provides an estimate of overall valvular competence, or the severity of reﬂux in extremities with no venous obstruction.

Assessment of muscle pump function Active evacuation of blood from the venous system of the lower extremity against hydrostatic pressure is a function of muscle pumps that integrate the effects of muscle contractions with the ability of the venous valves to provide unidirectional ﬂow. Evaluation of muscle pump function in patients with chronic venous disease is important because its impairment contributes signiﬁcantly to the severity of chronic venous disease [1B].8 Improvement in muscle pump function through physical therapy [1A],9 and/or elastic compression [1B]10 can have beneﬁcial therapeutic effects. The decrease in calf volume following a single calf muscle contraction, and the amount of blood not expelled by repeated contractions, can be indexed to the functional

venous volume (ejection fraction and residual volume fraction respectively) to assess the calf muscle pump function. Plethysmographic ﬁndings correlate well with measurements of ambulatory venous pressure [1B],11 Its non-invasive nature makes this indirect test the only practicable option for evaluation of the calf muscle pump.

Clinical correlations Clinical correlations with the results of the indirect noninvasive tests remain to be deﬁned. Although potential for the prediction of ulceration has been demonstrated in early works [1C],12 more careful analysis revealed that deterioration of venous hemodynamics (as measured by plethysmography) parallels clinical severity only before skin changes develop [1B],11 or during ulcer healing [1B].8

Reliability Reliability and repeatability of plethysmography has been demonstrated by Nicolaides and Christopoulos,12 and later conﬁrmed by others [1B].13 The limits of reproducibility, however, differ signiﬁcantly between the reports and should be deﬁned by systematic investigation.

SUMMARY Plethysmography is the only existing practical noninvasive modality for global physiologic evaluation of the venous system of an extremity. It provides valuable information on the impact of reﬂux and obstruction on the overall venous function. In addition, it provides a measure of function of the calf muscle pump. Plethysmography is a complementary non-invasive modality to duplex ultrasound. It can be used for quantiﬁcation of reﬂux or obstruction, and possibly for monitoring venous hemodynamics over time, and for evaluation of treatment outcomes.

Guidelines 2.4.0 of the American Venous Forum on evaluation of venous function by indirect non-invasive testing (plethysmography) No.

Guideline

2.4.1 Plethysmography is recommended for non-invasive physiologic evaluation of the venous system of an extremity. Clinical correlations with abnormal ﬁndings need to be established

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest) 1

C

References 159

REFERENCES 1. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. 2. Rutherford RB, Padberg FT Jr, Comerota AJ, et al. Venous severity scoring: An adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. 3. Louisy F, Cauquil D, Andre-Deshays C, et al. Air plethysmography: an alternative method for assessing peripheral circulatory adaptations during spaceﬂights. Eur J Appl Physiol 2001; 85: 383–91. 4. Bays RA, Healy DA, Atnip RG, Neumyer M, Thiele BL. Validation of air plethysmography, photoplethysmography, and duplex ultrasonography in the evaluation of severe venous stasis. J Vasc Surg 1994; 20: 721–7. 5. Gillespie DL, Cordts PR, Hartono C, et al. The role of air plethysmography in monitoring results of venous surgery. J Vasc Surg 1992; 16: 674–8. 6. Rhodes JM, Gloviczki P, Canton L, et al. Endoscopic perforator vein division with ablation of superﬁcial reﬂux improves venous hemodynamics. J Vasc Surg 1998; 28: 839–47.

7. Barnes RW, Collicott PE, Sumner DS, Strandness DE Jr. Noninvasive quantitation of venous hemodynamics in postphlebitic syndrome. Arch Surg 1973; 107: 807–14. 8. Araki CT, Back TL, Padberg FT, et al. The signiﬁcance of calf muscle pump function in venous ulceration. J Vasc Surg 1994; 20: 872–7. 9. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufﬁciency: a randomized trial. J Vasc Surg 2004; 39: 79–87. 10. Christopoulos DG, Nicolaides AN, Szendro G, et al. Airplethysmography and the effect of elastic compression on venous hemodynamics of the leg. J Vasc Surg 1987; 5: 148–59. 11. Welkie JF, Comerota AJ, Katz ML, et al. Hemodynamic deterioration in chronic venous disease. J Vasc Surg 1992; 16: 733–40. 12. Christopoulos D, Nicolaides AN, Cook A, et al. Pathogenesis of venous ulceration in relation to the calf muscle pump function. Surgery 1989; 106: 829–35. 13. Yang D, Sacco P.Reproducibility of air plethysmography for the evaluation of arterial and venous function of the lower leg. Clin Physiol Funct Imaging 2002; 22: 379–82.

15 Lower extremity ascending and descending phlebography CURTIS B. KAMIDA, ROBERT L. KISTNER, BO EKLÖF AND ELNA M. MASUDA Introduction Indications for phlebography Techniques of phlebography Descending phlebography

160 160 162 164

INTRODUCTION Proper management of the patient with venous disease requires an accurate and objective diagnosis. Contrast phlebography has historically been considered the “gold standard” against which all modalities are measured.1 Recently, the widespread availability of duplex Doppler, color Doppler, and compression ultrasound has reduced the role of contrast phlebography in the diagnosis of venous disease.2 These non-invasive imaging methods have been shown to be accurate, relatively inexpensive, and safer than phlebography.3 However, there are still instances where the use of more invasive phlebographic procedures is necessary. This chapter will discuss the current role of these procedures in the clinical evaluation of the patient with venous disease. Phlebography in the lower extremity can be carried out using several techniques depending upon the need of the individual case. Classical ascending phlebography is performed by a needle placed into the dorsum of the foot. Contrast is injected in order to outline the veins of the foot, calf, thigh, and pelvis. Direct puncture of the popliteal vein or common femoral vein and subsequent passage of a catheter for selective injection of contrast will often show vein detail not easily seen with a foot injection. Similarly, puncture of the great saphenous vein or the posterior tibial veins at the ankle can be performed as a prelude to catheter-directed thrombolysis. Varicography is a method that can be used to locate the sites of origin and termination of individual varices and to identify perforators. This is performed by injecting contrast directly into the varix itself.

Complications of phlebography Conclusion References

166 166 167

Descending phlebography, ﬁrst performed by Gunnar Bauer,4 is a method of identifying the site of valves in the veins and studying their degree of competence.5–7 It is done by placing the contrast into the common femoral or external iliac vein with the patient in a semi-erect position.

INDICATIONS FOR PHLEBOGRAPHY Acute deep venous thrombosis In the diagnosis of acute deep venous thrombosis, the ultrasound examination has largely replaced phlebography for routine diagnosis, and the indications for phlebography are now selective.8 These include the following cases. ●

●

●

When the duplex scan is not deﬁnitive. Infrapopliteal veins are often difﬁcult to evaluate (Fig. 15.1). Three studies that evaluated conventional duplex for diagnosis of calf vein deep thrombosis had a cumulative positive predictive value of 81%, with a range of 69% to 85%.9–11 Where iliofemoral venous thrombosis exists and thrombectomy is planned (Fig. 15.2). In this instance, the precise location of the top of the thrombus is needed. Owing to overlying bowel gas and the depth of the vessels, iliac veins can often be difﬁcult to visualize on an ultrasound exam.3 When catheter-directed thrombosis is being considered (Fig. 15.3).

Indications for phlebography

161

Figure 15.1 The arrow points to clots in the tibial veins, which were not adequately seen with ultrasound.

●

Where the duplex scan does not satisfy the suspicions of the clinician. In particular, patients with a duplicated superﬁcial femoral vein may be a signiﬁcant source of error in the diagnosis of deep vein thrombosis.12–13 In one study, 46% of phlebograms demonstrated duplicated or even more complex superﬁcial femoral veins.12

In all of these instances, phlebography can clarify intraluminal details that are suggested by the ultrasound scan. A detailed and comprehensive duplex scan may be the only test required, but adoption of abbreviated ultrasound examination protocols may lead to a decrease in sensitivity and the need for a more deﬁnitive imaging procedure such as phlebography.14

Chronic venous disease The indications for phlebography in chronic venous disease depend upon the type of treatment that will be considered for the patient. Where the diagnosis is only a prelude for use of elastic support, there is little practical need to know the details of reﬂux and obstruction in a given extremity since the treatment will always be the same

Figure 15.2 Large thrombus in common iliac vein. The top of the thrombus is well visualized. A contralateral catheter can be pulled back into the opposite common iliac vein to determine the precise location of the iliac vein conﬂuence.

and phlebography will rarely be needed. Quite the opposite is the case for those who are candidates for surgical therapy, since the treatment will depend upon the precise details of obstruction and reﬂux, segment by segment, throughout the extremity. The contributions made by ascending phlebography in chronic venous disease are the following: ●

a map of the entire venous system in the extremity that is useful for study of relationship between the various ﬁnding in the extremity;

162

Lower extremity ascending and descending phlebography

Figure 15.3 A clot in the popliteal vein. In planning catheterdirected thrombolysis, the catheter should be directed into the vein containing the clot.

●

●

●

detailed study of perforating veins with the use of tourniquets and positioning to determine the site and size of perforating veins and their connections to the deep and superﬁcial veins (Fig. 15.4); differentiation of primary venous disease from secondary (post-thrombotic) disease (Fig. 15.5); identiﬁcation of collateral patterns, especially in the thigh, around the knee, and at the iliofemoral level;

In cases where these advantages are useful in planning surgery or deciding whether the patient is a surgical candidate, ascending phlebography is indicated. The points gained from descending phlebography are as follows:15 ●

identiﬁcation of the site of proximal valves down to the ﬁrst component valve in each axial vein of the

Figure 15.4 Incompetent perforating vein observed during phlebogram performed with an ankle tourniquet, which forces contrast into the deep system.

● ●

●

extremity, including the greater saphenous vein, superﬁcial femoral vein, and profunda femoris vein; deﬁnition of the degree of competence of each valve; an accurate differential diagnosis between primary and secondary valve incompetence; determination of the distal extent of incompetence in the femoral and popliteal segments down to the tibeal and perforating veins.

Descending phlebography is an absolute necessity for the patient who is considered for valvuloplasty operations in primary venous insufﬁciency or for valve substitution procedures in secondary venous insufﬁciency.

TECHNIQUES OF PHLEBOGRAPHY Patient preparation for phlebography involves the usual precautions taken before administration of any

Techniques of phlebography 163

Figure 15.5 Webs and synechiae in the popliteal vein are evidence of a previous thrombosis and recanalization.

intravascular X-ray contrast material. Anticoagulation is not a contraindication. A tilting table capable of ﬂuoroscopy, spot ﬁlming, and overhead ﬁlms is recommended. Videotaping capabilities are often useful but not an absolute requirement. The contrast material most commonly used is of moderate concentration. This is generally 200–400 mg/mL iodine. Higher concentrations of contrast are associated with an increase in patient discomfort and an increased risk of contrast-associated thrombosis.16 The use of non-ionic or low-osmolality contrast media reduces patient discomfort, “allergic” reactions, nephrotoxicity, and post-phlebographic thrombosis, but with a considerable increase in the cost of the examination. The American College of Radiology has not taken a position on whether non-ionic contrast media should be used universally or selectively, but it does publish guidelines for identifying high-risk patients who would beneﬁt from non-ionic contrast media.17

Ascending phlebography An adaptation of the method of Rabinov and Paulin18 is used in our institution. Approximately 100 cm3 of contrast

is injected per leg. Venipuncture is performed with a small needle (usually a 22 or 21 gauge butterﬂy) inserted into a vein on the dorsum of the foot. Ideally, the examination is done with the patient upright. The leg to be examined is made non-weight-bearing by placing a box under the other foot. Since muscle contractions decrease deep venous ﬁlling, the patient is instructed to relax the nonweight-bearing leg. The upright position (60 degrees is usually sufﬁcient) produces an increase in hydrostatic pressure, which results in better opaciﬁcation of the veins and delays venous emptying, giving the examiner more time for positioning and ﬁlming. Directing the needle toward the toes may give better ﬁlling of the foot veins.19 The use of an ankle tourniquet increases the risk of contrast extravasation at the venipuncture site. It can also cause non-ﬁlling of the anterior tibial veins and poor opaciﬁcation of the gastrocnemius muscular veins.20 We do initially use an ankle tourniquet unless there is so much superﬁcial vein ﬁlling that the deep veins are inadequately visualized. However, the use of a tourniquet above the knee can aid in calf ﬁlling if the patient cannot be examined in the upright position, and can be used if the only available venipuncture site is a superﬁcial vein in an area other than the dorsum of the foot.21 When ascending phlebography is performed to evaluate perforating veins, ankle tourniquets are used initially. Contrast selectively enters the deep veins, and incompetent perforating veins can be identiﬁed when the contrast ﬂows from the deep to the superﬁcial system. Overhead ﬁlms are taken of the entire extremity. In the upright position, orthogonal views of the calf and then the knee and lower thigh are obtained after 50–70 mL of contrast has been injected. The table is lowered to 15–30 degrees and a ﬁlm of the upper thigh and groin is obtained. The last ﬁlm is an overhead supine view of the iliac veins and lower inferior vena cava. This is obtained by rapidly lowering the table, elevating the leg, or having the patient dorsiﬂex the foot against resistance and taking an immediate radiograph. Better opaciﬁcation of the pelvic veins and lower inferior vena cava can also be obtained by manual compression over the femoral vein at the groin prior to lowering the table. This decrease in vein emptying can be augmented by having the patient perform a Valsalva maneuver. When the table is brought to the horizontal position, the compression is released and a deep inspiration is performed.22

Phlebography23 Direct puncture of varices can be carried out with a small needle and contrast injected under ﬂuoroscopic observation. The table tilt may be adjusted to guide ﬁlling in the proximal or distal direction. This test is used to ﬁnd communications between the varices and the deep system, and to identify sites of perforator veins. It is particularly useful in the thigh, whereas ascending phlebography with

164

Lower extremity ascending and descending phlebography

foot injection and ankle tourniquets usually adequately identiﬁes perforators in the calf.24

Ascending popliteal, femoral, posterior tibial and saphenous phlebography In angiographic evaluation of the arterial system, it is a well-known fact that selective or super-selective catheterization with contract injection close to the area to be evaluated usually gives better visualization. In a similar fashion, contrast injection close to areas of concern in the venous system allows for better delineation of normal and abnormal anatomy. In fact, although aortic injection is often used for opaciﬁcation of pedal arteries, injection of contrast in foot veins does not usually result in adequate opaciﬁcation of the inferior vena cava. This is predominantly due to the inﬂow of unopaciﬁed blood and venous return, which dilutes contrast injected at a site distant from the area to be examined. Several techniques have been developed to aid in the evaluation of the larger axial veins. These all involve either a venipuncture site close to the area of interest, or the passage of angiographic catheters from a distant site to the area of interest. Ascending popliteal phlebography is carried out by puncturing the popliteal vein in the popliteal fossa and introducing a catheter into the popliteal vein by the Seldinger technique25 Puncture is aided by ultrasound guidance or by ﬂuoroscopic identiﬁcation of the popliteal vein after foot injection. In the prone position, contrast injection through a catheter can locate perforators, duplications, valves, and post-thrombotic changes. In a similar fashion, optimal visualization of the pelvic veins and inferior vena cava is easily obtained with direct puncture of the common femoral vein and passage of a multi-sidehole angiographic catheter with power injection. Although primarily used as a prelude to catheterdirected thrombolysis, access to the venous system via the posterior tibial veins or great saphenous vein at the ankle allows for catheter passage into many of the veins for more selective contrast injections.26

Interpretation of the ascending phlebogram The deﬁnitive ﬁnding on ascending phlebography in acute deep venous thrombosis is the presence of an intraluminal ﬁlling defect. A non-ﬁlling segment of vein or the abrupt termination of a contrast column is not a reliable sign of deep venous thrombosis. Both extrinsic and intrinsic pressure phenomena can change the ﬂow pattern within the veins and can lead to interpretive errors. The presence of “well-developed” collaterals implies venous occlusion, but the age is often difﬁcult to determine and the cause may not be intraluminal thrombus.18 Linear webs and synechiae within the veins usually imply chronic changes,

but an acute clot can be superimposed and present as more rounded and larger ﬁlling defects. Difﬁculty in interpretation can often be reduced by a more careful and detailed examination using appropriate amounts of contrast, positioning the patient to facilitate deep vein ﬁlling, and the judicious use of tourniquets. Fluoroscopic observation of the pattern of vein ﬁlling is mandatory when the site of incompetent perforating veins is being determined.

DESCENDING PHLEBOGRAPHY Technique This is performed on a ﬂuoroscopic table of at least 60 degrees of tilt. We strongly believe in videotaping the procedure and obtaining spot ﬁlms during the course of the examination. An audio tract is usually necessary for independent review of the tape after the procedure. The catheter generally needs to be positioned above the valve to be examined so that contrast can be injected retrograde to venous return. The contralateral common femoral vein is the usual site of the venipuncture, although a brachial or antecubital approach can also be used. Contrast is hand injected in 10–20 mL boluses with the patient in an upright position. The examined leg is non-weight-bearing, similar to ascending phlebography. The level of reﬂux is observed under ﬂuoroscopy and graded according to the classiﬁcation of Kistner and associates.6 Controversy exists regarding the ideal patient position during the performance of descending phlebography. We feel that the semi-erect position is ideal, and have found that the horizontal (supine) position underestimates the extent and degree of reﬂux, as published by Raju and Fredericks.7 Contrast injection is carried out during a forced Valsalva maneuver, and heparin (5000 units) is given intravenously prior to selective catheterization of any of the vein segments. Selective catheterization of the axial veins is usually easy to perform. All manipulations across the valve are done while the patient is supine. Slight ankle plantar ﬂexion against resistance increases venous return ﬂow and prevents valve leaﬂet closure when maneuvering across the valve. Selective catheterization is used to deﬁne venous incompetence in any segment independent of the dynamics in an adjacent segment. For example, if the great saphenous vein shows massive reﬂux when contrast is injected in the common femoral vein, it is possible to mask important reﬂux in the superﬁcial femoral or profunda femoral vein. Catheter manipulation with injection below the great saphenous vein oriﬁce allows for separate evaluation of the other axial veins (Figs 15.6 and 15.7). With a catheter of sufﬁcient length, selective catheterization can be carried out down the superﬁcial femoral vein to search for perforators and to study the popliteal vein valves more directly.

Descending phlebography

Figure 15.6 Descending venogram spot ﬁlm showing competent valves. The proximal axial veins are often superimposed on the anteroposterior view.

165

Figure 15.7 The same patient as in Fig. 15.6. In the ipsilateral anterior oblique view and with selective catheterization, the origins of the axial veins are no longer superimposed.

Interpretation of descending phlebography Accurate interpretation requires demonstration of the valves in each major axial segment, including the great saphenous vein, superﬁcial femoral vein, profunda femoris vein, and any collateral pathways. Normally, blood ﬂow is toward the heart with quiet breathing. A Valsalva maneuver initially causes cessation of prograde ﬂow, and then actual ﬂow reversal. It is this retrograde blood ﬂow that causes the valve cusps to close. Contrast will outline the cusps in sharp relief, with the vein at the valve station visibly dilating in its sinus portion. No contrast leaks through the competent valve except for a small wisp, which may be accepted as normal physiologic reﬂux occurring as the valve cusps close. If the proximal valves are fully competent, descending phlebography will not visualize the more distal vein unless selective catheterization through the valve is performed (Fig. 15.8). The Valsalva maneuver is essential to the performance of accurate descending phlebography. It can be standardized by having the patient practice the maneuver prior to the venogram by blowing against a blood pressure manometer up to 40 mmHg resistance. The inability to

perform an adequate and effective Valsalva maneuver limits the phlebographic accuracy in an uncooperative patient. We strongly feel that videotaping the examination is important as real-time visualization of the ﬂow dynamics and a narrated description of the position of the patient and the performance of the Valsalva maneuver are essential for the clinician. Since the valves remain open to allow blood ﬂow to return in the erect position, normal reﬂux of small amounts of contrast with quiet breathing can be erroneously reported as reﬂux. Slight retrograde ﬂow of contrast will also occur in the beginning stages of the forced Valsalva maneuver, as the initial retrograde blood ﬂow is insufﬁcient to cause the proximal resistance which forces the competent valve to close. A spot ﬁlm obtained during these stages can give the erroneous appearance of reﬂux and a false-positive result. A falsenegative result can also be obtained if the injection of contrast and the Valsalva maneuver is too weak. In this instance, poorly opaciﬁed blood will ﬂow toward the heart along with normal venous return, and no information regarding the valve’s competency will be elicited.

166

Lower extremity ascending and descending phlebography

Figure 15.8 Competent popliteal vein valve. Selective injection into the superﬁcial femoral vein beyond a competent common femoral vein valve.

The grading of reﬂux is according to the system previously reported:6 ●

● ●

●

●

Grade 0: competent valve with no reﬂux. There is a clear outline of the valve cusps during the Valsalva maneuver (Fig. 15.9). Grade 1: wisps of reﬂux limited to upper thigh. Grade 2: deﬁnite reﬂux, but limited to the upper thigh by competent valves in the distal thigh or popliteal vein. Grade 3: reﬂux through the popliteal vein and into the calf. Grade 4: massive cascading reﬂux through the popliteal vein, into the calf, and frequently through incompetent perforating veins.

COMPLICATIONS OF PHLEBOGRAPHY Phlebography introduces expense, discomfort, and risks to the patient, which need to be taken into account in the work-up of the patient with a venous disorder.27 These risks include the usual reactions to iodinated contrast. This does not differ from other procedures such as intravenous pyelography. The most important risk is the potential for post-procedural vein thrombosis. Contrast agents are an irritant to the intima, and can result in thrombosis. Prospective clinical trial data suggest that this occurs in

Figure 15.9 Descending phlebogram demonstrates a competent valve in the common femoral vein, which precludes ﬁlling of the superﬁcial femoral, great saphenous, and profuna femoral veins.

1–2% of cases.28 This can be further reduced by frequent ﬂushing of the veins with saline to minimize prolonged contact of the contrast with the venous intima, using dilute contrast for certain examinations such as varicography, the use of non-ionic contrast material, and the concurrent use of 3000–5000 units of heparin during selective catheterization. Extravasation of contrast can result in skin necrosis and can be avoided by careful monitoring of the injection site with ﬂuoroscopy. Treatment of extravasation is controversial and can include cold compresses to reduce pain as well as hot compresses to increase local blood ﬂow and absorption of the extravasated dye.17

CONCLUSION The diagnosis of acute and chronic venous disease requires accurate delineation of the venous system, including the deep veins, superﬁcial veins, and perforating veins. With

References 167

Guidelines 2.5.0 of the American Venous Forum on direct contrast venography No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

2.5.1 Contrast venography is recommended before performing endovenous reconstructions for acute or chronic venous obstructions

1

B

2.5.2 Contrast venography is suggested for patients with high clinical suspicion for deep venous thrombosis if other treatment modalities are inconclusive

2

B

the development of sophisticated duplex scan techniques, the need for contrast phlebography has been drastically reduced, but it remains a valuable tool in selected circumstances. Ascending phlebography is often more accurate than ultrasound in detecting thrombi in the calf and pelvis. In the instance of a difﬁcult duplex exam, phlebography can be used to resolve unanswered questions. Phlebography is still the most accurate method to differentiate primary from secondary causes of chronic venous disease. We believe that descending phlebography is necessary in the candidate for deep venous reconstructive surgery, and gives better anatomic detail of the valves and valve stations. Although ultrasound is the initial and often the only imaging modality used in the work-up of the patient with venous disease, contrast phlebography continues to be a necessary part of the deﬁnitive evaluation of venous disease in the difﬁcult diagnostic case and in the preoperative evaluation for deep vein reconstructive surgery. A recent letter by Reid and Hardwick29 in the British Medical Journal makes an interesting point. When communicating on an abbreviated duplex ultrasonography scanning protocol, they state that “venography is as invasive as taking a blood sample, and reactions to modern contrast material are as rare as hen’s teeth. Slavish pursuit of non-invasive alternatives to an accurate test which can never be considered a serious intervention may not be worth the trade-off.”29 Phlebography is a necessity in acute deep vein thrombosis to: ●

●

identify the top of the thrombus before surgery for iliofemoral DVT; “fracture” of a thrombus popping up into the inferior vena cava can kill the patient; identify the extent of the thrombus before catheterdirected thrombolysis, and to evaluate morphology and function of treated valves;

Phlebography is important in chronic venous disease to: ● ●

●

differentiate between primary and secondary disease; identify the extent and nature of any obstruction, particularly of the common femoral and iliac veins; evaluate the degree of reﬂux and the morphology of the valves.

REFERENCES 1. Cranley JJ, Canos AJ, Sull WF. The diagnosis of deep venous thrombosis: fallibility of clinical symptoms and signs. Arch Surg 1976; 111: 34–6. 2. Montefusco-van Kliest CM, Bakal C, Spraygen S, et al. Comparison of duplex ultrasonography and ascending venography in the diagnosis of venous thrombosis. Angiology 1993; 44: 169–75. 3. Douglas MG, Sumner DS 1996. Duplex scanning for deep vein thrombosis: has it replaced both phlebography and non-invasive testing? Semin Vasc Surg 1993; 9: 3–12. 4. Bauer G. The etiology of leg ulcers and their treatment by resection of the popliteal vein. J Int Chir 1948; 8: 937–67. 5. Herman RJ, Neiman HL, Yao JST, et al. Descending venography: a method of evaluating lower extremity venous valvular function. Radiology 1980; 137: 63–9. 6. Kistner, RL, Ferris RG, Randhawa G, Kamida CB. A method of performing descending venography. J Vasc. Surg 1986; 4: 464–8. 7. Raju S, Fredericks R. Evaluation of methods for detecting venous reﬂux. Arch Surg 1990; 125: 1463–7. 8. Quintavalla R, Larini P, Miselli A, et al. Duplex ultrasound diagnosis of symptomatic proximal deep vein thrombosis of lower limbs. Eur J Radiol 1992; 15: 32–6. 9. Elias A, LeCorff G, Bouvier JL. Value of real-time ultrasound imaging in the diagnosis of deep vein thrombosis of the lower limbs. Int Angiol 1987; 6: 175–82.

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Lower extremity ascending and descending phlebography

10. Fletcher JP, Kershaw LZ, Barker DS, et al. Ultrasound Diagnosis of lower limb deep venous thrombosis. Med J Aust 1990; 153: 453–5. 11. Mitchell DC, Grasty MS, Stebbings WSL, et al. Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis Br J Surg 1991; 78: 611–13. 12. Screaton NJ, Gillard JH, Berman LH Kemp PM. Duplicated superﬁcial femoral veins: a source of error in the sonographic investigation of deep vein thrombosis. Radiology 1998; 206: 397–401. 13. Pasquariello F, Kurol M, Wilberg S, et al. Diagnosis Of Deep venous thrombosis of the lower limbs: is it premature to introduce ultrasound as a routine method. Angiology 1999; 50: 31–6. 14. Cogo A, Lensing AWA, Koopman MMW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 17–20. 15. Kistner RL, Kamida CB. 1994 update on phlebology and varicography. Dermatologic Surg 1995; 21: 71–6. 16. Albrightson U, Olsson CG. Thrombotic side effects of lower limb phlebography. Lancet 1976; 1: 723–4. 17. American College of Radiology. Manual on Contrast Media, 4th edn. Reston, VA: ACR, 1998. 18. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 104: 134–44. 19. Kadir S. Diagnostic Angiography. Philadelphia, PA: WB Saunders, 1972; 536–83. 20. Kalebo P, Anthmyr BA, Erikkson BI, Zachrisson BE Optimization of ascending phlebography of the leg for screening of deep vein thrombosis in thromboprophylacatic trials. Acta Radiolog 1997; 38: 320–6.

21. Gordon DH, Glanz S, Stillman R, Sawyer PN. descending varicose venography of the lower extremities: an alternate method to evaluate the deep venous system. Radiology 1982; 145: 832–4. 22. Kim D, Orron DE, Porter DH. Venographic anatomy, techniqe and interpretation. In: Kim D, Orron DE, eds, Peripheral Vascular Imaging and Intervention. St. Louis, MO: Mosby Year Book, 1992; 269–350. 23. Thomas ML, Bowles JN. Incompetent perforating veins: comparison of varicography and ascending phlebography. Radiology 1985; 154: 619–23. 24. Savolainen H, Toivio I, Mokka R. Recurrent varicose veins: is there a role for varicography? Ann Chir Gynecol 1998; 77: 70. 25. Perrin J, Bolot JE, Genevois A, Hiltbrand B. dynamic popliteal phlebography. Phlebology 1998; 3: 227–35. 26. Cragg AH. Lower extremity deep venous thrombolysis: a new approach to obtaining access. J Vasc Interv Radiol 1996; 7: 283–6. 27. Bettman MA, Paulin S. Leg phlebography: the incidence, nature and modiﬁcation of undesirable side effects. Radiology 1977; 122: 101–4. 28. Hull R, Hirsch J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64: 622–5. 29. Reid JH, Hardwich DJ. compression ultrasonography for diagnosing deep vein thrombosis: venography is more accurate. BMJ 1998; 316: 1532.

16 Computed tomography and magnetic resonance imaging in venous disease TERRI J. VRTISKA AND JAMES F. GLOCKNER Introduction Imaging technologies: computed tomography of venous disease

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INTRODUCTION Current diagnostic evaluation of disorders of the venous system beneﬁt from advances in state-of-the-art computed tomography (CT) and magnetic resonance imaging (MRI) imaging applications. An understanding of the fundamentals and the appropriate utilization of each technology will accurately provide useful information for medical management and decisions regarding surgical interventions for venous disease.

IMAGING TECHNOLOGIES: COMPUTED TOMOGRAPHY OF VENOUS DISEASE During the past decade, CT has become a standard noninvasive imaging modality for depiction of a wide variety of vascular anatomy and pathology. Modern CT acquisitions have evolved from single-detector spiral scanners to multichannel helical CT (4, 8 and 16 detectors) examinations. More recently, 64-multichannel CT systems have become available in many practices and have replaced catheter-directed vascular imaging for many diagnostic studies. The proper application of modern CT techniques provides an extremely accurate, time-efﬁcient, and costeffective diagnostic evaluation prior to surgical intervention. The two dominant advantages of CT are the speed and resolution of image acquisition. Modern CT acquisitions can be acquired in less than a minute during a single breath-hold. In addition, the submillimeter resolution details are available with accurate depiction of imaging details communicated to clinicians using advanced post-

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processing techniques and 3D display (Fig. 16.1). One additional distinct advantage of CT compared with MRI is the ability to demonstrate calciﬁed densities such as calciﬁed granulomatous lymph nodes as a cause for superior vena cava (SVC) obstruction on precontrast acquisitions. The two primary disadvantages of CT imaging of the venous system include radiation exposure and the necessity for administration of iodinated contrast material. A typical abdominal and pelvic CT evaluation includes a radiation exposure of approximately 5–10 mSv. Ongoing efforts within the CT physics community continually strive to optimize the necessary radiation required for CT acquisitions by tailoring the dose to the individual patient size via modulation of the radiation beam.1 Administration of iodinated contrast material is necessary for accurate evaluation of the venous system and, therefore, patients with a signiﬁcant allergic reaction to iodinated contrast material or decreased renal function should be evaluated with alternate imaging techniques including ultrasound or MR.

Clinical applications SUPERIOR VENA CAVA AND BRACHIOCEPHALIC VEINS

Computed tomography evaluation of the SVC is most commonly performed for evaluation of acute or chronic occlusive changes and has been shown to be a useful noninvasive imaging technique for diagnosis of SVC and central venous disorders.2–5 Evaluation of post-procedural changes including endovascular stent patency or

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helpful to ﬂush the contrast material from the brachial and axillary veins into the central venous system. Computed tomography acquisition using thin collimation (1–2 mm) is useful in order to provide both traditional axial images as well as appropriate reconstructions that can be analyzed in the coronal, sagittal, or tailored off-axis planes. Careful review of the axial images and dedicated reconstructions are useful for optimal visualization of venous patency, obstructed venous segments, intraluminal thrombus and collateral venous pathways. On contrast-enhanced CT images, acute thrombus within the SVC or central venous structures is characterized by a low attenuation ﬁlling defect within the lumen of the vessel (Fig. 16.3). The involved venous segment may be normal caliber or expanded. Chronic occlusive changes are most commonly visualized as small non-opaciﬁed ﬁbrotic-appearing linear densities. Extensive upper chest wall and azygous collaterals can be precisely depicted by 3D images (Fig. 16.4). An advantage of evaluation of the SVC and central venous structures by CT rather than catheter venography is the ability of CT to accurately depict the pathology resulting in the venous occlusive changes. The most common cause of obstruction of the SVC and upper venous structures is malignancy, most commonly pulmonary neoplasm. The obstruction may result from extrinsic compression from primary or metastatic neoplasm or from direct invasive changes. Other common causes of SVC obstruction include granulomatous disease, iatrogenic occlusive changes (transvenous cardiac pacers, central venous catheters, post-radiation changes). Anatomic variants of the SVC can also be accurately visualized by CT evaluation such as a left-sided SVC. INFERIOR VENA CAVA

(b) Figure 16.1 Current computed tomography technology combined with tailored acquisition techniques and postprocessing applications provide accurate depiction of (a) the thoracic and (b) abdominal venous vasculature.

postoperative changes of surgically placed bypass grafts can also be performed. Regardless of the indication, CT acquisitions are optimally performed by simultaneous injection of the antecubital veins using 90–100 mL of dilute contrast material in each extremity at an injection rate of 2–3 mL/second. The bilateral arm injections provide homogeneous opaciﬁcation of the innominate veins and SVC and avoids potential artifact from unopaciﬁed blood within the central venous structures (Fig. 16.2). Subsequent injection of 20–30 mL of saline is

Accurate evaluation of the inferior vena cava (IVC) requires knowledge of potential ﬂow artifacts that are especially prominent due to the rapid acquisitions provided by modern CT scanning (Fig 16.5, page 170). In addition, knowledge of anatomic variation of the IVC is important to determine the accurate evaluation of ﬁndings due to anatomic variation rather than pathology (Fig. 16.6 and 16.7, pages 170, 171).6–9 The ﬂow artifacts visualized with the IVC are due to the unopaciﬁed blood from the lower extremities entering the infrarenal IVC, whereas the suprarenal IVC receives an admixture of opaciﬁed blood due to the rapid transit of the contrast material through the kidneys. Anatomic variants of the IVC are due to persistent embryologic remnants. The prevalence of the most common anatomic variants include persistence of a solitary left-sided IVC (< 1%), duplication of the infrarenal IVC segment (1–3%), retroaortic left renal vein (2–3%) and circumaortic left renal vein (2–9%).7 Optimal opaciﬁcation of the IVC typically requires delayed CT imaging at 60–70 seconds following the administration of iodinated contrast material to allow

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homogeneous opaciﬁcation of the entire infrarenal cava. As with the SVC, current CT evaluation provides accurate off-axis display of the entire caval segment in any orientation; however, the coronal display most commonly provides the most complete depiction because of the longitudinal orientation of the IVC within the abdominal cavity. The most common pathology depicted within the IVC is bland thrombus due to thrombotic disease and may be visualized within the central cava (Fig 16.8, page 171) or due to extension of thrombus from malignant occlusive changes (Fig 16.9). Thrombus may also be visualized within venous branches such as the renal veins or common femoral veins (Fig 16.10, page 172). Tumor thrombus within the IVC is most commonly due to local extension from adjacent organs such as the kidneys (renal cell carcinoma), liver (hepatocell carcinoma) or adrenal glands (adrenal cortical carcinoma). An uncommon cause of a

Figure 16.2 (a, b) Contrast-enhanced axial and (c) coronal computed tomography of the chest demonstrate artifactual lowdensity ﬁlling defects because of unopaciﬁed blood ﬂow from the right jugular vein and unopaciﬁed blood from the left brachiocephalic vein entering the opaciﬁed right brachiocephalic vein (a and c, arrows) and the superior vena cava (b and c, arrowheads).

ﬁlling defect within the IVC is due to a primary tumor arising in the smooth muscle of the IVC as seen with leiomyosarcoma.10,11 Rarely, the IVC may be traumatically disrupted (Fig. 16.11, page 172). The ability of the CT evaluation to display the orientation of an IVC ﬁlter can be helpful to depict associated thrombus or migration (Fig. 16.12, page 173). PULMONARY ARTERIES

Computed tomography of the pulmonary arteries has largely replaced catheter-directed pulmonary angiography and ventilation and perfusion scintigraphy (VQ scans) of the pulmonary arteries because of the rapidity of the scan acquisition and the high sensitivity and speciﬁcity approaching 100% for central pulmonary emboli.12,13 In other studies, the detection of small subsegmental

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pulmonary emboli has been shown to be less accurate with a sensitivity of 83% and speciﬁcity of 96% for computed tomography angiography.14 However, further research using 64-channel technology may provide improved accuracy in small peripheral pulmonary arteries with accurate detection of pulmonary emboli of all sizes (Fig. 16.13, page 173). In addition, the stratiﬁcation of patients based on clinical assessment will provide the optimal diagnostic strategy for the diagnosis of pulmonary emboli.15 Acute pulmonary emboli are diagnosed by ﬁlling defects within the involved pulmonary arterial segments, which are often slightly enlarged. The optimum administration of the IV contrast material is the key factor in acquisition of accurate pulmonary arterial CT evaluation and may be acquired in a single breath-hold by using a ﬁxed acquisition delay of approximately 20–25 seconds after initiating the contrast injection or by using bolus tracking software that optimizes the CT acquisition based on the peak enhancement of the central pulmonary

Figure 16.3 Thrombotic occlusion of the superior vena cava. (a) Unenhanced axial image of the chest demonstrates the location of a tunneled central venous catheter (arrows). (b) Coronal CT image acquired with iodinated contrast material injected simultaneously via bilateral antecubital iv access shows low attenuation thrombus in the right and left brachiocephalic veins (arrows). (c) Subsequent post-lysis catheter venogram with widely patent brachiocephalic veins.

arterial vasculature. Chronic pulmonary emboli are often represented by recanalization of the thrombosed pulmonary arterial segment (Fig. 16.14, page 174). Speciﬁc CT ﬁndings for chronic pulmonary emboli include peripheral eccentric thickening of the involved pulmonary arterial vasculature represented by soft tissue rinds or linear webs. On reconstructed arterial segments there may be abrupt caliber change of the involved pulmonary arterial segments. MAY–THURNER SYNDROME

Obstruction of the common iliac and external veins may be due to bland tumor thrombus or malignancy as described for the IVC. One unique diagnosis seen with the iliac veins is that of May–Thurner syndrome, which is deﬁned as isolated left lower extremity swelling due to compression of the left iliac vein by the right common iliac artery. On axial CT evaluation the maximum diameter of the left common iliac vein is decreased, measuring 3–4 mm

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in maximum diameter (Fig. 16.15, page 174) versus a normal caliber iliac vein measuring 10–12 mm in average diameter.16 Treatment for May–Thurner syndrome has historically involved anticoagulant therapy, but advances in interventional therapy allow relief of the associated mechanical compression by open surgical or endovascular repair (Fig. 16.16, page 175). The success of primary and secondary endovascular techniques approaches 90%.17,18 TAILORED APPLICATIONS

State-of-the-art CT technology allows rapid (less than 30 second) acquisition of 0.4 mm high-resolution CT scans that can be interrogated and displayed in any imaging plane using 3D volumetric imaging analysis for accurate characterization of the sites of obstruction and patency of

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Figure 16.4 Contrast-enhanced axial computed tomography demonstrates (a) occlusion of the SVC (arrow) with (b) dilatation of the azygous and hemiazygous systems (arrowheads). (c) Volume-rendered 3D image of the chest demonstrates occlusion of the brachiocephalic veins bilaterally (arrows) with extensive chest wall collaterals.

treated venous segments. Manipulation of the datasets allows exquisite display of complex anatomic and pathologic relationships, including complex pulmonary arteriovenous malformations (Fig. 16.17, page 175), complex intra-abdominal or pelvic venous malformations (Fig. 16.18, page 176) or direct lower extremity venography (Fig. 16.19, page 177).

IMAGING TECHNOLOGIES: MAGNETIC RESONANCE IMAGING OF VENOUS DISEASE Magnetic resonance venography Magnetic resonance (MR) venography is usually not the ﬁrst examination performed to evaluate the venous

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(a) Figure 16.5 (a, b) Contrast enhanced axial computed tomography demonstrates ﬂow artifact (arrow) from unopaciﬁed blood from the infrarenal inferior vena cava streaming into the juxtrarenal (IVC) with admixture of opaciﬁed blood from the renal veins (arrowheads).

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Figure 16.6 (a, b) Contrast-enhanced computed tomography with axial and coronal volume-rendered images demonstrates the anatomic relationships of a single retroaortic left renal vein (arrow)

system, but it has a wide range of applications and is often successful where other techniques yield ambiguous results. Magnetic resonance venography comprises a number of different techniques, with different mechanisms of achieving vascular contrast. As such, ﬂexibility is a major advantage of MR venography over most competing technologies: where one technique may not be particularly successful for a given application, it is usually possible to apply a different method and achieve satisfactory results.

This ﬂexibility can also be something of a limitation, however, since the range of choices can be somewhat daunting to those with limited experience. Advantages of MR venography over CT venography include superior contrast-to-noise ratios of venous blood, and the ability to perform multiple acquisitions while waiting for contrast to appear in veins without incurring penalties in additional radiation dose. MR venography is limited by generally lower spatial resolution in comparison

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(b) Figure 16.7 (a, b) Contrast-enhanced axial computed tomography demonstrates duplication of the infrarenal inferior vena cava (IVC) with a right-sided (arrows) and left-sided infrarenal IVC (arrowheads).

(b) Figure 16.8 Inferior vena cava (IVC) bland thrombus. (a) Contrast-enhanced axial and (b) coronal computed tomography images with low attenuation thrombus in the infrarenal IVC consistent with bland thrombus (arrows).

Figure 16.9 Inferior vena cava (IVC) malignant thrombus. Contrast-enhanced coronal CT image with mixed density tumor and bland thrombus ﬁlling the suprarenal and infrarenal IVC (arrows).

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Figure 16.10 Venous branch thrombus. Contrast-enhanced axial CT images with (a) acute thrombus within the left renal vein (arrow) and (b) within the left common femoral vein (arrow).

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Figure 16.11 Traumatic disruption of the inferior vena cava (IVC). (a, b) Axial and coronal CT exams show extraluminal extravasation of contrast material (arrows) consistent with infrahepatic disruption of the IVC. This ﬁnding was conﬁrmed on subsequent catheter directed cavagram (c, arrow).

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Figure 16.12 Inferior vena cava (IVC) ﬁlter migration. (a) Volumerendered coronal and (b) sagittal computed tomography images demonstrate migration of an IVC ﬁlter caudally near the common iliac vein bifurcation (arrows) rather than at the level of the renal veins (arrowhead).

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Figure 16.13 Acute pulmonary emboli in three patients. (a) Axial computed tomography imaging of pulmonary emboli in a small segmental pulmonary artery (arrowhead), (b) bilateral pulmonary emboli (arrowheads) and a (c) large central pulmonary embolus (arrowheads) in the main right pulmonary artery (“saddle” embolus).

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▲ ▲ Figure 16.14 Chronic pulmonary emboli. Axial computed tomography imaging with chronic pulmonary emboli characterized by recanalization and irregular wall thickening (arrowheads).

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Figure 16.15 May–Thurner syndrome. Contrast-enhanced axial computed tomography shows marked compression of the left common iliac vein by the right common iliac artery (arrow a, c) and associated prominent left pelvic venous collaterals (arrowheads b).

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Figure 16.16 Post-procedural stent occlusion with venous collaterals. (a, b) Contrast enhanced axial computed tomography demonstrates occlusion of the left iliac venous stent (arrows). (c) Volume-rendered 3D reconstructions demonstrate the extensive venous collaterals overlying the pubic symphysis (arrowheads).

Figure 16.17 Computed tomography evaluation including (a) maximum intensity projection and (b) volume-rendered images with depiction of a complex pulmonary arteriovenous malformation communicating with the thoracic aorta (arrows) and pulmonary arteries (arrowheads) and pulmonary veins (curved arrows).

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Figure 16.18 Contrast enhanced computed tomography of the abdomen and pelvis demonstrates a large arteriovenous malformation surrounding the left hemipelvis on the (a) axial (arrows), (b) coronal (arrows), and (c, d) volume-rendered 3D reconstructions (arrows).

to CT, by longer examination times, and by the exclusion of patients who are unstable, have pacemakers or automatic implantable cardioverter deﬁbrillators, and certain cerebral aneurysm clips.

Techniques A large number of MR venography techniques are available. We have arbitrarily divided these into black blood, bright blood, and contrast-enhanced techniques. Black blood MR venography pulse sequences are employed relatively infrequently as a dedicated venography technique; however, black blood effects are commonly seen in spin-echo and fast spin-echo sequences because of excited spins in blood ﬂowing out of the imaging plane during acquisition (Figs 16.20 and 16.21).

Spin echo and fast spin echo sequences employ a series of 90°–180° radiofrequency (RF) pulses prior to data acquisition. Stationary spins experience both pulses, and contribute to the resulting signal in the expected manner. Moving spins, on the other hand, may pass through the imaging slice between the initial 90° pulse and data acquisition, replaced by non-excited spins that never experienced the initial pulse and therefore do not contribute signal to the image. This leads to a signal void, or black blood effect. More sophisticated black blood sequences employ ECG gating as well as two inversion pulses to improve the reliability of this effect. Most black blood vascular sequences are designed for arterial imaging, but are also effective for venography, or can be optimized for venography by adjusting a few imaging parameters. Black blood venography sequences can clearly demonstrate ﬁlling defects in veins, and often provide high-

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Figure 16.19 Lower extremity direct computed tomography (CT) venography. (a) Volume-rendered images acquired via direct CT venography with injection of contrast material into a dorsal vein of the foot demonstrates a patent covered stent in the left iliac vein (arrows) and a patent greater saphenous vein (arrowheads). (b) Patent stent in the proximal superﬁcial femoral vein (curved arrows) with chronic changes due to deep venous thrombosis in the superﬁcial femoral vein adjacent to the stent (notched arrow).

quality anatomic images. It should be noted, however, that these techniques are notoriously artifact prone – slowﬂowing blood, for example, often yields an incomplete signal void and can simulate venous thrombus. Likewise, in-plane rather than through-plane ﬂow can lead to positive signal within veins that can be misinterpreted as thrombus. Most bright blood techniques rely on enhancing the signal of blood ﬂowing into the imaging plane. These methods generally employ gradient echo or spoiled gradient echo sequences with sequential acquisition, in which all of the data for a single image is acquired before moving on to the next slice. In sequential imaging, stationary spins in a given slice are continually excited, and the magnetization does not have sufﬁcient time to recover fully before the next excitation. This phenomenon of spin saturation results in a reduced signal in the stationary spins within the imaging slice. Moving spins, on the other

hand, may enter the slice and contribute unsaturated signal to the image, leading to a higher signal intensity, or bright blood effect (Fig. 16.20). Sequential gradient echo pulse sequences represent the most common form of bright blood venography – these are also known as timeof-ﬂight techniques, and have been used in both MR angiography and venography.19–21 Since blood ﬂowing into the slice carries a bright signal from either direction, saturation pulses are applied either above or below the imaging slice to eliminate the inﬂow signal from arteries or veins. Time-of-ﬂight MR venography is generally performed as a contiguous stack of thin 2D slices, ideally oriented perpendicular to the veins of interest. The 2D data can then be used to obtain 3D reconstructions, applying standard algorithms such as volume rendering or maximum intensity projection. Time-of-ﬂight MR venography is a more robust technique than black blood methods, but remains prone to ﬂow-related artifacts. Slow ﬂow or in-plane ﬂow may lead to pseudo-ﬁlling defects or poor vessel visualization. A signiﬁcant limitation of time-of-ﬂight MR venography is the long acquisition times, typically on the order of 5–15 minutes, depending on the in-plane spatial resolution, slice thickness, and anatomic coverage. This is most problematic for imaging in the chest and abdomen, where motion artifact from breathing can severely limit image quality. Images can be obtained during breath holding – in this case, thicker slices are usually acquired with lower spatial resolution, so that breath holds and total acquisition times are reasonable. This generally precludes 3D reconstructions of acceptable quality, however. Steady-state free precession (SSFP) pulse sequences represent another bright blood technique. These sequences maintain a steady state of both longitudinal and transverse magnetization by application of a series of balanced RF pulses. They are generally faster than gradient echo or spoiled gradient echo acquisitions and have higher signal-to-noise ratio (SNR). The most important difference, however, is that the bright blood appearance in SSFP images is primarily the result of the intrinsic magnetic relaxation properties of blood rather than an inﬂow effect. This in turn means that there are fewer artifacts related to slow ﬂow or in-plane ﬂow. Acquisition times (particularly if used in conjunction with parallel imaging) are fast enough that two to four images can be obtained per second, and image quality is usually acceptable even in patients unable to suspend respiration (Fig. 16.21).22,23 The limitations of SSFP sequences include fairly high background signal, even with fat suppression, so that 3D reconstructions are usually not practical. Banding artifacts near the edge of the ﬁeld of view, and adjacent to gascontaining structures are occasionally problematic. Optimal SSFP images with minimal artifact require highperformance gradients, which are not universally available. Phase contrast pulse sequences are relatively uncommon in MR venography. In this technique, additional positive and negative gradient pulses are

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Figure 16.20 (a) Black blood and (b, c) bright blood noncontrast magnetic resonance venography in patient with ﬁbrosing mediastinitis and superior vena cava (SVC) occlusion. Note the absence of ﬂow void (arrow) in the double inversion recovery fast spin echo image (a), and lack of bright blood signal in the SVC and right pulmonary artery (arrowhead) in bright blood fast gradient echo images (b, c).

applied to a standard gradient recalled echo (GRE) or spoiled gradient recalled echo (SPGR) sequence. Stationary spins experience no net accumulation of phase, whereas spins moving across the gradient accumulate a phase proportional to velocity. By adjusting the strength of these velocity-encoding gradients, a range of velocities can be detected and measured. The major advantage of phase contrast venography is that it generates images in which the velocity of each pixel can be determined. By incorporating ECG triggering, venous ﬂow can be measured with high accuracy. This can be useful in the setting of chronic mesenteric ischemia, and in evaluating the signiﬁcance of a venous stenosis. The major limitation of phase contrast techniques is that the acquisition times are longer than time-of-ﬂight and SSFP sequences. Contrast-enhanced MR venography is probably the most widely used technique currently. This technique is essentially identical to 3D contrast-enhanced MR angiography, employing a 3D spoiled gradient echo sequence with or without fat saturation in conjunction with a bolus of gadolinium-based contrast (Figs 16.21–16.24). Vascular contrast is the result of the T1shortening effects of gadolinium on adjacent water protons, and has relatively little dependence on inﬂow effects. The T1-weighted 3D SPGR sequence provides a moderate amount of background suppression.24–26 The simplest 3D contrast-enhanced (CE) MR venography techniques involve one or more additional acquisitions after performing MRA: the contrast bolus is injected and MRA is performed when the concentration of the gadolinium contrast agent is maximal in the arteries. Additional phases are then acquired until venous contrast is maximal. Alternatively, a test bolus or ﬂuoroscopic triggering can be used to optimize the timing of the acquisition to maximize venous rather than arterial concentration: this reduces the total number of acquisitions, but does limit opportunities for subtraction of arterial phase data. A signiﬁcant advantage of 3D CE MR venography relative to time-of-ﬂight MR venography techniques is that the acquisition times are generally short enough to acquire in a single breath-hold. Since there is no reliance on vascular inﬂow effects, the plane of acquisition has no effect on the vascular signal. The 3D acquisition volume can therefore be optimized for maximum efﬁciency: oblique coronal for visualizing the IVC, pelvic veins, and extremity veins, for example, achieving maximal volumetric coverage within a breath-hold. Contrast enhanced MR venography has some limitations compared with the more common MRA technique: the contrast bolus is less compact and more dilute by the time it reaches the venous system, and therefore the maximal contrast enhancement in veins is generally lower than that achieved in arteries. Nevertheless, it is usually more than adequate for diagnostic purposes. The addition of fat saturation (usually via chemical saturation pulses) is often helpful in reducing

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Figure 16.21 Renal cell carcinoma with renal vein and inferior vena cava (IVC) tumor thrombus. (a) Arterial phase 3D fatsaturated spoiled gradient echo image reveals extensive renal vein and IVC thrombus (arrows). Note linear enhancing thrombus in the left renal vein. (b) Black blood single shot fast spin echo image reveals ﬁlling defect in IVC and right atrium (arrows) consistent with tumor thrombus. (c) Axial steady state free precession image reveals left renal mass (arrowhead) and renal vein thrombus (arrow).

background signal and improving venous contrast, albeit at a cost in slightly longer acquisition times. Finally, the requirement for breath-hold imaging places fundamental constraints on achievable spatial resolution and SNR: increments in both spatial resolution and SNR generally require increased acquisition times, and increased spatial resolution results in reduced SNR. Breath-hold imaging is not a requirement in some anatomic regions, such as the pelvis and extremities: in these cases, multiple acquisitions can be performed with relatively high spatial resolution and high SNR. However, acquisition times remain limited by the vascular half-life of the contrast agent, and an additional problem in these situations is separation of the arterial and venous structures, both of which contain contrast.

Three-dimensional MR venography data can be reconstructed using standard techniques such as reformatting, maximum intensity projection, and volume rendering. Partial volume minimum intensity projection images may be useful to accentuate venous thrombosis. Subtraction techniques are sometimes useful to remove background signal or arterial signal. If pure arterial phase images are acquired, for example, these can be subtracted from venous phase images to generate a purely venous dataset (Fig. 16.25). Likewise, simply subtracting a precontrast mask acquisition from the optimal venous phase data will reduce the amount of background signal and may improve the quality of the 3D reconstructed images. Subtraction techniques rely on the assumption that there is no shift in position between the two

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Figure 16.22 Chronic inferior vena cava (IVC) occlusion with collateral formation. Maximum intensity projection image from contrast-enhanced fat-saturated 3D spoiled gradient echo acquisition reveals occlusion of the IVC below the renal veins (arrow) with massive dilatation of the left gonadal vein (arrowheads).

(b) Figure 16.24 Axillary and subclavian vein thrombosis. Source images from 3D contrast-enhanced magnetic resonance venography reveal occlusive thrombus (arrows).

Figure 16.23 Inferior vena cava (IVC) thrombosis. Partial volume minimum intensity projection image from 3D fatsaturated spoiled gradient echo sequence reveals extensive bland thrombus in the IVC and left renal vein (arrows).

acquisitions: this is not always the case, particularly in patients who are not consistent breath-holders. Two-dimensional post-contrast spoiled gradient echo images are also effective in demonstrating venous abnormalities. In general 2D sequences have higher background signal but better overall contrast compared with 3D sequences. Acquisition times for similar volumetric coverage may be longer, but depend heavily on the sequence parameters chosen. Limitations of the contrast-enhanced MR venography techniques include the need for intravenous contrast: there is a very small risk of allergic reaction, and a link has recently been suggested between gadolinium contrast administration and nephrogenic sclerosing dermopathy in patients with severe renal insufﬁciency. In general, however, gadolinium is considered much less nephrotoxic

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Figure 16.25 (a) Arterial and (b) venous phase maximum intensity projection images from contrast-enhanced magnetic resonance angiography/magnetic resonance venography in patient with severe inferior vena cava (IVC) stenosis following radiation therapy to a lumbar vertebral metastasis. Note threadlike IVC (arrow) in (b). Residual arterial contrast was removed from the venous phase image by subtracting the arterial phase source images from the venous phase source images.

than iodinated contrast agents used in CT. Occasionally the amount of contrast in the veins is not adequate for optimal visualization: this is probably most common in the lower extremities and pelvis in patients with very slow venous return. In these cases, an increased contrast dose or multi-excitation acquisitions may improve image quality. An important advantage of MR venography with respect to CT is that the exact timing of the venous phase acquisition is less important: there is no penalty in MRI for acquiring multiple 3D acquisitions until the venous contrast is optimal, whereas the cumulative radiation dose is a signiﬁcant consideration in CT. Direct MR venography is a technique advocated by several authors in which a dilute bolus of gadolinium contrast is injected directly into the venous territory of interest while simultaneously scanning (Fig. 16.26). This avoids the problem of contrast dilution that occurs when the contrast bolus ﬁrst passes through the arterial system. The two major limitations of this technique are that venous access needs to be established in a peripheral vein of interest (typically the hand or foot), and that unless both arms or legs are injected simultaneously there will be only minimal visualization of contralateral veins.27,28

Clinical applications Magnetic resonance venography generally plays a secondary role in venous imaging. Duplex Doppler

Figure 16.26 Direct venogram in patient with subclavian vein thrombosis. Volume-rendered image from contrast-enhanced 3D spoiled gradient echo sequence obtained while injecting dilute gadolinium contrast into a peripheral right sided vein reveals patent superior vena cava (arrow), occluded distal right subclavian vein (arrowhead), and extensive collateral formation (asterisks).

sonography is generally the ﬁrst test performed in assessing lower or upper extremity veins for thrombosis. Sonography is accurate, portable, and considerably less expensive than MR venography, but is occasionally limited. Sonography is less effective in visualizing the central veins of the thorax, the entire extent of the IVC, and the iliac veins. ILIAC AND LOWER EXTREMITY DEEP VEIN THROMBOSIS

Deep vein thrombosis (DVT) is a fairly common problem, with approximately 260 000 cases diagnosed in the USA every year. The diagnosis is most often made with duplex sonography, which is usually highly accurate for the detection of femoral and popliteal DVT but is somewhat limited in evaluation of pelvic and calf veins, obese patients, and chronic asymptomatic thrombus. Several studies have demonstrated the effectiveness of MR venography for detecting pelvic and lower extremity venous thrombosis.19,20,29–31 Carpenter et al.19 reported a sensitivity of 100% and speciﬁcity 96% for evaluation of DVT from the IVC to the popliteal vein comparing 2D time-of-ﬂight MR venography and conventional venography. Evans et al.20 found MR venography to be more sensitive than sonography but of equivalent speciﬁcity for femoropopliteal DVT. More recently, Fraser et al.29 employed a contrast-enhanced subtraction

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technique to evaluate femoral and iliac veins for DVT, ﬁnding sensitivity and speciﬁcity of 100% in comparison to conventional venography. Ruehm et al.30 achieved excellent image quality in a contrast-enhanced direct MR venography study of the lower extremity veins. Although non-contrast techniques have proved sensitive and speciﬁc in several studies, acquisition times can be quite long, potentially reducing patient cooperation and image quality – the major advantage of the more recently introduced contrast-enhanced methods is probably in the much shorter acquisitions and reduced total examination time (Figs 16.27 and 16.28). An additional advantage of MR and CT venography compared with conventional venography in the evaluation of iliac and lower extremity veins is the excellent soft tissue detail inherent in these techniques, which can provide insight into the cause of venous thrombosis (Fig. 16.29).

Venous extension is an important consideration in staging and treating renal cell carcinoma: the renal vein is invaded in as many as 20% of cases and the IVC in approximately 10%. MRI is an ideal technique for evaluation of renal cell carcinoma. It is highly accurate in detecting and characterizing renal masses. Regional adenopathy, direct invasion of adjacent structures, and distant metastases are easily visualized. Vascular staging including MR venography reveals the presence or absence of bland or

tumor thrombus in the renal veins and IVC as well as the venous anatomy, and this information plays a role in choosing the most appropriate surgical approach and technique.24,32–34 Tumor thrombus enhances after contrast administration and is generally heterogeneous in appearance, whereas bland thrombus is uniformly dark on all pre- and post-contrast sequences (Figs 16.21 and 16.30). Several recent studies have compared MRI with multidetector CT for the vascular staging of renal cell carcinoma, and have generally found both techniques to be highly accurate.33,34 Adrenal carcinoma is also notorious for extension into the IVC, and MRI is similarly effective in staging venous extension in this entity. IVC and iliac vein patency is well demonstrated by both non-contrast and contrastenhanced MR venography sequences. Often rapid assessment for IVC thrombus can be performed without contrast using sequential thick section GRE, SPGR, or SSFP sequences. When thrombus is present, MR venography is very effective in demonstrating the presence of collateral veins. Narrowing or occlusion of the intrahepatic IVC and hepatic veins can result from a number of pathologies, including tumors, such as hepatocellular carcinoma and cholangiocarcinoma, polycystic liver disease, Budd–Chiari syndrome, and post-transplant-related stenosis. Visualization of the hepatic veins and IVC is generally excellent on standard 3D axial dynamic contrast-enhanced SPGR images performed in most standard hepatic MRI

(a)

(b)

RENAL VEINS AND THE INFERIOR VENA CAVA

Figure 16.27 Contrast-enhanced multi-station magnetic resonance venogram in patient with Klippel–Trenauny–Weber syndrome. Maximum intensity projection images from (a) thigh station and (b) calf station reveal enlarged patent central veins (arrow) as well as numerous dilated superﬁcial collateral veins in the left leg (arrowheads).

Imaging technologies: magnetic resonance imaging of venous disease 187

(a)

(b)

(c)

Figure 16.28 Superﬁcial venous thrombosis in the calf. (a,b) Coronal and (c) axial contrast-enhanced fat-saturated spoiled gradient echo images reveal ﬁlling defects in bilateral veins (arrowheads), surrounded by inﬂammatory enhancement of the vessel walls and adjacent muscle.

examinations; however, additional MR venography sequences can be added in situations where venous patency is the primary question. Both MRI and CT are commonly used to screen potential living renal transplant donors: the number and location of renal arteries and veins is important in surgical planning. MR venography in conjunction with MRA can answer these questions effectively, without exposing patients to iodinated contrast and ionizing radiation.35 Mesenteric veins are usually well seen on standard dynamic contrast-enhanced MRI sequences used to evaluate the liver and other abdominal organs – these are typically fat-saturated 3D SPGR sequences. Portal, splenic, or mesenteric vein thrombosis can easily be demonstrated, and often the underlying cause elucidated. Varices in the setting of portal hypertension can be demonstrated, and the direction of portal venous ﬂow determined using phase contrast techniques.36 Some authors have also advocated the use of phase contrast techniques in patients with suspected chronic mesenteric ischemia, demonstrating a lack of normal increased ﬂow in the superior mesenteric vein following a fatty meal. Venous anastomoses in hepatic transplants are occasionally problematic. MR venography techniques can clearly reveal

stenosis or thrombosis of portal and hepatic veins. Phase contrast techniques can measure velocities in stenotic veins to estimate pressure gradients across the lesion. Thoracic central veins are largely inaccessible to sonography, and therefore MR venography is an excellent technique to evaluate central veins for stenosis or thrombosis.25,28 3D contrast-enhanced SPGR sequences with multiple acquisitions usually demonstrate venous anatomy effectively, and can be combined with additional sequences as needed. Pulmonary vein stenosis is a wellknown complication of radiofrequency ablation of arrhythmogenic foci in the atria. The pulmonary veins can be evaluated with standard contrast-enhanced MR venography sequences. Enhancement of the atrial walls after contrast administration has also been described, and may be useful in assessing the extent of atrial injury. Anomalous pulmonary venous drainage is also easily demonstrated with MRI (Fig. 16.31).37 There is a strong association of anomalous pulmonary venous return with concurrent cardiac anomalies: these can also be assessed with MRI, and the severity of the shunt quantiﬁed by measuring the ratio of pulmonary artery to aortic blood ﬂow (Qp/Qs ratio).

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(a)

(b)

(c)

Figure 16.29 Ewing sarcoma with venous extension. (a, b) Axial contrastenhanced fat-saturated spoiled gradient echo (SPGR) images reveal a mass in the right iliac bone with soft tissue extension (arrow). Note enlarged right internal iliac vein ﬁlled with tumor thrombus (a) (arrowhead), and bland thrombus in the external iliac vein at a lower level (b) (arrowhead). (c) Coronal 3D SPGR image again demonstrates tumor thrombus in the right common iliac vein (arrowhead).

Magnetic resonance versus computed tomography venography The major advantages of CT with respect to MR are speed and spatial resolution. Large volumes can be covered in only a few seconds with state-of-the-art 64-row multidetector CT, with isotropic spatial resolution of less than 1 mm. Standard acquisition times for 3D SPGR MR venography sequences are generally between 10 and 20 seconds, which is occasionally problematic for patients who are short of breath. In-plane spatial resolution for typical MR venography acquisitions is ≤ 1 mm; however, slice thickness is generally in the range of 2–4 mm, signiﬁcantly lower than CT, but generally adequate for most applications. Computed tomography is also preferable in patients with claustrophobia, pacemakers, or other contraindications to MR. On the other hand, MR is a much more ﬂexible technique, with numerous non-contrast and contrastenhanced methods relying on different contrast mechanisms, so that more choices are available in difﬁcult cases. In general, contrast-to-noise ratios of venous blood are signiﬁcantly higher with MRI, although SNR is occasionally lower. Magnetic resonance venography is preferred in patients with allergies to iodinated contrast or renal insufﬁciency. Magnetic resonance venography is also the test of choice in patients without venous access, since

many non-contrast techniques are available with MRI and not with CT. Radiation dose is also a consideration, particularly in pediatric or pregnant patients or other radiation-sensitive populations (Table 16.1).

Future prospects Intravascular or blood pool MR contrast agents are nearing approval for clinical use. These agents have a vascular half life of several hours, and therefore to some

Table 16.1 Advantages and disadvantages of computed tomography (CT) and magnetic resonance imaging (MRI) for evaluation of venous disease

CT

MRI

Advantages

Disadvantages

Speed Superior spatial resolution Calciﬁcations No radiation exposure No iodinated contrast Multiple acquisitions possible Superior contrast resolution

Iodinated contrast Radiation Contraindications Pacemaker Aneurysm clips Claustrophobia

Imaging technologies: magnetic resonance imaging of venous disease 189

(a)

(b)

(c)

Figure 16.30 Renal cell carcinoma (asterisk) with tumor thrombus and bland thrombus. (a) Coronal fat-saturated steadystate free precession image reveals right renal mass with enlargement of the renal vein and inferior vena cava (IVC). Note the difference between the more heterogeneous and higher signal intensity tumor thrombus extending superiorly (arrows) and the bland thrombus in the IVC below the level of the renal vein (arrowhead). (b, c) Axial contrast-enhanced fat-saturated spoiled gradient echo images show similar ﬁndings, with enhancing, heterogeneous tumor thrombus at the level of the left renal vein (b) (arrow), and uniform, non-enhancing bland thrombus more inferiorly (c) (arrowhead).

(a)

(b)

Figure 16.31 (a) Anterior and (b) posterior volume-rendered images from contrast-enhanced pulmonary venogram in patient with scimitar syndrome demonstrate a large anomalous vein draining the right lower lobe and entering the inferior vena cava at the level of the diaphragm.

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Computed tomography and magnetic resonance imaging in venous disease

Guidelines 2.6.0 of the American Venous Forum on computed tomography and magnetic resonance imaging in venous disease No.

Guideline

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest)

2.6.1 Computed tomography with intravenous contrast is recommended for evaluation of obstruction of large veins in the chest, abdomen and pelvis. Computed tomography accurately depicts the underlying pathology, conﬁrms extrinsic compression, tumor invasion, traumatic disruption, anatomic variations, extent of thrombus and position of a caval ﬁlter

1

B

2.6.2 Computed tomography with intravenous contrast is recommended to diagnose pulmonary embolism. Sensitivity and speciﬁcity approaches 100% for central emboli, whereas for small, subsegmental pulmonary emboli sensitivity and speciﬁcity are 83% and 96%, respectively

1

A

2.6.3 Magnetic resonance venography is recommended for diagnosis of acute iliofemoral and caval deep vein thrombosis. A sensitivity of 100% and speciﬁcity 96% was reported. The study is also recommended to diagnose portal, splenic, or mesenteric venous thrombosis

1

A

2.6.4 Magnetic resonance imaging and magnetic resonance venography are highly accurate to image inferior vena cava thrombus associated with renal, adrenal, retroperitoneal, primary caval, or metastatic malignancies. Magnetic resonance venography reveals the presence or absence of bland thrombus or tumor thrombus in the renal veins and inferior vena cava

1

A

extent eliminate the need for time-resolved imaging.38 In theory, the acquisition time therefore becomes open ended, allowing MR venography images to be obtained with spatial resolution equivalent to state-of-the-art CT and superior contrast-to-noise and SNR. Longer acquisition times would only be effective in anatomic regions without motion artifact, for example, the pelvis and lower extremities, although pulse sequences using respiratory gating could be performed in the chest and abdomen. An additional problem is segmentation of arteries and veins – this is particularly difﬁcult in the extremities, with small arteries and veins running in close proximity to each other. Direct imaging of thrombus has been performed by a few groups – this technique uses the relaxation properties of subacute thrombus (short T1) in conjunction with a fatsuppressed 3D sequence to generate images where thrombus is bright and everything else is dark.39 Other investigators have developed novel contrast agents in which gadolinium-labeled antibodies are delivered to thrombin or other targets.

SUMMARY CT and MR are both effective tools in answering a large number of clinical questions regarding the venous system. Each technique has unique advantages and disadvantages, as outlined above. Advances in each technology will continue to provide optimal imaging evaluation for a wide variety of venous disorders.

REFERENCES ● ◆

= Key primary paper = Major review article ◆1.

McCollough CH, Bruesewitz MR, Koﬂer JM Jr. CT dose reduction and dose management tools: overview of available options. Radiographics 2006; 26: 503–12. 2. Eren S, Karaman A, Okur A. The superior vena cava syndrome caused by malignant disease. Imaging with multi-detector row CT. Eur J Radiol 2006; 59: 93–103.

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3. Cihangiroglu M, Lin BH, Dachman AH. Collateral pathways in superior vena caval obstruction as seen on CT. J Comput Assist Tomogr 2001; 25: 1–8. 4. Siegel MJ. Multiplanar and three-dimensional multidetector row CT of thoracic vessels and airways in the pediatric population. Radiology 2003; 229: 641–50. 5. Lawler LP, Fishman EK. Multi-detector row CT of thoracic disease with emphasis on 3D volume rendering and CT angiography. Radiographics 2001; 21: 1257–73. ◆6. Zhang L, Yang G, Shen W, Qi J. Spectrum of inferior vena cava: MDCT ﬁndings. Abdom Imaging 2007; 32: 495–503. 7. Minniti S, Visentini S, Procacci C. Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 2002; 12: 2040–55. 8. Bass JE, Redwine MD, Kramer LA, et al. Spectrum of congenital anomalies of the inferior vena cava: crosssectional imaging ﬁndings. Radiographics 2000; 20: 649–52. 9. Trigaux JP, Vandroogenbroek S, De wispelaere JF, et al. Congenital anomalies of the inferior vena cava and left renal vein: evaluation with spiral CT. J Vasc Interv Radiol 1998; 9: 339–45. 10. Alfuhaid TR, Khalili K, Kirpalani A, et al. Neoplasms of the inferior vena cava – pictorial essay. Can Assoc Radiol J 2005; 56: 140–7. 11. Ameeri S, Butany J, Collins MJ, et al. Leiomyosarcoma of the inferior vena cava. Cardiovasc Pathol 2006; 15: 171–3. 12. Remy-Jardin M, Remy J, Deschildre F, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996; 200: 699–706. ●13. Remy-Jardin M, Remy J, Wattinne L, Giraud F: Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique— comparison with pulmonary angiography. Radiology 1992; 185: 381–7. ●14. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006; 354: 2317–27 ●15. Stein PD, Woodard PK, Weg JG, et al. diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007; 242: 15–21. 16. Oguzkurt L, Tercan F, Pourbagher MA, et al. Computed tomography ﬁndings in 10 cases of iliac vein compression (May-Thurner) syndrome. Eur J Radiol 2005; 55: 421–5 17. Lamont JP, Pearl GJ, Patetsios P, et al. Prospective evaluation of endoluminal venous stents in the treatment of May-Thurner syndrome. Ann Vasc Surg 2002; 16: 61–4. 18. O’Sullivan GJ, Semba CP, Bittner CA, et al. Endovascular management of iliac vein compression syndrome. J Vasc Interv Radiol 2000; 11: 823–36. ●19. Carpenter JP, Holland GA, Baum RA, et al. Magnetic resonance venography for detection of deep venous thrombosis: comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 1993; 18: 233–8.

●20.

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32.

33.

34.

Evans AJ, Sostman HD, Knelson MH, et al. Detection of deep venous thrombosis: prospective comparison of MR imaging with contrast venography. AJR AM J Roentgenol 1993; 161: 131–9. Vogt FM, Herborn CU, Goyen M. MR venography. Magn Reson Imaging Clin N Am 2005; 13: 113–29. Cantwell CP, Cradock A, Bruzzi J, et al. MR venography with true fast imaging with steady-state precession for suspected lower-limb deep vein thrombosis. J Vasc Interv Radiol 2006; 17: 1763–9. Wilson MW, LaBerge JM, Kerlan RK, et al. MR portal venography: preliminary results of fast acquisition without contrast material or breath holding. Acad Radiol 2002; 9: 1179–84. Choyke PL, Walther MCM, Wagner JR, et al. Renal cancer: preoperative evaluation with dual-phase, threedimensional MR angiography. Radiology 1997; 205: 767–71. Shinde TS, Lee VS, Rofsky NM, et al. Three-dimensional gadolinium-enhanced MR venographic evaluation of patency of central veins in the thorax: initial experience. Radiology 1999; 213: 555–60. Lin J, Zhou KR, Chen ZW, et al. Vena cava 3D contrastenhanced MR venography: a pictorial review. Cardiovasc Intervent Radiol 2005; 28: 795–805. Ruehm SG, Zimny K, Debatin JF. Direct contrast-enhanced 3D MR venography. Eur Radiol 2001; 11: 102–12. Tanju S, Sancak T, Dusunceli E, et al. Direct contrastenhanced 3D MR venography evaluation of upper extremity deep venous system. Diagn Interv Radiol 2006; 12: 74–9. Fraser DGW, Moody AR, Davidson IR, et al. Deep venous thrombosis: diagnosis using venous enhanced subtracted peak arterial MR venography versus conventional venography. Radiology 2003; 226: 812–20. Ruehm SG, Wiesner W, Debatin JF. Pelvic and lower extremity veins: contrast-enhanced three-dimensional MR venography with a dedicated vascular coil – initial experience. Radiology 2000; 215: 421–7. Kluge A, Mueller C, Strunk J, et al. Experience in 207 combined MRI examinations for acute pulmonary embolism and deep vein thrombosis. Am J Roentgenol 2006; 186: 1686–96. Laissy JP, Menegazzo D, Debray MP, et al. Renal carcinoma: diagnosis of venous invasion with Gdenhanced MR venography. Eur Radiol 2000; 10: 1138–43. Hallscheidt PJ, Bock M, Riedasch G, et al. Diagnostic accuracy of staging renal cell carcinoma using multidetector-row computed tomography and magnetic resonance imaging. J Comput Assist Tomogr 2004; 28: 333–9. Hallscheidt PJ, Fink C, Haferkamp A, et al. Preoperative staging of renal cell carcinoma with inferior vena cava thrombus using multidetector CT and MRI: prospective study with histopathological correlation. J Comput Assist Tomogr 2005; 29: 64–8.

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35. Hussain SM, Kock MCJM, Ifzermans JNM, et al. MR imaging: a one-stop shop modality for preoperative evaluation of potential living kidney donors. Radiographics 2003; 23: 505–20. 36. Liu H, Cao H, Wu ZY. Magnetic resonance angiography in the management of patients with portal hypertension. Hepatobiliary Pancreat Dis Int 2005; 4: 239–43. 37. Valsangiacomo ER, Levasseur S, McCrindle BW, et al. Contrast-enhanced MR angiography of pulmonary venous abnormalities in children. Pediatr Radiol 2003; 33: 92–8.

38. Aschauer M, Deutschmann HA, Stollberger R, et al. Value of a blood pool contrast agent in MR venography of the lower extremities and pelvis: preliminary results in 12 patients. Mag Reson Med 2003; 50: 993–1002. 39. Schmitz SA, O’Regan DP, Gibson D, et al. Magnetic resonance direct thrombus imaging at 3T ﬁeld strength in patients with lower limb deep vein thrombosis: a feasibility study. Clin Radiol 2006; 61: 282–6.

PART

3

MANAGEMENT OF ACUTE THROMBOSIS Edited by Thomas W. Wakeﬁeld

17 The clinical presentation and natural history of acute deep venous thrombosis Mark H. Meissner 18 Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism Joann Lohr, Daniel Kim and Kelli Krallman 19 Medical treatment of acute deep vein thrombosis and pulmonary embolism Russell D. Hull and Graham F. Pineo 20 Catheter-directed thrombolysis for treatment of acute deep vein thrombosis Anthony J. Comerota and Jorge L. Martinez Trabal 21 Surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral venous thrombosis Bo Eklöf and Robert B. McLafferty 22 Treatment algorithm for acute deep venous thrombosis: current guidelines Thomas W. Wakeﬁeld 23 Current recommendations for prevention of deep venous thrombosis Robert D. McBane and John A. Heit 24 The management of axillo–subclavian venous thrombosis in the setting of thoracic outlet syndrome Richard M. Green and Robert Rosen 25 Indications, techniques, and results of inferior vena cava filters Venkataramu N. Krishnamurthy, Lazar J. Greenﬁeld, Mary C. Proctor and John E. Rectenwald 26 Superficial venous thrombophlebitis Anil Hingorani and Enrico Ascher 27 Mesenteric vein thrombosis Waldemar E. Wysokinski and Robert D. McBane

195 208 221 239 255

265 277 292 299 314 320

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17 The clinical presentation and natural history of acute deep venous thrombosis MARK H. MEISSNER Introduction Clinical presentation of acute DVT Complications of acute deep vein thrombosis The natural history of acute deep vein thrombosis

195 195 196 197

INTRODUCTION The spectrum of venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Among 2119 patients enrolled in a prospective, multicenter registry, 72.7% had DVT, 9.7% had PE, and 17.5% had both DVT and PE.1 First episodes of clinically recognized DVT occur with an ageadjusted incidence of 50.4 per 100 000 person–years.2 However, many episodes are asymptomatic and the symptoms of acute DVT, including edema, pain, and erythema,1 are non-speciﬁc. At least three-quarters of patients having lower extremity symptoms consistent with DVT have non-thrombotic causes of their symptoms. Conﬁrmatory testing is therefore always required, both to insure appropriate treatment of those with conﬁrmed DVT and to prevent the complications of inappropriate anticoagulation in those with other disorders. The treatment of DVT is aimed at preventing its complications – PE, recurrent DVT, post-thrombotic syndrome, and death. These complications are closely related to the natural history of DVT, an understanding of which is required in determining optimal management. The formation of thrombi in the venous system depends in large measure on imbalances within the coagulation and ﬁbrinolytic systems and similar interactions continue to be important throughout the subsequent evolution of these thrombi. Over time, the processes of recanalization and organization compete with thrombus extension and rethrombosis. Although our understanding remains incomplete, the most important chronic manifestation of acute DVT, the post-thrombotic

The natural history of the post-thrombotic syndrome Clinical applications of natural history studies References

200 202 204

syndrome, can now be related to its natural history. More importantly, identiﬁcation of the determinants of valvular incompetence and persistent obstruction may provide opportunities to correct or modify the changes contributing to a poor outcome.

CLINICAL PRESENTATION OF ACUTE DVT The clinical presentation of an acute DVT varies with the anatomic distribution, extent, and degree of occlusion of the thrombus. Symptoms may accordingly range from their absence to massive swelling and cyanosis with impending venous gangrene (phlegmasia cerulea dolens). Three patterns of thrombosis are commonly recognized – isolated calf vein (distal), femoropopliteal, and iliofemoral thrombosis – and symptoms tend to be more severe as thrombosis extends more proximally. However, up to 50% of patients with an acute DVT may lack any speciﬁc sign or symptom.3,4 Postoperative patients are, in particular, more likely to have small, asymptomatic, distal, non-occlusive thrombi. When present, signs and symptoms of acute DVT may include pain, edema, erythema, tenderness, fever, prominent superﬁcial veins, pain with passive dorsiﬂexion of the foot (Homan’s sign), and peripheral cyanosis. Although potentially associated with concurrent DVT, a palpable cord is more suggestive of superﬁcial venous thrombosis. Phlegmasia cerulea dolens, characterized by the triad of massive swelling, cyanosis, and pain,5 is the most severe form of acute DVT and results from near complete thrombosis of an extremity’s

196

The clinical presentation and natural history of acute deep venous thrombosis

venous outﬂow. In advanced cases, it is marked by severe venous hypertension with collateral and microvascular thrombosis leading to venous gangrene. Venous gangrene has been particularly associated with warfarin-mediated protein C depletion in patients with cancer or heparininduced thrombocytopenia.6,7 Unfortunately, the diagnosis of DVT based upon clinical signs and symptoms is notoriously inaccurate. The signs and symptoms of DVT are non-speciﬁc and may be associated with other lower extremity disorders including lymphedema, the post-thrombotic syndrome, superﬁcial venous thrombosis, cellulitis, musculoskeletal trauma, and Baker’s cysts. Among patients referred to the vascular laboratory for exclusion of DVT, only 12–31% will have a positive ultrasound study.8–10 The most common presenting symptoms have a wide range of reported sensitivities and speciﬁcities: calf pain, sensitivity 75–91% and speciﬁcity 3–87%; and calf swelling, sensitivity 35–97% and speciﬁcity 8–88%.11–16 None of the signs or symptoms are sufﬁciently sensitive or speciﬁc, either alone or in combination, to accurately diagnose or exclude thrombosis.17 For example, although Markel9 found a history of swelling in 83% of patients with a DVT, it was also present in 63% of those with a clinical suspicion but no documented DVT. Limb pain was similarly present in 51% and 41% of patients with and without DVT, respectively. The overall sensitivity and speciﬁcity of the clinical examination have ranged from 60% to 96% and 20% to 72% respectively.18 The accuracy of the clinical signs and symptoms of DVT also differs between inpatients and outpatients. Inpatients are more often post-operative or critically ill, whereas outpatients are less likely to have had recent surgery, trauma, or a prior DVT.8 Additionally, the incidence of DVT is lower among outpatients but speciﬁc leg symptoms are more common. The absence of certain risk factors, signs, or symptoms may thus have a higher negative predictive value in outpatients.10 As the clinical presentation of acute DVT is nonspeciﬁc, the presence or absence of associated thrombotic risk factors may alter diagnostic suspicion. For example, in outpatients without cancer, a duration of symptoms greater than 7 days and a differential thigh circumference of < 3 cm has a negative predictive value of 95%.10 Unfortunately, the positive predictive value is only 28.6%. Similarly, a difference in calf circumference of < 2 cm demonstrated a negative predictive value of 85% among outpatients, and 93% in inpatients.8 However, when combined with the absence of risk factors, the negative predictive value of the absence of swelling increased to 97% in outpatients and 92% in inpatients. Despite these observations, withholding treatment based only on empiric clinical observations poses an unacceptable thromboembolic risk of 2–4% in secondary referral outpatients, 8% in inpatients, and 12% in primary care patients.8,10,19 Further diagnostic testing is therefore always required when there is a clinical suspicion of DVT.

Clinical assessment does, however, have a role in determining pre-test probability in algorithms incorporating further diagnostic modalities such as venous duplex ultrasonography and D-dimer measurements. The probability model developed and validated by Wells20 has been widely used and is further reviewed in Chapter 18. According to this model, patients can be stratiﬁed into low, moderate, and high probability groups based on the presence of eight clinical features or risk factors as well as the likelihood of an alternative diagnosis. A valid alternative diagnosis is present in 56% of those without DVT compared with only 17% of those with a conﬁrmed DVT.21 Cellulitis and musculoskeletal disorders account for half to three-quarters of these diagnoses.21,22 Unfortunately, although such models are useful in guiding further diagnostic tests, the 3% prevalence of DVT in lowprobability patients precludes diagnosis based on clinical strategies alone.20 Delayed diagnosis of DVT is not uncommon. Among 2047 patients with symptomatic DVT, a diagnosis was established within 5 days of the onset of symptoms in only 47.1%, whereas it was delayed beyond 10 days in 22.6%.1 Much of this time can be attributed to delays in presentation, patients on average presenting for medical attention 4.4 days after the onset of symptoms.23 Although diagnostic delays are often shorter,23 many of these can be attributed to inadequate appreciation of a patient’s underlying risk factors.1

COMPLICATIONS OF ACUTE DEEP VEIN THROMBOSIS Pulmonary embolism The potentially life-threatening consequences of PE make it the most important short-term complication of acute DVT. Symptomatic PE accompanies approximately 10% of DVTs24 and hospital discharge data suggest an incidence of 23 per 100 000 population.25 Extrapolated to the population of the USA, this would correspond to an incidence of 55 000 initial diagnoses of PE per year. Mathematical estimates, based on a number of assumptions, have yielded a substantially higher incidence of 630 000 cases per year in the USA.26 However, respiratory symptoms correlate poorly with the presence or absence of objectively documented PE and as many as 75% of pulmonary emboli may be asymptomatic.27,28 Routine diagnostic testing suggests that PE accompanies acute DVT much more frequently than appreciated. As many as 25–52% of patients with documented DVT but no symptoms of PE will have highprobability lung scans at presentation.27–30 Although regarded as an unusual source of symptomatic PE, highprobability scans have also been noted in 18–29% of patients with isolated calf vein thrombosis.

The natural history of acute deep vein thrombosis

The post-thrombotic syndrome The post-thrombotic syndrome, with symptoms including pain, edema, skin changes, and ulceration, is the most important late complication of DVT. Older studies, many with methodological ﬂaws, reported post-thrombotic manifestations in up to two-thirds of patients with an acute DVT. More recent studies suggest that, although the incidence of the post-thrombotic syndrome is still underappreciated, it occurs less commonly than in historical studies. Among 224 patients followed for 5 years after venographically conﬁrmed DVT, the postthrombotic syndrome developed in 29.6% of those with proximal thrombosis and 30% of those with isolated calf vein thrombosis.31 Population-based studies have suggested that skin changes and ulceration are present in 6–7 million and 400 000–500 000 people in the USA, respectively.32 In addition to the substantial economic costs, the physical limitations of patients with postthrombotic symptoms are similar to those of patients with other serious chronic medical conditions.24

Mortality after acute deep vein thrombosis Mortality after an episode of acute DVT exceeds that expected in age-matched populations. Although the inhospital case–fatality rate for DVT is only 5%, 1, 3 and 5 year mortality rates of 22%, 30%, and 39% respectively have been noted.24,25,33 Early mortality is most frequently secondary to cancer, PE, and cardiac disease. Among patients ≥ 45 years of age, cancer is the most important predictor of early death,34 28 day mortality rates among those with cancer being as high as 25.4%.35 In comparison to the 12.6% rate in patients without cancer, 1 year mortality rates are as high as 63.4%.33 Although deaths among cancer patients and those with idiopathic DVT remain high for at least 3 years beyond the index event, mortality rates for those with secondary VTE unrelated to cancer return to those of the general population after 6 months.33 Deep vein thrombosis is also associated with an increased risk of cardiovascular death, for which the presence of residual thrombus at the time anticoagulants are stopped may be a marker.36,37 Although the reasons for this are not clear, it has been postulated that the presence of residual thrombus is associated with generalized hypercoagulability. Such a relationship is supported by the higher levels of activated coagulation seen in DVT patients with cardiac disease38 and the observation that both delayed recanalization and myocardial infarction are both associated with increased levels of plasminogen activator inhibitor (PAI-1).39 Clinically, there does appear to be an association between idiopathic VTE and cardiovascular events.36 For example, the 10 year cumulative risk of a symptomatic vascular event among patients with

197

idiopathic DVT is 25.4% compared with 12.9% in those with secondary VTE.40 Patients with idiopathic DVT also have a higher prevalence of atherosclerotic risk factors (diabetes, hypertension, and hypercholesterolemia) and coronary artery calcium than control subjects without VTE.41

THE NATURAL HISTORY OF ACUTE DEEP VEIN THROMBOSIS Venous thrombogenesis As initially proposed by Virchow, three factors are of primary importance in the development of venous thrombosis – abnormalities of blood ﬂow, abnormalities of blood, and vessel wall injury. However, despite the accuracy of Virchow’s postulates, it is now apparent that all three components are not equally important in individual patients. The role of structural injury to the venous wall is disputable; even in the presence of stasis, overt endothelial injury appears to be neither a necessary nor a sufﬁcient condition for thrombosis.42 With the notable exceptions of direct venous trauma, hip arthroplasty, and central venous catheters, there is little evidence that either gross or microscopic endothelial injury plays a signiﬁcant role in venous thrombogenesis. In contrast, data are accumulating that biologic injury to the endothelium may have a very important role in the origin of DVT. The venous endothelium is normally antithrombotic, producing prostaglandin I2 , thrombomodulin, tissue plasminogen activator (tPA), and glycosaminoglycan cofactors of antithrombin. Under conditions favoring thrombosis, the endothelium may become prothrombotic, producing tissue factor, von Willebrand factor, and ﬁbronectin. Leukocytes may be a key mediator of both endothelial injury and hypercoagulability, with the early phases of thrombosis marked by increases in permeability followed by leukocyte adhesion, migration, and endothelial disruption.43,44 Associated cytokines may also be of importance, factors such as interleukin 1 (IL-1) increasing tissue factor expression while diminishing protein C activation.45 Although most venous thrombi originate in areas of low blood ﬂow, stasis alone is also an inadequate stimulus in the absence of low levels of activated coagulation factors.46,47 Although stasis may facilitate endothelial leukocyte adhesion43 and cause endothelial hypoxia leading to a procoagulant state,48 its most important role may be in permitting the accumulation of activated coagulation factors in areas prone to thrombosis. Stasis may thus be a permissive factor for the other events required for thrombosis. Imbalanced activation of the coagulation system appears to be the most important factor underlying many episodes of acute DVT. Although the hemostatic system is continuously active, thrombus formation is ordinarily

198

The clinical presentation and natural history of acute deep venous thrombosis

conﬁned to sites of local injury by a precise balance between activators and inhibitors of coagulation and ﬁbrinolysis. A prethrombotic state may result either from imbalances in the regulatory and inhibitory systems or from activation exceeding antithrombotic capacity.49 Some component of imbalanced coagulation appears to be associated with many thrombotic risk factors including age, malignancy, surgery, trauma, primary hypercoagulable states, pregnancy, and oral contraceptive use. Lower extremity thrombi originate in areas where imbalanced coagulation is localized by stasis – in the soleal sinuses, behind venous valve pockets, and at venous conﬂuences. The calf veins are the most common site of origin, although 40% of proximal thrombi arise primarily in the femoral or iliac veins, presumably in the regions behind the valves.50 In ﬂow models, vortices produced beyond the valve cusps tend to trap red cells in a low shear ﬁeld near the apex of the cusp.51 Red cell aggregates forming within these eddies are likely the early niduses for thrombus formation.52 However, such aggregates are probably transient until stabilized by ﬁbrin in the setting of locally activated coagulation. After their formation, these early thrombi may become anchored to the endothelium near the apex of the valve cusp,53,54 a process postulated to be mediated by adherent leukocytes.44 Propagation of thrombi beyond areas of stasis probably depends largely on the relative balance between activated coagulation and thrombolysis. If local conditions favor propagation, laminated appositional growth occurs outward from the apex as platelets are surrounded by a red cell, ﬁbrin, and leukocyte network. In contrast to arterial thrombi, venous thrombi are composed largely of red cells and ﬁbrin with relatively few platelets. Once luminal ﬂow is disturbed, prograde and retrograde propagation may also be promoted by hemodynamic factors. Conversely, such early thrombi may fail to propagate, aborted thrombi appearing as endothelialized ﬁbrin fragments within the valve pockets.

Recanalization Once formed, the competing processes of recanalization and recurrent venous thrombosis characterize the natural history of acute DVT. The development of chronic sequelae is closely related to the balance between these two processes. The venous lumen is most often reestablished after both experimental and clinical thrombosis.55 The mechanisms of thrombus organization and recanalization have been extensively investigated in animal models of DVT. As reviewed in Chapter 8, both the vein wall and thrombus play important roles in these processes. In short, there is rapid regeneration of a ﬁbrinolytically active neoendothelium soon after thrombosis with an early neutrophillic inﬁltrate within the thrombus and vein wall followed by a predominantly monocyte inﬁltrate.56,57 Monocytes appear to play a particularly important role in

thrombus organization and recanalization, functioning as a source of both ﬁbrinolytic and cytokine mediators. Experimental thrombi show complete recanalization by 3 weeks, with the thrombus reduced to an endothelialized subintimal streak. Although less extensively investigated, histologic studies suggest that clinical DVT follows a similar course. As in the animal models, recanalization appears to be a complex process involving intrinsic and extrinsic ﬁbrinolysis, peripheral fragmentation, neovascularization, and retraction. Thrombus organization begins in the attachment zone with the migration of surfacing cells, presumably derived from the endothelium, over the thrombus.53 Pockets formed between the thrombus and the vein walls then progressively enlarge through peripheral fragmentation and ﬁbrinolysis. The thrombus simultaneously undergoes central softening as well as contraction. In the absence of propagation, the ultimate result is a restored venous lumen with a slightly raised ﬁbroelastic plaque at the site of initial thrombus adherence to the vein wall. Serial non-invasive diagnostic tests, permitting venous thrombi to be followed over time, have conﬁrmed the clinical importance of these processes. Among 21 patients prospectively followed with ultrasound, Killewich58 noted that some recanalization was present by 7 days in 44% of patients and by 90 days in 100% of patients. The percentage of initially involved segments that remained occluded decreased to a mean of 44% by 30 days and 14% by 90 days. van Ramshorst et al.59 similarly noted an exponential decrease in thrombus load over the ﬁrst 6 months after femoropopliteal thrombosis. Most recanalization occurred within the ﬁrst 6 weeks, with ﬂow re-established in 87% of 23 completely occluded segments during this interval. Although thrombus resolution proceeds at a similar rate in the proximal venous segments,59 some39,60 have found more rapid clearance from the tibial segments, perhaps reﬂecting the increased efﬁciency of thrombolysis in small veins. Approximately 55% of subjects will show complete recanalization within 6–9 months of thrombosis.61,62 However, some reduction in thrombus load may continue, albeit at a slower rate, for months to years after the acute event (Fig. 17.1). The degree of recanalization is related to both the degree of activated coagulation and ﬁbrinolytic inhibition (Fig. 17.2). Recanalization is negatively correlated with levels of thrombin activation products (prothrombin fragment 1+2) at the time of presentation.39 Others39,62 have found higher PAI-1 levels in patients with poor thrombus resolution. From a clinical perspective, more complete recanalization has been reported in older patients, those with asymptomatic post-operative thrombosis, and patients with involvement of only one venous segment.63 Cancer is associated with less complete recanalization. The presence of a permanent risk factor has also been associated with an 11-fold higher risk of delayed recanalization.64

The natural history of acute deep vein thrombosis

199

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(a) 25

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Figure 17.1 Boxplot shows reduction in thrombus score determined by serial ultrasound examinations over the ﬁrst year after deep vein thrombosis. Top, middle, and bottom lines of the box represent the 75th, 50th (median), and 25th percentiles. Closed square shows the mean with top and bottom error bars representing the 90th and 10th percentiles. Progressive recanalization occurs with a reduction in mean thrombus score from 5.1 at the time of presentation to 1.8 at 12 months. Mean percent recanalization was 52.4% at 6 months, 57.9% at 9 months, and 58.8% at 12 months. (Meissner et al.39 Reprinted with permission).

0

Percent recanalization

15

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5

Recurrent venous thrombosis Recurrent thrombotic events compete with recanalization early after an acute DVT. Most clinical studies have included both symptomatic recurrent DVT and PE, with rates depending on treatment, proximal or distal location of thrombus, and duration of follow-up. Fortunately, standard anticoagulation is very effective in preventing recurrent VTE while patients are being treated. Among patients with proximal DVT, recurrent thromboembolic events occurred in 5.2% of patients treated with standard anticoagulation measures for 3 months65 compared with 47% of patients inadequately treated with a 3 month course of low-dose subcutaneous heparin.66 Others67 have reported a 7% rate of recurrent VTE during 3 months of anticoagulant treatment. Not surprisingly, most symptomatic events occur after anticoagulation has been stopped. Sarasin and Bounameaux68 calculated a theoretical recurrence rate of 0.9% per month after discontinuing anticoagulant therapy for proximal DVT, similar to observed annual recurrence rates of 7.0–12.9%.34,37 The risk of recurrent VTE is highest over the ﬁrst 6–12 months after the index event, although cumulative rates are as high as 24% at 5 years and 30% at 8 years after initial presentation.37,67,69 The risk of recurrence is at least as great in the contralateral as in the ipsilateral extremity.69 The risk of recurrence is highly related to the underlying thrombotic risk factors. Data from the

0 605040302010

0

10 20 30 40 50 60 70 80 90 100

Percent recanalization

(b) Figure 17.2 (a) Scatterplot of percent recanalization versus prothrombin fragment 1+2 and (b) plasminogen activator inhibitor (PAI-1) activity at presentation among patients followed at least 9 months (n = 44). Solid regression lines show correlation between recanalization and initial F1+2 (R = –0.53, P = 0.0004) and PAI-1 (R = –48, P = 0.002), levels. Patients with negative percent recanalization values had progression of thrombus during follow-up. (Meissner et al.,39 Reprinted with permission).

Duration of Anticoagulation (DURAC) trial suggest a 2 year recurrence rate of 12% in patients with idiopathic DVT or irreversible risk factors and 4.8% in patients with reversible risk factors if treated with 6 months of anticoagulants.70 Others37,67 have similarly noted that patients with idiopathic DVT or thrombophilia are at three times higher risk for recurrent VTE than those with secondary thrombosis. Other risk factors for symptomatic recurrent DVT include advanced age, male gender, increased body mass index, lower extremity paresis and active malignancy.71 Recurrent VTE in the setting of thrombosis isolated to the calf veins requires special consideration. Limited data suggest that isolated calf vein thrombosis is associated with

200

The clinical presentation and natural history of acute deep venous thrombosis

Cumulative incidence of recurrent DVT (%)

less extensive activation of coagulation than proximal venous thrombosis, perhaps implying some difference in pathophysiology.38 At least two types of calf vein thrombosis may be differentiated – those with involvement of the paired posterior tibial and peroneal venae commitantes (axial calf vein thrombosis) and those isolated to the veins draining the gastrocnemial and soleal muscles (muscular calf vein thrombosis) – and their natural history may be different. In patients with thrombosis isolated to the axial calf veins, proximal propagation occurred in 23% of untreated patients and 10% of patients treated with only intravenous heparin.72 As ultrasound technology has improved, muscular calf vein thrombi are more often identiﬁed and now account for approximately 40% of isolated calf vein thrombi. The natural history of these thrombi has only recently been described. Among 135 limbs followed after isolated muscular calf vein thrombosis, 16.3% propagated to the axial tibial veins or higher, the majority (90.9%) within 2 weeks of presentation and only 2.9% to the level of the popliteal vein.73 Cancer was the only risk factor associated with propagation of these thrombi. Although such data suggest that thrombosis isolated to the muscular calf veins may be more benign than that involving the axial calf veins, there are conﬂicting reports74 of associated PE in 7% of patients at the time of presentation and long-term recurrence rates of 18.8%. More information is needed regarding the natural history and management of these thrombi. Not surprisingly, non-invasive natural history studies have disclosed a much higher rate of asymptomatic recurrence than is suggested by clinical studies. Serial duplex studies have shown propagation of thrombus in 26–38% of treated patients within the ﬁrst few weeks after presentation (Fig. 17.3).75,76 In a larger series of 177 patients followed for a median of 9.3 months, ultrasound-

40

30 25.9% 20

documented recurrent thrombotic events were observed in 52% of patients.77 Among initially involved extremities, propagation to new segments occurred in 30% and rethrombosis of a partially occluded or recanalized segment in 31%. New thrombi were also observed in 6% of initially uninvolved contralateral extremities. Although asymptomatic ultrasound-documented recurrences are not clearly associated with underlying risk factors,77 they are related to the degree of activated coagulation and the adequacy of anticoagulation. Recognized thrombophilic states, particularly the factor V Leiden mutation,78 lupus anticoagulant,79 and homocysteinemia,80 have been associated with recurrent thromboembolic events. Furthermore, from a pathophysiological point of view, initial levels of thrombin activation products (prothrombin fragment 1+2) and D-dimer are signiﬁcantly higher in patients with subsequent ultrasound documented recurrence.38 In the case of isolated calf vein thrombosis, D-dimer levels ≥ 2000 ng/mL at the time of presentation had a sensitivity and speciﬁcity of 88.9% and 76.5% respectively in predicting recurrent events. Asymptomatic recurrence is prevented by adequate anticoagulation, the risk of new thrombotic events increasing 1.4-fold for each 20% reduction in the time that anticoagulation is adequate according to standard laboratory measures.76 Given their importance, it is perhaps not surprising that recanalization and recurrent thrombosis are related, and failure of recanalization is now recognized as an independent predictor of recurrent DVT. Among 313 patients followed for up to 6 years after a ﬁrst episode of DVT, 41 of 58 episodes of recurrent VTE occurred in patients with residual thrombus present.67 Others have similarly shown a 2.2-fold to greater than ﬁvefold increased risk of recurrent thrombosis among those with incomplete recanalization.37,63 As many recurrent events occur in the contralateral leg or are episodes of PE, it is likely that the risk of residual thrombus is related to underlying hypercoagulability rather than mechanical abnormalities of the venous system.36,37 The presence of ongoing hypercoagulability is, in fact, perhaps a better predictor of the risk of recurrent VTE.81 At least one study has found that, although residual thrombus was not an independent predictor, a D-dimer level of > 500 ng/mL measured 1 month after discontinuing anticoagulants was associated with a 3.3-fold increased risk of recurrence.82

10

0 0

7

14

21

32

17

THE NATURAL HISTORY OF THE POSTTHROMBOTIC SYNDROME

Time (days) N

71

49

Figure 17.3 Cumulative incidence of ultrasound-documented recurrent thrombotic events during the ﬁrst 3 weeks of therapy. DVT, deep vein thrombosis. (Caps et al.76 Reprinted with permission).

Pathophysiology of the post-thrombotic syndrome As discussed above, manifestations of the post-thrombotic syndrome include pain, edema, skin changes, and ultimately ulceration. Ambulatory venous hypertension is

The natural history of the post-thrombotic syndrome 201

responsible for the more severe post-thrombotic sequelae, which in turn is related to both valvular incompetence and residual venous obstruction. Although accurate hemodynamic tests for venous obstruction are currently lacking, within the limits of currently available tests, valvular incompetence appears to be clinically more important. Post-thrombotic symptoms correlate more closely with a reduction in venous reﬁlling time than with residual abnormalities of venous outﬂow.83 However, limbs developing edema, hyperpigmentation or ulceration are more likely to have a combination of reﬂux and residual obstruction than either abnormality alone (Fig. 17.4).16 In addition to its direct effects on ambulatory venous pressure, obstruction may indirectly contribute to the development of reﬂux. Although the majority of incompetent venous segments have been rendered so by the presence of thrombus, as many as 30% of segments developing reﬂux during follow-up have not been previously thrombosed.84 The precise mechanism by which reﬂux develops in initially uninvolved segments remains unclear, but may be related to persistent proximal obstruction. There may therefore be at least two different means by which reﬂux develops – a more common mechanism related to recanalization of a thrombosed segment and a less common mechanism related to

70

60

Percent legs affected

50

40

30

20

proximal obstruction of uninvolved segments. The risk of developing reﬂux in segments involved by thrombus is almost three times that in uninvolved segments.84 Although experimentally produced thrombi frequently recanalize to produce a patent but valveless lumen, valvular destruction is not a universal consequence of clinical DVT. Many patients remain free of chronic symptoms after an episode of acute DVT and only 69% of extremities have ultrasound-documented reﬂux 1 year after thrombosis.85 The incidence of reﬂux in individual venous segments is even lower, with only 33–59% of involved segments becoming incompetent. Histologic examination of post-thrombotic veins provides some explanation for the differential development of reﬂux after DVT. In extremities with established post-thrombotic syndrome, approximately 50% of popliteal valves will demonstrate thrombus formation on the valve leaﬂets whereas others show endothelial erosion with basement membrane thickening and atypical subintimal collagen ﬁbers.86 However, most episodes of acute DVT are not associated with such extensive histologic changes. In contrast to the observations in patients with established post-thrombotic syndrome, early ﬁbrocellular organization after an acute DVT rarely involves the valve cusps.53,87 Thrombus adherence to the valve cusp was noted in only four of 44 specimens examined by Sevitt.87 In the majority of cases, the thrombus was separated from the valve cusp by a cleft postulated to arise from the local ﬁbrinolytic activity of the valvular endothelium. These observations may reﬂect the recognized intense plasminogen activator activity of the venous valve cusps and may act to preserve some valves during recanalization. These histologic observations are consistent with the natural history of valvular reﬂux. Serial duplex studies have shown the development of reﬂux to coincide with or slightly precede complete recanalization of a segment.60 As with recanalization, the rate at which reﬂux develops is highest during the ﬁrst 6–12 months after DVT.84 Reﬂux may be transient in up to 23% of involved segments, resolving during the course of follow-up.84 This phenomenon conceivably occurs when valves protected by the lytic clefts described above remain partially encumbered by residual thrombus. Normal valvular function then presumably returns with complete recanalization.

10

0

N

R

O

RO

Figure 17.4 Proportion of limbs demonstrating no abnormality (N), reﬂux alone (R), obstruction alone (O), and reﬂux with obstruction (R+O) after deep vein thrombosis with respect to symptoms. Dark bars indicate asymptomatic legs; white bars indicate legs with post-thrombotic symptoms. (Johnson et al.16 Reprinted with permission).

Determinants of the post-thrombotic syndrome Although our understanding remains incomplete, an appreciation of the factors involved in the development of the post-thrombotic syndrome is important in its prevention and management. Most investigators have not found a clear relationship between the initial extent of the thrombus and the ultimate outcome. However, other

The clinical presentation and natural history of acute deep venous thrombosis

potential determinants of post-thrombotic manifestations include the rate of recanalization, recurrent thrombotic events, the global extent of reﬂux, and the anatomic distribution of reﬂux and obstruction. The application of thrombolytic therapy to acute DVT would appear an ideal model for examining the relationship between the rate of recanalization and ultimate valve function. Unfortunately, although thrombolytic therapy clearly has the ability to restore a patent lumen, implications for preservation of valve function are limited by the absence of well-controlled follow-up studies. Other evidence does however suggest a relationship between early recanalization and valve function. In the long-term ultrasound follow-up of 113 patients with an acute DVT, the majority of whom were treated with standard anticoagulation measures, the time to complete recanalization was related to the ultimate development of reﬂux.60 Depending upon the venous segment involved, complete recanalization required 2.3–7.3 times longer in segments developing reﬂux than in segments in which valve function was preserved (Fig. 17.5). Recurrent thrombotic events also have a detrimental effect on valvular competence and development of the post-thrombotic syndrome. Extension of thrombus to initially uninvolved segments obviously places these segments at risk for valvular destruction. However, rethrombosis of a partially occluded or recanalized segment further increases the risk of reﬂux.77 Reﬂux has been noted to develop in 36–73% of such segments, considerably higher than the incidence in segments without rethrombosis (Fig. 17.6). Consistent with these observations, recurrent thrombotic events have been noted in 45% of patients with post-thrombotic symptoms

Median lysis times (days)

700 600 500 400 300 200 100 0

CFV

PFV

Mid SFV

POP

PTV

GSV

Venous segment

Figure 17.5 Median time from thrombosis to complete recanalization, grouped according to ultimate reﬂux status. Error bars denote interquartile range. Segments: common femoral vein (CFV), profunda femoris vein (PFV), mid femoral vein (SFV), popliteal vein (PPV), posterior tibial vein (PTV), and great saphenous vein (GSV). dark blue, reﬂux; light blue, no reﬂux (Meissner et al.60 Reprinted with permission).

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Figure 17.6 The development of reﬂux in initially involved venous segments with and without subsequent rethrombosis. Segments: common femoral vein (CFV); great saphenous (GSV); profunda femoris vein (PFV); proximal, mid, and distal femoral vein (SFP, SFM, SFD), popliteal vein (PPV), and posterior tibial vein (PTV). Numbers above bars indicate the number of segments in which reﬂux was observed over the number of segments in which reﬂux could be deﬁnitively assessed. Differences between segments with and without rethrombosis are statistically signiﬁcant (*P < 0.005) for the SFM, SFD, and PPV segments. dark blue, rethrombosis; light blue, no rethrombosis (Meissner et al.77 Reprinted with permission).

compared with only 17% of asymptomatic subjects.24 The risk of post-thrombotic syndrome is six times greater among patients with recurrent thrombosis.31 Finally, the development of clinical signs and symptoms is related to the global extent of reﬂux88 and the anatomic distribution of reﬂux and obstruction. Reﬂux in the distal deep venous segments, particularly the popliteal and posterior tibial veins, is most signiﬁcantly associated with post-thrombotic skin changes.89–91 However, associated superﬁcial reﬂux has been reported in 84–94% of patients with chronic skin changes and 60–100% of patients with venous ulceration. Although pressure transmission through incompetent perforating veins may play a role, direct thrombotic involvement of the superﬁcial veins and thrombus-independent degenerative processes also appear important in the development of superﬁcial venous incompetence.92 With respect to venous obstruction, the severity of post-thrombotic manifestations is most signiﬁcantly related to persistent popliteal thrombosis.88

CLINICAL APPLICATIONS OF NATURAL HISTORY STUDIES The natural history of acute DVT has management implications that afford some opportunity to modify outcome. When combined with the application of

Clinical applications of natural history studies

compression, early ambulation results in faster resolution of acute pain and edema93 with no increased risk of pulmonary embolism93,94 (grade 1A). Furthermore, despite uncertainties, the risk of post-thrombotic sequelae may be predicted in at least some patients. Patterns of reﬂux involving the popliteal, posterior tibial veins, and superﬁcial veins appear to be associated with a higher incidence of the post-thrombotic syndrome. These patients may warrant particular attention to the use of adjunctive measures such as compression stockings, which may reduce the incidence of objectively documented postthrombotic syndrome by approximately 50% (grade 1A).95 Based on our current understanding, recurrent venous thrombosis is the most powerful predictor of the postthrombotic syndrome. At least some data suggest that early ambulation may decrease the long-term incidence of objectively documented post-thrombotic syndrome (grade 1C).96 As randomized trials have not shown exercise to improve recanalization,97 the beneﬁcial effects of ambulation most likely reﬂect the reduced risk of thrombus propagation.93,94 Most importantly, insuring an adequate duration and intensity of anticoagulation is critical in preventing recurrent thrombosis. The incidence of recurrent thromboembolic events is 15 times higher among patients with inadequate early anticoagulation,65

and the low-molecular-weight heparins offer some theoretical advantage over unfractionated heparin in this regard (grade 1A).98–100 The increased bioavailability and more predictable dose–response of these agents are associated with more rapid inhibition of coagulation.101 Although a difference in the incidence of symptomatic recurrent thromboembolism among those treated with low-molecular-weight and unfractionated heparin has not been consistently demonstrated in clinical trials.102,103 at least some studies have suggested lower rates of asymptomatic extension among patients treated with low molecular weight heparins.104 It is increasingly recognized that the risk of recurrent thromboembolism differs among patients, and that patients with idiopathic DVT or irreversible risk factors warrant a longer duration of treatment. Data are also accumulating that the risk of recurrent VTE is inﬂuenced by ongoing hypercoagulability. Management trials based on D-dimer levels are currently in progress, but the ﬁrst of these has demonstrated a signiﬁcant beneﬁt to continuing anticoagulation in patients with idiopathic DVT and an elevated D-dimer level 1 month after a standard course of anticoagulation (grade 1B).81 With respect to recanalization, the degree and rate at which this proceeds are important determinants of both

Guidelines 3.1.0 of the American Venous Forum on the clinical presentation and natural history of acute deep venous thrombosis No.

203

Guideline

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest)

3.1.1 The term venous thromboembolism should include both deep vein thrombosis and pulmonary embolism

1

A

3.1.2 Presentation of deep vein thrombosis is non-speciﬁc and clinical examination alone is inaccurate for diagnosis

1

A

3.1.3 Early ambulation, combined with compression, is recommended for patients with deep vein thrombosis. Pain and swelling resolves faster and the risk of PE is not increased

1

A

3.1.4 Early ambulation is recommended to patients with deep vein thrombosis to decrease the risk of post-thrombotic syndrome

1

C

3.1.5 Compression is recommended to patients with deep vein thrombosis to decrease the risk of post-thrombotic syndrome

1

A

3.1.6 Early anticoagulation with heparin and adequate duration and intensity of oral anticoagulation is recommended to decrease the risk of recurrent venous thromboembolism

1

A

3.1.7 Thrombolytic therapy is suggested for selected patients with deep vein thrombosis to promote recanalization

2

B

3.1.8 Low-molecular-weight heparin is recommended for deep vein thrombosis in cancer patients with early or limited disease to improve survival

1

A

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The clinical presentation and natural history of acute deep venous thrombosis

valve function and recurrent thrombosis. As for recurrent thrombosis, thrombus resolution is also related to the adequacy of anticoagulation. Use of the low-molecularweight heparins during the maintenance phase of therapy may have some advantages over warfarin. In comparison to standard oral anticoagulation, 3–6 months of treatment with low-molecular-weight heparin has been associated with greater degrees of recanalization, variable improvements in short-term clinical outcome, and a nonsigniﬁcant trend towards less reﬂux (grade 2C).100,105 The potential role of these agents in the long-term management of DVT awaits further clinical trials. Thrombolytic therapy potentially has a role in promoting rapid and complete recanalization in at least some patients (grade 2B). These considerations must, however, be qualiﬁed, since no well-designed randomized study exists to deﬁnitively prove that thrombolytic therapy reduces the incidence of the post-thrombotic syndrome. Finally, early application of compression hosiery may also have a role in promoting early recanalization. In a small randomized trial comparing immediate versus delayed use of compression stockings, complete recanalization at 90 days was achieved in 82% of occluded segments in the early compression group compared with 60% of those in the delayed group.106 As most late deaths associated with DVT are due to cardiac and malignant disease, few interventions are likely to reduce mortality. Notably, the routine use of vena cava ﬁlters has not been shown to decrease either immediate or long-term mortality.107 However, several studies have now suggested a survival advantage among cancer patients with early or limited disease treated with low-molecular-weight heparins (Grade 1A).108 No similar advantage has been noted for patients with advanced metastatic disease.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

1. Ageno W, Agnelli G, Imberti D, et al. Factors associated with the timing of diagnosis of venous thromboembolism: results from the MASTER registry. Thromb Res 2007; 121: 751–6. ◆2. Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg 2003; 25: 1–5. 3. Sevitt S, Gallagher N. Venous thrombosis and pulmonary embolism. A clinico-pathological study in injured and burned victims. Br J Surg 1961; 48: 475–89. 4. McLachlin J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962; 85: 738–44. 5. Weaver FA, Meacham PW, Adkins RB, Dean RH. Phlegmasia cerulea dolens: therapeutic considerations. South Med J 1988; 81: 306–12.

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59. van Ramshorst B, van Bemmelen PS, Honeveld H, et al. Thrombus regression in deep venous thrombosis. Quantiﬁcation of spontaneous thrombolysis with duplex scanning. Circulation 1992; 86: 414–9. ●60. Meissner MH, Manzo RA, Bergelin RO, et al. Deep venous insufﬁciency: the relationship between lysis and subsequent reﬂux. J Vasc Surg 1993; 18: 596–608. 61. Killewich LA, Macko RF, Cox K, et al. Regression of proximal deep venous thrombosis is associated with ﬁbrinolytic enhancement. J Vasc Surg 1997; 26: 861–8. 62. Arcelus JI, Caprini JA, Hoffman KN, et al. Laboratory assays and duplex scanning outcomes after symptomatic deep vein thrombosis: preliminary results. J Vasc Surg 1996; 23: 616–21. ●63. Piovella F, Crippa L, Barone M, et al. Normalization rates of compression ultrasonography in patients with a ﬁrst episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 515–22. 64. Ageno W, Steidl L, Piantanida E, et al. Predictors of residual venous obstruction after deep vein thrombosis of the lower limbs: a prospective cohort study. Thromb Res 2003; 108: 203–7. 65. Hull RD, Raskob GE, Hirsch J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109–14. 66. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the treatment of venous thrombosis. N Engl J Med 1979; 301: 855–8. ●67. Prandoni P, Lensing AW, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955–60. 68. Sarasin FP, Bounameaux H. Duration of oral anticoagulant therapy after proximal deep vein thrombosis: a decision analysis. Thromb Haemost 1994; 71: 286–91. 69. Lindmarker P, Schulman S. The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. The DURAC Trial Study Group. J Intern Med 2000; 247: 601–6. 70. Watzke HH. Oral anticoagulation after a ﬁrst episode of venous thromboembolism: how long? How strong? Thromb Haemost 1999; 82 (Suppl 1): 124–6. 71. Heit JA. The epidemiology of venous thromboembolism in the community: implications for prevention and management. J Thromb Thrombolysis 2006; 21: 23–9. ◆72. Philbrick JT, Becker DM. Calf deep venous thrombosis. A wolf in sheep’s clothing? Arch Intern Med 1988; 148: 2131–8. 73. MacDonald PS, Kahn SR, Miller N, Obrand D. Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. J Vasc Surg 2003; 37: 523–7. 74. Gillet J-L, Perrun MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007; 46: 513–9. 75. Krupski WC, Bass A, Dilley RB, et al. Propagation of deep venous thrombosis by duplex ultrasonography. J Vasc Surg 1990; 12: 467–75.

76. Caps MT, Meissner MH, Tullis MJ, et al. Venous thrombus stability during acute phase of therapy. Vasc Med 1999; 4: 9–14. 77. Meissner MH, Caps MT, Bergelin RO, et al. Propagation, rethrombosis, and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995; 22: 558–67. 78. Simioni P, Prandoni P, Lensing AW, et al. The risk of recurrent venous thromboembolism in patients with an Arg506—>Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336: 399–403. 79. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a ﬁrst episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901–7. 80. den Heijer M, Blom HJ, Gerrits WB, et al. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345: 882–5. ★81. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780–9. 82. Cosmi B, Legnani C, Cini M, et al. D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a ﬁrst idiopathic deep vein thrombosis. Thromb Haemost 2005; 94: 969–74. 83. Killewich LA, Martin R, Cramer M, et al. An objective assessment of the physiological changes in the postthrombotic syndrome. Arch Surg 1985; 120: 424–6. 84. Caps MT, Manzo RA, Bergelin RO, et al. Venous valvular reﬂux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg 1995; 22: 524–31. 85. Markel A, Manzo RA, Bergelin RO, Strandness DE. Valvular reﬂux after deep vein thrombosis: Incidence and time of occurrence. J Vasc Surg 1992; 15: 377–84. 86. Budd TW, Meenaghan MA, Wirth J, Taheri SA. Histopathology of veins and venous valves of patients with venous insufﬁciency syndrome: ultrastructure. J Med 1990; 21: 181–99. 87. Sevitt S. The mechanisms of canalisation in deep vein thrombosis. J Pathol 1973; 110: 153–65. 88. Meissner MH, Caps MT, Zierler BK, et al. Determinants of chronic venous disease after acute deep venous thrombosis. J Vasc Surg 1998; 28: 826–33. 89. Gooley NA, Sumner DS. Relationship of venous reﬂux to the site of venous valvular incompetence: implications for venous reconstructive surgery. J Vasc Surg 1988; 7: 50–9. 90. Rosfors S, Lamke LO, Nordstroem E, Bygdeman S. Severity and location of venous valvular insufﬁciency: the importance of distal valve function. Acta Chir Scand 1990; 156: 689–94. 91. van Bemmelen PS, Bedford G, Beach K, Strandness DE, Jr. Status of the valves in the superﬁcial and deep venous system in chronic venous disease. Surgery 1991; 109: 730–4. 92. Meissner MH, Caps MT, Zierler BK, et al. Deep venous thrombosis and superﬁcial venous reﬂux. J Vasc Surg 2000; 32: 48–56.

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18 Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism JOANN LOHR, DANIEL KIM AND KELLI KRALLMAN Deep venous thrombosis Pulmonary embolism

208 213

DEEP VENOUS THROMBOSIS Introduction Venous thromboembolism encompasses a spectrum of disease beginning with deep vein thrombosis (DVT) and commonly resulting in pulmonary embolism or postthrombotic syndrome. Given the numerous diagnostic studies now available, the task of accurately and costeffectively ruling venous thromboembolism out can at times be daunting. The intent of this chapter is to provide a brief overview of the widely available diagnostic studies as well as an algorithm, seen in Fig. 18.1, to assist in the work-up of patients with suspected venous thromboembolism.

Signs and symptoms The classic “textbook” patient is rarely encountered in medicine, and this is especially true with regards to the presentation of patients with possible DVT. The “textbook” patient is one who presents with pain, pitting edema, and blanching (phlegmasia alba dolens) or a painful blue leg (phlegmasia cerulea dolens). Much of the time, presenting complaints are vague and can be attributable to a host of other etiologies. Up to 70% of patients presenting with complaints compatible with DVT will not have the disease and many patients with DVT will not have any symptoms. In a study of patients presenting to their primary care physicians with symptoms of DVT, a multivariate regression analysis of 17 predictors led to the establishment of nine independent predictors of DVT.1 Interestingly, despite identifying these independent risk

References

217

factors, the authors noted that the predictive value of the variables was low. In fact, the patients categorized as low risk based on these variables had a 15% prevalence of DVT. A prevalence rate of 35% was found for the patients labeled as moderate risk, and the prevalence in the high-risk group was 100%, but consisted of only a few patients. In the primary care setting, patient history and physical examination are insufﬁcient to rule in or out the presence of DVT.1,2 It is therefore the responsibility of the care provider to maintain a high clinical suspicion of DVT and to order the appropriate conﬁrming studies.

Clinical decision/scale With technological advances in medicine, the emphasis on proper diagnosis appears to have shifted from the clinician’s skills of observation and examination to the clinician’s ability to order the correct diagnostic study. As mentioned earlier, the classically taught methods of diagnosis may indeed be lacking in both sensitivity and speciﬁcity when compared with the diagnostic modalities available today.1,2 In 1997, Wells et al.3 developed a clinical model for predicting pretest probability of DVT based upon nine variables that can be seen in Table 18.1. Implementing these variables, symptomatic patients were stratiﬁed into high, moderate, and low probability groups with overall prevalence of venous thromboembolism at 75%, 17%, and 3% respectively. A subsequent comparison of the Wells score and empirical assessment demonstrated poor agreement between the two.4 The Wells score was better at categorizing the low-risk patients and empirical assessment was better at identifying high-risk patients.

Deep venous thrombosis 209

Suspected acute DVT

Calculate pretest clinical probability*

Low/moderate probability

High probability

D-Dimer

Venous US

Negative

Positive/indeterminate

Negative

Positive

Indeterminate

No treatment

Venous US

Serial US 5–7 days

Treatment

MRI/CV

Negative

Positive

Indeterminate

No treatment

Treatment

MRI/CV

Negative

Positive

No treatment

Treatment

Negative

Positive

Negative

Positive

No treatment

Treatment

No treatment

Treatment

Figure 18.1 Algorithm for diagnosing deep vein thrombosis (DVT) in symptomatic outpatients. CV, contrast venography; MRI, magnetic resonance imaging; US, ultrasound. Table 18.1 Clinical Model for predicting the pretest clinical probability of deep vein thrombosis* Clinical characteristic

Score

Active cancer (patient receiving treatment for cancer within the previous 6 months or currently receiving palliative treatment) Paralysis, paresis, or recent plaster immobilization of the lower extremities Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity) Pitting edema conﬁned to the symptomatic leg Collateral superﬁcial veins (non-varicose) Previously documented deep vein thrombosis Alternative diagnosis at least as likely as deep vein thrombosis

1 1 1 1 1 1 1 1 1 –2

*A score of two or higher indicates that the probability of deep vein thrombosis is likely; a score of less than two indicates that the probability of deep vein thrombosis is unlikely. In patients with symptoms in both legs, the more symptomatic leg is used. Reprinted with permission from Wells, et al.,32

Other studies comparing clinical intuition to validated scoring systems have been published with similar results of poor correlation.5 Close to 40% of patients evaluated were underestimated by physicians in one study whereas the

patients were overestimated by physicians in a different study.4,5 Although the Wells scoring system is the most widely used, its validity has been questioned. Oudega et al.2

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studied patients with suspected DVT based upon the presence of a painful, swollen leg for less than 30 days. Contrary to the previous study by Wells et al.,3 their results demonstrated that based on the Wells pretest probability score 15% of the patients in the lowest risk group were diagnosed with DVT using compression ultrasound. However, a more recent meta-analysis of 14 studies by Wells et al.6 maintains their earlier ﬁndings with a pooled prevalence of DVT in the low, moderate, and high-risk groups of 5%, 17%, and 53% respectively. No study suggested that clinical probability scoring alone was adequate to rule DVT in or out, as the utility of the scoring system is to combine a low/moderate probability score with an additional study to rule out the presence of DVT. There is a large degree of variability with regards to clinical assessment, labeling its usefulness suspect at best.

Contrast venography Contrast venography (CV) has by default been long hailed as the gold standard for detection of symptomatic DVT. As of late, its current role in diagnosis of DVT has been largely relegated to one of historical interest. The study is limited in its practicality by both the availability of highly sensitive, non-invasive studies and by its own disadvantages, including the risk of phlebitis, intravenous contrast load with associated risk of nephrotoxicity and allergic reactions, increased cost, and the need for adequate intravenous access. Of the available methods for performing CV, two techniques have emerged as being dominant. The ﬁrst technique, described by Rabinov-Paulin, involves spot ﬁlms, whereas the second technique involves long-leg ﬁlms. Lensing et al.7 compared the two techniques and documented an inadequacy rate for interpretation of 20% for the Rabinov-Paulin technique versus an inadequacy rate of 2% for the long-leg ﬁlms (P < 0.001). There was also a much higher level of interobserver disagreement using the Rabinov-Paulin technique (21%) versus the long-leg technique (4%). If CV is to be performed, the long-leg technique is preferable. Given CV’s role as the gold standard for the detection of symptomatic DVT, subsequent studies have been compared with CV in order to establish their suitability. Motonobu et al. compared CV to ultrasound (US) in the same group of patients and noted a sensitivity and speciﬁcity of 95.5% and 91.4% for CV and a sensitivity and speciﬁcity of 78.3% and 96.5% for US.8 US sensitivity was inferior to CV especially in the calf, detecting only 73.6% of the DVTs noted on CV. An additional smaller study by Ozbudak et al.9 reported that 11.8% of the patients were discovered to have DVT by CV that US did not demonstrate. de Valois et al.10 echoed that opinion in a study that compared CV with duplex sonography and strain-gauge plethysmography. The authors admitted that

duplex sonography was promising, but concluded that CV should be used as a “golden backup” in case of doubt. In recent years, newer imaging modalities and technologies have emerged which may rival CV with regards to sensitivity and speciﬁcity. Additionally, the newer methods seek to address, in some part, the shortcomings or inconveniences of CV. A role for CV may still exist when non-invasive studies are unavailable, nondiagnostic, or in the presence of a clinical condition known to produce false results (e.g., D-dimer levels postoperatively or during pregnancy, compression of the iliac veins by the uterus in pregnant or recently postpartum women on a magnetic resonance venography study, etc.). Rarely is CV a ﬁrst-line study.

Impedance plethysmography Impedance plethysmography (IPG) is based upon the physiologic principle that the impedance between two points on the skin of an extremity will decrease as the volume of blood contained in the extremity increases. The technique examines the rate at which venous outﬂow occurs, thereby deducing the presence or absence of venous outﬂow obstruction. The presence of DVT in the major vessels of the lower extremity, including the popliteal vein and proximally, should reduce the rate of venous outﬂow and subsequently affect the tracing. In the instance of non-ﬂow-limiting thrombi, the study will be negative. Contemporary studies examining IPG are increasingly difﬁcult to ﬁnd as the clinical role of IPG continues to decrease. In a study by Anderson et al.,11 testing of outpatients with suspected DVT resulted in 15% of patients with abnormal IPG ﬁndings and an additional 22% of patients with normal IPG ﬁndings but high clinical suspicion of DVT. For proximal DVT, IPG had a positive predictive value of only 65% and sensitivity of 66% when compared with CV or compression ultrasound (CUS). This low sensitivity is supported by another study in which the sensitivity of IPG for proximal DVT was 65% and speciﬁcity was 93%.12 IPG detected only 23% of the DVT that involved the popliteal but not the superﬁcial femoral vein. In the inpatient setting, when IPG was compared with CV, IPG was noted to have 96% sensitivity and 83% speciﬁcity for proximal DVT.13 Kearon and Hirsh14 performed a literature review to identify the reasons for the large discrepancy in the sensitivity and speciﬁcity of IPG. Several biases were found including repeated IPG before CV and inclusion of patients with known abnormal IPGs. Additionally, the conversion rate from a negative to positive study for IPG is higher than for ultrasound. This difference may result from IPG missing smaller proximal DVT which propagate or become ﬂow limiting. Given the inconsistent sensitivity and speciﬁcity demonstrated by IPG, especially in the outpatient setting,

Deep venous thrombosis 211

as well as the inability for IPG to detect DVT distal to the popliteal vein, there is little to recommend the use of IPG as a ﬁrst-line study. Even in the setting of a negative IPG study, adjunctive studies are recommended for patients with high clinical suspicion of DVT.14 Alternate imaging studies of higher sensitivity, speciﬁcity, and convenience are readily available at most institutions.

Duplex ultrasound Ultrasound (US) has almost completely replaced CV as the diagnostic test of choice for the detection of DVT. Its beneﬁts over CV include lack of radiation, portability, non-invasiveness, and cost-effectiveness. In addition, US also has the ability to distinguish non-vascular pathology such as inguinal adenopathy, Baker’s cysts, abscesses, and hematomas. Duplex ultrasound (DUS) combines compression using real-time B-mode ultrasound with Doppler venous ﬂow detection. The main concern is whether or not US is similar to CV in its diagnostic ability. In a meta-analysis, Goodacre et al.15 compared US to CV. The overall sensitivity for proximal DVT was 94.2% and 63.5% for distal DVT. Speciﬁcity was 93.5%. The combined color Doppler technique was noted to have a higher sensitivity, whereas CUS had optimal speciﬁcity. A similar study of CUS and CV measured a sensitivity of 97% with a speciﬁcity of 87% for CUS.13 The role of repeat US exams in a patient with documented DVT was examined by Ascher et al.16 Patients were retrospectively analyzed after initial diagnosis of lower extremity DVT. Proximal extension of DVT was noted in 19% despite adequate heparin and warfarin therapy. In addition, those with proximal extension were noted to have an increased prevalence of pulmonary embolism (P < 0.05). Given the results of this study, repeat DUS may help to distinguish those high-risk patients who may beneﬁt from placement of an inferior vena cava ﬁlter. Debate continues regarding the role of repeat/serial ultrasound in the diagnosis of DVT. The sensitivity of compression ultrasonography is high for proximal DVT and lower for non-occluding or isolated calf vein thrombosis. As a result, the missed thrombus may propagate and produce pulmonary emboli. After a single normal ultrasound exam with no additional testing, a venous thromboembolism rate of 2.5% is noted.17,18 With the addition of repeat ultrasound 7–14 days after an initial negative exam, the rate of thromboembolic complications is reduced to approximately 1% during 3 months of follow-up.19 Based on similar studies, the consensus has been to repeat ultrasound exams when persistent clinical concern remains despite a negative initial exam, although this has not been clearly validated.15,20 Additionally, the vast majority of repeat ultrasound exams will be negative proving this method both costly and time-consuming.3 Further studies have examined the role of combining Ddimer and ultrasonography to reduce the number of

repeat ultrasound exams required. Those patients with a negative D-dimer assay and a negative initial ultrasound were noted to have a thromboembolic complication rate of 1.3% in 3 months of follow-up, a rate similar to repeat sonography at a greatly reduced cost and time commitment.19,21 In these situations, repeat ultrasound should still be employed, but only in those with positive Ddimer tests and negative initial ultrasounds.19,22 The pitfalls of venous duplex imaging include misidentiﬁcation of veins, duplicated vein systems, systemic illness or hypovolemia decreasing venous distention, suboptimal imaging in obese or edematous patients, or areas not amenable to compression such as the iliac veins and adductor canal. As with most US-based imaging studies, the quality of the exam depends largely on the technician performing the exam.

Magnetic resonance imaging/magnetic resonance venography Magnetic resonance imaging/magnetic resonance venography (MRI/MRV) has gained momentum in recent years for the detection of DVT. In addition to being less invasive than CV, MRV overcomes some of the limitations of CUS and IPG. Since MRV directly visualizes the thrombus, even non-ﬂow-limiting thrombi should be detectable, unlike with IPG. MRV should also be able to detect thrombus proximal to the inguinal ligament, an area which has been problematic for CUS in the past. MRV results are also independent of the technologist’s experience and availability in contrast to CUS. When Carpenter et al.23 compared MRV to CV, the results were identical in 97% of the patients scanned. In fact, the extent of the thrombus and whether it was partially or totally occlusive was in complete agreement between the two studies. MRV had a sensitivity and speciﬁcity of 100% and 96% respectively. Similar results were noted by Laissy et al.24 with MRV demonstrating 100% sensitivity and speciﬁcity compared with CV. MRV was once again noted to have a high sensitivity of 95% in detecting the extent of the DVT. As with most studies involving DVT in the lower extremities, the sensitivity of MRV decreases the more peripherally a thrombus is located. In a prospective, blinded study, MRV direct thrombus imaging had a sensitivity of 94% or 96% depending on the reader.25 When isolated calf DVTs were examined, the sensitivity of MRV was 83% and 92% for the two readers. For DVT involving the femoropopliteal segment, sensitivities were signiﬁcantly higher at 97% for both readers. When the ileofemoral segment was examined, sensitivity rose to 100% for both readers. An additional beneﬁt that MRV may share with CUS is in the aging of thrombus. In a comparison study of venous enhanced subtracted peak arterial (VESPA) MRV to CV, 100% sensitivity and speciﬁcity for DVT in the iliac and

212

Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism

femoral veins was noted.26 Of interest, vessel wall enhancement was noted for acute thrombosis and not for chronic thrombosis. Tempering the enthusiasm for MRI/MRV is the time requirements and patient cooperation needed to perform the study. Using MRV to diagnosis DVT might limit availability of MRI for other uses because of scheduling difﬁculties. In addition, patients with certain implants may not be able to undergo testing. Lastly, the cost of MRV is signiﬁcantly higher than most other DVT studies. In one study, MRV cost was 1.4 times that of CV and 2.5 times that of duplex scanning.23 Recently, concerns have been raised regarding the safety of gadolinium in patients with renal insufﬁciency. There is evidence to suggest that gadolinium is associated with nephrogenic systemic ﬁbrosis.27–30 D-dimer

Using D-dimer to preselect patients likely to have DVT has gained considerable interest in an effort to reduce costs and expedite patient work-up. The D-dimer assays currently available include turbidimetry, enzyme-linked immunosorbent assay (ELISA), latex particle agglutination, ﬂuorescence immunoassay, and immunoﬁltration tests. Each assay has a corresponding normal reference range which is typically not interchangeable. A combination of the Wells pretest clinical probability (PCP) score and quantitative D-dimer testing was used by Yamaki et al.31 to reduce the number of venous duplex scans performed. A 100% sensitivity and 100% negative predictive value (NPV) was noted in the study. The authors recommended no further testing to rule out DVT in patients with low to moderate PCP and a negative D-dimer test. This recommendation reﬂects the ﬁndings of previous studies, where the NPV of D-dimer using the SimpliRED assay decreased from 94.1% in the moderate PCP group to 86.7% in the high probability patients.32 A systematic review by Fancher et al.33 and a meta-analysis by Wells et al.6 concluded that DVT could effectively be ruled out in patients with low to moderate clinical probability and a negative D-dimer assay. D-dimer levels in patients without a PCP score were measured by Diamond et al.34 Compared with duplex imaging, the D-dimer results revealed 100% sensitivity, 100% NPV, but only a 48.8% speciﬁcity due to the large number of false positives. It was estimated that 42% of the venous duplex studies could have been eliminated based on D-dimer assay alone. Five different quantitative D-dimer assays were compared by Stevens et al.,35 and the NPV was uniformly high as long as the cut-off level for the D-dimer assays were set for high sensitivity. The high sensitivity of the study is maintained even in the presence of cellulitis.36 In a review of 97 studies by Goodacre et al.,15 the sensitivity and speciﬁcity of the D-dimer assays were

observed to vary widely. The post hoc thresholds yielded higher sensitivity since levels that maximize sensitivity were likely chosen, and the use of D-dimer in patients with low clinical probability was likely to yield a higher speciﬁcity secondary to the lower number of false positives. There are situations where the D-dimer assay may be falsely positive. These situations include pregnancy, malignancy, recent postoperative state, and total bilirubin greater than 2 mg/dL. Further confounding factors may include the age of the clot as signiﬁcant declines in the D-dimer level may occur with time, position of the clot (isolated calf DVT reduces sensitivity), and heparin use, which may signiﬁcantly reduce D-dimer levels.37 Despite its limitations, D-dimer is a useful tool to rule out DVT as long as the threshold is set low enough to keep the sensitivity high. If a higher speciﬁcity is desired, the D-dimer assay should be used in conjunction with a pretest clinical probability score.

Additional studies Studies examining other diagnostic modalities including computed tomography, liquid crystal contact thermography, C reactive protein, rheography, and photo plethysmography have been performed with varying degrees of success.38–43 At this time, however, none of the alternate imaging modalities have reached mainstream status, limiting their usefulness in the clinical setting.

Deep venous thrombosis in pregnancy The diagnosis of deep venous thrombosis during pregnancy adds an additional level of complexity. There are the obvious concerns for the well-being of the fetus as well as questions regarding the diagnostic accuracy of DVT studies during this period. The amount of ionizing radiation the fetus would be exposed to during venous thromboembolism work-up is only considered signiﬁcant in the induction of malignancy.44 Even then, the dose received during DVT workup would be less than the background radiation received during the 9 months of pregnancy. The contrast agent may pose a risk of anaphylaxis in addition to crossing the placenta and possibly suppressing thyroid function in the fetus.44 Ultrasound remains the front-line study for detection of DVT in pregnancy. If the quality of the US study is suboptimal or there is suspicion for pelvic thrombus, MRI/MRV should be considered. D-dimer levels have been known to increase even during the course of a normal pregnancy and are of unproven usefulness.37 In pregnant patients, repeat US is recommended if the initial scan is negative for DVT.

Pulmonary embolism 213

Intravenous drug users

PULMONARY EMBOLISM

This group poses special challenges for the diagnosis of DVT. These patients will frequently have a positive Ddimer assay secondary to infection. Furthermore, on duplex scanning, chronic vein wall changes may be present as well. A negative initial scan in this group should be followed up with a repeat study in 7–10 days although compliance is frequently problematic.

Background

Controversies The role of unilateral venous scanning has been greatly debated. The IntraSocietal Commission of Accreditation of Vascular Laboratories has acknowledged the need for unilateral or limited scans and published revised guidelines. However, the frequency and importance of ﬁnding thrombi in the asymptomatic limb is unresolved.45–47 Ultimately, the diagnosis and treatment of DVT continues to evolve. Even the nomenclature of veins has evolved. Among the changes are the renaming of the superﬁcial femoral vein as the femoral vein, the greater/long saphenous vein as the great saphenous vein and the lesser saphenous vein as the small saphenous vein in an effort to more accurately reﬂect their true anatomy.48

As is the case with DVT, pulmonary embolism (PE) is a diagnosis that must be conﬁrmed through objective testing. The non-speciﬁc signs and symptoms of PE in association with risk factors are insufﬁcient to allow for a deﬁnitive diagnosis and should prompt the clinician to further investigation.49 The importance of correct diagnosis and timely treatment cannot be overstated as the mortality after PE is much higher than with DVT alone.50 Figure 18.2 displays the algorithm described in the following sections.

Signs and symptoms The most common signs of PE are tachypnea and tachycardia. Less common signs including syncope, hypoxemia, and sudden hypotension are also associated with PE. However, all of these signs are non-speciﬁc and can be found in other illnesses or conditions as well. The symptoms of PE range widely and include anxiety, dyspnea, pleuritic chest pain, and lightheadedness.51 Although it appears that the ability to accurately determine

Suspected acute PE

Clinical assessment/probability

Low probability

Moderate probability

High probability

D-Dimer

D-Dimer

CT angio vs CTV/CTA

Negative

Positive

Negative

Positive

Negative

Positive

No treatment

CT angio vs CTV/CTA

No treatment

CT angio vs CTV/CTA

• Repeat if poor quality • If CTA only, US or MRI venography • Pulmonary scintigraphy • Digital subtraction angiography • Serial US

Treat

Negative No treatment

Positive

Segmental or subsegmental

Main or Lobar PE

• Repeat CT angio or CTV/CTA if poor quality • If CT angio only, US or MRV • Pulmonary scintigraphy • Digital subtraction angiography • Serial ultrasound

Treat

Negative

Positive

No treatment

Treat

Option if CT angio only, US or MRV

Figure 18.2 Algorithm for diagnosing pulmonary embolism. CT, computed tomography; CTA, computed tomography angiography; CTV, computed tomography venography; MRV, magnetic resonance venography; PE, pulmonary embolism; US, ultrasound. Adapted with permission from Stein, et al.54

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Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism

the pretest probability of PE increases with experience, the difference is not sufﬁciently large and almost a quarter of the patients with PE will have sudden death as the ﬁrst clinical presentation.50,52

Clinical probability scoring The use of a validated pretest probability score is recommended as the ﬁrst step in the workup of patients suspected to have PE.53 Calculating the pretest clinical probability is both a cost-effective and expedient way to stratify patients into low/intermediate/high probability or unlikely/likely groups depending on the assessment tool employed. Based upon the results, patients should then undergo additional testing to conﬁrm/exclude the diagnosis of PE. Used appropriately, the scoring system can reduce the need for imaging studies and associated costs. In a study which reviewed the Wells simpliﬁed score, Geneva score, and empirical assessment, the authors concluded that all three methods were clinically useful, although empirical assessment tended to classify fewer patients as low probability.53 It is the low/moderate probability group that is of particular interest since this group of patients can have the diagnosis of PE effectively ruled out with an adjunctive study.54,55 Using the Wells clinical decision rule shown in Table 18.2, a combination of unlikely probability and a normal D-dimer test resulted in a subsequent venous thromboembolism rate of only 0.5% in untreated patients.56 Other validated scoring systems, like the one in Table 18.3, have proven similarly useful.54 Table 18.2 Wells et al. short clinical score list for pulmonary embolism Criteria Clinical signs and symptoms of deep vein thrombosis (DVT): minimal swelling of the leg and pain on palpation of the deep leg veins Pulmonary embolism more likely than an alternative diagnosis Heart beat frequency > 100 beats per minute Recent immobilization or surgery within < 4 weeks Documented history of DVT and/or pulmonary embolism Hemoptysis Recent history of malignancy < 6 months (treatment or palliative treatment)

Score 3.0

3.0 1.5 1.5 1.5 1.0 1.0

Clinical score for pulmonary embolism Low ≤2 Moderate 2.0–6.0 High ≥6 With permission from Michiels et al., The rehabilitation of clinical assessment for the diagnosis of pulmonary embolism. Semin Vasc Med, 2002; 2 (4): 345–51.

Ventilation-perfusion scintigraphy Prior to the widespread use of spiral computed tomography (s-CT), ventilation-perfusion (VP) scintigraphy was often the ﬁrst-line study. Compared with pulmonary angiography it is less invasive and a normal study can effectively exclude pulmonary embolism. A positive study is also highly speciﬁc for PE allowing for directed treatment.57 However, one of the major shortcomings of VP scintigraphy is the high number of intermediate probability scans. As noted in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, up to 70% of VP scans are nondiagnostic and require additional studies.57 In addition, the sensitivity of VP scans is suboptimal. In patients with PE, the results of VP scans are high probability in only about 40%. The majority of patients with PE will have intermediate or low probability results.58 Table 18.3 Antwerp clinical score list for pulmonary embolism Criteria

Score

Age > 60 years 0.5 One or more risk factors for venous thromboembolism 1.5 One or more eliciting circumstances for venous thromboembolism 1.0 Respiratory signs and symptoms Dyspnea 1.5 Pleuritic pain 1.0 Non-retrosternal, non-pleural chest pain 1.0 PaO2 < 92% (< 3 L of O2) 1.0 Hemoptysis 1.0 Pleural rub 1.0 Cardiac and other signs and symptoms Heart beat frequency > 100 beats per minute 1.0 Temperature 37.5 and 38.6°C 1.0 Chest radiograph: atelectasis and/or unilateral diaphragm elevation suspicious for pulmonary embolism and no other explanation 1.0 Leg symptoms suspicious of DVT (swelling, pain, etc.) (clinical score of Wells et al. for DVT) 3.0 Signs of circulatory and/or of respiratory insufﬁciency: 1, 2, or 3 6.0 1 Hypotension (systolic RR < 90 mmHg and heart frequency > 100 beats per minute) 2 Respiratory insufﬁciency (artiﬁcial breathing > 3 L O2) 3 Recent decompensation cordis right Clinical score for pulmonary embolism Low <3 Moderate 3.0–6.0 High >6 DVT, deep vein thrombosis; PaO2, partial pressure of oxygen in arterial blood. With permission from Michiels et al., The rehabilitation of clinical assessment for the diagnosis of pulmonary embolism. Semin Vasc Med, 2002; 2 (4): 345–51.

Pulmonary embolism 215

There have been subsequent attempts to improve on the diagnostic capability of VP scans. In the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED), only perfusion scans were performed after patients were assigned a clinical probability.59 Using the combined approach, a positive predictive value of 92–99% and a negative predictive value of 97% was obtained. Other studies have examined VP scans in conjunction with s-CT and noted improvements in the diagnostic performance.60–62 Ventilation-perfusion scintigraphy may still be the ﬁrstline study in patients with contraindications to iodinated contrast due to dye allergy or renal insufﬁciency. Furthermore, the higher radiation exposure of s-CT in young women may be of clinical signiﬁcance.63 In pregnant women, 69% of the PIOPED II investigators recommended pulmonary scintigraphy over CT angiography.54

Pulmonary angiography Long considered the gold standard for diagnosing PE, pulmonary angiography is no longer routinely used. Considering the invasive nature of the procedure, the potential for higher radiation exposure, and the signiﬁcantly higher cost, there is little evidence to support the use of pulmonary angiography as a ﬁrst-line study.54 Based on the PIOPED patient population, an analysis of pulmonary angiography demonstrated a 98% interobserver agreement for PE in the main or lobar pulmonary arteries and 90% for PE limited to the segmental or subsegmental pulmonary arteries. When PE limited to the subsegmental arteries was studied, there was only 66% interobserver agreement.64 In earlier studies, pulmonary angiography demonstrated considerably higher sensitivity than s-CT (67%).65 Even with considerable improvement in multidetector CT technology, pulmonary angiography continues to show higher sensitivity although the gap is smaller and may be of limited clinical signiﬁcance.66 After a negative pulmonary angiogram, 0.6% of the patients followed were noted to have a PE.67 The complications associated with pulmonary angiography are limited but not insigniﬁcant. In a study based on the PIOPED patients, complications were noted as death in 0.5%, major non-fatal complications in 1%, and less signiﬁcant events in 5%.67 One percent of patients experience renal dysfunction after the study.67 D-dimer

The utility of D-dimer assays in the workup of PE and DVT are quite similar. Both are a part of the same disease spectrum and it stands to reason that the ﬁndings would show a high degree of congruity.

A systematic review of prospective studies on the diagnostic role of D-dimer concluded that the ELISA and quantitative rapid ELISA had the highest sensitivity (96%) and negative likelihood ratios (0.13) among the various assays.68 Similar results of high sensitivity but moderate speciﬁcity were noted in other studies as well.69–71 In one study, it was also suggested that D-dimer levels were of greater beneﬁt in the outpatient setting since conditions which could lead to false-positive results (inﬂammation, trauma, and surgery) were more often seen in the inpatient setting.68 As for the diagnostic role of D-dimer in pregnant patients, there is of yet no clear consensus.69 With high sensitivity and only moderate speciﬁcity, the D-dimer assay is limited in its ability to accurately rule in PE. However, the combination of a low to moderate probability score using a clinical assessment scale and a normal D-dimer assay result can effectively rule out the presence of PE.55,56,70 Unfortunately, negative D-dimer assay results in patients with high-probability clinical assessments that are still associated with PE rates of more than 15% and should not should relied upon. Further testing is indicated in the high-risk group.70

Spiral computed tomography Spiral computed tomography has emerged as one of the predominant studies for the diagnosis of PE. Not only is the study less invasive than pulmonary angiography, it also has the ability to depict other conditions that may be confused with PE. Pneumonia, pneumothorax, pneumomediastinum, pleural/pericardial effusion, aortic dissections, and other various conditions can mimic the signs and symptoms of PE and have been noted in 11–70% of CT exams performed for suspected PE.58 In the 1990s, studies comparing s-CT with VP scans and angiography were based on single-detector CT scanners. Despite technological limitations, s-CT was noted to be useful in the diagnosis of PE especially in the scenario of intermediate probability VP scans. In one prospective study comparing scintigraphy with s-CT with pulmonary angiography as the gold standard, s-CT was in concordance with angiography 80% of the time in patients noted to have intermediate probability VP scans.72 A separate study of patients with intermediate probability VP scans demonstrated a PE rate of 24.4% using s-CT.73 The superiority of s-CT over VP is supported by other studies as well, but the reported sensitivity of s-CT has ranged widely from 53% to 100%.58,65,74,75 With the single-detector CT, subsegmental and peripheral pulmonary arteries were poorly visualized and sensitivities for PE in these locations were especially low.76 False-negative rates of single-detector CT were as high as 30% when used alone.77,78 The current generation of multidetector CT scanners are faster and able to visualize smaller pulmonary arteries.79 As a result, higher sensitivities have been

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Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism

reported that rival even pulmonary angiography.66 For subsegmental pulmonary arteries evaluated with singledetector, 4-multidetector CT, and 16-multidetector CT scanners, the arteries were well visualized in 36%, 75%, and 88% of the scans respectively.58 In recent years, the impetus has been to perform synchronous indirect CT venography and CT pulmonary angiography scans. By doing so, the presence of both PE and DVT can be evaluated with higher sensitivity and similar speciﬁcity.54,58,80 These analyses however are biased regarding DVT sensitivity ± speciﬁcity, as the samples are derived from PE patient groups that have a higher incidence of DVT.

resonance imaging may also prove to be valuable in the follow-up of acute PE to determine thrombus age.84 Of note, recent studies have questioned the traditional thinking that gadolinium was less nephrotoxic than iodinated contrast. In fact, at angiographic concentrations, gadolinium has demonstrated equal or greater renal cell toxicity than iodinated contrast.27 There is also mounting evidence that gadolinium administration may play a signiﬁcant role in the development of nephrogenic systemic ﬁbrosis.28–30

Magnetic resonance imaging/magnetic resonance angiography

Other modalities have been studied with the intention of using them for the diagnosis of PE with varying levels of success. Although ECG changes may be present, they are neither sensitive nor speciﬁc for PE.85 The changes may, however, indicate a way to stratify risk since patients with acute or major PE and ECG changes have worse outcomes than those without the changes.86 Likewise, although arterial blood gas changes may be present, they are nonspeciﬁc and therefore of limited diagnostic utility in the workup of PE.87 Lastly, although chest radiographs are routinely ordered in those experiencing respiratory distress, the results are most often normal even in the presence of PE. Chest radiographs may be useful in determining which patients should undergo s-CT versus VP scintigraphy since abnormal chest radiographs increase the likelihood of indeterminate-probability VP scans.88

The use of MRI/MRA for the diagnosis of PE has received greater attention in recent years. Even with the increased interest, most diagnostic algorithms and recommendations including PIOPED II only mention MRI brieﬂy.54 The sensitivity of MRA when compared with conventional angiography ranges from 77% to 100% depending on the study.81,82 With the addition of MR perfusion imaging, there is a subsequent increase in sensitivity rivaling that of 16-multidetector CT angiography.83 The current role for MRI/MRA is as a backup when conventional diagnostic methods are unavailable or contraindicated due to dye allergy, renal insufﬁciency, or concerns about radiation exposure.54,81,82 Magnetic

Other studies

Guidelines 3.2.0 of the American Venous Forum on diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism No.

Guideline

3.2.1 In symptomatic outpatients with suspected acute deep vein thrombosis, a clinical score and D-dimer level should be obtained ﬁrst to select patients for further diagnostic studies

Grade of Grade of evidence (A, high recommendation quality; B, moderate quality; (1, we recommend; C, low or very low quality) 2, we suggest) 1

B

1

B

3.2.3 Negative duplex studies in patients with high clinical suspicion of deep vein thrombosis should be followed up with a repeat duplex scan or alternate imaging modality

1

B

3.2.4 Magnetic resonance venography has excellent sensitivity and speciﬁcity to diagnose above-the-knee acute DVT. We suggest MRV instead of contrast venography

2

B

3.2.5 Gadolinium should be used judiciously in patients with renal insufﬁciency because of the risk of nephrogenic systemic ﬁbrosis

2

C

3.2.2

D-dimer

levels are inaccurate to diagnose deep vein thrombosis in several clinical conditions including recent surgery, pregnancy, malignancy, infection, elevated bilirubin, trauma, and heparin use. In these situations alternate diagnostic modalities are recommended

References 217

Algorithm use for deep vein thrombosis and pulmonary embolism The use of algorithms seeks to separate patients into risk groups for testing and evaluation while not missing any signiﬁcant pathologies. The algorithms only apply to symptomatic outpatients using exclusion criteria to increase sensitivity and speciﬁcity. They have not been validated for inpatients or asymptomatic patients. Algorithms perform differently in different populations and when used by different care providers. A standardized treatment management plan is also deﬁned through the algorithms. These may be useful with inexperienced staff and decrease practice variation, and may provide some control over risk management. Algorithms do not include the diagnostic uncertainty and patient anxiety while waiting for a deﬁnitive diagnosis. Clinician and patient acceptance are required to use an algorithm, and the algorithm should utilize tests that are widely available.

REFERENCES 1. Donner-Banzhoff N, Limited value of patient history and physical examination in diagnosing deep vein thrombosis in primary care. Fam Pract 2005. 22: 579. 2. Oudega R, Hoes AW, Moons KG. The Wells rule does not adequately rule out deep venous thrombosis in primary care patients. Ann Intern Med 2005. 143 (2): 100–7. 3. Wells PS, Anderson DR, Bormanis J. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795–8. 4. Miron MJ, Perrier A, Bounameaux H. Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment. J Intern Med 2000; 247 (2): 249–54. 5. Smithline HA, Mader TJ, Ali FM, Cocchi MN. Determining pretest probability of DVT: clinical intuition vs. validated scoring systems. Am J Emerg Med 2003; 21 (2): 161–2. 6. Wells PS, Owen C, Doucette S, Fergusson D. Does this patient have deep vein thrombosis? JAMA 2006; 295 (2): 199–207. 7. Lensing AW, Büller HR, Prandoni P, et al. Contrast venography, the gold standard for the diagnosis of deepvein thrombosis: improvement in observer agreement. Thromb Haemost 1992; 67 (1): 8–12. 8. Terao M, Ozaki T, Sato T. Diagnosis of deep vein thrombosis after operation for fracture of the proximal femur: comparative study of ultrasonography and venography. J Orthop Sci 2006; 11 (2): 146–53. 9. Ozbudak O, Erogullari I, Ogüs C, Cilli A, et al. Doppler ultrasonography versus venography in the detection of deep vein thrombosis in patients with pulmonary embolism. J Thromb Thrombolysis 2006; 21 (2): 159–62.

10. de Valois JC, van Schaik CC, Verzijlbergen F, et al. Contrast venography: from gold standard to ‘golden backup’ in clinically suspected deep vein thrombosis. Eur J Radiol 1990; 11 (2): 131–7. 11. Anderson DR, Lensing AW, Wells PS, et al. Limitations of impedance plethysmography in the diagnosis of clinically suspected deep-vein thrombosis. Ann Intern Med 1993; 118 (1): 25–30. 12. Ginsberg JS, Wells PS, Hirsh J, et al. Reevaluation of the sensitivity of impedance plethysmography for the detection of proximal deep vein thrombosis. Arch Intern Med 1994; 154: 1930–3. 13. Heijboer H, Cogo A, Buller HR, et al. Detection of deep vein thrombosis with impedance plethysmography and realtime compression ultrasonography in hospitalized patients. Arch Intern Med 1992; 152: 1901–3. 14. Kearon C, Hirsh J. Factors inﬂuencing the reported sensitivity and speciﬁcity of impedance plethysmography for proximal deep vein thrombosis. Thromb Haemost 1994; 72: 652–8. 15. Goodacre S, Sampson F, Thomas S, van Beek E. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005; 5: 6. 16. Ascher E, Depippo PS, Hingorani A, et al. Does repeat duplex ultrasound for lower extremity deep vein thrombosis inﬂuence patient management? Vasc Endovasc Surg 2004; 38: 525–31. 17. Birdwell BG, Birdwell BG, Raskob GE, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998; 128 (1): 1–7. 18. Cogo A, Lensing AW, Koopman MM. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 17–20. 19. Kraaijenhagen RA, Piovella F, Bernardi E, et al. Simpliﬁcation of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med 2002; 162: 907–11. 20. Andrews EJ, Jr, Fleischer AC, Sonography for deep venous thrombosis: current and future applications. Ultrasound Q 2005; 21 (4): 213–25. 21. Tick LW, Ton E, van Voorthuizen T, et al. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography, and D-dimer test. Am J Med 2002; 113: 630–5. 22. Bernardi E, Prandoni P, Lensing A, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. The Multicentre Italian D-dimer Ultrasound Study Investigators Group. BMJ 1998; 317: 1037–40. 23. Carpenter JP, Holland GA, Baum RA, et al. Magnetic resonance venography for the detection of deep venous thrombosis: comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 1993; 18: 734–41.

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24. Laissy JP, Cinqualbre A, Loshkajian A, et al. Assessment of deep venous thrombosis in the lower limbs and pelvis: MR venography versus duplex Doppler sonography. Am J Roentgenol, 1996; 167: 971–5. 25. Fraser DG, Moody AR, Morgan PS, et al. Diagnosis of lowerlimb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002; 136 (2): 89–98. 26. Fraser DG, Moody AR, Davidson IR et al. Deep venous thrombosis: diagnosis by using venous enhanced subtracted peak arterial MR venography versus conventional venography. Radiology 2003; 226: 812–20. 27. Heinrich MC, Kuhlmann MK, Kohlbacher S, et al. Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: in vitro study. Radiology 2007; 242 (2): 425–34. 28. Nephrogenic ﬁbrosing dermopathy associated with exposure to gadolinium-containing contrast agents–St. Louis, Missouri, 2002–2006. Morb Mortal Wkly Rep 2007; 56 (7): 137–41. 29. Broome DR, Girguis MS, Baron PW, et al. Gadodiamideassociated nephrogenic systemic ﬁbrosis: why radiologists should be concerned. Am J Roentgenol, 2007; 188: 586–92. 30. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadoliniumbased MR contrast agents and nephrogenic systemic ﬁbrosis. Radiology 2007; 242 (3): 647–9. 31. Yamaki T, Nozaki M, Sakurai H, et al. Prospective evaluation of a screening protocol to exclude deep vein thrombosis on the basis of a combination of quantitative D-dimer testing and pretest clinical probability score. J Am Coll Surg 2005; 201 (5): 701–9. 32. Wells PS, Anderson DR, Rodger M, et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–35. 33. Fancher TL, White RH, Kravitz RL. Combined use of rapid Ddimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004; 329: 821. 34. Diamond S, Goldbweber R, Katz S. Use of D-dimer to aid in excluding deep venous thrombosis in ambulatory patients. Am J Surg 2005; 189 (1): 23–6. 35. Stevens SM, Elliott GC, Woller SC, et al. The use of a ﬁxed high sensitivity to evaluate ﬁve D-dimer assays’ ability to rule out deep venous thrombosis: a novel approach. Br J Haematol 2005; 131 (3): 341–7. 36. Shitrit D, Levi H, Huerta M, et al. Appropriate indications for venous duplex scanning based on D-dimer assay. Ann Vasc Surg 2002; 16 (3): 304–8. 37. Keeling DM, Mackie IJ, Moody A, et al. The diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging. Br J Haematol 2004; 124 (1): 15–25. 38. Baldt MM, Zontsich T, Stumplﬂen A, et al. Deep venous thrombosis of the lower extremity: efﬁcacy of spiral CT

39.

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52.

53.

54.

venography compared with conventional venography in diagnosis. Radiology 1996; 200: 423–8. Lim KE, Hsu WC, Hsu YY, et al. Deep venous thrombosis: comparison of indirect multidetector CT venography and sonography of lower extremities in 26 patients. Clin Imaging 2004; 28: 439–44. Kohler A, Hoffmann R. Platz A, Bino M. Diagnostic value of duplex ultrasound and liquid crystal contact thermography in preclinical detection of deep vein thrombosis after proximal femur fractures. Arch Orthop Trauma Surg 1998; 117 (1–2): 39–42. Bucek RA, Reiter M, Quehenberger P, Minar E. C-reactive protein in the diagnosis of deep vein thrombosis. Br J Haematol 2002; 119: 385–9. Locker T, Goodacre S, Sampson F, et al. Meta-analysis of plethysmography and rheography in the diagnosis of deep vein thrombosis. Emerg Med J 2006; 23: 630–5. Tan YK, da Silva AF. Digital photoplethysmography in the diagnosis of suspected lower limb DVT: is it useful? Eur J Vasc Endovasc Surg 1999; 18 (1): 71–9. Scarsbrook AF, Evans AL, Owen AR, Gleeson FV. Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin Radiol 2006; 61 (1): 1–12. Sheiman RG, McArdle CR. Bilateral lower extremity US in the patient with unilateral symptoms of deep venous thrombosis: assessment of need. Radiology 1995; 194 (1): 171–3. Strothman G, Blebea J, Fowl RJ, Rosenthal G. Contralateral duplex scanning for deep venous thrombosis is unnecessary in patients with symptoms. J Vasc Surg 1995; 22: 543–7. Lohr J. Bilateral lower extremity duplex scanning revisited. Dis Mon 2005; 51 (2–3): 79–85. Mozes G, Gloviczki P. New discoveries in anatomy and new terminology of leg veins: clinical implications. Vasc Endovascular Surg 2004; 38: 367–74. Langan CJ, Weingart S. New diagnostic and treatment modalities for pulmonary embolism: one path through the confusion. Mt Sinai J Med 2006; 73: 528–41. Heit JA, Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3 (8): 1611–7. Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med 1999; 160: 1043–66. Doyle NM, Ramirez MM, Mastrobattista JM, et al. Diagnosis of pulmonary embolism: a cost-effectiveness analysis. Am J Obstet Gynecol 2004; 191: 1019–23. Kelly J, Hunt BJ. The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism. J Thromb Haemost 2003; 1: 1888–96. Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators. Radiology 2007; 242 (1): 15–21.

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55. Sohne M, Ruip MJH, Nijkeuter M, et al. Accuracy of clinical decision rule, D-dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism. J Thromb Haemost 2006; 4: 1042–6. 56. van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295 (2): 172–9. 57. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990; 263: 2753–9. 58. Patel S, Kazerooni EA. Helical CT for the evaluation of acute pulmonary embolism. Am J Roentgenol, 2005; 185 (1): 135–49. 59. Miniati M, Pistolesi M, Marini C, et al. Value of perfusion lung scan in the diagnosis of pulmonary embolism: results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med 1996; 154: 1387–93. 60. Gleeson FV, Turner S, Scarsbrook AF. Improving the diagnostic performance of lung scintigraphy in suspected pulmonary embolic disease. Clin Radiol 2006; 61: 1010–5. 61. Wilson HT, Meagher TM, Williams SJ. Combined helical computed tomographic pulmonary angiography and lung perfusion scintigraphy for investigating acute pulmonary embolism. Clin Radiol 2002; 57 (1): 33–6. 62. Gottschalk A, New criteria for ventilation-perfusion lung scan interpretation: a basis for optimal interaction with helical CT angiography. Radiographics 2000; 20: 1206–10. 63. Parker MS, Hui FK, Camacho MA, et al. Female breast radiation exposure during CT pulmonary angiography. Am J Roentgenol, 2005; 185: 1228–33. 64. Stein PD, Henry JW, Gottschalk A. Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology 1999; 210: 689–91. 65. Garg K, Welsh CH, Feyerabend AJ, et al. Pulmonary embolism: diagnosis with spiral CT and ventilationperfusion scanning—correlation with pulmonary angiographic results or clinical outcome. Radiology 1998; 208 (1): 201–8. 66. Winer-Muram HT, Rydberg J, Johnson JS, et al. Suspected acute pulmonary embolism: evaluation with multi-detector row CT versus digital subtraction pulmonary arteriography. Radiology 2004; 233: 806–15. 67. Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 1992; 85: 462–8. 68. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004; 140: 589–602.

69. Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: a systematic review. J Thromb Haemost 2006; 4: 496–500. 70. Brown MD, Rowe BH, Reeves MJ, et al. The accuracy of the enzyme-linked immunosorbent assay D-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Ann Emerg Med 2002; 40 (2): 133–44. 71. Ota S, Wada H, Nobori T, et al. Diagnosis of deep vein thrombosis by plasma-soluble ﬁbrin or D-dimer. Am J Hematol 2005; 79 (4): 274–80. 72. Mayo JR, Remy-Jardin M, Muller NL, et al. Pulmonary embolism: prospective comparison of spiral CT with ventilation-perfusion scintigraphy. Radiology 1997; 205: 447–52. 73. Ferretti GR, Bosson JL, Buffaz PD, et al. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex US of the legs. Radiology 1997; 205: 453–8. 74. Powell T. Muller NL Imaging of acute pulmonary thromboembolism: should spiral computed tomography replace the ventilation-perfusion scan? Clin Chest Med 2003; 24 (1): 29–38. 75. Coche E, Verschuren F, Keyeux A. Diagnosis of acute pulmonary embolism in outpatients: comparison of thincollimation multi-detector row spiral CT and planar ventilation-perfusion scintigraphy. Radiology 2003; 229: 757–65. 76. Van Strijen MJ, De Monye W, Kieft GJ, et al. Accuracy of single-detector spiral CT in the diagnosis of pulmonary embolism: a prospective multicenter cohort study of consecutive patients with abnormal perfusion scintigraphy. J Thromb Haemost 2005; 3 (1): 17–25. 77. Perrier A, Howarth N, Didier D, et al. Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism. Ann Intern Med 2001; 135 (2): 88–97. 78. Anderson DR, Kovacs MJ, Dennie C, et al. Use of spiral computed tomography contrast angiography and ultrasonography to exclude the diagnosis of pulmonary embolism in the emergency department. J Emerg Med 2005; 29: 399–404. 79. Schoepf UJ, Savino G, Lake DR, et al. The age of CT pulmonary angiography. J Thorac Imaging 2005; 20 (4): 273–9. 80. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006; 354: 2317–27. 81. Stein PD, Woodard PK, Hull RD, et al. Gadolinium-enhanced magnetic resonance angiography for detection of acute pulmonary embolism: an in-depth review. Chest 2003; 124: 2324–8. 82. Pleszewski B, Chartrand-Lefebvre C, Qanadli S, et al. Gadolinium-enhanced pulmonary magnetic resonance angiography in the diagnosis of acute pulmonary embolism: a prospective study on 48 patients. Clin Imaging 2006; 30 (3): 166–72.

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83. Kluge A, Luboldt W, Bachmann G. Acute pulmonary embolism to the subsegmental level: diagnostic accuracy of three MRI techniques compared with 16-MDCT. Am J Roentgenol, 2006; 187 (1): W7–14. 84. Kluge A, Gerriets T, Lange U, Bachman G. MRI for shortterm follow-up of acute pulmonary embolism. Assessment of thrombus appearance and pulmonary perfusion: a feasibility study. Eur Radiol 2005; 15: 1969–77. 85. Brown G, K. Hogg, Best evidence topic report. Diagnostic utility of electrocardiogram for diagnosing pulmonary embolism. Emerg Med J 2005; 22: 729–30.

86. Geibel A, Zehender1 W. Kasper, M. Prognostic value of the ECG on admission in patients with acute major pulmonary embolism. Eur Respir J 2005; 25: 843–8. 87. Maloba M, K. Hogg, Best evidence topic report. Diagnostic utility of arterial blood gases for investigation of pulmonary embolus. Emerg Med J 2005; 22: 435–6. 88. Daftary A, Gregory M, Daftary A, et al. Chest radiograph as a triage tool in the imaging-based diagnosis of pulmonary embolism. Am J Roentgenol, 2005; 185 (1): 132–4.

19 Medical treatment of acute deep vein thrombosis and pulmonary embolism RUSSELL D. HULL AND GRAHAM F. PINEO Introduction Treatment of venous thromboembolism Oral vitamin K antagonists

221 221 229

INTRODUCTION

Long-term treatment of venous thromboembolism using vitamin K antagonists Conclusion References

● ●

Unfractionated heparin, given by a continuous intravenous infusion with laboratory monitoring using the activated partial thromboplastin time (aPTT), with warfarin starting on day 1 or day 2 and continued for 3 months, has been the standard treatment of established venous thromboembolism (VTE). Heparin is used in a number of other clinical settings and constitutes one of the most frequently used agents in hospital medicine. Over the past 20 years, various low-molecular-weight heparins (LMWHs) have been evaluated against a number of different controls, including unfractionated heparin, for many of these clinical problems. Increasingly, LMWH is replacing unfractionated heparin for both the prevention and the treatment of VTE for most patients. The optimal duration of oral anticoagulant therapy after an initial episode or recurrent episodes of VTE remains uncertain. This chapter will review the medical management of VTE with particular emphasis on (a) unfractionated heparin, the use of which is declining, (b) LMWH which is replacing unfractionated heparin for most indications, and (c) oral anticoagulation. Detailed evidence-based guideline recommendations for the medical treatment of VTE are provided in this chapter. The quality of the evidence used to make key recommendations is summarized in Box 19.1.

TREATMENT OF VENOUS THROMBOEMBOLISM The objectives of treatment in patients with VTE are

●

230 235 235

to prevent death from pulmonary embolism to prevent recurrent VTE to prevent the post-phlebitic syndrome.

The anticoagulant drugs heparin, LMWH and warfarin, constitute the mainstay of treatment of venous thrombosis. The use of graduated compression stockings for 24 months signiﬁcantly decreases the incidence of the post-thrombotic syndrome. Furthermore, the incidence of the post-thrombotic syndrome has been decreasing in recent years, suggesting that the more efﬁcient treatment of VTE and the prevention of recurrent deep vein thrombosis are having a positive impact on this complication.

Heparin therapy The anticoagulant activity of unfractionated heparin depends upon a unique pentasaccharide that binds to antithrombin III (ATIII) and potentiates the inhibition of thrombin and activated factor X (Xa) by ATIII. About one-third of all heparin molecules contain the unique pentasaccharide sequence, regardless of whether they are low- or high-molecular-weight fractions.1–3 It is the pentasaccharide sequence which confers the molecular high afﬁnity for ATIII.1–3 In addition, heparin catalyses the inactivation of thrombin by another plasma cofactor, (cofactor II) that acts independently of ATIII.3 Heparin has a number of other effects. These include the release of tissue factor pathway inhibitor binding to numerous plasma and platelet proteins, endothelial cells, and leucocytes,1 suppression of platelet function, and an

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BOX 19.1 Evidence-based guideline: quality of evidence.6,66 With few exceptions, patients with DVT or PE are treated similarly Initial treatment of patients with venous thromboembolism Initial regimen ●

●

●

●

●

For patients with objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE), short-term treatment with subcutaneous low-molecular-weight heparin (SC LMWH), fondaparinux, or intravenous unfractionated heparin (IV UFH) is recommended (Grade 1A). Subcutaneous unfractionated heparin (SC UFH) may be used in DVT patients (Grade 1A). For patients with a high clinical suspicion of DVT or PE, treatment with anticoagulants while awaiting the outcome of diagnostic tests is recommended (Grade 1C). In patients with DVT or acute non-massive PE, LMWH over unfractionated heparin (UFH) is recommended (Grade 1A). Uncomplicated DVT patients may be treated as an outpatient. In patients with acute DVT or non-massive PE treated with LMWH, routine monitoring with anti-factor Xa levels is not recommended (Grade 1A). In patients with severe renal failure, IV UFH over LMWH or fondaparinux is suggested (Grade 2C).

Duration of initial treatment: ●

In acute DVT or PE, initial treatment with LMWH, fondaparinux or UFH for at least 5 days is suggested (Grade 1C).

Commencing vitamin K antagonist therapy ●

Initiation of vitamin K antagonist together with LMWH or UFH on the ﬁrst treatment day and discontinuation of heparin when the INR is stable and > 2.0 is recommended (consider for two consecutive days) (Grade 1A).

Adjunctive initial therapy Thrombolytic therapy ● ●

●

● ●

In patients with DVT or PE, the routine use of systemic thrombolytic treatment is not recommended (Grade 1A). In selected DVT patients, such as those with massive ileofemoral DVT at risk of limb gangrene secondary to venous occlusion, IV thrombolysis is suggested (Grade 2C). In selected patients with PE, systemic administration of thrombolytic therapy is suggested (Grade 2B). For PE patients who are hemodynamically unstable, use of thrombolytic therapy is suggested (Grade 2B). For patients with PE who receive thrombolytic regimens, use of thrombolytic regimens with a short infusion time over those with prolonged infusion times is suggested (Grade 2C). In PE patients, it is suggested that local administration of thrombolytic therapy via a catheter should not be used (Grade 1C). In patients with DVT, the routine use of catheter-directed thrombolysis is not suggested (Grade 1C). In DVT patients, conﬁning catheter-directed thrombolysis to selected patients such as those requiring limb salvage is suggested (Grade 2C).

Non-steroidal anti-inﬂammatory agents ●

For the initial treatment of DVT, the use of non-steroidal anti-inflammatory agents is not suggested (Grade 2B).

Ambulation ●

For DVT patients, it is recommended that these patients be permitted ambulation as tolerated (Grade 1B).

Long-term treatment of patients with venous thromboembolism Intensity of long-term vitamin K antagonist therapy ●

In patients with DVT or PE, adjusting the dose of VKA to maintain a target INR of 2.5 (range, 2.0 and 3.0) for all treatment durations is recommended (Grade 1A). High-intensity vitamin K antagonist therapy (INR range 3.1–4.0) is not recommended (Grade 1A). Low-intensity therapy (INR range 1.5–1.9) compared with INR range of 2.0–3.0 is not recommended (Grade 1A).

Long-term LMWH treatment ●

For most patients with DVT or PE and concurrent cancer, treatment with LMWH for at least the ﬁrst 3–to 6 months of long-term treatment is recommended (Grade 1A). For these patients, anticoagulant therapy indeﬁnitely or until the cancer is resolved is recommended (Grade 1C).

Treatment of venous thromboembolism

223

Duration of long-term vitamin K antagonist therapy Transient (reversible) risk factors ●

For patients with a ﬁrst episode of DVT or PE secondary to a transient (reversible) risk factor, long-term treatment with a vitamin K antagonist for at least 3 months over treatment for shorter periods is recommended (Grade 1A).

Idiopathic ●

●

For patients with a ﬁrst episode of idiopathic DVT or PE, treatment with a vitamin K antagonist at least 6–12 months is recommended (Grade 1A). Considering patients with ﬁrst-episode idiopathic DVT or PE for indeﬁnite anticoagulant therapy is suggested (Grade 2A).

Presence of a thrombophilia ●

●

For patients with a ﬁrst episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions (e.g., combined factor V Leiden and prothrombin 20210 gene mutations), treatment for 12 months is recommended (Grade 1C). Indeﬁnite anticoagulant therapy in these patients is suggested (Grade 2C). For patients with a ﬁrst episode of DVT or PE who have documented deﬁciency of antithrombin, deﬁciency of protein C or protein S, or the factor V Leiden or prothrombin 20210 gene mutation, homocysteinemia, or high factor VIII levels (> 90th percentile of normal), treatment for 6–12 months is recommended (Grade 1A). Indeﬁnite therapy as for patients with idiopathic thrombosis is suggested (Grade 2C).

Recurrent venous thromboembolism ●

For patients with two or more episodes of objectively documented DVT or PE, indeﬁnite treatment is recommended (Grade 1A).

Indeﬁnite anticoagulant treatment ●

In DVT or PE patients who receive indeﬁnite anticoagulant treatment, the risk-beneﬁt of continuing such treatment should be reassessed in the individual patient at periodic intervals (Grade 1C).

Prognostic testing ●

In patients with DVT or PE, repeat testing with compression ultrasonography for the presence or absence of residual thrombosis or measurement of plasma D-dimer is suggested (Grade 2C).

Vena caval ﬁlter ● ●

For most patients with DVT, the routine use of a vena cava ﬁlter in addition to anticoagulants is not recommended (Grade 1A). In DVT or PE patients the placement of an inferior vena caval ﬁlter in patients with a contraindication for or a complication of anticoagulant treatment, is suggested (in appropriate patients consider a retrievable ﬁlter) (Grade 2C), as well as in those with recurrent thromboembolism despite adequate anticoagulation (Grade 2C).

Catheter interventions ●

For most patients with PE, use of mechanical approaches is not recommended (Grade 1C). In selected highly compromised patients who are unable to receive thrombolytic therapy or whose critical status does not allow sufﬁcient time to infuse thrombolytic therapy, use of mechanical approaches is suggested (Grade 2C).

Thromboectomy and embolectomy ● ●

●

In patients with DVT, the routine use of venous thrombectomy is not recommended (Grade 1C). In selected patients such as patients with massive iliofemoral DVT at risk of limb gangrene secondary to venous occlusion, venous thrombectomy is suggested (Grade 2C). For most patients with PE, pulmonary embolectomy is not recommended (Grade 1C). In selected highly compromised patients who are unable to receive thrombolytic therapy or whose critical status does not allow sufﬁcient time to infuse thrombolytic therapy, pulmonary embolectomy is suggested (Grade 2C).

Post-thrombotic syndrome ●

● ●

The use of an elastic compression stocking with a pressure of 30–40 mmHg at the ankle during 2 years after an episode of DVT is recommended (Grade 1A). A course of intermittent pneumatic compression for patients with severe edema of the leg due to PTS is suggested (Grade 2B). The use of elastic compression stockings for patients with mild edema of the leg due to the PTS is suggested (Grade 2C).

Adapted from the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy6, and Hull66, with permission.

224

Medical treatment of acute deep vein thrombosis and pulmonary embolism

increase in vascular permeability.3 The anticoagulant response to a standard dose of heparin varies widely between patients. This makes it necessary to monitor the anticoagulant response of heparin, using either the aPTT or the heparin levels and to titrate the dose to the individual patient.3 The accepted classic anticoagulant therapy for VTE is a combination of continuous intravenous heparin and oral warfarin. Unfractionated heparin’s shortcomings, many of which are avoided with LMWH, subcutaneously have resulted in a declining use of unfractionated heparin. The length of the initial therapy has been reduced to 5 days, thus shortening the hospital stay and leading to signiﬁcant cost saving.4,5 The simultaneous use of initial heparin and warfarin and subsequently initial LMWH subcutaneously (which avoids the need for anticoagulant monitoring) and warfarin has become standard clinical practice for all patients with VTE who are medically stable.4–6 Exceptions include patients who require immediate medical or surgical intervention, such as in thrombolysis or insertion of a vena cava ﬁlter, or patients at very high risk of bleeding. Heparin is continued until the international normalized ratio (INR) has been within the therapeutic range (2.0–3.0) for two consecutive days.6 It has been established from experimental studies and clinical trials that the efﬁcacy of heparin therapy depends upon achieving a critical therapeutic level of heparin within the ﬁrst 24 hours of treatment.5,7,8 This ﬁnding was challenged in an overview of the available relevant literature where the authors were unable to ﬁnd convincing evidence that the risk of recurrent VTE was dependent on achieving a therapeutic aPTT result at 24–48 hours. However, data from three consecutive double blind clinical trials indicate that failure to achieve the therapeutic aPTT threshold by 24 hours was associated with a 23.3% subsequent recurrent VTE rate, compared with a rate of 4–6% for the patient group who were therapeutic at 24 hours.8 The recurrences occurred throughout the 3 month follow-up period and could not be attributed to inadequate oral anticoagulant therapy.7,8 Recently, the importance of achieving the therapeutic range by 24 hours was conﬁrmed by the Galilei investigators; failure to do so was accompanied by an excess of recurrent VTE.9 The critical therapeutic level of heparin, as measured by the aPTT, is 1.5 times the mean of the control value or the upper limit of the normal aPTT range.7 This corresponds to a heparin blood level of 0.2–0.4 U/mL by the protamine sulfate titration assay, and 0.35–0.70 by the antifactor Xa assay. There is a wide variability in the aPTT and heparin blood levels with different reagents and even with different batches of the same reagent. It is therefore vital for each laboratory to establish the minimal therapeutic level of heparin, as measured by the aPTT, that will provide a heparin blood level of at least 0.35 U/mL by the antifactor Xa assay for each batch of thromboplastin reagent being

used, particularly if the reagent is provided by a different manufacturer.3 Although there is a strong correlation between subtherapeutic aPTT values and recurrent thromboembolism, the relationship between supratherapeutic aPTT and bleeding (aPTT ratio 2.5 or more) is less deﬁnite.7 Indeed, bleeding during heparin therapy is more closely related to underlying clinical risk factors than to aPTT elevation above the therapeutic range.7 Studies conﬁrm that weight and age > 65 are independent risk factors for bleeding on heparin. Numerous audits of heparin therapy indicate that administration of intravenous heparin is fraught with difﬁculty, and that the clinical practice of using an ad hoc approach to heparin dose titration frequently results in inadequate therapy. For example, an audit of physician practices at three university-afﬁliated hospitals documented that 60% of patients failed to achieve an adequate aPTT response (ratio 1.5) during the initial 24

BOX 19.2 Heparin protocol 1 Administer initial intravenous heparin bolus: 5000 U. 2 Administer continuous intravenous heparin infusion: commence at 42 mL/h of 20 000 U (1680 U/h) in 500 mL of two-thirds dextrose and one-third saline (a 24 hour heparin dose of 40 320 U), except in the following patients, in whom heparin infusion is commenced at a rate of 31 mL/h (1240 U/h, a 24 hour dose of 29 760 U): ● Patients who have undergone surgery within the previous 2 weeks. ● Patients with a previous history of peptic ulcer disease or gastrointestinal or genitourinary bleeding. ● Patients with recent stroke (i.e., thrombotic stroke within 2 weeks previously). ● Patients with a platelet count < 150 × 109/L. ● Patients with miscellaneous reasons for a high risk of bleeding (e.g., hepatic failure, renal failure, or vitamin K deﬁciency) 3 Adjust heparin dose by use of the aPTT. The aPTT test is performed in all patients as follows: ● 4–6 hours after commencing heparin; the heparin dose is then adjusted ● 4–6 hours after the ﬁrst dosage adjustment ● Then, as indicated by the nomogram for the ﬁrst 24 hours of therapy ● Thereafter, once daily, unless the patient is subtherapeutic,* in which case the aPTT test is repeated 4–6 hours after the heparin dose is increased aPTT, activated partial thromboplastin time. *Subtherapeutic, aPTT < 1.5 times the mean normal control value for the thromboplastin reagent being used. Adapted from Hull et al.,7 with permission.

Treatment of venous thromboembolism

hours of therapy, and, further, that 30–40% of patients remained “subtherapeutic” over the next 3–4 days. The use of a prescriptive approach or protocol for administering intravenous heparin therapy has been evaluated in two prospective studies in patients with VTE.7,10 In one clinical trial for the treatment of proximal venous thrombosis, patients were given either intravenous heparin alone followed by warfarin, or intravenous heparin and simultaneous warfarin.7 The heparin nomogram is summarized in Box 19.2 and Table 19.1. Only 1% and 2% of the patients were undertreated for more than 24 hours in the heparin group and in the heparin and warfarin groups, respectively. Recurrent VTE (objectively documented) occurred infrequently in both groups (7%), rates similar to those previously reported. These ﬁndings demonstrated that subtherapy was avoided in most patients and that the heparin protocol resulted in effective delivery of heparin therapy in both groups avoiding subtherapy in most patients. Raschke and colleagues10 compared a weight-based heparin dosage nomogram with a standard-care approach (Table 19.2). Patients on the weight-adjusted heparin nomogram received a starting dose of 80 U/kg as a bolus

and 18 U/kg/h as an infusion. The heparin dose was adjusted to maintain an aPTT of 1.5–2.3 times the control. In the weight-adjusted group, 89% of patients achieved the therapeutic range within 24 hours compared with 75% in the standard-care group. The risk of recurrent thromboembolism was more frequent in the standard-care group, supporting the previous observation that subtherapeutic heparin during the initial 24 hours is associated with a higher incidence of recurrences. This study included patients with unstable angina and arterial thromboembolism in addition to VTE, which suggests that the principles applied to a heparin nomogram for the treatment of VTE may be generalizable to other clinical conditions. Continued use of the weight-based nomogram has been similarly effective.

Fixed-dose body weight-adjusted subcutaneous unfractionated heparin A recent randomized clinical trial suggests that ﬁxed-dose (body weight-adjusted) subcutaneous unfractionated heparin may be as effective as LMWH for the initial

Table 19.1 Intravenous heparin dose titration nomogram according to the activated partial thromboplastin time (aPTT) APTT (seconds)

Rate change (mL/h)

Dose change (IU/24 hours)*

Additional action

≤ 45 46–54 55–85 86–110

+6 +3 0 –3

+5760 +2880 0 –2880

> 110

–6

–5760

Repeated aPTT† in 4–6 hours Repeated aPTT in 4–6 hours None‡ Stop heparin sodium treatment for 1 hour; repeated aPTT 4–6 hours after restarting heparin treatment Stop heparin treatment for 1h; repeated aPTT 4–6 hours after restarting heparin treatment

*Heparin sodium concentration 20 000 IU in 500 mL = 40 IU/mL. †With the use of actin-FS thromboplastin reagent (Dade, Mississauga, Ontario, Canada). ‡During the ﬁrst 24 hours, repeated activated partial thromboplastin time in 4–6 hours. Thereafter, the aPTT will be determined once daily, unless subtherapeutic. Adapted from Hull RD et al.,7 with permission.

Table 19.2 Weight-based nomogram for initial intravenous heparin therapy: ﬁgures in parentheses show comparison with control Dose (IU/kg) Initial dose aPTT < 35 seconds (< 1.2×) aPTT 35–45 seconds (1.2–1.5×) APTT 46–70 seconds (1.5–2.3×) APTT 71–90 seconds (2.3–3.0×) APTT > 90 seconds (> 3.0×)

80 bolus, then 18/hour 80 bolus, then 4/hour 40 bolus, then 2/hour No change Decrease infusion rate by 2/hour Hold infusion 1 hour, then decrease infusion rate by 3/h

aPTT, activated partial thromboplastin time. Adapted from Raschke et al.,10 with permission.

225

226

Medical treatment of acute deep vein thrombosis and pulmonary embolism

treatment of patients with newly diagnosed VTE.11 This study may have been insufﬁciently powered and the consensus at present is that the ﬁndings require conﬁrmation by further randomized clinical trials before this approach is applied to clinical practice routinely.

Complications of heparin therapy The main adverse effects of heparin therapy include bleeding, thrombocytopenia, and osteoporosis. Patients at particular risk are those who have had recent surgery or trauma, or who have other clinical factors which predispose to bleeding on heparin, such as peptic ulcer, occult malignancy, liver disease, hemostatic defects, excessive weight, age > 65 years and female gender. The management of bleeding on heparin will depend on the location and severity of bleeding, the risk of recurrent VTE and the aPTT. Heparin should be discontinued temporarily or permanently. Patients with recent VTE may be candidates for insertion of an inferior vena cava ﬁlter. If urgent reversal of the heparin effect is required, protamine sulfate can be administered.3 Heparin-induced thrombocytopenia is a well recognized complication of heparin therapy, usually occurring within 5–10 days after heparin treatment has started.12–15 Approximately 1–2% of patients receiving unfractionated heparin will experience a fall in platelet count to less than the normal range or a 50% fall in the platelet count within the normal range. In the majority of cases, this mild to moderate thrombocytopenia appears to be a direct effect of heparin on platelets and is of no consequence. However, approximately 0.1–0.2% of patients receiving heparin develop an immune thrombocytopenia mediated by IgG antibody directed against a complex of PF4 and heparin.14 Recent reviews conﬁrm that heparin-induced thrombocytopenia, although uncommon, is a potentially devastating complication of anticoagulation with unfractionated heparin or LMWH. The inverse varianceweighted average that determined the absolute risk for heparin-induced thrombocytopenia with LMWH was 0.2%, and with unfractionated heparin the risk was 2.6%.16 Accordingly, heparin-induced thrombocytopenia occurs much less frequently with LMWH. Importantly, harm associated with heparin-associated thrombocytopenia occurs more frequently in patients receiving unfractionated heparin than LMWH. Venous thromboembolism is associated with heparin-induced thrombocytopenia infrequently (< 1%) in LMWH-treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients.17 The development of thrombocytopenia may be accompanied by arterial or venous thrombosis, which may lead to serious consequences such as death or limb amputation.14 The diagnosis of heparin-induced thrombocytopenia, with or without thrombosis, must be

made on clinical grounds, because the assays with the highest sensitivity and speciﬁcity are not readily available and have a slow turnaround time. When the diagnosis of heparin-induced thrombocytopenia is made, heparin in all forms must be stopped immediately. In those patients requiring ongoing anticoagulation, several alternatives exist:14 the agents most extensively used include the heparinoid danaparoid,15 hirudin/hirudin derivatives,14,18 and, most recently, the speciﬁc anti-thrombin argatraban.14 Danaparoid is available for limited use on compassionate grounds and hirudin has recently been approved for use in the USA and Canada. Warfarin may be used, but should not be started until one of the above agents has been used for 3 or 4 days to suppress thrombin generation. The deﬁbrinogenating snake venom arvin has been used quite extensively in the past but has been replaced by other agents including argatraban or hirudin derivative. Insertion of an inferior vena cava ﬁlter is often indicated. Osteoporosis has been reported in patients receiving unfractionated heparin in dosages of 20 000 U/day (or more) for more than 6 months. Demineralization can progress to the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible.3

Low-molecular-weight heparin Heparin currently in use clinically is polydispersed unmodiﬁed heparin, with a mean molecular weight ranging from 10 to 16 kD. Low-molecular-weight derivatives of commercial heparin have been prepared that have a mean molecular weight of 4–5 kD.19,20 The LMWHs commercially available are made by different processes (such as nitrous acid, alkaline, or enzymatic depolymerization) and they differ chemically and pharmacokinetically.19,20 The clinical signiﬁcance of these differences, however, is unclear, and there have been very few studies comparing different LMWHs with respect to clinical outcomes.20 The doses of the different LMWHs have been established empirically and are not necessarily interchangeable. Therefore, at this time, the effectiveness and safety of each of the LMWHs must be tested separately.20 The LMWHs differ from unfractionated heparin in numerous ways. Of particular importance are the following: increased bioavailability3,19,20 (> 90% after subcutaneous injection), prolonged half-life and predictable clearance enabling once or twice daily injection, and predictable antithrombotic response based on body weight permitting treatment without laboratory monitoring.3,19,20 Other possible advantages are their ability to inactivate platelet-bound factor Xa, resistance to inhibition by platelet factor IV, and their decreased effect on platelet function and vascular permeability3 (possibly accounting for less hemorrhagic effects at comparable antithrombotic doses).

Treatment of venous thromboembolism

There has been a hope that the LMWHs will have fewer serious complications, such as bleeding,20 heparin-induced thrombocytopenia,12,14 and osteoporosis,21 when compared with unfractionated heparin. Evidence is accumulating that these complications are indeed less serious and less frequent with the use of LMWH. Recent reviews suggest the absolute risk for heparininduced thrombocytopenia with LMWH was 0.2%, and with unfractionated heparin the risk was 2.6%. Accordingly there is advantage in this regard using LMWH.16 Importantly, harm associated with heparinassociated thrombocytopenia occurs more frequently in patients receiving unfractionated heparin than those receiving LMWH. Venous thromboembolism is associated with heparin-induced thrombocytopenia infrequently (< 1%) in LMWH-treated patients, yet often (approximately one in eight cases) in unfractionated heparintreated patients.17 A recent randomized trial shows that a higher proportion of patients with thrombocytopenia in the usual-care group died than those receiving LMWH who had thrombocytopenia (P = 0.03). The greater harm associated with usual-care thrombocytopenia requires further study.22 If heparin-induced thrombocytopenia occurs, LMWH should be discontinued immediately and an alternate commenced; such as argatraban or hirudin derivative. The LMWHs all cross-react with unfractionated heparin and they can therefore not be used as alternative therapy in patients who develop heparin-induced thrombocytopenia. LMWH has not been approved for the prevention or treatment of VTE in pregnancy. These drugs do not cross the placenta3,20 and small case series suggest they may be both effective and safe. LMWH use may increase in pregnancy, supplanting unfractionated heparin if the accumulating evidence supports the use of LMWH in pregnancy. An obvious problem in using LMWH in this context is the frequent use of epidural analgesia during labor or delivery. The standard treatment for VTE in pregnancy has been twice daily-adjusted dose subcutaneous unfractionated heparin.23 Several different LMWHs and fondaparinux are available for the prevention and treatment of VTE in various countries. Four LMWHs and fondaparinux are approved for clinical use in Canada and three LMWHs and fondaparinux have been approved for use in the United States. In a number of early clinical trials (some of which were dose ﬁnding), LMWH given by subcutaneous or intravenous injection was compared with continuous intravenous unfractionated heparin with repeat venography at days 7–10 being the primary end-point. These studies demonstrated that LMWH was at least as effective as unfractionated heparin in preventing extension or increasing resolution of thrombi on repeat venography (Fig. 19.1).24–35 Subcutaneous unmonitored LMWH has been compared with continuous intravenous heparin in a

227

Kakkar, 200324 Breddin, 200125 Harenberg, 200626 Gonzalez-Fajardo, 199927 Kirchmaier, 199828 Fiessinger, 199629 Luomanmaki, 199630 Lindmarker, 199431 Prandoni, 199232 Ninet, 199133 Bratt, 199034

Overall risk ratio (95% CI) Therapy under evaluation 0.25 0.5

1

2

0.82 (0.76, 0.88) 0.56 (0.42–0.76) 4

Figure 19.1 Risk ratios for improved clot–burden score and recurrent venous thromboembolism (VTE) outcomes and combined improved clot-burden score and recurrent VTE outcomes. A strong relationship between clot–burden score and recurrence (correlation = 0.81, P = 0.005); less clot–burden indicates a lower risk of recurrent venous thromboembolism. Red, risk ratios for recurrent VTE outcomes; blue, risk ratios for improved clot-burden score. Hull et al.,35 reprinted with permission.

number of clinical trials for the treatment of proximal venous thrombosis or pulmonary embolism using long term follow-up as an outcome measure (Table 19.3).36–46 These studies have shown that LMWH is at least as effective and safe as unfractionated heparin in the treatment of proximal venous thrombosis. Pooling of the most methodologically sound studies indicates a signiﬁcant advantage for LMWH in the reduction of major bleeding and mortality. LMWH used predominantly out of hospital was as effective and safe as intravenous unfractionated heparin given in hospital.41,42,47 (Table 19.4). Economic analysis of treatment with LMWH versus intravenous heparin demonstrated that LMWH was costeffective for treatment in hospital49 as well as out of hospital. As these agents become more widely available for treatment, they have replaced intravenous unfractionated heparin in the initial management of most patients with VTE.

Special patient groups OBESITY

In obese patients the clinician should review the pharmacopeia recommendations for the particular LMWH agent being used concerning dosage guidelines.

228

Medical treatment of acute deep vein thrombosis and pulmonary embolism

Table 19.3 Randomized trials of low-molecular-weight heparin for the treatment of proximal deep vein thrombosis or acute pulmonary embolism: results of long-term follow up Reference

Hull et al. (1992)36 Prandoni et al. (1992)32 Lopaciuk et al. (1992)37 Simonneau et al. (1993)38 Lindmarker et al. (1994)31 Simonneau et al. (1997)39 Decousus et al. (1998)40 Levine et al. (1996)41 Koopman et al. (1996)42 Hull et al. (2000)43 Merli et al. (2001)44

Breddin et al. (2001)25

Lee et al. (2003)45 Hull et al. (2006)46

Treatment

Recurrent venous thromboembolism no. (%)

Major bleeding no. (%)

Mortality no. (%)

Tinzaparin Heparin Nadroparin Heparin Nadroparin Heparin Enoxaparin Heparin Dalteparin Heparin Tinzaparin Heparin Enoxaparin Heparin Enoxaparin Heparin Nadroparin Heparin LMWH Heparin Enoxaparin twice daily Enoxaparin once/day Heparin Reviparin bid Reviparin once/day Heparin Dalteparin/VKA therapy Dalteparin/dalteparin Tinzaparin Heparin/VKA therapy

6/213 (2.8) 15/219 (6.8) 6/85 (7.1) 12/85 (14.1) 0/74 (0) 3/72 (4.2) 0/67 0/67 5/101 (5.0) 3/103 (2.9) 5/304 (1.6) 6/308 (1.9) 10/195 (5.1) 12/205 (5.0) 13/247 (5.3) 17/253 (6.7) 14/202 (6.9) 17/198 (8.6) 0/97 7/103 (6.8) 9/312 (2.9) 13/298 (4.4) 12/290 (4.1) 7/388 (1.8) 13/374 (3.5) 24/375 (6.4) 53/336 (15.8) 27/336 (8.0) 7/100 (7.0) 16/100 (16.0)

1/213 (0.5) 11/219 (5.0) 1/85 (1.2) 3/85 (3.8) 0/74 1/72 (1.4) 0/67 0/67 1/101 0/103 3/304 (1.0) 5/308 (1.6) 7/195 (3.6) 8/205 (3.9) 5/247 (2.0) 3/253 (1.2) 1/202 (0.5) 4/198 (2.0) 1/97 (1.0) 2/103 (1.9) 4/312 (1.3) 5/298 (1.7) 6/290 (2.1) 3/388 (0.8) 2/374 (0.5) 2/375 (0.5) 12/335 (3.6) 19/338 (5.6) 7/100 (7.0) 7/100 (7.0)

10/213 (4.7) 21/219 (9.6) 6/85 (7.1) 12/85 (14.1) 0/74 1/72 (1.4) 3/67 (4.5) 2/67 (3.0) 2/101 (2.0) 3/103 (2.9) 12/304 (3.9) 14/308 (4.5) 10/195 (5.1) 15/205 (7.3) 11/247 (4.5) 17/253 (6.7) 14/202 (6.9) 16/198 (8.1) 6/97 (6.2) 9/103 (8.7 ) 7/312 (2.2) 11/298 (3.7) 9/290 (3.1) 9/388 (2.3) 15/374 (4.0) 11/375 (2.9) 136/336 (40.5) 130/336 (38.7) 47/100 (47.0) 47/100 (47.0)

RENAL IMPAIRMENT

For patients with signiﬁcant renal impairment the clinician should review the pharmacopeia guidelines for dosage modiﬁcations for the individual LMWH agent. In patients with severe renal failure it may be preferable to use unfractionated heparin.

New antithrombotic agents for initial therapy Several new antithrombotic agents have been developed in recent years. In patients with deep vein thrombosis or pulmonary embolism, the synthetic pentasaccharide fondaparinux administered subcutaneous once daily has

been evaluated for initial therapy. The study ﬁndings indicate that fondaparinux has comparable efﬁcacy and safety to unfractionated heparin or LMWH6 for initial therapy.

Long-term low-molecular-weight heparin The use of LMWH for the long-term treatment of acute VTE has been evaluated in randomized clinical trials (Fig. 19.2). Taken together, these studies45,46 indicate that longterm treatment with subcutaneous LMWH for 3–6 months is at least as effective, and in cancer patients, more effective, than adjusted doses of oral vitamin K antagonist therapy (INR, 2.0–3.0) for preventing recurrent VTE.

Oral vitamin K antagonists 229

Table 19.4 Predominantly outpatient treatment of proximal deep vein thrombosis (DVT) with lowmolecular-weight heparin versus inpatient treatment with intravenous heparin Study Koopman et al. (1996)42

Levine et al. (1996)41

Columbus Study. (1997)47

Treatment

Recurrent DVT

Major bleeding

Nadroparin vs Heparin Enoxaparin vs Heparin Reviparin vs Heparin

14/202 (6.9%)

1/202 (0.5%)

17/198 (8.6%) 13/247 (5.3%)

4/198 (2.0%) 5/247 (2.0%)

17/253 (6.7%) 27/510 (5.3%)

3/253 (1.2%) 16/510 (3.1%)

24/511 (4.9%)

12/511 (2.3%)

Minimal requirements for early hospital discharge or outpatient therapy of venous thromboembolism (VTE) The responsible physician must ensure that all of the following conditions apply: The patient is ambulatory and in stable condition, with normal vital signs There is a low a priori risk of bleeding in the patient Severe renal insufﬁciency is not present There is a practical system in place for the following: Administration of low-molecular weight heparin and/or warfarin with appropriate monitoring, and Surveillance and treatment of recurrent VTE and bleeding complications Reprinted with permission from UpToDate48

Study year (ref.)

Design

Patient population

LMWH regimen

Meyer, 2002

Multicentre open-label

Venous Thromboembolism Cancer

T*

Deitcher, 2003

Multicentre open-label

Venous Thromboembolism Cancer

T and M† T

Lee, 2003

Multicentre open-label

Venous Thromboembolism Cancer

T and M†

Hull, 2006

Multicentre Proximal vein thrombosis Broad spectrum open-label

T*

Patients with recurrent venous thromboembolism Patients with hemorrhagic complications Risk ratio Risk ratio (95% CI) %Weight LMWH Vitamin K antagonists (95% CI) LMWH Vitamin K antagonists

2/71 (2.8%)

3/75 (4.0%)

0.70 (0.12, 4.09)

3.8

1/31 (3.2%)

0.49 (0.11, 2.29)

27/336 (8.0%) 53/336 (15.8%)

0.51 (0.33, 0.79) 69.8

‡

6/100 (6.0%) 10/100 (10.0%) 7/100 (7.0%) 16/100 (16.0%)

12/75 (16.0%)

0.44 (0.16, 1.19) 11.8

47/336 (14.0%) 63/336 (18.8%)

0.75 (0.53, 1.05) 63.8

5.3

2/28 (7.1%) 3/29 (10.3%)

§

5/71 (7.0%)

27/100 (27.0%) 24/100 (24.0%) 1.12 (0.70, 1.81) 24.3

0.44 (0.19, 1.02) 21.1 0.50 (0.35, 0.72)

0.10 Results favour LMWH

%Weight

1.00

0.80 (0.61, 1.05)

10.0

Results favour Vitamin K antagonists

0.10 Results favour LMWH

1.00

10.0

Results favour Vitamin K antagonists

Figure 19.2 Randomized clinical trials of long-term low-molecular-weight heparin (LMWH) therapy compared with vitamin K antagonist therapy in cancer patients with venous thromboembolism. *Treatment duration 3 months; †treatment duration 6 months; ‡follow-up 3 months; §follow-up 12 months. CI, conﬁdence interval; T, treatment dose; P, prophylactic dose; M, reduced maintenance dose. Deitcher, LMWH treatment groups pooled; bleeding proportions not reported. Hull et al.,46 reprinted with permission.

LMWH was also associated with less bleeding complications than vitamin K antagonists treatment, because of a reduction in minor bleeding.6 The ACCP Consensus panel states that: “For most patients with deep vein thrombosis and cancer, we recommend treatment with LMWH for at least the ﬁrst 3 to 6 months of longterm treatment.”6

ORAL VITAMIN K ANTAGONISTS Oral anticoagulant therapy There are two distinct chemical groups of oral anticoagulants: the 4-hydroxy coumarin derivatives (e.g., warfarin) and the indanedione derivatives (e.g., phenindione). The coumarin derivatives are the oral

230

Medical treatment of acute deep vein thrombosis and pulmonary embolism

anticoagulants of choice because they are associated with fewer non-hemorrhagic adverse effects than are the indanedione derivatives. The anticoagulant effect of warfarin is mediated by the inhibition of the vitamin K-dependent γ-carboxylation of coagulation factors II, VII, IX, and X.50,51 This results in the synthesis of immunologically detectable but biologically inactive forms of these coagulation proteins. Warfarin also inhibits the vitamin K-dependent γcarboxylation of proteins C and S. Protein C circulates as a pro-enzyme that is activated on endothelial cells by the thrombin–thrombomodulin complex to form activated protein C. Activated protein C in the presence of protein S inhibits activated factor VIII and activated factor V activity.50,51 Therefore, vitamin K antagonists such as warfarin create a biochemical paradox by producing an anticoagulant effect due to the inhibition of procoagulants (factors II, VII, IX, and X) and a potentially thrombogenic effect by impairing the synthesis of naturally occurring inhibitors of coagulation (proteins C and S). Heparin and warfarin treatment should overlap by 4–5 days when warfarin treatment is initiated in patients with thrombotic disease. The anticoagulant effect of warfarin is delayed until the normal clotting factors are cleared from the circulation, and the peak effect does not occur until 36–72 hours after drug administration.51 During the ﬁrst few days of warfarin therapy the prothrombin time (PT) reﬂects mainly the depression of factor VII, which has a half-life of 5–7 hours. Equilibrium levels of factors II, IX, and X are not reached until about 1 week after the initiation of therapy. The use of small initial daily doses (e.g., 5–10 mg) is the preferred approach for initiating warfarin treatment. The dose–response relationship to warfarin therapy varies widely between individuals and, therefore, the dose must be carefully monitored to prevent overdosing or underdosing. A number of drugs interact with warfarin.50,52 Critical appraisal of the literature reporting such interactions indicates that the evidence substantiating many of the claims is limited.51 Nonetheless, patients must be warned against taking any new drugs without the knowledge of their attending physician.

Laboratory monitoring and therapeutic range The laboratory test most commonly used to measure the effects of warfarin is the one-stage PT test. The PT is sensitive to reduced activity of factors II, VII, and X, but is insensitive to reduced activity of factor IX. Confusion about the appropriate therapeutic range has occurred because the different tissue thromboplastins used for measuring the PT vary considerably in sensitivity to the vitamin K-dependent clotting factors and in response to warfarin. To promote the standardization of the PT for monitoring oral anticoagulant therapy, the World Health

Organization (WHO) developed an international reference thromboplastin from human brain tissue and recommended that the PT ratio be expressed as the international normalized ratio, or INR. The INR is the PT ratio obtained by testing a given sample using the WHO reference thromboplastin. For practical clinical purposes, the INR for a given plasma sample is equivalent to the PT ratio obtained using a standardized human brain thromboplastin known as the Manchester comparative reagent, which has been widely used in the UK.51 Warfarin is administered in an initial dosage of 5– 10 mg/day for the ﬁrst 2 days. The daily dose is then adjusted according to the INR. Heparin therapy is discontinued on the fourth or ﬁfth day following initiation of warfarin therapy, provided the INR is prolonged into the recommended therapeutic range (INR 2–3).51 Because some individuals are either fast or slow metabolizers of the drug, the selection of the correct dosage of warfarin must be individualized. Therefore, frequent INR determinations are required initially to establish therapeutic anticoagulation. Once the anticoagulant effect and patient’s warfarin dose requirements are stable, the INR should be monitored at regular intervals throughout the course of warfarin therapy for VTE. However, if there are factors that may produce an unpredictable response to warfarin (e.g., concomitant drug therapy), the INR should be monitored frequently to minimize the risk of complications due to poor anticoagulant control.51 Several warfarin nomograms and computer software programs are now available to assist care givers in the control of warfarin therapy. Also, there is increasing interest in the use of self-testing with portable INR monitors and, in selective cases, selfmanagement of oral anticoagulant therapy.

LONG-TERM TREATMENT OF VENOUS THROMBOEMBOLISM USING VITAMIN K ANTAGONISTS Patients with established venous thrombosis or pulmonary embolism require long-term anticoagulant therapy to prevent recurrent disease. Vitamin K-antagonist therapy is highly effective6,53 and is preferred in most but not all patients. In patients with proximal vein thrombosis, longterm therapy with warfarin effectively reduces the frequency of objectively documented recurrent VTE in most patients. Adjusted-dose subcutaneous heparin was the treatment of choice where long-term oral anticoagulants were contraindicated, such as in pregnancy, until LMWH became available. Adjusted-dose, subcutaneous heparin or unmonitored LMWHs have been used for the long-term treatment of patients in whom oral anticoagulant therapy proves to be very difﬁcult to control3 and LMWH is the preferred treatment in patients with deep vein thrombosis and cancer.6,45,46

Long-term treatment of venous thromboembolism using vitamin K antagonists

The use of a less intense warfarin regimen (INR 2.0–3.0) markedly reduces the risk of bleeding from 20% to 4%, without loss of effectiveness compared with more intense warfarin.53 With the improved safety of oral anticoagulant therapy using a less intense warfarin regimen, there has been renewed interest in evaluating the long-term treatment of thrombotic disorders. The preferred intensity of the anticoagulant effect of treatment with vitamin K antagonists has been conﬁrmed by the results of randomized trials.6,53–55 The results of two recent randomized trials54,55 indicate that although low-intensity warfarin therapy is more effective than placebo, it is less effective than standard-intensity therapy (INR 2.0–3.0), and does not reduce the incidence of bleeding complications. Additional important evidence regarding the intensity of anticoagulant therapy with vitamin K antagonists is provided by a recent randomized trial by Crowther et al.,56 who compared standard-intensity warfarin therapy (INR 2.0–3.0) with high-intensity warfarin therapy (INR 3.1–4.0) for the prevention of recurrent thromboembolism in patients with persistently positive antiphospholipid antibodies and a history of thromboembolism (venous or arterial). The high-intensity warfarin therapy (INR 3.1–4.0) did not provide improved antithrombotic protection. The high-intensity regimen has been previously shown to be associated with a high risk (20%) of clinically important bleeding in a series of randomized trials6,53,57,58 in patients with DVT. The evidence outlined above provides the basis for the recommendation of an INR of 2.0–3.0 as the preferred intensity of anticoagulant treatment with vitamin K antagonists. The safety of oral anticoagulant treatment depends heavily on the maintenance of a narrow therapeutic INR range. The importance of maintaining careful control of oral anticoagulant therapy is evident and may be enhanced with the use of anticoagulant management clinics if oral anticoagulants are going to be used for extended periods of time.

Duration of oral anticoagulants after a first episode of venous thromboembolism It has been recommended that all patients with a ﬁrst episode of VTE receive warfarin therapy for 3–6 months. Attempts to decrease the treatment to 4 weeks59,60 or 6 weeks61 resulted in higher rates of recurrent thromboembolism in comparison with either 12 or 26 weeks of treatment (11–18% recurrent thromboembolism in the following 1–2 years). Most of the recurrent thromboembolic events occurred in the 6–8 weeks immediately after anticoagulant treatment was stopped, and the incidence was higher in patients with continuing risk factors, such as cancer and immobilization. Treatment with oral anticoagulants for 6 months reduced the incidence of recurrent thromboembolic events, but there

231

was a cumulative incidence of recurrent events at 2 years (11%) and an ongoing risk of recurrent thromboembolism of approximately 5–6% per year.61 The risk–beneﬁt of an extended course of anticoagulant treatment using a vitamin K antagonist for patients with idiopathic DVT has been evaluated by three randomized trials54,62,63 that evaluated extended treatment for 1–2 years compared with the control groups who received the conventional duration of treatment of 3–6 months. The results indicate that extended treatment with warfarin is highly effective in reducing the incidence of recurrent VTE, but the beneﬁt is lost once therapy is discontinued. In patients with a ﬁrst episode of idiopathic VTE treated with intravenous heparin followed by warfarin for 3 months, continuation of warfarin for 24 months led to a signiﬁcant reduction in the incidence of recurrent VTE compared with placebo.62 The authors concluded that anticoagulant therapy for more than 3 months was required in such patients but the optimal duration of treatment remains undetermined. Agnelli et al.63 reported that the incidence of recurrent VTE was lower in patients treated for 12 months compared with 3 months after a ﬁrst episode of DVT but that at 2 years follow-up the recurrence rates were the same. This continued risk of recurrent thromboembolism even with 6 months’ treatment after a ﬁrst episode of DVT has encouraged the development of clinical trials evaluating the effectiveness of long-term anticoagulant treatment beyond 6 months. Data from clinical trials have documented an unacceptably high incidence of recurrent VTE, including fatal pulmonary embolism, for patients with proximal DVT who are treated according to the current practice with intravenous heparin for several days, followed by oral anticoagulant treatment for only 3–6 months.6,62,63 Patients who have a poor prognosis64 include patients with idiopathic recurrent VTE, patients who are carriers of genetic mutations which predispose to VTE such as factor V Leiden mutation, and patients with cancer.6 Evidence is building that patients with extensive residual clot burden as well as patients with a positive Ddimer (after cessation of therapy) are at a higher risk of recurrent VTE.65

Duration of oral anticoagulant treatment in patients with recurrent venous thromboembolism In a multicentre clinical trial, Schulman et al.67 randomized patients with a ﬁrst recurrent episode of VTE, to receive either 6 months or continued oral anticoagulants indeﬁnitely, with a targeted INR of 2.0–2.85. The analysis was reported at 4 years. In the patients receiving anticoagulants for 6 months, recurrent thromboembolism occurred in 20.7%, compared with 2.6% of patients on the indeﬁnite treatment (P < 0.001). However, the rates of major bleeding were 2.7% in the 6

232

Medical treatment of acute deep vein thrombosis and pulmonary embolism

month group, compared with 8.6% in the indeﬁnite group. In the indeﬁnite group, two of the major hemorrhages were fatal, whereas there were no fatal hemorrhages in the 6 month group. This study showed that extending the duration of oral anticoagulants for approximately 4 years resulted in a signiﬁcant decrease in the incidence of recurrent VTE, but with a higher incidence of major bleeding. Without a mortality difference, the risk of hemorrhage versus the beneﬁt of decreased recurrent thromboembolism with the use of extended warfarin treatment remains uncertain and will require further clinical trials.

In summary Patients with reversible or time-limited risk factors should be treated with oral anticoagulants for 3–6 months. For patients experiencing a ﬁrst episode of idiopathic VTE, long-term anticoagulant therapy should be continued for at least 6–12 months using oral anticoagulants to prolong the prothrombin time to and INR of 2.0–3.0.6 For patients with recurrent VTE or a continuing risk factor such as immobilization, heart failure, cancer, or the antiphospholipid antibody syndrome, anticoagulants should be continued for a longer period of time and possibly indeﬁnitely, particularly for those patients with more than one recurrent episode of thrombosis.6 Patients with the factor V Leiden defect should probably receive indeﬁnite anticoagulant treatment if they have recurrent

disease or are homozygous for the gene. Recommendations for long-term anticoagulant therapy for the other thrombophilic conditions are less deﬁnite but constitute the topic for a number of epidemiologic studies.

Innovations in decision-making involving the patient in planning to the duration of longterm anticoagulant therapy In many patients there will be considerable uncertainty as to the duration of long-term anticoagulant therapy (see evidence-based guideline recommendations for the longterm treatment of patients with VTE). For this reason it is important to include patient preferences in the decisionmaking process concerning the duration of anticoagulant therapy (Fig. 19.3). In DVT or pulmonary embolism patients who receive indeﬁnite anticoagulant treatment, the risk–beneﬁt of continuing such treatment should be reassessed in the individual patient at periodic intervals. Where appropriate the patient should be involved in the decision process.66

Adverse effects The major side-effect of oral anticoagulant therapy is bleeding.51 Bleeding during well-controlled oral anticoagulant therapy is usually due to surgery or other

Patient planner What would you like to know by the end of your visit? Please list your three most important questions here. 1. 2. 3. Is there anything in particular worrying you about your problem (complaints, symptoms, and feelings)?

How much control do you want to have in deciding which treatment options are best for you? Please number them in order of preference. A. ______ I prefer to make the decision about which treatment I will receive B. ______ I prefer to make the final decision about my treatment after seriously considering my doctor’s opinion C. ______ I prefer that my doctor and I share responsibility for deciding which treatment is best for me. D. ______ I prefer that my doctor makes the final decision about which treatment will be used, but seriously considers my opinion. E. I prefer to leave all the decision regarding treatment to my doctor.

Figure 19.3 Patient contracting. In individual deep vein thrombosis (DVT) or pulmonary embolism (PE) patients who, for example, receive indeﬁnite anticoagulant treatment, the risk–beneﬁt of continuing such treatment should be reassessed in the individual patient at periodic intervals. Where appropriate the patient should be involved in the decision process. The patient provides guidance in the assessment process by completing the Patient Consultation Planner prior to the review in our clinic. Hull,66 reprinted with permission from the Journal of Vascular Surgery.

Long-term treatment of venous thromboembolism using vitamin K antagonists

forms of trauma, or to local lesions, such as peptic ulcer or carcinoma. Spontaneous bleeding may occur if warfarin sodium is given in an excessive dose, resulting in marked prolongation of the INR; this bleeding may be severe and even life-threatening. Non-hemorrhagic side-effects of oral anticoagulants differ according to whether coumarin derivatives (e.g., warfarin sodium) or indanediones are administered. Such side-effects are uncommon with coumarin anticoagulants, and the coumarins are therefore the oral anticoagulants of choice. Coumarin-induced skin necrosis is a rare but serious complication that requires immediate cessation of oral anticoagulant therapy.51 It usually occurs between 3 and 10 days after therapy has commenced, is commoner in women, and most often involves areas of abundant subcutaneous tissues, such as the abdomen, buttocks, thighs, and breast. The mechanism of coumarin-induced skin necrosis, which is associated with microvascular thrombosis, is uncertain but appears to be related, at least in some patients, to depression of the protein C level. Patients with congenital deﬁciencies of protein C may be particularly prone to the development of coumarin skin necrosis.

Management of patients on long-term oral anticoagulants requiring surgical intervention Physicians are commonly confronted with the problem of managing oral anticoagulants in individuals who require temporary interruption of treatment for surgery or other invasive procedures. In the absence of data from randomized clinical trials, recommendations can only be made based on cohort studies, retrospective reviews, and expert opinions. The most common conditions requiring long-term anticoagulant therapy are atrial ﬁbrillation, mechanical or prosthetic heart valve replacement, and VTE. For each of these conditions, the risk of arterial or VTE when anticoagulants have been discontinued must be weighed against the risk of bleeding if intravenous heparin is applied before or after the surgical procedure, or if oral anticoagulant therapy is continued at the therapeutic level. The possible choices based on the risk–beneﬁt assessment in the individual patient include (a) discontinuing warfarin for 3–5 days before the procedure to allow the INR to return to normal and then restarting therapy shortly after surgery, (b) lowering the warfarin dose to maintain an INR in the lower or subtherapeutic range during the surgical procedure, and (c) discontinuing warfarin and treating the patient in-hospital with intravenous heparin before and after the surgical procedure, until warfarin therapy can be reinstituted. Low-molecular-weight heparin subcutaneously is now being used in many of these circumstances as an alternative to unfractionated heparin. Low-molecularweight heparin as bridging therapy may become a standard

233

regimen (inpatients or outpatients) in appropriate patients in whom vitamin K antagonist therapy is interrupted.

Antidote to vitamin K antagonists The antidote to the vitamin K antagonists is vitamin K1. If an excessive increase of the INR occurs, the treatment depends on the degree of the increase and whether or not the patient is bleeding. If the increase is mild and the patient is not bleeding, no speciﬁc treatment is necessary other than reduction in the warfarin dose. The INR can be expected to decrease during the next 24 hours with this approach. With more marked increase in the INR in patients who are not bleeding, treatment with small doses of vitamin K1, given either orally or by subcutaneous injection (1.0–5.0 mg), could be considered; oral administration of vitamin K1 is preferred. With a very marked increase in the INR, particularly in a patient who is either actively bleeding or at risk of bleeding, the coagulation defect should be corrected. Reported side-effects of vitamin K include ﬂushing, dizziness, tachycardia, hypotension, dyspnea, and sweating.51 Intravenous administration of vitamin K1 should be performed with caution to avoid inducing an anaphylactoid reaction. The risk of anaphylactoid reaction can be reduced by slow administration of vitamin K1 at a rate no faster than 1 mg/min IV. In most patients, intravenous administration of vitamin K1 produces a demonstrable effect on the INR within 6–8 hours and corrects the increased INR within 12–24 hours. Because the half-life of vitamin K1 is less than that of warfarin sodium, a repeat course of vitamin K1 may be necessary. If bleeding is very severe and life-threatening, vitamin K therapy can be supplemented with concentrations of factors II, VII, IX and X.

Upper extremity deep vein thrombosis The treatment of upper extremity deep vein thrombosis is the same as for proximal venous thrombosis, i.e., heparin or LMWH plus warfarin for at least 3 months.68 Patients with recent-onset upper extremity DVT have been treated with thrombolytic agents, but there is no evidence from clinical trials that this decreases long-term sequelae. The rare patient with a thoracic outlet obstruction may beneﬁt from surgery.

Treatment of superficial thrombophlebitis In the absence of associated DVT, the treatment of superﬁcial thrombophlebitis is usually conﬁned to symptomatic relief with analgesia and rest of the affected limb. The exception is the patient with superﬁcial thrombophlebitis involving a large segment of the long

234

Medical treatment of acute deep vein thrombosis and pulmonary embolism

saphenous vein, particularly when it occurs above the knee. These patients should be treated with heparin or LMWH with or without oral anticoagulant therapy or superﬁcial venous ligation. The presence of associated DVT requires the usual treatment with heparin or LMWH along with warfarin for at least 3 months.

The post-thrombotic syndrome Randomized trials69–71 have addressed the efﬁcacy of compression stockings for the prevention of postthrombotic syndrome after an episode of DVT. The ﬁndings support the use of an elastic compression stocking

Guidelines 3.3.0 of the American Venous Forum on medical treatment of acute deep vein thrombosis and pulmonary embolism. Based on recommendations of The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy, Buller et al.6 No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.3.1

For patients with objectively conﬁrmed deep vein thrombosis we recommend short-term treatment with subcutaneous low-molecularweight heparin or, alternatively, intravenous unfractionated heparin

1

A

3.3.2

For patients with a high clinical suspicion of deep vein thrombosis we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests

1

C

3.3.3

In acute deep vein thrombosis we recommend initial treatment with low-molecular-weight heparin or unfractionated heparin for at least 5 days

1

C

3.3.4

In acute deep vein thrombosis we recommend initiation of vitamin K antagonist together with low-molecular-weight heparin or unfractionated heparin on the ﬁrst treatment day, and discontinuation of heparin when the international normalized ratio is stable and > 2.0 (consider for 2 consecutive days)

1

A

3.3.5

For patients with a ﬁrst episode of deep vein thrombosis secondary to a transient (reversible) risk factor, we recommend long-term treatment with a vitamin K antagonist for 3 months over treatment for shorter periods

1

A

3.3.6.

For patients with a ﬁrst episode of idiopathic deep vein thrombosis, we recommend treatment with a vitamin K antagonist for at least 6–12 months

1

A

3.3.7

We recommend that the dose of vitamin K antagonist be adjusted to maintain a target international normalized ratio of 2.5 (2.0–3.0) for all treatment durations

1

A

3.3.8

We recommend against high-intensity vitamin K antagonist therapy (international normalized ratio range 3.1–4.0) and against low-intensity therapy (international normalized ratio range 1.5–1.9) compared with international normalized ratio range of 2.0–3.0

1

A

3.3.9

For patients with objectively conﬁrmed non-massive pulmonary embolism, we recommend acute treatment with subcutaneous low-molecular-weight heparin or, alternatively, iv unfractionated heparin

1

A

3.3.10 For most patients with pulmonary embolism, we recommend clinicians do not use systemic thrombolytic therapy

1

A

3.3.11 For the duration and intensity of treatment for pulmonary embolism, the recommendations are similar to those for deep vein thrombosis

1

A

References 235

with a pressure of 30–40 mmHg at the ankle during 2 years after an episode of DVT.

Adjunctive therapy The limited role of thrombolysis72–75 and the use of inferior vena caval ﬁlters76 is summarized in Box 19.1. Thrombectomy is rarely performed.77,78

Evidence-based guideline recommendations The evidence-based guidelines for treatment of VTE are supported by strong evidence from many trials for many of the recommendations (Box 19.1). The abundance of level A evidence has resulted in many 1A recommendations, which the clinician will be wise to adhere to in appropriate patients. Owing to the large number of recommendations, the levels of evidence are summarized in Box 19.1 rather than in the text.

CONCLUSION Based on a large number of level A clinical trials the accepted medical treatment for acute DVT has been established. Historically this consisted of unfractionated heparin given by continuous intravenous infusion with warfarin starting on days 1 or 2 and continued for 3 months with a targeted INR of 2.0–3.0. A number of LMWHs have been shown to be at least as effective as unfractionated heparin in decreasing recurrent VTE, and in fact, are associated with less major bleeding. Lowmolecular-weight heparin has become the treatment of choice for both in-hospital and out-of-hospital treatment of DVT and, more recently, sub-massive pulmonary embolism as well. Long-term LMWH is the therapy of choice in patients with VTE and cancer. Although vitamin K antagonists have been used for years for the long-term treatment of patients suffering VTE, the optimal duration of treatment after a ﬁrst episode or recurrent episodes of venous thrombosis remains uncertain. Patients with a ﬁrst episode of idiopathic deep venous thrombosis require at least 6 months of long-term anticoagulant treatment and patients who have a ﬁrst recurrence require at least 12 months of anticoagulant treatment. Because the risk of recurrent VTE continues even after these extended periods of treatment, it is likely that future recommendations will be for even longer periods of treatment. Indeed, current guidelines suggest considering indeﬁnite anticoagulation in appropriate patients. These and other unanswered questions related to the management of acute DVT will be further clariﬁed by the results of ongoing clinical trials.

REFERENCES 1. Lane DA. Heparin binding and neutralizing protein. In: Lane DA, Lindahl U, eds. Heparin, Chemical And Biological Properties, Clinical Applications. London: Edward Arnold, 1989: 363–91. 2. Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci 1979; 76: 1218–22. 3. Hirsh J, Raschke R. Heparin and LMWH: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S–203S. 4. Gallus A, Jackaman J, Tillett J, et al. Safety and efﬁcacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; II: 1293–6. 5. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322: 1260–4. 6. Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 401S-428S. 7. Hull RD, Raskob GE, Rosenbloom DR, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992; 152: 1589–95. 8. Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. Arch Intern Med 1997; 157: 2317–21. 9. Writing Committee for the Galilei Investigators. Subcutaneous adjusted-dose unfractionated heparin vs ﬁxed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Arch Intern Med 2004; 164: 1077–108. 10. Raschke RA, Reilly BM, Guidry JR, et al. The weight based heparin dosing nomogram compared with a ‘standard care’ nomogram. Ann Intern Med 1993; 119: 874–81. 11. Kearon C, Ginsberg JS, Julian JA, et al. for the ﬁxed-dose heparin (ﬁdo) investigators. Comparison of ﬁxed-dose weight-adjusted unfractionated heparin for acute treatment of venous thromboembolism. JAMA 2006; 296: 935–92. 12. Warkentin TE, Levine MN, Hirsh J, et al. Heparin induced thrombocytopenia in patients treated with LMWH or unfractionated heparin. N Engl J Med 1995; 332: 1330–5. 13. Kelton JG. Heparin-induced thrombocytopenia. Haemostasis 1986; 16: 173–86. 14. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment and prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S–337S. 15. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70: 554–61.

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16. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecularweight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710–15 17. Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thromobcytopenia? Chest 2006; 130: 681–7. 18. Greinacher A. Lepirudin for the treatment of heparininduced thrombocytopenia: a prospective study. Blood 1998; 92 (10): 362a (abstract 1490). 19. Barrowcliffe TW, Curtis AD, Johnson EA, et al. An international standard for LMWH. Thromb Haemost 1988; 60: 1–7. 20. Weitz JI. Low molecular weight heparins. N Engl J Med 1997; 337: 688–98. 21. Shaughnessy SG, Young E, Deschamps P, Hirsh J. The effects of low-molecular-weight and standard heparin on calcium loss from fetal rat calvaria. Blood 1995; 86: 1368–73. 22. Hull RD, Pineo GF, Brant RF, et al. for the LITE trial investigators. Self-managed long-term LMWH therapy: balance of beneﬁts and harms. Am J Med 2007; 120: 72–82. 23. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 627S–644S. 24. Kakkar VV, Gebska M, Kadziola Z, et al. on behalf of the Bemiparin investigators. Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis. Thromb Haemost 2003; 89: 674–80. 25. Breddin HK, Hach-Wunderle V, Nakov R, Kakkar VV, for the CORTES investigators. Effects of low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001; 334: 626–1. 26. Harenberg J, Schmidt JA, Koppenhagen K, et al. and the EASTERN investigators. Fixed-dose, body weightindependent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. Thromb Haemost 2000; 83: 652–6. 27. Gonzalez-Fajardo JA, Arreba E, Castrodeza J, et al. Venographic comparison of subcutaneous low-molecularweight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30 (2): 283–92 28. Kirchmaier CM, Wolf H, Schafer H, et al. for the Certoparin study group. Efﬁcacy of low-molecular-weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Intern Angiol 1998; 17 (3): 135–45 29. Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. Oncedaily subcutaneous dalteparin, a low-molecular-weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76 (2): 195–9.

30. Luomanmaki K, Grankvist S, Hallert C, et al. A multicentre comparison of once-daily subcutaneous dalteparin (lowmolecular-weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med 1996: 240: 85–92. 31. Lindmarker P, Holmstrom M, Granqvist S, et al. Comparison of once-daily subcutaneous fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72 (2): 186–90. 32. Prandoni P, Lensing AWA, Buller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441–5. 33. Ninet J, Bachet Ph, Prandoni P, et al. A randomised trial of subcutaneous low-molecular-weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1991; 65 (3): 251–6. 34. Bratt G, Aberg W, Johansson M, et al. Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT). Thromb Haemost 1990; 64 (4): 506–10. 35. Hull RD, Marder VJ, Mah AF, et al. Quantitative assessment of thrombus burden predicts the outcome of treatment for venous thrombosis: A systematic review. Am J Med 2005; 118: 456–64. 36. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous LMWH compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med 1992; 326: 975–88. 37. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous LMWH versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis. A Polish multicentre trial. Thromb Haemost 1992; 68: 14–8. 38. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous LMWH compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993; 153: 1541–6. 39. Simonneau G, Sors H, Charbonnier B, et al. A comparison of LMWH with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337: 663–9. 40. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval ﬁlters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis. N Engl J Med 1998; 338: 409–15. 41. Levine M, Gent M, Hirsh J, et al. A comparison of LMWH administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med 1996; 334: 677–81. 42. Koopman MMW, Prandoni P, Piovella F, Ockelford PA, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous LMWH administered at home. N Engl J Med 1996; 334: 682–7.

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43. Hull RD, Raskob GE, Brant RF, et al. Low-molecular-weight heparin versus heparin in the treatment of patients with pulmonary embolism. Arch Intern Med 2000; 160: 229–36. 44. Merli G, Spiro TE, Olsson C-G, et al. for the Enoxaparin Clinical Trial Group. Ann Intern Med 2001; 134: 191–202. 45. Lee AYY, Levine MN, Baker RI, et al. for the CLOT Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in cancer. N Engl J Med 2003; 349: 146–53. 46. Hull RD, Pineo GF, Brant RF, et al. for the LITE Trial Investigators, Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062–72. 47. The Columbus Investigators. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Eng. J Med 1997; 337: 657–62. 48. Lip GYH, Hull RD. Treatment of deep vein thrombosis. Available from http://www.uptodate.com. Accessed April 2006. 49. Hull RD, Raskob GE, Rosenbloom D, et al. Treatment of proximal vein thrombosis with subcutaneous LMWH vs. intravenous heparin. An economic perspective. Arch Intern Med 1997; 157: 289–94. 50. Freedman MD. Oral anticoagulants : pharmacodynamics, clinical indications and adverse effects. J Clin Pharmacol 1992; 32: 196–209. 51. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: The Seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 204S–33S. 52. Wells PS, Holbrook AM, Crowther R, Hirsh J. Warfarin and its drug/food interactions; A critical appraisal of the literature. Ann Intern Med 1994; 121: 676–83. 53. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal vein thrombosis. N Engl J Med 1982; 307: 1676–81. 54. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425–34 55. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 631–9. 56. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349: 1133–8. 57. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979; 301: 855–8. 58. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189–94.

59. Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep vein thrombosis and pulmonary embolism. Lancet 1992; 340: 873–6. 60. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: 606–11. 61. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulation therapy after a ﬁrst episode of venous thromboembolism. N Engl J Med 1995; 332: 1661–5. 62. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a ﬁrst episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901–7. 63. Agnelli G, Prandoni P, Santamaria MG, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345: 165–9. 64. Prandoni P, Lensing AWA, Cogo A, et al. The long term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1–7. 65. Palaretti G, Cosmi B, Legnani C, et al. for the PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780–9. 66. Meissner MH, Wakeﬁeld TW, Ascher E, et al. Acute venous disease: venous thrombosis and venous trauma. J Vasc Surg 2007; 46 (6 Suppl 1): S25–S53. 67. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997; 336: 393–398. 68. Prandoni P, Polistena P, Bernardi E, Cogo A, et al. Upperextremity deep vein thrombosis. Arch. Intern Med 1997; 157: 57–62. 69. Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759–62. 70. Prandoni P. Below-knee compression stockings for prevention of the post-thrombotic syndrome: a randomized study [abstract]. Pathophysiol Haemost Thromb 2002; 32 (Suppl 2): 72. 71. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med 2001; 161: 2105–9. 72. Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. Eur J Vasc Endovasc Surg. 2002; 24: 209–14. 73. Goldhaber SZ, Heit J, Sharma GVRK, et al. Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2: 293–8.

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74. Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: Results of a multicenter registry. Circulation 1997; 96: 882–8. 75. Dong B, Jirong Y, Liu G, et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev 2006; Issue 2. Art No.: CD004437. 76. PREPIC Study Group. Eight-year follow-up of patients with

permanent vena cava ﬁlters in the prevention of pulmonary embolism: the PREPIC randomized study. Circulation 2005; 112: 416–22. 77. Plate G, Akesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arteriovenous ﬁstula. Eur J Vasc Surg 1990; 4: 483–9. 78. Plate G. Venous thrombectomy for iliofemoral vein thrombosis – 10-year results of a prospective randomized study. European J Vasc Endovasc Surg 1997; 14: 367–34.

20 Catheter-directed thrombolysis for treatment of acute deep vein thrombosis ANTHONY J. COMEROTA AND JORGE L. MARTINEZ TRABAL Introduction Rationale for thrombus removal Systemic thrombolysis for acute DVT Intrathrombus catheter-directed thrombolysis

239 240 241 241

INTRODUCTION Thrombolytic therapy for acute deep vein thrombosis (DVT) is used as the initial treatment in order to clear the thrombus from the deep venous system. The underlying rationale for thrombolytic therapy is to avoid postthrombotic morbidity. It does not replace therapeutic anticoagulation for the treatment of these patients, since anticoagulation is important to prevent recurrence. Controversies surrounding thrombolytic therapy result from questions being raised regarding the effectiveness in preventing post-thrombotic morbidity and the increased risk of bleeding complications. Anticoagulation alone has been adopted as the predominant form of treatment in patients with acute DVT, whether limited to calf vein, femoropopliteal, or iliofemoral thrombosis. Unfortunately, the American College of Chest Physicians (ACCP) 7th Consensus Conference on Antithrombotic Therapy failed to recognize any beneﬁt from thrombolytic therapy and, indeed, diminished enthusiasm by physicians to adopt any strategy of thrombus removal as a result of their negative statements regarding operative venous thrombectomy and thrombolytic therapy. The ACCP guidelines on treatment of venous thromboembolism stated that “there is no evidence that supports the use of thrombolytic agents for the initial treatment of DVT.”1 They recommended against the routine use of catheter-directed thrombolysis (Grade 1C) and went on to state that “thrombolytic therapy be conﬁned to patients requiring limb salvage” (Grade 2C). However, venous thrombosis resulting in venous gangrene

Patient evaluation Pharmacomechanical thrombolysis References

246 247 252

is exceptionally rare and when it occurs is generally associated with a malignancy and often a terminal condition. Furthermore, the accompanying tissue necrosis is usually the result of small vessel thrombosis in addition to the extensive large vessel DVT. When the thrombotic process is this far advanced, it cannot be reversed with thrombolytic therapy or, for that matter, any strategy of large vein thrombus removal. Therefore, lytic therapy in these patients is unrewarding and mostly futile. Although the ACCP failed to recognize the beneﬁts of intrathrombus catheter delivery, it has been shown in a randomized trial to be more effective than systemic thrombolysis.2 This observation is consistent with the basic mechanism of thrombolysis, which occurs by way of activation of ﬁbrin-bound plasminogen.3 In addition to the randomized trial, vast clinical experience has demonstrated the improved effectiveness of catheterdirected intrathrombus delivery of plasminogen activators, thereby leading most physicians to recognize that delivery of the thrombolytic agent into the thrombus is considerably more effective than systemic administration. Most physicians would agree that the majority of patients with acute DVT are appropriately treated with anticoagulation alone. However, patients who have particularly severe symptoms due to extensive venous obstruction and those with iliofemoral DVT who are at a particularly high risk of serious post-thrombotic morbidity appear to beneﬁt the most from a strategy of thrombus removal. There is a large body of evidence documenting that patients with iliofemoral venous thrombosis suffer severe post-thrombotic morbidity.4–6

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Following anticoagulation alone for the management of iliofemoral DVT, post-thrombotic chronic venous insufﬁciency, which includes leg ulceration, venous claudication, and edema with skin changes, are common. It is the thesis of this chapter that reduction in thrombus burden by successful thrombolysis reduces postthrombotic morbidity and offers patients the best chance of a favorable outcome.

RATIONALE FOR THROMBUS REMOVAL Ambulatory venous hypertension is the underlying pathophysiology leading to chronic venous disease.7,8 Venous pressure in the lower leg and foot should drop to < 50% of the standing pressure upon ambulation. Patients with the post-thrombotic syndrome have higher than normal ambulating pressures, with the high pressure transmitted to the skin and subcutaneous tissues generally through perforating veins. In individuals with persistent venous obstruction, the ambulatory venous pressure may rise above standing pressure, which is the pathophysiology leading to the debilitating symptoms of venous claudication. The two pathophysiologic components leading to ambulatory venous hypertension are venous valvular incompetence and persistent luminal obstruction. Consistent observations indicate that the most severe postthrombotic morbidity is associated with the highest venous pressures, occurring in patients with valvular incompetence and luminal venous obstruction.7,9 Unfortunately, physicians fail to recognize the contribution of venous obstruction to the patient’s postthrombotic morbidity. Occlusion is deﬁned as complete obliteration of the lumen, whereas obstruction is a linear reduction of the vein lumen from 1% to occlusion. Regrettably, technology and our understanding of venous pathophysiology has not progressed to the point that

(b) (a)

allows physicians to assess the impact of partial lumen obstruction in an individual patient, preventing physicians from putting venous obstruction into proper pathophysiologic perspective in terms of its contribution to post-thrombotic morbidity (Fig. 20.1). Consequently, there is widespread underappreciation regarding the importance of luminal obstruction contributing to postthrombotic morbidity. Experimental observations, natural history studies of acute DVT, and a randomized trial of venous thrombectomy versus anticoagulation all conﬁrm that a strategy of thrombus removal reduces post-thrombotic morbidity. Thrombolytic treatment of experimental DVT in a canine model demonstrated preservation of endothelial function and valve competence compared with placebo. As might be expected, there was less residual thrombus in veins treated with a plasminogen activator, thereby preserving the vein’s structural integrity.10,11 Natural history studies of acute DVT in patients treated with anticoagulation assessed thrombus resolution and subsequent valve function. These investigators demonstrated that patients with persistent proximal vein obstruction developed distal valvular incompetence, even when distal veins were not involved with the thrombus.12 During follow-up, the patients with the combination of venous obstruction and valve incompetence had the most severe post-thrombotic morbidity.13 When thrombus spontaneously lysed, venous patency was naturally restored. If spontaneous lysis occurred within 90 days, valve function was frequently normal.14 It is logical that successful thrombus elimination (spontaneous, mechanical, or pharmacologically accelerated) eliminates luminal obstruction and increases the likelihood of preserving normal valve function. It follows that in patients whose thrombus is resolved (or eliminated), post-thrombotic morbidity will be avoided or at least substantially reduced.

Figure 20.1 (a, b) A patient who had iliofemoral deep vein thrombosis 10 years earlier suffered with post-thrombotic chronic venous insufﬁciency resulting in multiple hospitalizations for venous ulcers. Ascending phlebography revealed chronic venous disease interpreted as “no evidence of obstruction” and an impedance phlebography showed normal results. A classic Linton procedure was performed, demonstrating signiﬁcant luminal obstruction of the femoral vein, which escaped accurate depiction phlebographically or was not detected hemodynamically by measuring maximal venous outﬂow.

Intrathrombus catheter-directed thrombolysis

SYSTEMIC THROMBOLYSIS FOR ACUTE DVT Initial attempts to treat acute DVT with thrombolytic therapy were via peripheral intravenous administration. Although treatment has evolved to catheter-directed intrathrombus delivery, it is instructive and enlightening to review the information generated by trials of systemic thrombolytic therapy versus anticoagulation for acute DVT. Thirteen studies have been reported comparing anticoagulant therapy with thrombolytic therapy for acute DVT (Table 20.1).15–29 In these studies, the diagnosis was established with ascending phlebography, which was repeated after treatment to assess outcome. Pooled analysis (Table 20.2) indicates that only 4% of patients treated with anticoagulation alone had signiﬁcant or complete lysis, and an additional 14% had partial lysis. The majority (82%) had either no objective phlebographic clearing or actually had extension of their thrombi. Therefore, only a minority of patients had sufﬁcient clearing of thrombus to expect a return of normal venous valvular function. In patients treated with thrombolytic therapy, 45% had signiﬁcant or complete clearing of the clot and 18% had partial clearing. Thirty-seven percent failed to improve or worsened. Although 10 times as many patients had signiﬁcant or complete clearing with lytic therapy compared with anticoagulation, less than half of the lytic patients had a good-to-excellent phlebographic outcome. Four additional studies described the results of thrombolytic therapy for DVT but were considered unsuitable for inclusion in the collective data.30–33 Two studies failed to include an anticoagulation cohort30,31 and therefore comparative data were not available. In another series, Kakkar and Lawrence32 reported venous hemodynamic changes in patients followed for 24 months after initial randomization to lytic therapy or heparin. Unfortunately, the patients in their ﬁnal report represent less than a third of those initially randomized. Since the initial response to therapy was not clariﬁed in all patients, one cannot assume that the outcome of the subset followed for 2 years is representative of all patients initially randomized. Furthermore, there was no comment regarding the effectiveness of anticoagulation or the number of interim recurrences. Symptomatic patients are more likely to seek continued care than those who feel well; therefore, this report probably represents a pessimistic bias due to patients’ self-selection. The fourth excluded study described the results of calf vein thrombosis to treatment with either heparin or streptokinase.33 Although the authors reported treatment response as an average quantitative venographic score by the treatment group, they failed to report any individual patient response to treatment. Two randomized trials followed patients long-term and reported symptomatic results (Table 20.3).25,34 Although the follow-up was shorter in Elliot’s study than in

241

Arnesen’s study, 1.6 versus 6.5 years, respectively, both treatment protocols were similar and the same drug (streptokinase) was used. The investigators found that the majority of patients who were free of post-thrombotic symptoms were treated with streptokinase (SK), whereas the majority with severe symptoms of the post-thrombotic syndrome received anticoagulation alone. A practical question is whether lysis of deep venous thrombi preserves venous valvular function. In a longterm follow-up of a prospective randomized study, Jeffrey et al.27 have shown signiﬁcant functional beneﬁt 5–10 years after therapy of acute DVT in patients following successful lysis. Popliteal valve function and overall venous insufﬁciency using photoplethysmography, foot volumetry, and direct Doppler examination were used. Patients who had initially successful lysis were compared with patients who did not lyse. Patients who lysed demonstrated normal venous function tests compared with patients who did not lyse (P < 0.001). Only 9% of patients successfully lysed had an incompetent popliteal valve compared with 77% of those who failed to lyse (P < 0.001).

INTRATHROMBUS CATHETER-DIRECTED THROMBOLYSIS Although systemic lytic therapy is associated with better outcomes than anticoagulation alone, absolute failure rates of thrombolysis are high, most likely due to inadequate penetration of thrombus by the plasminogen activator resulting in failed lysis. The mechanism by which thrombolysis results in clot dissolution is the activation of ﬁbrin-bound plasminogen.3 When circulating GLU-plasminogen binds to ﬁbrin, it is modiﬁed to LYS-plasminogen, which has greater afﬁnity for plasminogen activators. Delivering a plasminogen activator into the thrombus efﬁciently actives LYSplasminogen to form plasmin. The intrathrombus delivery protects the plasminogen activator from neutralization by circulating plasminogen activator inhibitors and also protects the resulting plasmin from neutralization by circulating α-2-antiplasmins. Catheter-directed techniques that deliver the plasminogen activator into the thrombus accelerate thrombolysis, increasing the likelihood of a successful outcome. Direct intrathrombus delivery reduces the overall dose and duration of the infusion of the plasminogen activator; therefore, it is reasonable to expect that complications will be reduced compared with systemic lytic therapy. Numerous reports have been published over the years supporting favorable outcomes of catheter-directed thrombolysis for acute DVT (Table 20.4, page 240).35–55 Although three of the larger reports demonstrate approximately an 80% success rate (Table 20.5, page 241),35–37 initial success rates would likely have been higher if treatment had been restricted to only patients with acute

Table 20.1 Review of anticoagulation versus lytic therapy for deep vein thrombosis Author (year)

Investigation type/total no. of patients*

Treatment groups

Results Signiﬁcant/ complete resolution (%)

Partial resolution (%)

No resolution/ propagation (%)

Browse et al. (1968)15

PR/10

Robertson et al. (1968)16

PRB/16

Kakkar et al. (1969)17

PR/18

Tsapogas et al. (1973)18

PR/34

Duckert et al. (1975)19

PNRB/134

Porter et al. (1975)20§ Seaman et al. (1976)21§ Rosch et al. (1976)22§ Marder et al. (1977)23

PR/48

SK/5 Hep/5 SK/8 Hep/8 SK/9 Hep/9 SK/19 Hep/15 SK/92 Hep/42 SK/22 Hep/26

3 (60) 0 (0) 5 (63) 1 (12) 6 (67) 2 (22) 10 (53) 0 (0) 39 (42) 0 (0) 9 (40) 2 (8)

1 (20) 0 (0) 2 (25) 2 (25) 1 (11) 2 (22) 0 (0) 1 (7) 23 (25) 4 (10) 1 (5) 5 (19)

1 (20) 5 (100) 1 (12) 5 (63) 2 (22) 5 (56) 9 (47) 14 (93) 30 (33) 38 (90) 12 (55) 19 (73)

0 (0) 0 (0) 2 (25) 1 (12) 0 (0) 0 (0) 0 (0) NA 24 (26) 4 (10) 4 (17) 1 (0.4)

Arnesen et al. (1978)24

PR/42

Elliot et al. (1979)25

PR/51

Watz et al. (1979)26

PR/35

Jeffery et al. (1989)27

PR/40

Turpie et al. (1990)28

PRB/82

Goldhaber et al. (1990)29

PRB/67

SK/12 Hep/12 SK/21 Hep/21 SK/26 Hep/25 SK/18 Hep/17 SK/20 Hep/20 rt-PA/40 Hep/42 rt-PA/45 Hep/12

5 (42) 0 (0) 11 (52) 2 (10) 17 (65) 0 (0) 8 (44) 1 (6) 11 (55) 1 (5) 13 (33) 2 (5) 15 (33) 0 (0)

2 (16) 3 (25) 4 (19) 2 (14) 1 (4) 0 (0) 4 (22) 5 (29) 0 (0) 0 (0) 9 (22) 7 (17) 14 (31) 2 (17)

5 (42) 9 (75) 6 (29) 16 (76) 8 (31) 25 (100) 6 (34) 11 (65) 9 (45) 19 (95) 18 (45) 33 (78) 16 (36) 10 (83)

NA NA 1 (5) 1 (5) 1 (4) 0 (0) 3 (12) 2 (12) NA NA 3 (8) 1 (2) 11 (24) 0 (0)

PR/24

Complications Bleeding Minor Major (%) (%)

PE

Death due to Rx

0 (0) 0 (0) 2 (25) 1 (12)† 3 (33) 2 (22) 4 (21) NA 58 (62) 2 (5) 6 (25)† 7 (27)

None None NA NA None None NA NA 7 5 1 None

None None None 1 (12)b None 1 (11) None None None None 1 (4)b None

NA NA 2 (10) 2 (10) 2 (8) 0 (0) 0 (0) 0 (0) NA NA 2 (5) 1 (2) 1 (2)† 0 (0)

NA NA 1‡ None None 2 1 1 NA NA NA NA NA NA

1 (8) b None None None None None None None None None None None None None

*PR, prospective, randomized; PRB, prospective, randomized, blinded interpretation; PNRB, prospective, nonrandomized, blinded interpretation; SK, streptokinase; Hep, heparin; rt-PA, recombinant tissue plasminogen activator; PE, pulmonary embolism; NA, not available. †Intracranial hemorrhage. ‡Nonfatal pulmonary embolus prior to therapy. ¶Fatal pulmonary embolus during therapy. §Same study population.

Intrathrombus catheter-directed thrombolysis

243

Table 20.2 Phlebographic results of anticoagulation versus lytic therapy for acute deep vein thrombosis (13 studies)15–29 Rx (no.)

Heparin (254) Lytic Rx

None/worse (%)

Lysis Partial

Signiﬁcant/complete

82% 37%

14% 18%

4% 45%

Table 20.3 Long-term, symptomatic results of heparin versus lytic therapy for deep vein thrombosis (two studies)25,34 Rx

Heparin SK

Pts

Post-thrombotic symptoms Severe (%) Moderate (%)

None (%)

39 39

8 (21) 2 (5)

8 (21) 25 (64)

iliofemoral DVT. However, clinicians gained experience and patients with more chronic thrombotic presentations were treated in an effort to reduce the acute severe symptoms and minimize the anticipated post-thrombotic morbidity. In the three larger reports, 422 patients were treated with consistent rates of success and complications.35–37 Urokinase (UK) was the plasminogen activator used in each of these studies; however, most clinicians believe that rt-PA offers similar rates of success and complications. Underlying iliac vein stenoses were treated with balloon angioplasty, stenting, or both to provide unobstructed venous drainage into the vena cava and reduce the risk of recurrent thrombosis. Major bleeding occurred in 5–10% of cases, with the majority resulting from puncture site bleeding. Intracranial bleeding was rare, occurring in only two patients in the National Venous Registry, one of which was fatal.36 Symptomatic pulmonary embolism (PE) occurred in 1% of patients in the series reported by Bjarnason et al.35 and the National Venous Registry, with fatal PE occurring in only one out of 422 patients. Therefore, death as a result of catheter-directed thrombolysis is a rare occurrence. Until approximately 6 years ago, most patients treated with catheter-directed thrombolysis were managed with UK. Since UK was removed from the market, catheterdirected alteplase and reteplase have demonstrated similarly good results.39–41,56 A unique approach of sporadic intrathrombus bolus dosing of rt-PA was reported by Chang et al.39 in 12 lower extremities of 10 patients with acute DVT. They infused rt-PA intrathrombus using the pulse-spray technique with no more than 50 mg per treatment session. Following the pulse-spray bolus, patients were returned to their rooms

23 (59) 12 (31)

and brought back the following day for venographic examination and repeated infusion if indicated. Continuous rt-PA infusion was not used. Patients had treatment repeated for up to four daily sessions. The results were excellent: 11 lower extremities had signiﬁcant or complete lysis and the remaining leg had 50–75% lysis. Although the average total dose of rt-PA was 106 mg, bleeding complications were minor and no patient had a decrease in hematocrit more than 2%. This technique deserves further evaluation. The National Venous Registry tabulated the results of 287 patients treated with lytic therapy for DVT both in academic and community centers.36 Sixty-six percent of patients had acute DVT, 16% chronic DVT, and 19% had an acute episode superimposed upon a chronic condition. Seventy-one percent of patients were treated for iliofemoral DVT and 25% for femoropopliteal DVT. Catheter-directed thrombolysis with intrathrombus infusion of UK was the preferred approach. However, some patients were treated with UK infused into a foot vein, which was essentially systemic thrombolysis. Phlebographic evaluation demonstrated that 31% of patients had complete lytic success, and 52% had 50–99% lytic success. In 17% of patients, < 50% of the thrombus was dissolved. When UK was not infused into the thrombus, success rates fell dramatically. In the subgroup of patients with acute ﬁrst-time iliofemoral DVT, 65% had complete clot lysis. During follow-up, thrombosis-free survival was observed in 65% at 6 months and in 60% at 12 months. There was a signiﬁcant correlation (P < 0.001) of thrombosis-free survival with the results of initial therapy. Seventy-eight percent of patients with complete clot resolution had patent veins at 1 year, compared with only

Table 20.4 Review of studies of catheter-directed thrombolysis (CDT) for acute deep vein thrombosis Author (year)

Total no. of patients (limbs)

Intervention

Semba et al. (1994)42

21 (27)

Semba et al. (1996)43

32 (41)

Verhaeghe et al. (1997)38

24

Bjarnason et al. (1997)35

77 (87)

Mewissen et al. (1999)36

287 (312)

Comerota et al. (2000)71

54

Horne et al. (2000)45 Kasirajan et al. (2001)46 AbuRahma et al. (2001)47

10 9 51

Vedantham et al. (2002)48

20 (28)

Elsharawy et al. (2002)49

35

Castaneda et al. (2002)40 Grunwald et al. (2004)50

15 74 (82)

Laiho et al. (2004)51

32

Sillesen et al. (2005)41 Jackson et al. (2005)52 Ogawa et al. (2005)53

45 28 24

Kim et al. (2006)72

37 (45)

Lin et al. (2006)55

93 (98)

CDT with UK, angioplasty/stenting for residual stenosis CDT with UK, angioplasty/stenting for residual stenosis CDT with rt-PA, stenting for residual stenosis CDT with UK, angioplasty, stenting, thrombectomy, bypass for residual stenosis CDT with UK, stenting for residual stenosis; systemic lysis (n = 6) CDT with UK or rt-PA, thrombectomy for residual stenosis CDT with rt-PA CDT with UK, rt-PA, or rPA CDT w/UK or rt-PA, stents/18 Hep/33 CDT with UK, rt-PA, or rPA, thrombectomy, stenting CDT w/SK, angio, stent/18 Hep/17 CDT with rPA CDT with UK, tPA, or rPA, angioplasty, stenting CDT with rt-PA/16 Systemic lysis with rt-PA/16 CDT with rt-PA, angioplasty, stenting CDT with UK or rPA, stenting CDT with UK/10 CDT with UK + IPC/14 CDT with UK/23 CDT + PMT/14 CDT with rPA, rt-PA, or UK, angioplasty, stenting/46 PMT with rPA, rt-PA, or UK, angioplasty, stenting/52

Results Partial resolution (%)

No resolution (%)

Bleeding Minor (%)

Complications PE Major (%)

Death due to Rx (%)

18 (72)

5 (25)

2 (8)

1 (4)

0 (0)

None

None

21 (32)

9 (28)

2 (6)

0 (0)

0 (0)

None

None

19 (79)

5 (21)

0 (0))

0 (0)

6 (25)

None

None

69 (793)

0 (0)

18 (21)

11 (14)

5 (6)

1

None

96 (31)

162 (52)

54 (17)

15 (28)

54 (11)

6

2 (<1)

14 (26)

28 (52)

6 (11)

8 (15)

4 (7)

1

None

9 (90) 7 (78) 15 (83) 1 (3) 23 (82)

1 (10) 1 (11) NR NR NR

0 (0) 1 (11) NR NR NR

3 (30) NA 3 (17) 3 (9) None

None NA 2 (11) 2 (6) 3 (14)

2 (20) NA None 2 (6) None

None NA None None None

13 (72) 2 (12) 15 (100) 54 (73)

5 (28) 8 (47) NR 26 (32)

0 (0) 7 (41) NR NR

None None None 6 (8)

None None None 4 (5)

None None None None

None None None None

8 (50) 5 (31) 42 (93) 5 (18) 0 (0) 5 (36) 21 (81) 16 (84) 32 (70)

5 (31) 8 (50) NR 20 (72) 10 (100) 9 (64) 3 (11) 3 (16) 14 (30)

NR NR NR NR None None 2 (8) None 5 (11)

4 (25) 6 (38) 4 (8) 2 (7) None None 1 (4) None 2 (4)

2 (13) 1 (6) None None None None 2 (7) 1 (5) 1 (2)

2 (13) 5 (31) 1 (2) None None None 1 (4) 1 (5) None

None None None None None None None None None

39 (75)

13 (25)

4 (8)

2 (4)

None

None

None

Signiﬁcant/ complete resolution (%)

Hep, heparin; IPC, intermittent pneumatic compression; rPA, recombinant plasminogen activator; PMT, pharmacomechanical thrombolysis; rt-PA, recombinant tissue plasminogen activator; tPA, tissue plasminogen activator; UK, urokinase;

Intrathrombus catheter-directed thrombolysis

245

Table 20.5 Efﬁcacy and complications of catheter-directed thrombolysis in three series Efﬁcacy (%)

Initial success Iliac Femoral Primary patency at 1 year Iliac Femoral Iliac stent: patency at 1 year + stent – stent Complications (%) Major bleed Intracranial bleeding Pulmonary embolism Fatal pulmonary embolism Death secondary to lysis

Bjarnason et al.35 (n = 77)

Mewissen et al.36 (n = 287)

Comerota et al.37 (n = 58)

79 63 40 63 40

83 64 47 64 47

84 78 – 78 –

54 75

74 53

89 71

5 0 1 0 0

11 <1 1 0.2 0.4

9 0 0 0 0 (?2)*

*Death due to multiorgan system failure 30 days post lysis, thought not related to lytic therapy

37% of those in whom < 50% of the clot was dissolved. In the subgroup of patients with acute ﬁrst-time iliofemoral DVT who had successful thrombolysis, 96% of the veins remained patent at 1 year. In addition to sustained patency, early success directly correlated with valve function at 6 months. Sixty-two percent of patients with < 50% thrombolysis had venous valvular incompetence, whereas 72% of patients who had complete lysis had normal valve function (P < 0.02). The observations in the National Venous Registry permitted an evaluation of the impact of catheter-directed thrombolysis on health-related quality-of-life (QoL) in patients with iliofemoral DVT. A contemporary cohort of patients with iliofemoral DVT treated with anticoagulation in the same institutions was identiﬁed. All anticoagulated patients were candidates for lytic therapy but were treated with anticoagulation alone because of physician preference. A validated QoL questionnaire with disease-speciﬁc items was used to query patients at 16 and 22 months after treatment. Of the 98 patients studied, 68 were treated with catheter-directed thrombolysis as part of the National Venous Registry, and

30 were treated with anticoagulation alone. Those treated with catheter-directed thrombolysis reported a signiﬁcantly better QoL than those treated with anticoagulation alone. The QoL results were directly related to the initial success of thrombolysis. Patients who had a successful lytic outcome had a signiﬁcantly better health utilities index, better physical functioning, less stigma of chronic venous disease, less health distress, and fewer overall postthrombotic symptoms. Patients in whom catheterdirected thrombolysis failed had similar outcomes to patients treated with anticoagulation alone. Meissner and Mewissen57 recently reported follow-up results in 102 limbs of 98 patients with acute DVT treated in the National Venous Registry. This patient cohort had no history of venous thrombosis and was treated with catheter-directed thrombolysis for their initial DVT. The median follow-up time was 316 days. The authors correlated the lytic response with residual thrombus, vein valve function, and post-thrombotic symptoms. The results are summarized in Table 20.6. A good or excellent lytic response to catheter-directed thrombolysis was

Table 20.6 Results of catheter-directed thrombolysis for acute DVT: follow-up to the National Venous Registry57 Outcome at follow-up (316 days median) Residual thrombus (%) Reﬂux (%) Asymptomatic (%)

Lytic response to catheter-directed thrombolysis < 50% 50–99% 100% (n=11) (n=53) (n=38)

P-value

73 89 36

0.001 0.03 0.002

45 48 68

16 39 84

246

Catheter-directed thrombolysis for treatment of acute deep vein thrombosis

associated with signiﬁcantly less thrombus found at follow-up, less vein valve reﬂux, and a greater number of asymptomatic patients. A small randomized trial performed by Elsharawy et al.49 demonstrated that catheter-directed thrombolysis compared with anticoagulation alone offered signiﬁcantly better outcomes at 6 months. Assuming patients are properly managed with anticoagulation, the 6 month observation should reﬂect their long-term outcome. We believe that the results available to date support a strategy of catheter-directed thrombolysis for acute iliofemoral DVT in patients who have no contraindications to thrombolytic therapy. If a contraindication to lytic therapy exists, a contemporary venous thrombectomy or incorporating the new technique of isolated segmental pharmacomechanical thrombolysis should be considered.

(a)

PATIENT EVALUATION It is intuitive that patients with iliofemoral DVT have a large thrombus burden and therefore greater stimulus to thrombosis than most patients with acute DVT, thereby warranting a search for an underlying etiology. Asymptomatic pulmonary emboli are present in at least 50% of these patients. We believe it is important to identify PE early, since up to 25% will subsequently become symptomatic, manifesting as pleuritic chest discomfort once the inﬂammatory pulmonary process reaches the pleural surface.58 If the PE is not recognized, clinicians often mistakenly assume that the pleuritic symptoms are due to a new PE and failure of treatment. A spiral computed tomography (CT) scan of the chest with contrast evaluates the pulmonary vasculature for PE and other thoracic pathology. The CT is extended to the abdomen and pelvis to identify the proximal extent of thrombus and to evaluate for abdominal or pelvic pathology (Fig. 20.2). This has been an important addition to the evaluation of these patients as we have found pathology not previously diagnosed with surprising frequency. Renal cell carcinoma, adrenal tumors, retroperitoneal lymphoma, pulmonary adenocarcinoma, hepatic metastases, iliac vein aneurysms, and vena caval atresia have been identiﬁed. A full hematologic evaluation for an underlying thrombophilia is also performed. The technique of catheter-directed thrombolysis has evolved over the past several years. Our preferred approach is generally through an ultrasound-guided popliteal vein puncture with antegrade passage of the infusion catheter. Patients who have distal popliteal vein and tibial vein thrombosis are now approached through ultrasound-guided posterior tibial or anterior tibial vein access. Adjunctive mechanical techniques are routinely used to shorten the duration of lysis and speed clot resolution. The dose and volume of the plasminogen activator delivered has also evolved. Since the activation of ﬁbrin-

(b) Figure 20.2 A 65-year-old man with chronic low back pain presented with left lower extremity phlegmasia cerulea dolens. A chest computed tomography (CT) scan (a) reveals an asymptomatic pulmonary embolism (arrow), whereas the abdominal CT (b) shows extensive retroperitoneal and pelvic lymphadenopathy (arrows) compressing the distal vena cava and left iliac system. Ao, aorta; VC, vena cava.

bound plasminogen is not dose dependent, its exposure to the plasminogen activator appears to be the most important factor. The volume of lytic solution has increased over the years with a decrease in the concentration (dose) of the plasminogen activator. It is now our preference to increase the volume of lytic infusion to 80–100 mL/hour. The larger volume is intended to saturate the thrombus, exposing more ﬁbrin-bound plasminogen to the plasminogen activator. Phlebograms are generally repeated at 12 hour intervals and are used to monitor the success of lysis and reposition the catheters as necessary. Vena caval ﬁlters are not routinely used but are recommended for patients with free-ﬂoating thrombus in

Pharmacomechanical thrombolysis

247

the vena cava. A retrievable ﬁlter can be used in patients for whom only temporary protection is required. Following successful thrombolysis, the venous system is examined with completion phlebography. If an underlying stenosis exists, which is frequently observed in the left common iliac vein where it is compressed by the right common iliac artery, the vein is dilated and stented as necessary. The addition of intravascular ultrasonography has improved the evaluation of iliac compression and the precision of stent deployment. Residual areas of stenosis must be corrected to achieve long-term success; otherwise, the patient faces a high risk of rethrombosis. If a stent is used, it should be sized appropriate to the projected normal diameter of the recipient vein.

PHARMACOMECHANICAL THROMBOLYSIS The adjunctive use of mechanical techniques is rapidly becoming the standard for catheter-based management of extensive venous thrombosis. Percutaneous mechanical thrombectomy alone is much less successful than catheterdirected thrombolysis and is associated with unacceptably high pulmonary embolic complications. A prospective evaluation of pulse-spray pharmacomechanical thrombolysis of thrombosed hemodialysis grafts found that PE occurred in 18% of patients treated with a plasminogen activator pulse-spray solution versus 64% of patients treated with a heparinized saline pulse-spray solution (P = 0.04).59 Since thrombosed hemodialysis grafts are in direct communication with the venous circulation, they can be considered similar to proximal veins with acute DVT. Observations would likely be magniﬁed when treating thrombosed veins larger than the 6 mm hemodialysis graft. In an experimental model, Greenberg and associates60 evaluated mechanical, pharmacomechanical, and pharmacologic thrombolysis. Their ﬁndings are consistent with anecdotal clinical observations as well as the results reported by Kinney et al.59 They reported that pulse-spray mechanical thrombectomy was associated with the largest number and greatest size of distal emboli. When UK was added to the solution, the embolic particles diminished in number and size and increased the speed of lysis and reperfusion. Catheter-directed thrombolysis alone was associated with the slowest reperfusion but the fewest distal emboli. In general, mechanical thrombectomy alone most often is inadequate. Although rheolytic pharmacomechanical techniques have been helpful in many patients in clearing a difﬁcult lesion, hemolytic complications are common and occasionally result in anemia and renal dysfunction. A new device recently released for isolated segmental and controlled pharmacomechanical thrombolysis is the re-engineered Trellis catheter (Bachus Vascular, Santa Clara, CA) (Fig. 20.3). This hybrid catheter isolates the thrombosed vein segment between two occluding

Figure 20.3 The Trellis-8 peripheral infusion system (Bacchus Vascular, Santa Clara, CA) delivers the lytic agent into thrombus segmented between two occluding balloons. A dispersion wire inserted into the center of the catheter assumes a spiral conﬁguration, dispenses the lytic agent, and mechanically macerates the thrombus. The resulting liqueﬁed and small particulate thrombus is then aspirated, minimizing or avoiding any systemic lytic effect.

balloons. A lytic agent is infused into the thrombus between the occluding balloons. The intervening catheter shaft then assumes a spiral conﬁguration which is then motor activated and spins at 1500 rpm. After 15–20 minutes, the liqueﬁed thrombus and remaining fragments are aspirated. Phlebographic evaluation of the result is performed before moving on to treat additional thrombosed vein segments. The advantages of such a device include its ability to incorporate mechanical and pharmacologic therapies and to treat patients who have traditional contraindications to thrombolytic therapy. Since the infusate is aspirated and the clot is more rapidly lysed, treatment times are signiﬁcantly shortened. We analyzed the results of the ﬁrst 14 patients treated with isolated segmental pharmacomechanical thrombolysis compared with the last 10 consecutive patients treated with standard catheter-directed thrombolysis (Table 20.7). There was signiﬁcantly more rapid lysis and less plasminogen activator was used. An interesting new adjunct to catheter-directed thrombolysis is the incorporation of ultrasound transducers into the infusion catheter (Fig. 20.4). Ultrasound waves generated during infusion of the plasminogen activator increases surface area of ﬁbrin and speeds lysis. Several reports have emerged indicating that an infusion catheter with ultrasound transducers built into the infusion end of the catheter can be used to accelerate thrombolysis.61–63 In vitro studies have demonstrated that ultrasound enhances the ﬁbrinolytic activity of plasminogen activator (t-PA).62,64,65 The potential mechanism for augmented clot lysis has been extrapolated from in vitro studies showing that ultrasound produces

248

Catheter-directed thrombolysis for treatment of acute deep vein thrombosis

Table 20.7 Results of patients treated with catheter-directed thrombolysis + Trellis versus catheterdirected thrombolysis alone

Outcome LOS days ICU days Rt-PA total (mg) Treatment time (hours) Overall lysis (%) Venoplasty (%) Stent (%) Hct Transfusions (%) Bleeding (%) Major (%) Minor (%)

(a)

Catheter-directed thrombolysis + Trellis n = 14

Catheter-directed thrombolysis n = 10

7.6 (±3.3) 2.9 (±1.64) 24.1 (±21.1) 17.6 (±17.6) 90 (±13.6) 86 57 –17.6 (±9.38) 21 21 7 14

8.3 (±2.1) 3.4 (±0.96) 54.8 (±31.5) 51.3 (±24.5) 84.5 (±14) 80 60 –20 (±14.4) 10 30 0 30

P 0.55 0.43 0.011 0.0007 0.35

0.62 0.42 0.59

(b)

Figure 20.4 The EKOS Lysus Infusion Catheter System (EKOS, Bothell, WA) showing ultrasound transducers incorporated into the infusion catheter to accelerate clot lysis.

clot fragmentation in the presence of t-PA, and, consequently, more t-PA binds to ﬁbrin binding sites because of the larger available surface area.66–68 The concept of a transducer tip catheter that delivers a ﬁbrinolytic drug in combination with high-frequency, low-intensity ultrasound has been well described. In vivo models69 and clinical trials70 are now under way to assess the potential value of ultrasound enhancement of thrombolytics for the management of acute DVT. The patient with phlegmasia cerulea dolens summarized in Figs 20.5–20.8 illustrates the advantage of using isolated segmental pharmacomechanical thrombolysis and

Figure 20.5 The patient’s left lower extremity shows the swelling and cyanosis characteristic of phlegmasia cerulea dolens.

ultrasound-enhanced catheter-directed thrombolysis to shorten treatment duration and limit exposure of the thrombolytic agent, thereby maximizing the chance of a successful outcome. In conclusion, current catheter-based thrombolytic techniques are more effective and are safer. As technology continues to improve, lytic infusion times will shorten, more patients will be offered a treatment strategy that includes thrombus removal, and many more patients will be spared their otherwise certain post-thrombotic morbidity. Our current treatment algorithm is summarized in Fig. 20.9.

Pharmacomechanical thrombolysis

(a)

(d)

(b)

(e)

249

(c)

(f)

Figure 20.6 (a–c) Phlebogram of the patient’s extensive left iliofemoral, femoropopliteal, and posterior tibial deep vein thrombosis. Segmental pharmacomechanical thrombolysis with the Trellis peripheral infusion system (Bacchus Vascular, Santa Clara, CA) was used to shorten treatment duration and minimize exposure to the lytic agent. (d) The Trellis catheter isolates the thrombus between two occluding balloons (arrows), conﬁning the plasminogen activator to the vein segment being treated. (e, f) Phlebogram reveals resolution of the iliofemoral thrombus after 30 minutes of treatment with the Trellis system.

250

(a)

(e)

Catheter-directed thrombolysis for treatment of acute deep vein thrombosis

(b)

(c)

(f)

Figure 20.8 The patient with phlegmasia cerulea dolens of the left lower extremity at 16 months’ follow-up after treatment with pharmacomechanical thrombolysis.

(d)

Figure 20.7 (a) The EKOS LysUS System (EKOS, Bothell, WA) is an ultrasonic infusion system designed to accelerate thrombolysis while reducing treatment time. The catheter was advanced proximally from an ultrasound-guided posterior tibial vein puncture. (b) Phlebogram showing popliteal vein thrombus. (c) Post-ultrasound lysis, dissolution of thrombus in the distal femoral vein, (d) popliteal vein, and (e) posterior tibial vein. (f) Angioplasty and stenting were performed on the left iliac vein, establishing normal venous drainage into the inferior vena cava.

Pharmacomechanical thrombolysis

251

Iliofemoral DVT Immediate anticoagulation

Rapid CT scan with contrast

Leg elevation Long leg compression

Chest Abdomen Pelvis

Patient physically active

No

Anticoagulation* plus compression

Yes

Strategy of thrombus removal*

Contraindication to thrombolysis

No

Yes

PM thrombolysis and/or CD thrombolysis

Venous thrombectomy or segmental PM thrombolysis (Trellis catheter)

Correct underlying venous lesions

Figure 20.9 Algorithm of our current treatment protocol for patients with iliofemoral deep vein thrombosis (DVT). *Vena caval ﬁlter for free-ﬂoating vena caval thrombus.

Guidelines 3.4.0 of the American Venous Forum on catheter-directed thrombolysis for treatment of acute deep venous thrombosis No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.4.1 In patients with symptomatic deep vein thrombosis and large thrombus burden, particularly in iliofemoral deep vein thrombosis, we suggest a treatment strategy that includes thrombus removal

2

B

3.4.2 In selected patients with iliofemoral deep vein thrombosis with symptoms < 14 days’ duration we suggest catheter-directed thrombolysis, if appropriate expertise and resources are available, to reduce acute symptoms and post-thrombotic morbidity

2

B

3.4.3 We suggest pharmacomechanical thrombolysis, with thrombus fragmentation and aspiration, over catheter-directed thrombolysis alone in the treatment of iliofemoral deep vein thrombosis to shorten treatment time, if appropriate expertise and resources are available

2

B

3.4.4 In selected patients with iliofemoral deep vein thrombosis with symptoms < 14 days’ duration we suggest systemic thrombolysis as an alternative to catheter-directed thrombolysis, if appropriate expertise and resources are available, to reduce acute symptoms and post-thrombotic morbidity

2

B

252

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◆14.

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15.

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4.

●5.

●6.

●7.

8.

9.

●10.

●11.

◆12.

13.

Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 Suppl): 401S–28S. Berridge DC, Gregson RH, Hopkinson BR, Makin GS. Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis. Br J Surg 1991; 78: 988–95. Alkjaersig N, Fletcher AP, Sherry S. The mechanism of clot dissolution by plasmin. J Clin Invest 1959; 38: 1086–95. O’Donnell TF, Browse NL, Burnand KG, Thomas ML. The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res 1977; 22: 483–8. Akesson H, Brudin L, Dahlstrom JA, et al. Venous function assessed during a 5 year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 1990; 4 (1):43–8. Delis KT, Bountouroglou D, Mansﬁeld AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004; 239 (1):118–26. Shull KC, Nicolaides AN, Fernandes é Fernandes J, et al. Signiﬁcance of popliteal reﬂux in relation to ambulatory venous pressure and ulceration. Arch Surg 1979; 114: 1304–6. Nicolaides AN, Schull K, Fernandes E. Ambulatory venous pressure: new information. In: Nicolaides AN, Yao JS, editors. Investigation of Vascular Disorders. New York: Churchill Livingstone, 1981: 488–94. Johnson BF, Manzo RA, Bergelin RO, Strandness DE, Jr. Relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995; 21: 307–12. Cho JS, Martelli E, Mozes G, Miller VM, Gloviczki P. Effects of thrombolysis and venous thrombectomy on valvular competence, thrombogenicity, venous wall morphology, and function. J Vasc Surg 1998; 28: 787–99. Rhodes JM, Cho JS, Gloviczki P, et al. Thrombolysis for experimental deep venous thrombosis maintains valvular competence and vasoreactivity. J Vasc Surg 2000; 31: 1193–205. Killewich LA, Bedford GR, Beach KW, Strandness DE, Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vasc Surg 1989; 9 (1): 89–97. Markel A, Manzo RA, Bergelin RO, Strandness DE, Jr. Valvular reﬂux after deep vein thrombosis: incidence and time of occurrence. J Vasc Surg 1992; 15: 377–82.

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Meissner MH, Manzo RA, Bergelin RO, et al. Deep venous insufﬁciency: the relationship between lysis and subsequent reﬂux. J Vasc Surg 1993; 18: 596–605. Browse NL, Thomas ML, Pim HP. Streptokinase and deep vein thrombosis. BMJ 1968; 3: 717–20. Robertson BR, Nilsson IM, Nylander G. Value of streptokinase and heparin in treatment of acute deep venous thrombosis. A coded investigation. Acta Chir Scand 1968; 134 (3): 203–8. Kakkar VV, Flanc C, Howe CT, et al. Treatment of deep vein thrombosis. A trial of heparin, streptokinase, and arvin. BMJ 1969; 1: 806–10. Tsapogas MJ, Peabody RA, Wu KT, et al. Controlled study of thrombolytic therapy in deep vein thrombosis. Surgery 1973; 74: 973–84. Duckert F, Muller G, Nyman D, Benz A, Prisender S, Madar G, et al. Treatment of deep vein thrombosis with streptokinase. BMJ 1975; 1: 479–81. Porter JM, Seaman AJ, Common HH, et al. Comparison of heparin and streptokinase in the treatment of venous thrombosis. Am Surg 1975; 41: 511–9. Seaman AJ, Common HH, Rosch J, et al. Deep vein thrombosis treated with streptokinase or heparin. A randomized study. Angiology 1976; 27: 549–56. Rosch J, Dotter CT, Seaman AJ, et al. Healing of deep venous thrombosis: venographic ﬁndings in a randomized study comparing streptokinase and heparin. Am J Roentgenol 1976; 127: 553–8. Marder VJ, Soulen RL, Atichartakarn V, et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018–29. Arnesen H, Heilo A, Jakobsen E, et al. A prospective study of streptokinase and heparin in the treatment of deep vein thrombosis. Acta Med Scand 1978; 203: 457–63. Elliot MS, Immelman EJ, Jeffery P, et al. A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. Br J Surg 1979; 66: 838–43. Watz R, Savidge GF. Rapid thrombolysis and preservation of valvular venous function in high deep vein thrombosis. A comparative study between streptokinase and heparin therapy. Acta Med Scand 1979; 205 (4): 293–8. Jeffery P, Immelman EJ, Amoore J. Treatment of deep vein thrombosis with heparin or streptokinase: long-term venous function assessment. Proc Sec Int Vasc Symp London: 1986. Turpie AG, Levine MN, Hirsh J, et al. Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Results of a randomized trial. Chest 1990; 97 (4 Suppl): 172S–5S. Goldhaber SZ, Meyerovitz MF, Green D, et al. Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis. Am J Med 1990; 88 (3): 235–40.

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30. Albrechtsson U, Anderson J, Einarsson E, et al. Streptokinase treatment of deep venous thrombosis and the postthrombotic syndrome. Follow-up evaluation of venous function. Arch Surg 1981; 116 (1): 33–7. 31. van de Loo JC, Kriessmann A, Trubestein G, et al. Controlled multicenter pilot study of urokinase- heparin and streptokinase in deep vein thrombosis. Thromb Haemost 1983; 50: 660–3. 32. Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis. A prospective study. Am J Surg 1985; 150 (4A): 54–63. 33. Schulman S, Granqvist S, Juhlin-Dannfelt A, Lockner D. Long-term sequelae of calf vein thrombosis treated with heparin or low-dose streptokinase. Acta Med Scand 1986; 219: 349–57. ●34. Arnesen H, Hoiseth A, Ly B. Streptokinase of heparin in the treatment of deep vein thrombosis. Follow-up results of a prospective study. Acta Med Scand 1982; 211 (1–2): 65–8. ◆35. Bjarnason H, Kruse JR, Asinger DA, et al. Iliofemoral deep venous thrombosis: safety and efﬁcacy outcome during 5 years of catheter-directed thrombolytic therapy. J Vasc Interv Radiol 1997; 8: 405–18. ◆36. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheterdirected thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999; 211 (1): 39–49. ◆37. Comerota AJ, Kagan SA. Catheter-directed thrombolysis for the treatment of acute iliofemoral deep venous thrombosis. Phlebology 2000; 15: 149–55. 38. Verhaeghe R, Stockx L, Lacroix H, et al. Catheter-directed lysis of iliofemoral vein thrombosis with use of rt-PA. Eur Radiol 1997; 7: 996–1001. 39. Chang R, Cannon RO, III, Chen CC, et al. Daily catheterdirected single dosing of t-PA in treatment of acute deep venous thrombosis of the lower extremity. J Vasc Interv Radiol 2001; 12 (2): 247–52. 40. Castaneda F, Li R, Young K, et al. Catheter-directed thrombolysis in deep venous thrombosis with use of reteplase: immediate results and complications from a pilot study. J Vasc Interv Radiol 2002; 13: 577–80. 41. Sillesen H, Just S, Jorgensen M, Baekgaard N. Catheterdirected thrombolysis for treatment of ilio-femoral deep venous thrombosis is durable, preserves venous valve function and may prevent chronic venous insufﬁciency. Eur J Vasc Endovasc Surg 2005; 30: 556–62. 42. Semba CP, Dake MD. Iliofemoral deep venous thrombosis: aggressive therapy with catheter-directed thrombolysis. Radiology 1994; 191: 487–94. 43. Semba CP, Dake MD. Catheter-directed thrombolysis for iliofemoral venous thrombosis. Semin Vasc Surg 1996; 9 (1): 26–33. ●44. Comerota AJ, Throm RC, Mathias SD, et al. Catheterdirected thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg 2000; 32 (1): 130–7.

45. Horne MK, III, Mayo DJ, Cannon RO, III, et al. Intraclot recombinant tissue plasminogen activator in the treatment of deep venous thrombosis of the lower and upper extremities. Am J Med 2000; 108 (3): 251–5. 46. Kasirajan K, Gray B, Ouriel K. Percutaneous AngioJet thrombectomy in the management of extensive deep venous thrombosis. J Vasc Interv Radiol 2001; 12 (2): 179–85. 47. AbuRahma AF, Perkins SE, Wulu JT, Ng HK. Iliofemoral deep vein thrombosis: conventional therapy versus lysis and percutaneous transluminal angioplasty and stenting. Ann Surg 2001; 233: 752–60. 48. Vedantham S, Vesely TM, Parti N, et al. Lower extremity venous thrombolysis with adjunctive mechanical thrombectomy. J Vasc Interv Radiol 2002; 13: 1001–8. ●49. Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. Eur J Vasc Endovasc Surg 2002; 24 (3): 209–14. 50. Grunwald MR, Hofmann LV. Comparison of urokinase, alteplase, and reteplase for catheter-directed thrombolysis of deep venous thrombosis. J Vasc Interv Radiol 2004; 15: 347–52. 51. Laiho MK, Oinonen A, Sugano N, et al. Preservation of venous valve function after catheter-directed and systemic thrombolysis for deep venous thrombosis. Eur J Vasc Endovasc Surg 2004; 28: 391–6. 52. Jackson LS, Wang XJ, Dudrick SJ, Gersten GD. Catheterdirected thrombolysis and/or thrombectomy with selective endovascular stenting as alternatives to systemic anticoagulation for treatment of acute deep vein thrombosis. Am J Surg 2005; 190: 864–8. 53. Ogawa T, Hoshino S, Midorikawa H, Sato K. Intermittent pneumatic compression of the foot and calf improves the outcome of catheter-directed thrombolysis using low-dose urokinase in patients with acute proximal venous thrombosis of the leg. J Vasc Surg 2005; 42: 940–4. 54. Kim HS, Patra A, Paxton BE, et al. Adjunctive percutaneous mechanical thrombectomy for lower-extremity deep vein thrombosis: clinical and economic outcomes. J Vasc Interv Radiol 2006; 17: 1099–104. 55. Lin PH, Zhou W, Dardik A, et al. Catheter-direct thrombolysis versus pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis. Am J Surg 2006; 192: 782–8. 56. Shortell CK, Queiroz R, Johansson M, et al. Safety and efﬁcacy of limited-dose tissue plasminogen activator in acute vascular occlusion. J Vasc Surg 2001; 34: 854–9. 57. Meissner AJ, Mewissen M. Early outcome after catheterdirected thrombolysis for acute deep venous thrombosis: follow-up of a national multicenter registry. J Vasc Surg 2007. ●58. Monreal M, Rey-Joly BC, Ruiz MJ, et al. Asymptomatic pulmonary embolism in patients with deep vein thrombosis. Is it useful to take a lung scan to rule out this condition? J Cardiovasc Surg (Torino) 1989; 30 (1): 104–7.

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59. Kinney TB, Valji K, Rose SC, et al. Pulmonary embolism from pulse-spray pharmacomechanical thrombolysis of clotted hemodialysis grafts: urokinase versus heparinized saline. J Vasc Interv Radiol 2000; 11: 1143–52. 60. Greenberg RK, Ouriel K, Srivastava S, et al. Mechanical versus chemical thrombolysis: an in vitro differentiation of thrombolytic mechanisms. J Vasc Interv Radiol 2000; 11 (2 Pt 1): 199–205. 61. Steffen W, Fishbein MC, Luo H, et al. High intensity, low frequency catheter-delivered ultrasound dissolution of occlusive coronary artery thrombi: an in vitro and in vivo study. J Am Coll Cardiol 1994; 24: 1571–9. 62. Rosenschein U, Bernstein JJ, DiSegni E, et al. Experimental ultrasonic angioplasty: disruption of atherosclerotic plaques and thrombi in vitro and arterial recanalization in vivo. J Am Coll Cardiol 1990; 15: 711–7. 63. Tachibana K, Tachibana S. Ultrasound energy for enhancement of ﬁbrinolysis and drug delivery: special emphasis on the use of a transducer-tipped ultrasound system. In: Siegel RJ, ed. Ultrasound Angioplasty. Boston: Kluwer, 1996: 121–33.

64. Trubestein G, Engel C, Etzel F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976; 3: 697s–8s. 65. Ariani M, Fishbein MC, Chae JS, et al. Dissolution of peripheral arterial thrombi by ultrasound. Circulation 1991; 84: 1680–8. 66. Lauer CG, Burge R, Tang DB, et al. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992; 86: 1257–64. 67. Hong AS, Chae JS, Dubin SB, et al. Ultrasonic clot disruption: an in vitro study. Am Heart J 1990; 120: 418–22. 68. Drobinski G, Brisset D, Philippe F, et al. Effects of ultrasound energy on total peripheral artery occlusions: initial angiographic and angioscopic results. J Interv Cardiol 1993; 6 (2): 157–63. 69. Atar S, Luo H, Nagai T, Siegel RJ. Ultrasonic thrombolysis: catheter-delivered and transcutaneous applications. Eur J Ultrasound 1999; 9 (1): 39–54. 70. EKOS Corporation, Bothell, WA. Retrospective evaluation of thrombolysis with EKOS Lysus System. 2005.

21 Surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral venous thrombosis BO EKLÖF AND ROBERT B. MCLAFFERTY Introduction Rationale for early thrombus removal Pathophysiological changes associated with deep vein thrombosis Diagnosis

255 255 256

Indications for intervention Summary Evidence-based recommendations References

257 261 262 263

257

INTRODUCTION The options for early removal of an acute thrombus in the proximal veins of the leg are1 catheter-directed thrombolysis (CDT),2 percutaneous mechanical thrombectomy (PMT), and surgical thrombectomy (TE).3 In the previous chapter the ﬁrst option is addressed. In this chapter we will propose that if CDT fails or is contraindicated, surgical TE or PMT ± CDT is a valid alternative, primarily in acute iliofemoral vein thrombosis (IFVT). The techniques and results of these procedures are also presented.

RATIONALE FOR EARLY THROMBUS REMOVAL When deep vein thrombosis (DVT) occurs, the goals of therapy are1 to prevent the extension or recurrence of the deep venous thrombus and fatal pulmonary embolism (PE) and2 minimize the early and late sequelae of DVT. Antithrombotic therapy can accomplish the former (Chapter 19), but contributes little to the second goal. Particularly in proximal DVT, i.e., IFVT, progressive swelling of the leg can lead to a condition known as phlegmasia cerulea dolens (literally, painful blue swelling), and to increased compartmental pressure which can progress to venous gangrene and limb loss. Later, the development of severe post-thrombotic syndrome (PTS) can result from persistent obstruction of the venous outﬂow and/or loss of valvular competence, and

pulmonary embolism can lead to chronic pulmonary hypertension. Most clinicians seem to focus on the initial treatment, i.e., preventing PE, the propagation of the thrombus or DVT recurrence, with little attention to the limb sequelae, possibly swayed by the medical literature which demonstrates, in randomized clinical trials (RCTs) that antithrombotic therapy, particularly low-molecularweight heparin (LMWH), can achieve these goals. There is a lack of appreciation that the end-points of these RCTs has not been prevention of post-thrombotic sequelae. However, two RCTs have compared the late outcome several years after acute, symptomatic proximal DVT in patients who wore compression stockings with those who did not.1,2 Both studies, one performed with custom-made thigh-length stockings and one using calf-length, readymade stockings, showed that consequent wearing of stockings could reduce the frequency of a post-thrombotic syndrome to one-half. Partsch et al.3 performed an RCT in 53 patients with proximal DVT, comparing bed rest without compression with walking exercises using either compression stockings or bandages, all undergoing anticoagulation with LMWH. At follow-up after 2 years a signiﬁcantly better outcome could be found in the mobile group than in the bed rest group judged by the Prandoni scale (median score 5.0 vs 8.0, P < 0.01). Furthermore, there is apparently also a lack of appreciation of the different natural history of IFVT compared with more distal DVT, as well as a lack of understanding of the

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different pathophysiologic changes that occur with time following DVT and their relative contribution to the pathogenesis and severity of the post-thrombotic sequelae. These will be reviewed in this chapter, to provide a selective basis for the decision to opt for early thrombus removal.

PATHOPHYSIOLOGICAL CHANGES ASSOCIATED WITH DEEP VEIN THROMBOSIS The clinical outcome after DVT can be categorized into four basic patient subgroups: those with neither detectable obstruction or valvular incompetence, those with obstruction alone, those with valvular incompetence alone, and those with both outﬂow obstruction and distal valvular incompetence. Non-invasive testing4 has shown that less than 20% of those with documented DVT have neither signiﬁcant obstruction nor reﬂux. In a 5 year follow-up of 20 patients treated with anticoagulation alone in a Swedish prospective, randomized study in acute IFVT5 there was residual iliac vein obstruction in 70% and valvular incompetence and pathological muscle pump function in all patients, creating severe venous hypertension and contributing to the severity of the postthrombotic sequelae. However, the overall outcome of DVT, in terms of disturbed venous physiology, depends to a great degree on the location of the thrombosed segments and the extent of involvement, i.e., single or multiple segments. The former relates to the likelihood of recanalization of the thrombosed segment, which, in the lower extremity, decreases as one moves proximally. Venographic studies, which were only commonly performed in the 1950s and 1960s, showed that close to 95% of popliteal or tibial thromboses recanalize completely,6 and at least 50% of femoral venous thrombosis recanalize.7 In contrast, the minority of iliofemoral thromboses (less than 20%) completely recanalize and form a normal, unobstructed lumen.8 However, although it is true that only 20% of the iliac vein segments involved in IFVT completely recanalize spontaneously, another 60% partly recanalize, or at least develop adequate enough collaterals that they do not test positive for obstruction on non-invasive study. Thus, in reality, only about 20% remain signiﬁcantly enough occluded and/or have such poor collaterals to produce symptomatic venous outﬂow obstruction detectable on non-invasive physiologic testing, if time (3–6 months) is allowed for complete resolution. Nevertheless, a signiﬁcant degree of obstruction persists for these 3–6 months in the majority of patients with iliofemoral venous thrombosis. What is not well appreciated is that persisting proximal obstruction, even if it is ultimately relieved by partial recanalization and/or collateral development, can lead to progressive breakdown of distal valves, resulting in reﬂux. This is important because, if the distal venous valves (and particularly those in the popliteal vein) remain competent,

the post-thrombotic sequelae are relatively modest, and controllable by conservative measures.9 The severity of post-thrombotic sequelae correlates with the level of ambulatory venous pressure (AVP), as shown by Nicolaides et al.10 It is impressive how steadily the frequency of ulceration climbs with increasing levels of AVP. It suggests that anything that signiﬁcantly reduces AVP will reduce the severity of the post-thrombotic sequelae, and vice versa. Nicolaides and Sumner11 have also shown that the highest levels of AVP are found in patients with both obstruction and reﬂux. These two observations underscore a major point to be made in regard to the disturbed pathophysiology associated with iliofemoral venous thrombosis and the pathogenesis of post-thrombotic sequelae. Obstruction alone is rarely sufﬁcient to cause venous claudication and mostly causes increased swelling with activity. Valvular incompetence alone causes most of the “stasis sequelae” (pigmentation, lipodermatosclerosis, and ulceration), but these too can be managed, in the compliant patient, with elastic stockings and elevation. However, those with both obstruction and valvular incompetence have severe post-thrombotic sequelae, so severe that conservative management is difﬁcult even in a compliant patient. The importance of the proximal obstruction for the development of distal valvular incompetence has been carefully studied by Strandness and his group. In a series of articles they have shown the following: from 20% to 50% of initially uninvolved distal veins become incompetent by 2 years; the combination of reﬂux and obstruction, as opposed to either alone, correlated with the severity of symptoms was present in 55% of symptomatic patients; 25% of all venous segments developed reﬂux in time, of which 32% were documented to not have been previously involved with thrombosis; and ﬁnally, in a study of the posterior tibial veins located below a popliteal segment involved with thrombosis, 55% of the distal veins became incompetent if the segment remained obstructed, compared with 7.5% of those below a popliteal vein that recanalized.12 These changes in the distal veins occur early enough that they cannot be blamed on proximal valvular reﬂux, although this also comes into play with time. Thus, it would appear that the early relief of obstructing thrombus, by thrombolysis or thrombectomy, should prevent more extensive post-thrombotic sequelae if only by protecting the distal veins against progressive valvular incompetence. This is a point that has not been well recognized not only in terms of basic pathogenesis but in judging the results of thrombolysis and thrombectomy, where critics have largely ignored the restoration of proximal patency while focusing on the presence or absence of valve reﬂux. Another aspect of the importance of early thrombus removal are the new data appearing on the inﬂammatory response to DVT. Thomas Wakeﬁeld and his group in Ann Arbor (Chapter 8) have shown that the leukocyte adhesion molecule – P-selectin – activates the leukocytes emigrating

Indications for intervention 257

into the venous wall, creating an inﬂammation that destroys the venous wall and the valves. John Harris13 and his group from Stanford showed in another experimental model that if the thrombus was removed early, the inﬂammatory changes were reversible. Finally, although modern venous reconstructive valvuloplasty can achieve good long-term results in primary venous disease with severe reﬂux, the results of vein segment transfer and autologous vein transplantation in secondary (i.e., post-thrombotic) venous disease are much less promising.14 Therefore, there are less suitable late interventions for the venous derangements typically seen in patients with severe PTS. The common mistake is for clinicians to treat all DVT patients with anticoagulation only, and belatedly refer those who complain of severe pain and swelling during follow-up for consideration of thrombolysis or thrombectomy – too late for them to achieve their goals. The conclusions from this and all the other studies cited above are clear: early removal of the thrombus conveys signiﬁcant beneﬁts, and the earlier the removal, the better the outcome.

longevity to prevent or mitigate potentially severe late post-thrombotic sequelae and (2) in those with massive swelling and phlegmasia cerulea dolens to mitigate early morbidity and prevent progression to venous gangrene. Older patients, with signiﬁcant intercurrent disease and serious comorbidities, who are unlikely to be active and live a long life, or those with distal (popliteal or calf vein) thrombosis, should be treated by anticoagulant therapy. Late post-thrombotic sequelae are not likely to be an issue with them. However, even these patients, if faced with the threat of venous gangrene, may deserve prompt clot removal. In terms of the choice of method of clot removal, CDT is an appropriate choice by removing the obstructing thrombus and thereby preserving valve function, though the latter has been presumed rather than proven. Techniques and their results are fully discussed in the previous chapter (Chapter 20). If CDT cannot be achieved, clot removal or dissolution is unsuccessful or does not progress satisfactorily, or the concomitant anticoagulation is contraindicated (e.g., IFVT in young women in the peripartum period, or in certain postoperative or trauma patients) then surgical TE or PMT ± CDT is an appropriate choice.

DIAGNOSIS Whether DVT is suspected on the basis of pain, discoloration or swelling of one leg, or in search of a source for pulmonary embolism, the diagnosis can be conﬁrmed with accuracy by duplex scanning using color ﬂow imaging (Chapter 12). Clinical signs are more likely to be present in proximal DVT, i.e, IFVT, but in bedridden patients there may be no apparent swelling and the ﬁrst signs may be those of PE (pleuritic chest pain, shortness of breath, and/or hemoptysis). Duplex scanning should interrogate not only the femoral and popliteal veins but the iliac and calf veins as well; otherwise 30% of DVT will be missed. Venography is mainly used now when catheter-directed interventions or surgical TE are indicated to guide and monitor them. Standard ascending venography using foot vein injection may miss isolated iliac vein thrombosis unless an adequate contrast load is infused (Chapter 15). In cases of IFVT, with extension into the iliac vein without visualization of the upper end of the thrombus, a femoral venogram from the contralateral side is performed to visualize the inferior vena cava and determine the upper extent of thrombus extension. An alternative to the conventional venogram is a CT venogram, particularly if this is indicated for diagnosis of PE.

INDICATIONS FOR INTERVENTION Early clot removal has clear beneﬁt in two categories of patients with IFVT, falling at the two ends of the clinical spectrum: (1) in active healthy patients with good

Surgical thrombectomy The ﬁrst TE for IFVT was performed by Läwen in Germany in 1937.15 Surgery today is performed under general intubation anesthesia with 10 cm PEEP added during manipulation of the thrombus to prevent perioperative PE. The involved leg, contralateral groin, and abdomen are prepared. A cell-saver is used to minimize blood loss. A longitudinal incision is made in the groin to expose the great saphenous vein (GSV), which is followed to its conﬂuence with the common femoral vein (CFV), which is dissected up to the inguinal ligament. The superﬁcial femoral artery is cleared 3–4 cm below the femoral bifurcation for construction of the arteriovenous ﬁstula (AVF). In primary IFVT, where the thrombus originates in the iliac vein with subsequent distal progression of the thrombus, a longitudinal venotomy is made in the CFV and a venous Fogarty TE catheter is passed upward through the thrombus into the IVC. The balloon is inﬂated and withdrawn, these maneuvers being repeated until no more thrombotic material can be extracted. With the balloon left inﬂated in the common iliac vein, a suction catheter is introduced to the level of the internal iliac vein to evacuate thrombi from this vein. Backﬂow is not a reliable sign of thrombus clearance since a proximal valve in the external iliac vein may be present in 25% of cases preventing retrograde ﬂow in a cleared vein. On the other hand, backﬂow can be excellent from the internal iliac vein and its tributaries despite a remaining occlusion of the common iliac vein. Therefore, an intraoperative completion venogram is mandatory. An

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alternative is the use of an angioscope, which enables removal of residual thrombus material under direct vision, or intravascular ultrasound (IVUS). In early cases, the distal thrombus is usually readily extruded through the venotomy by manual massage of the leg distally, starting at the foot. The Fogarty venous catheter, with soft ﬂexible tip, can sometimes be advanced in retrograde fashion without signiﬁcant trauma. The aim is to remove all fresh thrombi from the leg. The venotomy is closed with continuous suture and an AVF created using the saphenous vein, anastomosing it end-to-side to the superﬁcial femoral artery (for illustrations see Eklöf and Rutherford12). An intraoperative venogram is performed through a catheter inserted in a branch of the AVF. After a satisfactory completion venogram the wound is closed in layers and a closed suction drain is placed in the wound to evacuate blood and lymphatic ﬂuid that may accumulate after the operation. In IFVT secondary to ascending thrombosis from the calf, the thrombus in the femoral vein may be old and adherent to the venous wall. In such case the chance of preserving valve function has been already lost and the opportunity to restore patency signiﬁcantly diminished. A femoral segment without functioning valves will lead to distal valve dysfunction in time, much as will failure to achieve proximal patency. However, a patent iliac venous outﬂow plus a competent profunda collateral system will most of the time achieve normal venous function. Therefore, if iliac patency is established but the thrombus in the femoral vein is too old to remove, it is preferable to ligate the femoral vein. If normal ﬂow in the femoral vein cannot be re-established, we recommend extending the incision distally and exploring the oriﬁces of the deep femoral branches. These are isolated and venous ﬂow is restored with a small Fogarty catheter. The femoral vein is then ligated distal to the profunda branches. In a 13 year follow-up after femoral vein ligation in this setting, Masuda et al.16 found excellent clinical and physiological results without PTS. Finally, if there is evidence of iliac vein compression on the completion venogram, which can occur in about 50% of left-sided IFVT, we recommend intraoperative endovenous iliac angioplasty and stenting. If phlegmasia cerulea dolens is the indication, because of the threat of impending venous gangrene, we start the operation with fasciotomy of the calf compartments in order to release the pressure and improve the circulation immediately. If there is extension of the thrombus into the IVC, the cava is approached transperitoneally through a subcostal incision. The IVC is exposed by deﬂecting the ascending colon and duodenum medially. Depending upon the venographic ﬁndings relative to the top of the thrombus, the IVC is controlled, usually just below the renal veins. The IVC is opened and the thrombus is removed by massage, especially of the iliac venous system, then if the femoral segment is involved, the operation is continued in the groin as described above. When laparotomy is contraindicated in patients in poor

condition, a retrievable caval ﬁlter can be introduced before the TE to protect against fatal PE. Heparin is continued at least 5 days postoperatively and warfarin is started the ﬁrst postoperative day and continued routinely for 6 months. The patient is ambulated the day after the operation wearing a compression stocking and is usually discharged after a week, to return after 6 weeks for closure of the ﬁstula. The objectives of a temporary AVF are to increase blood ﬂow in the thrombectomized iliac segment to prevent immediate rethrombosis, to allow time for healing of the endothelium and to promote development of collaterals in case of incomplete clearance or immediate rethrombosis of the iliac segment. Usually the AVF is performed between the saphenous vein and the superﬁcial femoral artery. A more distally placed AVF does not function well in our experience. A new percutaneous technique for ﬁstula closure was developed by Endrys et al.17 in Kuwait. Through a puncture of the femoral artery on the opposite, surgically untouched side a catheter is inserted and positioned at the ﬁstula level. Prior to release of a coil, an arteriovenogram can be performed to evaluate the patency of the iliac and caval veins, which is of prognostic value. More than 10% of patients have been shown to have signiﬁcant stenosis of the iliac vein remaining despite initial successful surgery. A percutaneous, transvenous angioplasty and stenting can be performed under the protection of the AVF which is closed 4 weeks later.

Complications and results of surgical thrombectomy One of the reasons that induced surgeons to abandon thrombectomy in the 1960s was the high mortality associated with early thombectomy. In our series of over 200 patients mortality was less than 1%. There were no cases of fatal PE in the perioperative period. In an RCT from Sweden18 perfusion lung scans were positive on admission in 45% of all patients, with additional defects seen after 1 and 4 weeks in the conservatively treated group, in 11% and 12% respectively, and in the thrombectomized group in 20% and 0% respectively. Tables with results from the literature are available in the latest edition of Vascular Surgery.12 In the RCT from Sweden where TE was combined with a temporary AVF, 13% had early re-thrombosis of the iliac vein.19 In the Swedish RCT iliac vein patency at 6 months was 76% in the surgical group compared with 35% in the conservative group, demonstrated by venography.19 This signiﬁcant difference was upheld after 5 and 10 years with 77% and 83% patency in the surgical group, respectively, versus 30% and 41% in the conservative group, respectively.20,21 Femoropopliteal valvular competence at 6 months was 52% in the surgical group compared with 26% in the conservatively treated group, monitored by descending

Indications for intervention 259

venography with Valsalva, a signiﬁcant difference.19 After 5 years combining the results of all functional tests, 36% of the surgical patients had normal venous function compared with 11% of the conservatively treated group.20 These differences were not statistically signiﬁcant because of loss of patients. At 10 years using duplex scanning, popliteal reﬂux was found in 32% in the surgical group compared with 67% in the conservative group.21

New developments to improve surgical thrombectomy There has been a signiﬁcant improvement in the results of surgical TE with the understanding to immediately restore iliac vein outﬂow in patients with iliac vein obstruction as the major cause of their DVT. Control of iliac vein outﬂow immediately after TE can be achieved by intraoperative venogram, angioscopy, or IVUS. In the remaining obstruction, intraoperative endovenous angioplasty and stenting is recommended. Schwarzbach et al.22 report excellent results in 18 of 20 patients who maintained patency after 21 months’ follow-up. To improve patency and preservation of the valves in the deep veins of the leg Blättler et al.23 have combined TE of the iliac vein with thrombolysis applied under ischemic conditions to the leg veins. None of the 33 patients experienced clinically apparent recurrence within the ﬁrst year. Clinical signs of the post-thrombotic syndrome were absent in all but one patient. With improved outﬂow through the iliac system by angioplasty and stenting and increased inﬂow from the improved distal patency by regional thrombolysis, the temporary AVF may not be necessary. An excellent review of contemporary venous thrombectomy was published by Comerota and Gale in 2006.24

Percutaneous mechanical thrombectomy The use of PMT devices in combination with pharmacologic thrombolytic therapy has become the preferred means of rapid dissolution and removal of venous thrombus. Percutaneous mechanical thrombectomy offers many advantages over traditional TE and CDT. Current PMT devices can now be complimented with simultaneous lytic therapy, which uses lower doses of drug. This in turn obviates the need for prolonged CDT, thereby decreasing the risk of bleeding. Additionally, patients treated with PMT avoid the morbidity of open operation and its associated risks. Acute DVT in the iliofemoral and femoral–popliteal vein distribution should respond promptly to PMT in combination with simultaneous lytic therapy. Goals include rapid restoration of venous ﬂow, decreased risk of PE, prompt improvement in pain and edema, preservation of venous valvular function, discovery and endovascular management of

obstructing lesions, and prevention of post-thrombotic symptoms.

Percutaneous mechanical thrombectomy devices and techniques There are two devices primarily used for PMT in combination with simultaneous lytic therapy for DVT. These include the Power-Pulse Angiojet (Possis, Minneapolis, MN) and the Trellis-8 (Bacchus Vascular, Santa Clara, CA). Both devices are unique in their design and differ markedly in their mode of action. Recently, a third novel device has been developed and is available for endovascular treatment of DVT. The device, made by Ekos (Bothell, Washington), consists of an infusion wire that can simultaneous emit ultrasound energy. All three of these devices are approved by the United States Food and Drug Administration. What follows is a description of each device and the following section will review the small amount of clinical data surrounding these devices for treatment of DVT. The Power-Pulse Angiojet system, a technique originally described by Allie et al.25 for use in the peripheral arterial system, represents a simple modiﬁcation of the Angiojet PMT catheter. The Angiojet catheter system consists of a drive unit, a pump set, and the different types of catheters. The company manufacture seven types of catheters that all function in the same basic way, but vary according to the diameter of thrombus that can be treated, wire and size capabilities, overall lengths, and added characteristics to improve crossing ability. The Angiojet relies on the Bernoulli principle for its mechanism of action. This principle essentially states that as speed increases, pressure decreases, and a vacuum is created. The Angiojet creates the Bernoulli effect by powering saline jets from the tip of the inside of the catheter in a retrograde fashion at approximately half the speed of sound (8–10 000 psi), thus creating a low-pressure zone along the side holes of the catheter. Thrombus is drawn into the jets through the side holes and becomes mechanically fragmented into microscopic pieces. These fragments are then evacuated through the efﬂuent portion of the catheter. Angiojet catheters require a wire traversing the thrombus. As thrombus is evacuated, the drive unit measures the amount of ﬂuid evacuated. Typically not more than 500 cm3 should be evacuated during one treatment. Approximately half of the efﬂuent lost represents blood loss (not thrombus) from the patient. Additionally, as blood is also drawn into the catheter, erythrocyte lysis occurs, and free hemoglobin enters the circulation. The kidneys clear the free hemoglobin and the urine may become brown to black in color. Caution should be exercised in patients with renal impairment. Hemolysis from the angiojet in these patients has been associated with pancreatitis.26 All patients should be well hydrated prior to PMT by the Angiojet. Fig. 21.1a,b

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(a)

(b)

Figure 21.1 (a) Saline jets powered at half the speed of sound (8–10 000 psi) to create a low-pressure zone. (b) Thrombus is drawn into the catheter where it is fragmented by the jets and evacuated from the body.

illustrates the action of the Angiojet without using the power-pulse spray technique. The power-pulse spray technique incorporates the use of a lytic drug to the Angiojet system. For example, instead of providing the Angiojet with saline jets, the drive unit can be loaded with 100 cm3 of water that is mixed with tissue plasminogen activator (tPA) (typically 5–15 mg). A three-way stopcock attached to the efﬂuent channel on the pump set is turned to the closed position, preventing ﬂuid evacuation by the catheter. With wire across the thrombus, the Angiojet is then methodically brought though the thrombus in a stepwise progression. After every 1–2 cm, the pump drive is activated by intermittently depressing the foot pedal and the water/tPA mixture is driven into the thrombus under high pressure. After the thrombus has been treated by power pulsation, a wait time of approximately 20–30 minutes is recommended for lytic activation. The drive unit is then reloaded with a liter of saline, the efﬂuent channel is opened, and the Angiojet is used in its standard fashion to remove thrombus that is presumably “softened” and has partially undergone thrombolysis. The Trellis-8 device uses a completely different method of PMT in combination with a lytic drug. Whereas the Angiojet can be used with or without a lytic drug, the Trellis-8 is speciﬁcally designed to use a lytic drug in

combination with PMT. The device comes as one unit comprising an 8 French catheter, battery-powered motor drive unit attached to the catheter, occlusion balloon ports, an infusion port, and a suction port (Fig. 21.2). The device kit also comes with a stiff sinusoidal wire that facilitates clot mixing and maceration with lytic drug and syringes that are speciﬁcally labeled and designed for each port. Brieﬂy, after crossing thrombus with a 0.09 cm guidewire, the catheter is positioned in such a way as to conﬁne DVT between the two occlusion balloons. The proximal and distal balloons are inﬂated with a salinecontrast mixture using ﬂuoroscopy. Balloon inﬂation can treat 5–16 mm veins and usually this translates to the opportunity to treat DVT from the common iliac vein to the popliteal vein. Trellis-8 treatment catheters come in 15 cm and 30 cm treatment zone lengths. Once the proximal and distal balloons are inﬂated, the guidewire is removed and a stiff “sinusoidal” wire is inserted through the same end port. This sinusoidal wire connects to the drive unit, which is attached to the catheter. Lytic drug is infused incrementally through side holes between the two balloons. The drive unit spins the stiff sinusoidal wire up to 3000 rpm to mechanically mix the lytic drug with the acute thrombus. Another interesting feature of the drive unit is that it has the capability of switching the nodes a full wavelength on the sinusoidal wire. This further facilitates thorough vessel wall contact with the lytic drug along the entire length of the designated treatment zone. Theoretically, the advantage of the Trellis-8 is the use of a lower dose of lytic drug that is focally applied to the thrombus and prevented from becoming systemic because of the occlusion balloons. Furthermore, the clot and its maceration into pieces is contained between the two

BA

LL

IN

OO

FU

N

O SI

BA

AS

P IR

O AT

AS

PI

TI RA

LL

N

S LI EL TR

N

-2

ON

Figure 21.2 Trellis-8 device manufactured by (Bacchus Vascular, Santa Clara, CA). Note the balloon, infusion, and aspiration ports.

OO

N

Evidence-based recommendations 261

balloons thus preventing possible PE during the mechanical action of the catheter. Between each of two or three treatments over 10 minutes, the proximal balloon is deﬂated and suction is manually applied with a large airtight interlocking syringe that pulls ﬂuid and small pieces of clot through a hole in the catheter that is just proximal to the distal balloon. Again, in the venous system, this facilitates prevention of clot debris moving to the central circulation prior to the restoration of ﬂow with deﬂation of the distal balloon. Additionally, contrast can be injected through the same port used for the lytic drug. This can provide a more evenly distributed contrast load through a low-pressure system. The Lysus Peripheral Infusion System uses a completely different technology to “mechanically” disseminate lytic drug more effectively into thrombus. The system utilizes a multi side-port lytic drug infusion catheter system in combination with a simultaneous high-frequency, lowpower ultrasound core wire. A series of tiny ultrasound transducers placed evenly along the length of the wire ensure an even distribution of ultrasound waves. The catheter can treat thrombus up to 50 cm in length. The theory behind the added beneﬁts of ultrasound to an infusion catheter is multifold. First, high-frequency, low-power ultrasound provides increased micropermeability of the lytic drug into thrombus by loosening the ﬁbrin bonds. This, in turn, further exposes plasminogen activation receptor sites. The use of ultrasound energy transmitted simultaneously through the wire translates into further drug penetration behind venous valves and decreases overall infusion times with equal effectiveness of clot dissolution.

had follow-up for a mean of 5.3 months of which two experienced symptoms of leg swelling. Another series published by Bush et al.28 examined the safety and feasibility of the Angiojet power pulse technique for the treatment of symptomatic DVT in 20 patients (23 limbs). Sixty-ﬁve percent of limbs had complete removal of thrombus and the remaining 35% had partial removal. The mean age of thrombus from time of diagnosis with duplex was 14 days (range 0–34 days). Catheter-directed thrombolysis was performed in all patients with partial removal of DVT, with improved results in all patients and an average of 5.7 hours in duration. Seventeen patients were noted to have improved clinical symptoms within 24 hours. The mean follow-up was 10.2 months with three patients having recurrent ipsilateral DVT. Clinical publications related to the Trellis device are limited to case reports only. The treatment of iliofemoral thrombosis and axillosubclavian thrombosis are reported with good results with very limited follow-up.29,30 Data regarding the use of the ultrasound wire and infusion system made by Ekos is limited to the treatment of ischemic stroke.31 There are still many unanswered questions about the optimal use of PMT in combination with lytic therapy. The window for successful treatment, overall thrombus burden, concomitant anticoagulation use, and interplay of comorbidities affecting patient selection remain important topics that must be addressed in clinical trials with adequate follow-up.

SUMMARY Clinical data and percutaneous mechanical thrombectomy Although the three aforementioned devices have FDA approval for the treatment of DVT, there remains a paucity of clinical data examining their effectiveness. Hence, evidence-based recommendations are difﬁcult to reach because of the lack of reasonable prospective or retrospective data and appropriate controls. Nevertheless, some knowledge can be gained from reviewing pertinent small case series thus far. Cynamon et al.27 ﬁrst described the power-pulse technique using the Angiojet for the treatment of iliofemoral DVT. In this retrospective series of 24 patients, 20 patients were diagnosed with acute iliofemoral DVT (< 14 days) and four were diagnosed with subacute iliofemoral DVT (> 14 days). Of the entire cohort, 12 had complete thrombus removal (> 90%), seven had substantial thrombus removal (50–90%), and ﬁve had partial thrombus removal (< 50%). Two of the four with subacute DVT required additional CDT. All patients had resolution of presenting symptoms and two patients required blood transfusion. Twenty-one patients

Acute iliofemoral deep venous thrombosis remains a severely debilitating problem. Prevention of the extension of thrombus, PE, and the post-thrombotic syndrome remain the primary objectives in treating these patients. More and more data now show that early removal of thrombus has a better outcome for patients than anticoagulation alone. Multiple treatment modalities such as CDT and PMT are now available in addition to surgical thrombectomy. In the proper hands, percutaneous techniques for thrombus removal are becoming the ﬁrstline treatment, with durable outcomes being reported. More clinical trials are needed to assist in determining optimal patient selection to improve immediate success, limit complications, and provide long-term freedom from disease. Fig. 21.3 suggests a treatment algorithm for acute iliofemoral thrombosis.

EVIDENCE-BASED RECOMMENDATIONS The ACCP recommendations from 200432 for treatment of acute venous thromboembolism concerning early thrombus removal are listed below.

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Surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral venous thrombosis

●

Iliofemoral venous thrombosis Indications for early thrombus removal? Yes

●

Contraindications to thrombolysis ●

Yes

No No

Catheter access

In patients with DVT, the routine use of CDT is not suggested (Grade 2 C). Catheter-directed thrombolysis is suggested to selected patients with DVT, such as those requiring limb salvage (Grade 2 C). In patients with DVT, the routine use of venous thrombectomy is not recommended (Grade 2 C). In selected patients, such as patients with massive iliofemoral DVT at risk of limb gangrene secondary to venous occlusion, venous thrombectomy is suggested (Grade 2 C).

Yes PMT*/CDT No

Successful?

Surgical thrombectomy

Yes

Anticoagulation/compression

Anticoagulation/compression

Figure 21.3 Suggested algorithm for the treatment of acute iliofemoral deep venous thrombosis. *Percutaneous mechanical thrombolysis; †catheter-directed thrombolysis.

The recommendations from the 2006 International Consensus Statement: Guidelines according to scientiﬁc evidence33 are listed below. ●

●

●

●

●

In patients with DVT or PE the routine use of systemic thrombolytic treatment is not recommended (Grade 1A). In selected DVT patients, such as those with massive iliofemoral DVT at risk of limb gangrene secondary to venous occlusion, i.v. thrombolysis is suggested (Grade 2 C).

Catheter-directed thrombolysis should be considered for proximal DVT, especially in iliofemoral thrombosis, in active patients at low risk for bleeding. (Grade B). Systemic thrombolysis should be avoided. Surgical venous thrombectomy should be considered for patients with symptomatic iliofemoral DVT who are not candidates for CDT (Grade C). Data concerning the short- and long-term effects of catheter-based mechanical intervention on the vessel wall, venous valve, and pulmonary vasculature are lacking and are required before its role can be clearly deﬁned. This technique needs further short- and longterm evaluation and eventually randomized controlled trials before any recommendations can be made.

The recommendations from the 2006 guidelines are more positive for methods leading to early thrombus

Guidelines 3.5.0 of the American Venous Forum on surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral venous thrombosis No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.5.1 We suggest catheter-directed thrombolysis for proximal DVT, especially in iliofemoral thrombosis in active patients at low risk for bleeding. Systemic thrombolysis is not suggested

2

B

3.5.2 For patients with symptomatic iliofemoral deep vein thrombosis who are not candidates for catheter-directed thrombolysis we suggest surgical thrombectomy

2

C

3.5.3 For patients with massive iliofemoral deep vein thrombosis at risk of limb gangrene secondary to venous occlusion we recommend surgical thrombectomy

1

C

3.5.4 To shorten time for thrombolysis and rapidly decrease thrombus load, we suggest adding catheter-based mechanical thrombectomy to catheter-based thrombolysis for patients with iliofemoral deep vein thrombosis

2

C

References 263

removal. The Swedish RCT gives venous thrombectomy a Grade 1B recommendation, whereas the scientiﬁc evidence for percutaneous mechanical thrombectomy will need further studies.19 Based on these data, the American Venous Forum has adopted the recommendations 3.5.1–3.5.4 for percutaneous mechanical thrombectomy and surgical thrombectomy, in addition to Guidelines 3.4.1–3.4.4 (see Chapter 20).

15. 16.

17.

REFERENCES 18. = Key primary paper ◆ = Major review article ●

1. Brandjes DPM, Buller H, Hejboer H, et al. Incidence of the postthrombotic syndrome and the effects of compression stockings in patients with proximal venous thrombosis. Lancet 1997; 349: 759–62. 2. Prandoni P, Lensing AWA, Prins MH, et al. Below-knee elastic stockings to prevent the post-thrombotic syndrome. Ann Intern Med 2004; 141: 249–56. 3. Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute venous thrombosis reduces postthrombotic syndrome. Int Angiology 2004; 23: 206–12. 4. Lindner DJ, Edwards JM, Phinney ES, et al. Long-term hemodynamic and clinical sequelae of lower extremity deep vein thrombosis. J Vasc Surg 1986; 4:436. ◆5. Åkesson H, Brundin L, Dahlström JA, et al. Venous function assessed during a 5 year period after acute iliofemoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 1990; 4: 43–8. 6. Arenander E: Varicosity and ulceration of the lower limb: A clinical follow-up study of 247 patients examined phlebographically. Acta Chir Scand 1957; 12: 135. 7. Thomas ML, McAllister V. The radiological progression of deep venous thrombosis. Radiology 1971; 99: 37. 8. Mavor GE, Galloway JMD: Iliofemoral venous thrombosis: Pathological considerations and surgical management. Br J Surg 1969; 56: 45. 9. Schull KC, Nicolaides AN, Fernandes é Fernandes J, et al.: Signiﬁcance of popliteal reﬂux in relation to ambulatory venous pressure. Arch Surg 1979; 114: 1304. 10. Nicolaides AN, Hussein MK, Szendro G, et al. The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 1993; 17: 414. 11. Nicolaides AN, Sumner DS (eds). Investigation of Patients with Deep Vein Thrombosis and Chronic Venous Insufﬁciency. Los Angeles: Med-Orion Publishing, 1991. ◆12. Eklöf B, Rutherford RB. Surgical thrombectomy for acute deep venous thrombosis. In: Rutherford RB, ed., Vascular Surgery, 6th edition. Elsevier, Saunders, 2005: 2188–98. 13. See-Tho K, Harris EJ Jr. Thrombosis with outﬂow obstruction delays thrombolysis and results in chronic wall thickening of rat veins. J Vasc Surg 1998; 28: 115–22. 14. Kistner RL. Valve repair and segment transposition in primary valvular insufﬁciency. In: Bergan JJ, Yao JST, eds,

●◆19.

◆20.

◆21.

22.

23.

◆24.

25.

26.

27.

28.

29.

30.

Venous Disorders. Philadelphia: WB Saunders, 1991: 261–72. Läwen A. Uber Thrombectomie bei Venenthrombose und Arteriespasmus. Zentralbl Chir 1937; 64: 961–8. Masuda EM, Kistner RL, Ferris EB. Long-term effects of superﬁcial femoral vein ligation: thirteen-year follow-up. J Vasc Surg 1992; 16: 741–9. Endrys J, Eklöf B, Neglén P, et al. Percutaneous balloon occlusion of surgical arteriovenous ﬁstulae following venous thrombectomy. Cardiovasc Intervent Radiol 1989; 12: 226–9. Plate G, Ohlin P, Eklöf B. Pulmonary embolism in acute iliofemoral venous thrombosis. Br J Surg 1985; 72: 912. Plate G, Einarsson E, Ohlin P, et al. Thrombectomy with temporary arteriovenous ﬁstula: the treatment of choice in acute iliofemoral venous thrombosis. J Vasc Surg 1984; 1: 867–76. Plate G, Åkesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arteriovenous ﬁstula. Eur J Vasc Surg 1990; 4: 483–9. Plate G, Eklöf B, Norgren L, et al. Venous thrombectomy for iliofemoral vein thrombosis: 10-year results of a prospective randomized study. Europ J Endo Vasc Surg 1997; 14: 367–74. Schwarzbach MH, Schumacher H, Böckler D, et al. Surgical thrombectomy followed by intraoperative endovascular reconstruction for symptomatic iliofemoral venous thrombosis. Eur J Vasc Endovasc Surg 2005; 29: 58–66. Blättler W, Heller G, Largiadèr J, et al. Combined regional thrombolysis and surgical thrombectomy for treatment of iliofemoral vein thrombosis. J Vasc Surg 2004; 40: 620–5. Comerota AJ, Gale SS. Technique of contemporary iliofemoral and infrainguinal venous thrombectomy. J Vasc Surg 2006; 43: 185–91. Allie DE, Herbert CJ, Lirtzman MD, et al. Novel simultaneous combination chemical thrombolysis/rheolytic thrombectomy therapy for acute critical limb ischemia: the power-pulse spray technique. Cathet Cardiovasc Interv 2004; 63: 512–22. Danetz JS, McLafferty RB, Ayerdi J, et al. Pancreatitis caused by rheolytic thrombolysis: an unexpected complication. J Vasc Interv Radiol 2004; 15: 857–60. Cynamon J, Stein EG, Dym RJ, et al. A new method for aggressive management of deep vein thrombosis: retrospective study of the power pulse technique. J Vasc Interv Radiol 17: 1043–49. Bush RL, Lin RH, Bates JT, et al. Pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis: Safety and feasibility study. J Vasc Surg 2004; 40: 965–70. Ramaiah V, Del Santo PB, Rodriguez-Lopez JA, et al. Trellis thrombectomy system for the treatment of iliofemoral deep venous thrombosis. J Endovasc Ther 2003; 10: 585–9. Arko FR, Cipriano P, Lee E, et al. Treatment of axillosubclavian vein thrombosis: a novel technique for rapid removal of clot using low-dose thrombolysis. J Endovasc Ther 2003; 10: 733–8.

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31. Mahon BR, Nesbit GM, Barnwell SL, et al. North American clinical experience with Ekos MicroLysUS infusion catheter for the treatment of embolic stroke. Am J Neuroradiol 2003; 24: 534–8. ◆32. Buller HR, Agnelli C, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: The seventh ACCP

conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 401S–428S. ◆33. Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism: International consensus statement. (Guidelines according to scientiﬁc evidence). Int Angiol 2006; 25: 101–61.

22 Treatment algorithm for acute deep venous thrombosis: current guidelines THOMAS W. WAKEFIELD Incidence, risk factors, and categories Venous disease diagnosis Standard therapy for VTE Special features of low-molecular-weight heparin Alternative/future medical treatments for DVT/PE Aggressive therapies

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INCIDENCE, RISK FACTORS, AND CATEGORIES Deep vein thrombosis (DVT) remains a serious healthcare problem in the USA (see Chapter 17). Acquired risk factors for venous thromboembolism (VTE), DVT and pulmonary embolism (PE) include age (1000 times thrombosis difference in the very young vs the very old), malignancy (3–20% among those with venous thrombosis), surgery and trauma (up to 50–60% incidence without prophylaxis), immobilization (air ﬂight, incidence between 1/10 and 1/10 000), oral contraceptive use (4–8× increase), hormone replacement therapy (2–4× increase), pregnancy (10× increase) and the puerperium, obesity, neurological disease, cardiac disease, and antiphospholipid antibodies (10× increase).1 Genetic causes include deﬁciencies of natural coagulation inhibitors (antithrombin, proteins C and S; 10× increase), factor V Leiden (incidence up to 20% in an unselected and 50% in a selected population of patients with VTE; 3–8× increase in thrombosis with the heterozygous and 80× with the homozygous state), prothrombin 20210A (incidence up to 6% in a selected population of patients with venous thrombosis; 3× increase in thrombosis), blood group non-O (2–4× increase), hyperhomocysteinemia (5–10% of population: 2× increase in thrombosis), dysﬁbrinogenemia (incidence 3%), dysplasminogenemia (incidence < 1%), reduced heparin cofactor II activity, elevated levels of clotting factors such as factors XI, IX, VII, VIII, X, and II, and plasminogen activator inhibitor 1 (PAI-1, 2–3× increase).2

Inferior vena cava ﬁlters Non-pharmacological treatments Superﬁcial thrombophlebitis Algorithms Clinical guidelines References

271 271 272 272 272 274

Hematologic diseases associated with an increased incidence of VTE include disseminated intravascular coagulation (DIC), heparin-induced thrombocytopenia (HIT), antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. Venous thrombosis is associated with different hypercoagulable factors from arterial thrombosis, although there are factors shared between both. Arterial thrombosis is speciﬁcally associated with elevated levels of ﬁbrinogen, abnormal platelet aggregation, atherosclerosis, and elevated levels of lipoprotein(a). Venous thrombosis is most associated with factor V Leiden and prothrombin 20210A gene abnormalities, antithrombin deﬁciency, proteins C and S deﬁciencies, dysﬁbrinogenemias, and elevated coagulation factor levels. Both arterial and venous thrombosis can be associated with hyperhomocysteinemia, antiphospholipid antibodies, heparin-induced thrombosis, and elevated levels of PAI-1.2 For patients with arterial thrombosis, screening has been advocated for those with previous arterial thrombosis, arterial thrombosis and age < 50 (male) and < 55 (women), no signiﬁcant artery stenosis on imaging study, idiopathic thrombosis, and arterial thrombosis in the presence of a strong family history.3 For venous thrombosis, indications for screening include venous thrombosis in unusual locations (i.e., mesenteric venous, portal venous, etc.), idiopathic venous thrombosis, recurrent venous thrombosis, thrombosis while on oral

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Treatment algorithm for acute deep venous thrombosis: current guidelines

contraceptives, and episodes of aggressive superﬁcial thrombophlebitis.

VENOUS DISEASE DIAGNOSIS Deep venous thrombosis The diagnosis of DVT must be made with conﬁrmatory laboratory testing, for in up to 50% of patients with DVT, patients will be asymptomatic at presentation. When symptoms are present, patients often complain of a dull ache or pain in the calf or higher up on the leg. The most common physical ﬁnding is edema of the involved calf or ankle, although Wells4 has classiﬁed the clinical presentation of patients into a scoring system that emphasizes the physical presentation of patients. In his criteria, characteristics that score points include the presence of active cancer, paralysis or paresis or recent plaster immobilization of the lower extremity, being recently bedridden for 3 days or more, localized tenderness along the distribution of the deep venous system, the entire leg being swollen, calf swelling that is at least 3 cm larger on the involved side than the non-involved side, pitting edema in the symptomatic leg, and a history of a previous DVT.4 When there is extensive proximal DVT in the iliofemoral system, there may also be massive edema, cyanosis, and dilated superﬁcial collateral veins. Massive iliofemoral DVT may cause phlegmasia alba dolens (white swollen leg) and phlegmasia cerulea dolens (blue swollen leg). When the capillaries occlude, venous gangrene may result. This occurs as the arterial inﬂow becomes obstructed because of extreme levels of venous hypertension. Alternatively, arterial emboli or spasm may occur. The toes on the involved limb turn blue and black, and the skin blisters. Venous gangrene must be differentiated from gangrene caused by arterial insufﬁciency. The differentiation includes the fact that with arterial ischemia the limb is pale and cold without massive swelling. Venous gangrene is often associated with an underlying malignancy and is virtually always preceded by phlegmasia cerulea dolens. Amputation rates of 20–50% are noted, with PE rates of 12–40% and mortality rates of 20–40% due to the underlying medical conditions these patient often have.5 Tests for making the diagnosis of DVT of historical interest include hand-held Doppler examination, impedance plethysmography, radiolabeled ﬁbrinogen scanning, and phlebography. Because of its high sensitivity, speciﬁcity, and reproducibility, duplex ultrasound imaging has replaced contrast phlebography. Duplex ultrasound imaging includes a B-mode image and Doppler ﬂow analysis. Duplex imaging carries sensitivity and speciﬁcity rates of greater than 95%.6 Magnetic resonance imaging may be helpful to diagnose pelvic vein and caval thrombosis, and spiral CT scanning is also being used more frequently, especially when combined with

chest imaging during examination for PE.7 Even at the calf level, duplex imaging is an accurate technique in symptomatic patients in those laboratories that routinely perform calf imaging. However, not all laboratories perform imaging below the level of the knees. Other advantages of duplex ultrasound include the fact that it is painless, requires no contrast, can be serially repeated, and is safe during pregnancy. The test is also able to image other potential causes of a patient’s symptoms and for a complete examination, other possible sources of symptoms must be evaluated.8 In the asymptomatic patient, screening venous duplex imaging has been associated with conﬂicting levels of sensitivity/speciﬁcity. Combining clinical characteristics with the addition of the D-dimer assay may decrease the number of negative duplex scans.4 Importantly, a single complete and technically adequate negative compression duplex scan is accurate enough to base the withholding of anticoagulation with minimal long-term adverse thromboembolic complications.9 If the duplex scan is indeterminate, treatment may be based on biomarkers, with the duplex scan repeated in 24–72 hours based on a moderate to high clinical risk. However, a complete examination is emphasized, and repeat imaging is necessary if the patient’s symptoms change or worsen. Other conditions may be confused with DVT. Lymphedema may cause signiﬁcant leg swelling. However, swelling from lymphedema usually involves the forefoot and even the toes, and is not associated with changes of chronic venous insufﬁciency including stasis pigmentation and stasis dermatitis. Additionally, muscle strain or contusion may mimic DVT, and cellulitis may cause edema, localized pain, and erythema. Iliac vein obstruction in the retroperitoneum by a tumor or mass may lead to unilateral massive leg edema, and the presence of a Baker’s cyst behind the knee may produce unilateral leg pain and edema. Other causes of leg swelling (usually bilateral) include systemic problems involving cardiac, renal, or hepatic abnormalities. There are limited alternative techniques for ruling in DVT when duplex imaging is unavailable. In an attempt to develop techniques and algorithms that bypass or supplement duplex ultrasound imaging, clinical risk factor proﬁling combined with D-dimer analysis has been suggested. This combination has been shown to allow for withholding of anticoagulation if the risk status of the patient is low and the D-dimer level is within normal limits. However, other combinations have not been felt accurate enough to allow for clinical decision-making. We have performed a pilot study of 43 patients and 30 normal volunteers and demonstrated that a combination of microparticle analysis (procoagulant particles that are released from activated platelets, endothelial cells, and leukocytes upon activation), soluble P-selectin levels (the ﬁrst upregulated glycoprotein expressed by activated endothelial cells and platelets upon activation), and D-dimer levels produced sensitivity and speciﬁcity rates of

Standard therapy for VTE 267

73% and 81%. These preliminary data, although demonstrating proof of concept and allowing for the establishment of “cut-off points” for these assays, need to be validated in larger patient samples.10

Axillary/subclavian vein thrombosis Thrombosis of the axillary/subclavian vein is an uncommon event accounting for less than 5% of all cases of acute DVT. Nevertheless, axillary/subclavian venous thrombosis has been associated with PE in up to 10–15% of cases and can be the source of signiﬁcant disability.11 Primary axillary/subclavian vein thrombosis results from obstruction of the vein in the thoracic outlet (Paget–von Schrötter syndrome) in healthy muscular individuals. Strenuous exercise often precipitates the thrombosis. It may also occur in patients with hypercoagulable states. Secondary axillary/subclavian vein thrombosis results usually from indwelling catheters or pacemaker wires. Other less common secondary causes include congestive heart failure, nephrotic syndrome, mediastinal tumors, and malignancy. Patients with axillary/subclavian venous thrombosis often present with pain, edema, and cyanosis of the arm. Superﬁcial venous distension may be apparent in the arm, forearm, shoulder and anterior chest wall. Upper extremity venous duplex ultrasound is a good screening modality for patients with suspected axillarysubclavian vein thrombosis. If this study is positive, upper extremity venography and thrombolysis should be considered. If venography is performed, it is important that the patient undergo positional venography, abducting the arm 120 degrees to conﬁrm extrinsic compression of the subclavian vein at the thoracic outlet. Venous compromise is further evidenced by prominent collateral veins. A chest radiograph should be obtained from all patients to exclude the presence of a cervical rib, which can also cause compression of the subclavian vein.

Superficial venous thrombophlebitis Superﬁcial venous thrombophlebitis (SVT) occurs in over 125 000 patients per year, and is associated with varicose veins, pregnancy, thromboangiitis obliterans including Behçet’s disease, and indwelling catheters. Complications of SVT have been associated with severe chronic venous insufﬁciency (CVI), male gender, and history of VTE.12 Clinically, a painful, ﬁrm, palpable cord with inﬂammation and/or tenderness along the affected vein is found. Occasionally, arm edema is also noted. Associated factors include a history of venous puncture or intravenous canalization, trauma, physical inactivity, oral contraceptives, occult or known malignancy, and/or infections. The presence of migratory SVT suggests the presence of cancer (e.g., carcinoma of the pancreas, the socalled Trousseau’s sign). The incidence of DVT associated

with SVT on presentation is estimated between 0.75% and 40%, whereas the association of a non-contiguous DVT with SVT has been estimated between 25% and 75% in those patients who present with thrombosis in both the superﬁcial and deep venous systems.13 Pulmonary embolism, the most lethal and under-recognized complication associated with this entity, has an estimated occurrence of 0 to 17%.14 Suppurative SVT is associated with an intravenous catheter or multiple puncture sites secondary to intravenous drug abuse, most often in the upper extremity. The clinical presentation is similar to that of non-suppurative SVT, although there is often associated pyrexia, leukocytosis, and/or bacteremia. Local intravenous catheter site infections occur in up to 8% of cases, and bacteremia is detected in approximately 1 of every 400 intravenous catheterizations.13 Immunocompromised and burn patients are particularly susceptible to suppurative SVT. Hypercoagulability in the setting of SVT is relatively common. The risk of SVT in the absence of varicose veins, malignancy or autoimmune disorders is approximately 13-fold higher for patients with deﬁciencies of inhibitors of coagulation (antithrombin, proteins C or S), sixfold higher for factor V Leiden mutation, and fourfold higher for the prothrombin gene mutation.15 The same indications for hypercoagulable work-up in patients with DVT should be applied to patients with SVT.12 This includes patients without an associated history of trauma or inactivity, venipuncture, malignancy, or varicose veins, and patients with severe SVT, recurrence, family history, early age at presentation, and resistance to therapy.

STANDARD THERAPY FOR VTE The primary treatment of VTE is systemic anticoagulation, which reduces the risk of PE, and the extension and recurrence of venous thrombosis. Immediate systemic anticoagulation should be undertaken with heparin, as it has been shown that the recurrence rate for VTE is approximately four- to sixfold higher if anticoagulation is not therapeutic in the ﬁrst 24 hours.16 Adequate anticoagulation will prevent the development of fatal pulmonary embolism, both during the initial treatment and after treatment is completed.17 After adequate treatment of acute DVT, recurrent DVT may still occur in up to one-third of patients over an 8-year period.18 Traditionally, systemic intravenous unfractionated heparin (UFH) has been undertaken for 5 days, during which time oral anticoagulation with warfarin is instituted. However, because of dosing inconvenience and the bleeding risks of UFH, LMWH has been advanced as primary therapy for VTE. Low-molecular-weight heparins are derived from the lower molecular weight range of standard heparin with less direct thrombin inhibition and more antifactor Xa activity. Low-molecular-weight

268

Treatment algorithm for acute deep venous thrombosis: current guidelines

heparins have signiﬁcant improvement in bioavailability and have much less endothelial cell and protein binding than standard UFH. When summarizing multiple studies and meta-analyses, LMWHs are at least equivalent to UFH if not slightly superior regarding thrombus recurrence, with a lower risk for major hemorrhage.19 The advantages of LMWHs include a lower risk of bleeding, less antiplatelet activity (which also decrease the risk for bleeding), lower incidence of HIT, less interference with protein C and complement activation, and a lower risk of osteoporosis. As LMWHs can be administered subcutaneously and are weight based, they may be given in the outpatient setting. They do not require frequent monitoring except in certain circumstances such as renal failure, morbid obesity, and during pregnancy.20 A recent study has suggested equivalence of UFH to LMWH when given at a ﬁxed weight-based dosage. In this study involving 708 patients, UFH 333 units/kg followed by 250 units/kg every 12 hours was compared to enoxaparin (LMWH) 100 units/kg every 12 hours. All patients then were treated with warfarin. Recurrent VTE was noted in 3.8% versus 3.4%, major bleeding was noted in 1.1% versus 1.4%, and outpatient treatment was possible in 72% versus 68% of patients.21 Although this study demonstrates promise, other data published and pending suggest that the use of LMWH may actually decrease the incidence and severity of both post-phlebitic syndrome and heparin complications.22 Warfarin should be started only after heparinization is therapeutic to prevent the rare but morbid warfarininduced skin necrosis. This is a condition that occurs because of the transient hypercoagulability that occurs for the ﬁrst few days that warfarin is administered due to the inhibition of protein C and protein S before most of the coagulation factors are inhibited by warfarin. The goal for warfarin dosing is an international normalized ratio (INR) between 2.0 and 3.0. The recommended duration of anticoagulation after a ﬁrst episode of VTE is 3–6 months.23 After a second episode of VTE, the usual recommendation is lifelong warfarin unless the patient is very young at the time of presentation or there are other mitigating factors. The length of time of warfarin in other situations is controversial. Venous thromboembolism is increased signiﬁcantly in the presence of homozygous factor V Leiden and prothrombin 20210A mutation, protein C/S deﬁciency, antithrombin deﬁciency, antiphospholipid antibodies, and cancer until resolved.2 In these conditions, most agree with long-term warfarin. However, heterozygous factor V Leiden/prothrombin 20210A does not carry the same high risk as their homozygous counterparts, and the length of oral anticoagulation may be shortened. Idiopathic DVT is an interesting problem. Most believe that true idiopathic thrombosis requires more than 6 months of warfarin. A recent multicenter trial has suggested that for idiopathic DVT, low-dose warfarin (INR 1.5–2.0) is superior to placebo over a 4 year follow-

up period with a 64% risk reduction for recurrent DVT after the completion of an initial 6 months of standard warfarin therapy.24 A second study has suggested that fulldose warfarin (INR 2.0–3.0) is superior to low-dose warfarin in those same types of patients without a difference in bleeding morbidity.25 Finally, calf thrombi may be treated with 6–12 weeks of warfarin. Recently, there have been two additional criteria that have been suggested to be important in determining the length of anticoagulation. One involves the amount of scar tissue inside the venous circulation based on either venography or duplex imaging. The second and perhaps better validated criterion involves D-dimer testing obtained 1 month after warfarin is completed. If the D-dimer test is elevated above normal, warfarin may need to be continued long term, as this result suggests that the patient is still in a prothrombotic state.26–28 One recent study has demonstrated a statistically signiﬁcant advantage to resuming coumadin if the D-dimer assay is positive compared with remaining off coumadin over an average 1.4 year follow-up (OR 4.26, P = 0.02).29 The most common complication of anticoagulation is bleeding. With UFH, the bleeding risk is estimated to be approximately 10% over the ﬁrst 5 days. With the addition of warfarin and keeping the INR at 2.0–3.0, the incidence of major bleeding is approximately 6% yearly. In the treatment of patients for DVT and PE, major bleeding has been reported in 0–7% of patients, with fatal bleeding in 0–2% of patients.30 A meta-analysis showed a rate of hemorrhagic complications estimated at 9.1% for anticoagulation when continued beyond 3 months. In order to decrease bleeding, dose adjustments and the use of anticoagulation clinics are emphasized. Another complication of heparin anticoagulation is HIT. Heparin-induced thrombocytopenia occurs in 0.6–30% of patients in whom heparin is administered. Although historically morbidity and mortality have been high, early diagnosis and appropriate treatment have decreased the rates.31 Heparin-induced thrombocytopenia usually begins 3–14 days after starting heparin (earlier if the patient has been exposed to heparin in the past) and is caused by a heparin-dependent antibody, immunoglobulin G (IgG), which binds to platelets and induces them to aggregate in the presence of heparin.32 Both bovine and porcine UFH as well as LMWH have been associated with HIT. Arterial and venous thromboses have been reported, and even small exposures to heparin (heparin coating on indwelling catheters) have been known to cause the syndrome. The diagnosis should be suspected in a patient who experiences a 50% or more drop in platelet count or when there is a fall in platelet count below 100 000/μl during heparin therapy, or in any patient who experiences thrombosis during heparin administration.33 The test of choice for making this diagnosis today is an enzyme-linked immunosorbent assay that detects the antiheparin antibody in the patient’s plasma. Cessation of heparin is the most important step.

Aggressive therapies

Warfarin is contraindicated in this condition until an adequate alternative anticoagulant has been established in order to prevent paradoxical thrombosis. Low-molecularweight heparins (Enoxaparin, Sanoﬁ-Aventi, Paris, France, and dalteparin) have high cross-reactivity with standard heparin antibodies and therefore cannot be substituted for standard heparin in patients with HIT. The direct thrombin inhibitors hirudin (lepirudin/reﬂudan) and argatroban are the treatment now approved by the FDA, although other agents such as fondaparinux have been found to treat this syndrome.34,35 These agents show no cross-reactivity to heparin antibodies.

SPECIAL FEATURES OF LOW-MOLECULARWEIGHT HEPARIN The safety of LMWH compared with warfarin has led to a consideration of the long-term use of LMWH as a replacement for oral vitamin K antagonists. Although in general there is an absence of deﬁnitive evidence of the superiority for LMWH over UFH, rates of recanalization have been reported to be higher in certain venous segments using LMWH versus traditional oral agents. Additionally, the use of LMWH has been found to be better than warfarin in certain cancer patients when used for 6 months without major differences in bleeding,36 and has been found to provide improved DVT prophylaxis compared with placebo for extended prophylaxis (up to 4 weeks) for patients undergoing abdominal/pelvic cancer surgery.37 The use of once a day compared with twice a day LMWH dosing has been assessed in a meta-analysis of greater than 1500 patients with VTE.38 There was a nonsigniﬁcant difference in the incidence of recent thromboembolism, thrombosis size, hemorrhagic events, and mortality, suggesting that the more convenient oncedaily regimen is adequate for treatment. However, there may be instances when bid dosing is more appropriate. These include patients with marked obesity, and those with cancer.39

ALTERNATIVE/FUTURE MEDICAL TREATMENTS FOR DVT/PE Two new classes of agents for venous thrombosis treatment include direct thrombin inhibitors and speciﬁc factor Xa inhibitors. Ximelagatran is a direct thrombin inhibitor that is most like warfarin. The route of administration is oral, but the onset of action is rapid at 2 hours compared with 72–96 hours for warfarin. Ximelagatran has no food interactions or drug interactions and has a wide therapeutic window. Thus, no coagulation monitoring has been found necessary. Unfortunately, there is no widely available antidote for its effects. It has been tested successfully for both the prophylaxis of orthopedic surgery and the extended prophylaxis after

269

therapy for DVT/PE. However, ximelagatran causes an elevation in liver function tests in up to 6% of patients given the drug and because of this it has not been approved in the USA or Europe. Other drugs with similar mechanisms of action are currently being evaluated. Fondaparinux and the related idraparinux are most like LMWH. They target factor Xa without inhibiting thrombin. These drugs are given subcutaneously and demonstrate a half-life of 17 hours for fondaparinux and 80–130 hours for indraparinux (compared with 4 hours for LMWH). Importantly, they exhibit no endothelial or protein binding. However, they have no readily available antidote. Neither of these drugs produces thrombocytopenia. Fondaparinux has been tested for the prophylaxis of major orthopedic surgery. In a metaanalysis of over 7000 patients, there was a greater than 50% risk reduction using fondaparinux begun 6 hours after surgery compared with LMWH begun 12–24 hours after surgery.40 Although major bleeding was increased, critical bleeding was not different. Fondaparinux has also been effective in prophylaxis of general medical patients,41 in abdominal surgery patients,42 and for extended prophylaxis after hip fracture.43 Fondaparinux has also been evaluated in the treatment of both DVT and PE. For DVT it was found equal to LMWH,44 whereas for PE it was found equal to standard UFH.45 This drug has been approved as a once-daily, subcutaneous injection for the treatment of DVT/PE in acutely symptomatic patients. The dose given is based on body weight, such that 5 mg for body weight < 50 kg; 7.5 mg for body weight 50–100 kg; and 10 mg for body weight > 100kg. Treatment for at least 5 days with concurrent administration of oral anticoagulation is recommended, until the INR is therapeutic at a level of 2.0–3.0. It has also been approved for thrombosis prophylaxis in total hip, total knee and hip fracture patients and in the extended prophylaxis of hip fracture patients. Other antithrombotic agents are being evaluated including oral heparins, other direct thrombin inhibitors such as lepirudin, bivalirudin, and argatroban; deﬁbrinating agents such as ancrod; anti-inﬂammatory agents such as P-selectin inhibitors; factor VIIa inhibitors; tissue factor pathway inhibitor; and activated protein C.46,47 Lepirudin and argatroban have been approved for patients with HIT. The use of P-selectin inhibitors or an inhibitor to P-selectin receptor is an area of ongoing research in the author’s laboratory. Such an antiinﬂammatory approach promises use of an antithrombotic agent that does not cause direct anticoagulant activities, thus decreasing bleeding potential.

AGGRESSIVE THERAPIES For DVT, the goals of therapy are (1) to prevent the extension or recurrence of the DVT and the development of PE and (2) to minimize the early and late results of the

270

Treatment algorithm for acute deep venous thrombosis: current guidelines

DVT. Although anticoagulants accomplish the former, they contribute little or nothing to limit the development of the post-thrombotic syndrome. Thrombi are dynamic biologic processes. They organize and ﬁbrose, recanalize, and may embolize to the lungs. When thrombi resolve, the vein usually re-opens within the ﬁrst few months of the event. Approximately half of patients will show complete recanalization within 6–9 months of the clotting process. Clinical trials have demonstrated symptomatic recurrent DVT to occur in approximately 1 in 10 patients treated with standard anticoagulants and natural history studies have demonstrated that the incidence of events that are not symptomatic may be higher than those that are symptomatic. Additionally, serial ultrasound scans have demonstrated progression of clot in approximately a third of treated patients within the ﬁrst few weeks of presentation.48,49 In a large series of 177 patients followed for a median of 9 months, recurrent thrombosis occurred in approximately half the patients.50 Thus, standard bloodthinning medication, heparin, while preventing fatal PE, is not perfect therapy. The outcome after a DVT can thus be thought of as either dysfunction of the vein valves with vein wall ﬁbrosis and the development of reﬂux, or persistent venous obstruction that does not re-open, or the combination of both of these events. Patients with both reﬂux and obstruction have severe pain and swelling, making treatment difﬁcult. To limit the consequences of DVT, its early removal appears to be the best solution. It has been found that the longer a thrombus is in association with a vein valve, the more chance that the valve will no longer function.51 Additionally, the thrombus initiates an inﬂammatory

reaction between itself and the vein wall. Not only does valve dysfunction occur, but vein wall dysfunction can also occur as the vein wall scars.52 This also contributes to the valvular dysfunction. It is clear that not all DVTs are the same, and treatment should be individualized. The long-term results from DVT in the iliofemoral system are generally more severe than for thrombosis in the lower part of the leg. The two ways to remove a clot are mechanical (thrombectomy) or with medication (thrombolysis). Venous thrombectomy has been associated with long-term improvements in the patency and the rates of pain and swelling in the leg compared with standard heparin anticoagulation, both at 6 months’ and at 10 years’ follow-up.53,54 Thrombolysis has been evaluated with a number of quality of life scales and has been associated with improvements in many aspects of quality of life, leading to a decrease in long-term symptoms of pain and swelling (Table 22.1).55 Three large studies have demonstrated that excellent patency of the venous system can be achieved with administration of thrombolytic agents directly into the thrombus56–58 (see Table 20.5). A recent small randomized trial of thrombolytics versus anticoagulants alone has conﬁrmed this observation.59 In addition to these more traditional methods to remove DVT, newer mechanical devices have been developed or are being developed for this process. More than 10 devices are currently available for clearing thrombus from clotted kidney dialysis ﬁstula grafts. However, only one of these devices is approved by the FDA for use in DVT patients. One of the most common devices is a catheter that uses high-pressure jets of saline solution for creating the Venturi effect. This allows for dissolving

Table 22.1 Mean scale scores comparing patients who had either partial or complete lysis with patients who had heparin treatment* Complete + partial lysis (mean ± SE)

Heparin (mean ± SE)

P-value

Initial contact (mean, 16 months) Health Utilities Index Health interference Role functioning physical Treatment satisfaction Stigma Health distress Overall symptoms

n = 43 0.83 ± 0.03 75.01 ± 3.98 75.68 ± 4.57 86.59 ± 4.25 85.98 ± 4.11 82.48 ± 4.04 78.55 ± 3.44

n = 30 0.74 ± 0.03 67.29 ± 4.78 56.59 ± 5.56 81.72 ± 5.18 71.32 ± 5.00 64.11 ± 4.91 55.56 ± 4.19

0.032 0.24 0.013 0.49 0.033 0.007 <0.001

Follow-up (22 months) Health Utilities Index Health interference Role functioning physical Stigma Health distress Overall symptoms

n = 32 0.71 ± 0.04 68.25 ± 5.38 68.52 ± 5.14 90.48 ± 4.11 80.25 ± 4.19 74.11 ± 3.87

n = 13 0.73 ± 0.07 66.11 ± 8.63 56.07 ± 8.09 69.50 ± 6.71 56.32 ± 6.85 50.56 ± 6.66

0.77 0.84 0.23 0.014 0.006 0.006

Scale item

*Comerota et al.55

Non-pharmacological treatments

thrombus and evacuation through the catheter. There are some drawbacks with this catheter, however. Another catheter combines the use of a mechanical wire and the infusion of agents that dissolve the clot. The drug that dissolves the clot is contained between two occlusive balloons, thus preventing the drug from getting into the systemic circulation and decreasing the risk of bleeding. After the balloons are inﬂated, a thrombolytic agent is infused into the thrombus and then the wire rotates to bring the agent and the thrombus into close contact. After the thrombus is macerated the by-products are suctioned and the balloons deﬂated. Data are available comparing these two devices.60 Another technique is the use of ultrasound to explode microbubbles, which can cause either mechanical thrombus dissolution or release dissolving agents that are contained within the bubbles. The conclusions from the above studies are clear: early removal of the thrombus conveys signiﬁcant beneﬁts, and the earlier and more complete the removal, the better the outcome. The main limitations to early thrombus removal are twofold – the therapy is complicated, taking time to accomplish with the risk of bleeding (compared with outpatient LMWH), and there is a lack of strong evidence deﬁning the long-term value of such therapy. Two national/international summits have recently identiﬁed the need for studies in this area to be the most important priority for venous research at the present time – both from the Society of Interventional Radiology and the American Venous Forum Paciﬁc Vascular V Summit. Catheter-directed thrombolysis is also well accepted for axillary and subclavian venous thrombosis, particularly effort thrombosis in young patients.61 Rapid thrombolysis decreases the long-term risk of swelling and dependence of venous collateralization for outﬂow.62 Subclavian vein angioplasty/stenting for exertional axillary subclavian venous thrombosis has been reported.63 However, the stents may crimp, migrate, or erode through the vein, given the upper shoulder outlet motion, unless a thoracic outlet decompression (TOD) procedure is performed ﬁrst, as the underlying venous stenosis is most often caused by thoracic outlet compression. Thoracic outlet decompression follows thrombolysis. The timing of TOD, whether immediate or after a delay to allow for the vein wall inﬂammatory response to subside, is controversial. In cases of secondary axillary/subclavian or other upper extremity DVT, particularly when due to the presence of indwelling catheters, anticoagulation therapy along with the removal of the catheter is indicated. The duration of anticoagulation should be individualized and reﬂect the patient’s thrombotic risk.

INFERIOR VENA CAVA FILTERS The primary indications for the use of inferior vena cava (IVC) ﬁlters are a complication, a contraindication and/or failure of anticoagulant therapy. Over the past 30 years,

271

protection from PE has been greater than 95% successful using cone-shaped wire-based permanent IVC ﬁlters.64 Over time, the success achieved with ﬁlters has expanded the indications to prophylaxis. These include a freeﬂoating thrombus longer than 5 cm65 when anticoagulation risk is excessive (i.e., an older patient with DVT or following a major trauma66), when the risk of PE is felt to be sufﬁciently high (as in certain bone and gastric bypass operations67), and to allow for the use of perioperative epidural anesthesia. Filters can be permanent or temporary (retrievable). If a temporary ﬁlter is left in to become a permanent ﬁlter, its long-term fate has not yet been deﬁned. Filters are usually placed in an infrarenal location. Filters may also be placed in either the suprarenal location or in the superior vena cava in special circumstances. For suprarenal placement, indications include high-lying clot, pregnancy or a woman of childbearing potential, or a previous device that has ﬁlled with clot or failed. Sepsis is not a contraindication to the use of wire-based ﬁlters since the trapped material can be sterilized with antibiotics. However, IVCs larger than 28 mm usually require a different approach than cone-shaped, wire-based devices. Although traditionally ﬁlters have been placed under X-ray guidance, percutaneous techniques for ﬁlter insertion using bedside ultrasound or external ultrasound to reduce exposure to X-rays are now being used frequently. Transabdominal external ultrasound is ineffective in patients who are obese, if there is overlying bowel gas, or if there are open abdominal wounds. In these instances, intravascular ultrasound has been found to be more successful.68

NON-PHARMACOLOGICAL TREATMENTS The rate and severity of pain and swelling after above the knee DVT can be decreased by half by the use of strong compression stockings.69 Walking with good compression does not increase the risk of PE, while signiﬁcantly decreasing the incidence and severity of pain and swelling after DVT.70,71 It is recommended that once patients are therapeutic on anticoagulants they ambulate while wearing compression stockings if they have a DVT. In addition to the long-term problems related to DVT and PE, there is an associated increased death rate. In a study involving 665 248 patients from the Nationwide Inpatient Sample, the occurrence of either DVT or PE was associated with an increased death rate and unfavorable discharge (discharge to rehabilitation facility, nursing home, or another hospital) in patients admitted to the hospital for common medical illnesses. These included heart attack, heart failure, pneumonia, or stroke.72 Venous thromboembolism was also associated with increased cost and length of stay. Not surprisingly, VTE appears to confer a signiﬁcant risk of death in addition to its risk to the legs and to the lungs.

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Treatment algorithm for acute deep venous thrombosis: current guidelines

resolution of the cellulitis occurs, no treatment beyond a short course of antibiotics is required. However, if the patient becomes septic, immediate excision of the infected vein is required. With positive blood cultures, an extended course of antibiotics speciﬁc for the identiﬁed organism is indicated.

SUPERFICIAL VENOUS THROMBOPHLEBITIS The primary treatment of superﬁcial venous thrombophlebitis is the administration of non-steroidal antiinﬂammatory drugs, local heat, elevation, and support stockings or ACE wrap (elastic bandage). Ambulation is encouraged. In most cases, symptoms will resolve within 7–10 days. Excision of the involved vein is recommended for symptoms that persist over 2 weeks despite treatment or for recurrent phlebitis in the same vein segment. If there is progressive proximal extension with involvement of the saphenofemoral junction or cephalic–subclavian junction, ligation and resection of the vein at the junction should be performed. Alternatively, full-dose anticoagulation can be attempted and followed with monthly venous duplex scans. In general, medical treatment is somewhat superior for minimizing complications and preventing subsequent DVT/PE development, as opposed to surgical treatment with ligation of the great saphenous vein at the saphenofemoral junction or ligation and stripping, which tends to minimize the superﬁcial venous thrombus extension allowing for superior pain relief.73 Septic thrombophlebitis requires treatment with broad-spectrum intravenous antibiotics. If rapid

Duplex ultrasound not available

ALGORITHMS The algorithms in Figs 22.1 and 22.2 are advanced for patients with a low suspicion of DVT or moderate to high suspicion of DVT respectively. Regarding thrombosis, Figs 22.3 and 22.4 summarize approaches for superﬁcial thrombophlebitis and DVT respectively.

CLINICAL GUIDELINES ●

●

Duplex ultrasound is now the test of choice for the diagnosis of DVT.6,8 Low-molecular-weight heparin is now preferred over standard UFH for the initial treatment of DVT.19

Physical examination

Duplex Ultrasound

Biomarkers

Negative

Positive

Positive

Negative

Indeterminate

No treatment

Additional testing

Treatment

No treatment

Repeat Duplex ultrasound in 24–72 hours

Duplex ultrasound not available

Physical examination

Duplex Ultrasound

Biomarkers

Negative

Figure 22.1 Low suspicion for deep vein thrombosis.

Positive

Duplex ultrasound when available or alternative study –Ascending venography –MRV –Spiral CT scan

Positive

Treatment

Complete all segment study Negative

Indeterminate

Repeat No treatment Treatment based on biomarkers Duplex repeat Duplex ultrasound based ultrasound in on clinical suspicion 24–72 hours in 24–72 hours

Figure 22.2 Moderate to high suspicion for deep vein thrombosis.

Clinical guidelines

Duplex ultrasound not available

273

Physical examination

Duplex Ultrasound

Clinical suspicion

Positive (SVT)

Negative (SVT)

No treatment Duplex ultrasound when available

Treatment

Removal of thrombophlebitic veins (septic phlebitis towards brain)

Anticoagulation (to prevent embolization of DVT also present)

Figure 22.3 Superﬁcial venous thombophlebitis.

Aggressive therapy for proximal Iliofemoral DVT

Femoral/popliteal/ Iliofemoral DVT

Combined pharmaco mechanical lytic therapy

Intrathrombus thrombolytic therapy

Surgical thrombectomy

Heparin or LMWH for 5–7 days Surgical compression stockings Ambulation

Oral anticoagulation 3–6 months*

LMHW 3–6 months

IVC filter or alternative anticoagulation

Except: –Risk factors still present e.g. cancer –Hypercoagulable stages –Antithrombin deficiency –Protein C deficiency –Protein S deficiency –Factor V Leiden homozygous –Idiopathic thrombosis –Multiple episodes of thrombosis

Indications – Contraindications to coumadin – Failure to adjust to coumadin – Abdominal cancer

Indications Contraindication to heparin/LMHW/ coumadin Examples of alternatives – Argatroban – Fondaparinux – Refluclan

Figure 22.4 Deep vein thrombosis (DVT) therapy. *Calf level DVT therapy 6–12 weeks.

●

●

Criteria for discontinuation of oral anticoagulation include thrombosis risk, residual thrombus burden, and coagulation system activation (as suggested by D-dimer measurements).24–28 Heparin-induced thrombocytopenia remains a problem with all heparin preparations, but is more

●

frequent with UFH than LMWH. Alternate agents include hirudin, argatroban (both FDA approved) and fondaparinux.32–34 Aggressive therapies including thrombectomy, thrombolysis, and combined pharmacomechanical thrombolysis. These should be considered in patients

274

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Guidelines 3.6.0 of the American Venous Forum on treatment algorithm for acute deep vein thrombosis No.

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Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.6.1 Low-molecular-weight heparin is now preferred over standard unfractionated heparin for the initial treatment of deep vein thrombosis

1

A

3.6.2 Criteria for discontinuation of oral anticoagulation include thrombosis risk, residual thrombus burden, and coagulation system activation (as suggested by D-dimer measurements)

1

A

3.6.3 Heparin-induced thrombocytopenia remains a problem with all heparin preparations, but is more frequent with unfractionated heparin than low-molecular-weight heparin. Alternative agents include hirudin, argatroban and fondaparinux

1

C

3.6.4 The use of strong compression and early ambulation after deep vein thrombosis treatment can signiﬁcantly reduce the long-term morbidity of pain and swelling resulting from the deep vein thrombosis

1

A

with signiﬁcant iliofemoral venous thrombosis, not only in situations of limb threat (phlegmasia) but also to prevent the signiﬁcant sequel of venous insufﬁciency from post-thrombotic syndrome. 53–59 The use of strong compression and early ambulation after DVT treatment is initiated can signiﬁcantly reduce the long-term morbidity of pain and swelling resulting from the DVT.69–71

●7.

◆8.

9.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ●

10.

◆

◆1.

2.

3.

★4.

5. 6.

Bauer KA, Rosendaal FR, Heit JA. Hypercoagulability: too many tests, too much conﬂicting data. Hematology (Am Soc Hematol Educ Program) 2002; 353–68. Henke P. Thrombosis due to hypercoagulable states. In: Rutherford RB, ed., Rutherford’s Textbook of Vascular Surgery, 6th edn. Philadelphia, PA: Elsevier/Saunders 2004. Andreotti F, Becker RC. Atherothrombotic disorders: new insights from hematology. Circulation 2005; 111: 1855–63. Wells PS, Anderson DR, Rodger M, et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–35. Perkins JM, Magee TR, Galland RB. Phlegmasia caerulea dolens and venous gangrene. Br J Surg 1996; 83: 19–23. Fowl RJ, Strothman GB, Blebea J, et al. Inappropriate use of

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venous duplex scans: an analysis of indications and results. J Vasc Surg 1996; 23: 881–5; Discussion 885–6. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006; 354: 2317–27. Douglas MG, Sumner DS. Duplex scanning for deep vein thrombosis: has it replaced both phlebography and noninvasive testing? Semin Vasc Surg. 1996; 9: 3–12. Schellong SM, Schwarz T, Halbritter K, et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003; 89: 228–34. Rectenwald JE, Myers DD, Jr., Hawley AE, et al. D-dimer, Pselectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005; 94: 1312–7. Prandoni P, Bernardi E. Upper extremity deep vein thrombosis. Curr Opin Pulm Med 1999; 5: 222–6. Quenet S, Laporte S, Decousus H, et al. Factors predictive of venous thrombotic complications in patients with isolated superﬁcial vein thrombosis. J Vasc Surg. 2003; 38: 944–9. Sullivan V. Superﬁcial venous thrombosis. In: Pearce WH, Matsumara JS, Yao JST (eds), Trends in Vascular Surgery pp 463–472, Chicago, IL: Precept Press 2002. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452–63. Martinelli I, Cattaneo M, Taioli E, et al. Genetic risk factors for superﬁcial vein thrombosis. Thromb Haemost 1999; 82: 1215–7.

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Buller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695–702. Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 265S-286S. Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic. Curr Top Med Chem 2005; 5: 1677–95. Krupski WC, Bass A, Dilley RB, et al. Propagation of deep venous thrombosis identiﬁed by duplex ultrasonography. J Vasc Surg 1990; 12: 467–74; Discussion 474–5. Caps MT, Meissner MH, Tullis MJ, et al. Venous thrombus stability during acute phase of therapy. Vasc Med 1999; 4: 9–14. Meissner MH, Caps MT, Bergelin RO, et al. Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995; 22: 558–67. Meissner MH, Manzo RA, Bergelin RO, et al. Deep venous insufﬁciency: the relationship between lysis and subsequent reﬂux. J Vasc Surg 1993; 18: 596–605; Discussion 606–8. Myers DD, Hawley AE, Farris DM, et al. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075–89. Plate G, Akesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arteriovenous ﬁstula. Eur J Vasc Surg 1990; 4: 483–9. Plate G. Venous thrombectomy for iliofemoral vein thrombosis—10 -year results of a prospective randomized study. Eur J Vasc Endovasc Surg 1997; 14: 367–734. Comerota AJ, Throm RC, Mathias SD, et al. Catheterdirected thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg 2000; 32: 130–7. Bjarnason H, Kruse JR, Asinger DA, et al. Iliofemoral deep venous thrombosis: safety and efﬁcacy outcome during 5 years of catheter-directed thrombolytic therapy. J Vasc Interv Radiol 1997; 8: 405–18. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheterdirected thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999; 211: 39–49. Comerota AJ. Catheter-directed thrombolysis for the treatment of acute iliofemoral deep venous thrombosis. Phlebology. 2001; 15: 149–55. Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A

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23 Current recommendations for prevention of deep venous thrombosis ROBERT D. MCBANE AND JOHN A. HEIT Introduction Risk factors for venous thromboembolism Venous thromboembolism prophylaxis methods and regimens

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INTRODUCTION Venous thromboembolism (VTE) represents a major cause of morbidity and mortality in the USA.1–3 The incidence of VTE exceeds 1 per 1000 with approximately 201 000 ﬁrst life-time cases diagnosed annually in this country. The 7 day mortality of patients suffering a thrombotic event is 25% and up to 35% of patients with pulmonary embolism (PE) die suddenly. Venous thromboembolism is therefore the fourth leading cause of death in Western society and the third leading cause of cardiovascular death behind myocardial infarction and stroke. Furthermore, VTE is both a recurrent disease and a morbid disease. Of those individuals surviving the

Pharmacologic prophylaxis methods Prophylaxis recommendations Conclusions References

281 283 288 288

thrombotic event, 30% will develop recurrent venous thromboembolism within 10 years and 20–30% will develop the post-phlebitic syndrome over this time period. VTE is typically a disease of elderly people, with the incidence of thrombotic events increasing signiﬁcantly beyond age 60 (Fig. 23.1). As our population ages, the expected number of VTE annually will increase. Despite advances in radiographic detection, expanded knowledge of risk factors, and anticoagulant development, the incidence of VTE has been relatively constant over the past several decades (Fig. 23.2). Yet, venous thromboembolism can be a preventable disease particularly in the hospitalized patient.4 Appropriately delivered prophylaxis is cost-effective,

250

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Adjusted annual incidence (per 100 000)

Adjusted annual incidence (per 100 000)

1200

1200 600 400 200

80 ⬎

–7 9 70

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0–

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200 150 100 50 0 1966

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1980 Year

1985

1990

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Figure 23.1 Age- and sex-adjusted annual incidence of venous thromboembolism among Olmsted County, MN, residents, 1966–90. ⎯, Male; ——, female.

Figure 23.2 Annual incidence of venous thromboembolism (VTE) among Olmsted County, MN, residents, 1966–90. ––, All VTE; ….., pulmonary embolism + deep vein thrombosis (DVT); ⎯, DVT only.

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reduces VTE rates by 50–70%, and carries an acceptably low risk of hemorrhage. Without prophylaxis, VTE rates are high for both surgical and non-surgical hospitalized patients. Although the incidence of VTE varies by both patient- and surgery-speciﬁc variables, without prophylaxis, venous thrombotic events may occur in up to 20% of surgical patients. Underscoring the magnitude of this disease is the fact than more than 23 million surgical procedures are performed each year in the USA.5 Furthermore, more than 31 million non-surgical patients are admitted each year to US hospitals. Pulmonary embolism (PE) accounts for nearly 10% of all hospital deaths and is one of the most common preventable causes of mortality. Often, these pulmonary emboli occur without prior warning and sudden death may be the initial symptom of disease. With the evolution toward expanded outpatient delivery of medical and surgical services, only the sickest and frailest of patients are hospitalized. The thrombotic event rate may be as high as 16% in these nonsurgical patients if no prophylaxis is given.4,5 In summary, VTE is the most common preventable cause of death and suffering. Providing appropriate VTE prophylaxis is the highest ranked safety practice for patients at risk. The aims of this chapter are therefore to outline the risk factors for VTE, review the efﬁcacy and safety of various prophylactic regimens, and provide recommendations regarding the most suitable prophylaxis based on the estimated risk.

RISK FACTORS FOR VENOUS THROMBOEMBOLISM A number of patient characteristics have been identiﬁed as independent risk factors for VTE (Box 23.1).3 Increasing age is a major risk factor for VTE. There is a direct relationship with increasing age and the annual incidence of VTE for both men and women (Fig. 23.1). Beyond the ﬁfth decade of life the incidence increases precipitously. Below this age, VTE is relatively uncommon. Pulmonary embolism accounts for an increasing proportion of VTE with increasing age for both genders, which has important implications for the future of the USA (Fig. 23.3). As the average US population age increases, VTE mortality is likely to increase because of the signiﬁcantly worse survival after PE. Venous thromboembolism incidence also varies by ethnicity. The incidence is highest among Caucasian and African-Americans. Hispanic-Americans carry an intermediate risk, with the lowest risk racial group being Asian-Americans. The incidence among native Americans is unknown. Other important and independent risk factors for VTE include surgery, trauma, hospital or nursing home conﬁnement, malignancy (with and without concurrent chemotherapy), prior central vein catheterization or transvenous pacemaker (for upper extremity deep venous thrombosis), prior superﬁcial thrombosis, varicose veins, and neurologic disease with extremity paresis (Box

BOX 23.1 Clinical risk factors for venous thromboembolism General risk factors Increasing age Trauma Surgery Leg immobilization or paralysis Central venous catheter or transvenous pacemaker Hospital or nursing home conﬁnement Prior superﬁcial vein thrombosis Varicose veins Acquired or secondary thrombophilia Malignancy Myeloproliferative disorders Heparin-induced thrombocytopenia Nephrotic syndrome Disseminated intravascular coagulation (DIC) Hormonal contraceptives and replacement Lupus anticoagulant and antiphospholipid antibody syndrome Pregnancy and postpartum state Chemotherapy Inﬂammatory bowel disease Thromboangiitis obliterans (Buerger’s disease) Behçet’s syndrome Primary or familial thrombophilia Antithrombin deﬁciency Protein C deﬁciency Protein S deﬁciency Activated protein C resistance and factor V Leiden mutation Prothrombin G20210A mutation Elevated Factor VIII Hyperhomocysteinemia

23.1). Severe liver disease may be protective possibly because of reduced synthesis of procoagulant factors. The absolute incidence of VTE is strongly and directly related to body mass index and inversely related to physical activity.6

Hospitalization The VTE risk proﬁle of contemporary hospitalized patients has gradually increased, with most carrying more than one recognized risk factor. Furthermore, most cases of VTE occur in the peri-hospitalization period. In the DVT Free registry, a large multicenter prospective ultrasound study of 5451 patients, nearly 60% of VTEs were diagnosed within the peri-hospitalization period and

Risk factors for venous thromboembolism

Hormonal manipulation

1200 Adjusted annual incidence (per 100 000)

1000 800 600 400 200

⬎ 80

9 70

–6 60

–7

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9 –5

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Figure 23.3 Annual incidence of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) among Olmsted County, MN, residents, 1966–90. –––, DVT, alone; ….., PE + DVT; ⎯, all VTE.

38% occurred within 3 months of surgery.7 The combined identiﬁcation of patients at risk for VTE and implementation of prophylactic therapy for VTE prevention represent prudent and proven means of reducing VTE for most hospitalized patients. Most hospitalized patients have more than one risk factor for venous thrombosis and these risk factors are likely additive in nature. Although surgery and trauma represent the most potent acquired risk factors for VTE, the majority of thrombotic events occur in nonsurgical patients. For the non-surgical hospitalized patient, major risk factors include New York Heart Association class III–IV heart failure, chronic obstructive pulmonary disease exacerbation, sepsis, advanced age, history of prior VTE, cancer, stroke with limb paresis, and bed rest.2,3

Surgical factors Surgery represents a major risk for VTE and varies by the type, duration, and indication for surgery, type of anesthesia, associated risk factors, and patient-speciﬁc variables including age.2–4 In general, patients requiring anesthesia have a 22-fold increased risk of VTE. From a surgical perspective, the highest risk is associated with orthopedic procedures especially hip or knee replacement, hip fracture surgery, and trauma surgery, including patients with spinal cord injury. Patient-speciﬁc variables include cancer, congenital thrombophilia, prior history of VTE, obesity and increasing age (> 60 years).8 In general, spinal/epidural anesthesia carries a lower risk than general anesthesia. Outpatient surgery has a lower associated risk than inpatient surgery.9 Patients undergoing vascular surgery may have less risk than other surgeries, possibly because of the intraoperative use of heparin therapy. Aortic surgery carry a higher risk than distal bypass surgery.10,11

It is estimated that more than 100 million women worldwide use hormonal contraception. Venous thromboembolism is one of the most disconcerting complications of oral contraception (OCP).12 For women in their teens, twenties and thirties, the anticipated incidence of VTE ranges from 1 in 100 000 to 1 in 10 000 with increasing age. The risk of VTE in OCP users is between three- to sixfold greater than in non-users. This risk is exponentially higher in carriers of factor V Leiden or prothrombin G20210A gene mutations.12–14 The greatest risk occurs in the ﬁrst 6–12 months of therapy particularly in ﬁrst-time users.12 The risk remains until the third month following discontinuation. The risk of VTE is directly proportional to the estrogen dose. A number of studies have shown that third-generation OCPs confer greater VTE risk than second-generation agents. Progesterone only OCPs are associated with a lower risk than combination preparations.15 The limited data suggest that transdermal preparations carry less risk relative to oral preparations. Both postmenopausal hormone replacement therapy and selective estrogen receptor modulator use (tamoxifen and raloxifene) are associated with an increased risk of VTE. Data from three large randomized controlled studies enrolling more than 30 000 women have shown that oral hormone replacement therapy (HRT) is associated with a two- to threefold increased rate of VTE compared with non-users.6,16,17 The risk appears to be highest in the ﬁrst 6–12 months of therapy. Conjugated equine estrogen used alone carries a lower risk of VTE than the combined use of estrogen and medroxyprogesterone acetate (adjusted hazard ratio 0.59, 95% CI 0.37–0.94 for the comparison).6 Inherited thrombophilic states increase the risk of VTE exponentially in HRT users compared with non-users. For example, combining HRT with factor V Leiden increases the risk by 15-fold.18

Pregnancy Pregnancy increases the incidence of VTE in women by three- to sixfold and this incidence is evenly distributed across the three trimesters.19,20 The rate of venous thrombosis following pregnancy is 172–199 per 100 000 deliveries.21,22 The risk is higher following cesarean section than vaginal delivery. This increased risk of VTE may relate to high estrogen levels, venous stasis, pelvic trauma with delivery, and acquired hypercoagulability. This acquired thrombophilia has been attributed to elevated procoagulant variables (ﬁbrinogen, von Willebrand factor, and factor VIII) as well as decreased natural anticoagulants such as protein S. Risk factors associated with thrombosis during pregnancy include increasing age (> 35 years), immobility, obesity, and prior VTE. African-Americans appear to have a greater risk than Caucasians.22 DVT in the

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left leg occurs three times more frequently than the right leg, previously explained by left iliac compression by the right iliac artery. Furthermore, DVT is approximately three times more frequent than pulmonary embolism (PE) in these women.21 The puerperium, which encompasses the 6 week window following delivery, is a higher risk period than the pregnancy itself.

Inflammatory bowel disease Inﬂammatory bowel disease (IBD) is a generally accepted risk factor for VTE. However, the mechanism underlying this association remains unclear. The reported incidence of VTE in this disease is difﬁcult to ascertain whereby most studies are limited by referral bias. In one population based study in Manitoba, the incidence was 0.5%, which was signiﬁcantly greater than expected compared with the general population for both DVT (incidence rate ratio, IRR, 3.5; 95% CI 2.9–4.3) and PE (IRR, 3.3; 95% CI 2.5–4.3).23 Although the risk of VTE may be associated with disease activity, half of patients experiencing thrombosis have inactive disease at the time of the event.24–26 Surgery and especially colorectal surgery carries an increased risk of VTE in patients with IBD. In the Canadian Colorectal DVT Prophylaxis Trial, the rate of VTE following surgery for IBD was 9% in patients receiving unfractionated heparin (UFH) compared with 3% for those receiving low-molecular-weight heparin (LMWH).27

Nephrotic syndrome Thrombosis is a major source of morbidity in patients with nephrotic syndrome.28,29 Renal vein thrombosis is the most common site of venous thrombosis, occurring in approximately 35% of patients with nephrotic syndrome. Thrombosis in other venous segments can be seen in 20% of cases. Urinary excretion of antithrombin (antithrombin, not antithrombin III), platelet hyper-reactivity, and elevated plasma viscosity are cited pathophysiologic mechanisms of thrombosis in these patients.

Malignancy The incidence of VTE in patients with an active malignancy may be as high as 11%. Cancer involving the pancreas, gastrointestinal tract, ovary, prostate, and lung are particularly prone to develop VTE; however, all malignancies carry this association to some degree. Patients with active malignancy undergoing surgery are at increased risk with an incidence of thrombosis approaching 40%. Compared with non-cancer-related surgery, the risk of postoperative DVT is increased twofold with a threefold increased risk of fatal PE. Thrombosis may

be the ﬁrst manifestation of malignancy in some individuals. Trousseau’s syndrome, or migratory thrombophlebitis, is a prime example. In the now classic study by Prandoni et al.30 the prevalence of malignancy among 153 patients with idiopathic VTE was 3.3% at clinical presentation of the thrombus. During the 2 year follow up period, a new cancer diagnosis was conﬁrmed in 7.6% of patients with idiopathic VTE compared with 1.9% of patients with secondary thrombosis. If recurrent VTE occurred during this time period, the incidence of new malignancy was 17.1%.

Travel The association between prolonged travel and VTE is controversial. Documented associations have been shown primarily by retrospective studies assessing the history of recent travel in patients with a new VTE. The association appears to be related to duration of travel, with one study showing increased risk only when travel exceeded 10 hours.31 In another study, only 56 of 135 million travelers ﬂying to Paris had a conﬁrmed PE for a corresponding rate of 1:100 million passengers who traveled less than 6 hours, and 1:700 000 passengers who traveled more than 6 hours.32 Most individuals with VTE associated with prolonged travel have additional risk factors for thrombosis.4 Ascribing causality to the travel alone may therefore be incorrect.

VENOUS THROMBOEMBOLISM PROPHYLAXIS METHODS AND REGIMENS Venous thromboembolism prophylaxis may be divided into two general strategies: primary (mechanical and pharmacological) and secondary or “surveillance” prophylaxis. Surveillance prophylaxis is deﬁned as a strategy of serially screening for asymptomatic DVT, usually with duplex ultrasound. In this latter strategy, only patients discovered to have DVT are treated. Ultrasound screening for asymptomatic venous thrombosis however has limited sensitivity for this indication. Furthermore, this strategy does nothing to prevent venous thrombosis and is limited to the inpatient setting. In this current medical era where prompt hospital discharge is the standard, this strategy is ineffective in preventing VTE after discharge. In summary, surveillance strategies are neither effective nor cost-effective. Withholding primary prophylaxis in lieu of surveillance prophylaxis with duplex ultrasonography is therefore not prudent.

Mechanical prophylaxis Non-pharmacologic methods of VTE prophylaxis include elastic compressive stockings (ELS), intermittent pneumatic compression (IPC) devices, leg elevation, and early

Pharmacologic prophylaxis methods

ambulation. Each of these methods promote venous emptying and thus reduce static venous blood pooling. Both ELS and IPC devices have been shown to reduce venous thrombotic events by approximately 20%. Neither however has been shown to reduce the incidence of PE nor death from PE. The use of each of these interventions is primarily advocated for those situations where the risk of bleeding may be sufﬁciently high as to avoid the use of pharmacologic agents (Grade 1C). They should also be employed in combination with pharmacologic agents for those patients at very high risk for VTE (Grade 2A).

281

Pharmacologic prophylaxis can be broadly divided into several categories including heparinoids, vitamin K antagonists, and direct thrombin inhibitors. Antiplatelet agents such as aspirin, dipyridimole, or thienopyridines have either been ineffective or inferior to other agents for the prevention of venous thrombosis. Current guidelines recommend against their use for this indication.

antithrombin (formerly antithrombin III). Unfractionated heparin is a highly negatively charged proteoglycan extracted from either porcine or bovine intestinal mucosa. Each preparation contains a heterogeneous mixture of heparin molecules of variable lengths and molecular weights ranging from 5000 to 50 000 Da.34 A speciﬁc pentasaccharide sequence within the UFH molecule binds antithrombin at the heparin binding site thus activating the inhibitor. Only about 15–25% of heparin molecules within any heparin preparation contain this speciﬁc pentasaccharide sequence however and therefore much of the heparin is ineffective for this purpose. This point will become important when discussing fondaparinux. Unfractionated heparin binds both antithrombin and thrombin forming a ternary structure that enhances the afﬁnity of antithrombin for thrombin by 1000-fold. Once formed, the thrombin–antithrombin complex is essentially irreversible. Heparin dissociates from the complex and is then free to participate in another round of antithrombin activation. Antithrombin also effectively inhibits the coagulant activities of factors IXa, Xa, and XIa. Non-speciﬁc binding to a variety of cells and plasma proteins neutralizes the anticoagulant activity of heparin. For these reasons, the volume of distribution and efﬁcacy varies among individuals. Despite this, subcutaneous lowdose unfractionated heparin prophylaxis is safe and effective prophylaxis for moderate-risk general surgical patients. For high- and very high-risk patients, low-dose unfractionated heparin is effective, but provides inadequate risk reduction. In these higher risk patients, the postoperative increase in “acute-phase reactant” plasma proteins causes an increase in heparin non-speciﬁc binding and a reduction in the heparin anticoagulant effect. Realization of this problem led to the development of the adjusted dose unfractionated heparin regimen, whereby the postoperative dose of heparin is increased to maintain the activated partial thromboplastin time (aPTT) in the upper normal range. Although this regimen has proven very effective in high-risk patients, it has not been adopted widely because of the inconvenience of monitoring and repeated dose adjustment. Low-dose heparin is associated with an increased incidence of postoperative wound hematoma. In addition, there is a small but deﬁnite risk of heparin-induced thrombocytopenia and thrombosis (HITT), a potentially devastating thrombotic complication.35 Consequently, the platelet count should be monitored at least every other day and the heparin stopped if the platelet count decreases by 30–50% of the baseline count.

Unfractionated heparin

Low-molecular-weight heparin

The heparinoids include UFH, LMWH, and the synthetic pentasaccharide fondaparinux. The anticoagulant properties of each of these agents are achieved through activation of the circulating endogenous inhibitor,

Low-molecular-weight heparin is derived by either enzymatic or chemical depolymerization of standard heparin to achieve a preparation with more uniform molecular weight. Thus, the average molecular weight of

Inferior vena cava filters The routine placement of inferior vena cava (IVC) ﬁlters should be discouraged for the indication of venous thrombosis prophylaxis.33 IVC ﬁlter placement should be reserved for patients with clear indications. These indications include acute VTE in the face of urgent/ emergent surgery or other circumstances prohibiting anticoagulant delivery (Grade 1C). For this purpose, an “acute” DVT is deﬁned as one occurring within 1 month of the urgent/emergent surgery. Other indications include veriﬁable anticoagulant failure. An IVC ﬁlter may be suitable prophylaxis for the multiple trauma patient with bleeding risk precluding pharmacologic prophylaxis (Grade 2C). Trauma patients may have extensive leg injuries that may preclude the use of IPC and ELS. A number of retrievable ﬁlters have been developed and FDA approved. The advent of these retrievable IVC ﬁlters has increased enthusiasm for preoperative placement of these devices, which could then be removed postoperatively. Although attractive, the appropriate use of retrievable IVC ﬁlters for this indication has not been established. At this time, the indications for temporary, retrievable, or optional IVC ﬁlters are the same as those for permanent IVC ﬁlters (Grade 1C).

PHARMACOLOGIC PROPHYLAXIS METHODS

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Current recommendations for prevention of deep venous thrombosis

LMWH is between 4000 and 6000 kDa.34 The pharmacologic advantage of LMWH is that the net electrical charge is more neutral, thus substantially reducing non-speciﬁc protein or cellular binding. Absorption after subcutaneous injection is virtually complete. Consequently, the anticoagulant response after a LMWH subcutaneous injection is predictable and reproducible, such that laboratory monitoring and dose adjustment are rarely necessary. Low-molecular-weight heparins provide very effective prophylaxis for high- and very high-risk surgical patients. In North America, the initial LMWH dose usually is given 12–24 hours after surgery, whereas in Europe a dose is given 10–12 hours before surgery. There does not appear to be a signiﬁcant advantage of one approach over the other from randomized trial data. In the current absence of randomized controlled trial data, one LMWH cannot be recommended over another. At similar antithrombotic doses, LMWH causes less bleeding than UFH. However, among patients receiving total hip and knee replacement, LMWH causes more bleeding than adjusted-dose warfarin. Although the incidence of HITT is less frequent with LMWH than with unfractionated heparin, there is substantial cross-reactivity, and HITT patients cannot be switched safely to LMWH. Currently, the LMWH cost per dose is approximately 10-fold greater than UFH.

Fondaparinux Fondaparinux is a synthetic pentasaccharide with sequence speciﬁcity for the antithrombin heparin binding site.36 It is given subcutaneously on a semi-weightadjusted scale. Once given, absorption is rapid, complete, and predictable, with 94% of the drug protein bound to antithrombin. The half-life of the drug is quite long at between 17 and 22 hours. It is renally excreted and therefore may not be suitable for patients with renal insufﬁciency. Because of its very small molecular weight and neutral electrical charge, protamine is ineffective at neutralizing this drug. In trials of hip and knee replacement surgery, fondaparinux compared very favorably with other LMWHs in the reduction of thrombotic events and bleeding complications. Fondaparinux appears to be superior to other pharmacologic agents in hip fracture surgery. The daily cost of fondaparinux is similar to other LMWHs. Although it does not appear to cause heparin-induced thrombocytopenia (HIT), it remains unclear that this would be an acceptable alternative to heparinoids in the setting of HIT with or without thrombosis.

Warfarin Warfarin is an oral anticoagulant that acts by inhibiting the post-translational vitamin K-dependent carboxylation

of glutamic acid residues of hepatically synthesized clotting factors and anticoagulant proteins.37 These include factors II, VII, IX, and X, and the anticoagulant proteins C and S. Carboxylation enables protein incorporation of calcium necessary for proper folding and activation. In the absence of calcium, these proteins cannot become activated and functionality is lost. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K-dependent clotting factor by approximately 30% to 50%. A decrease in concentration of clotting factors is sequential and is related to the half-lives of the individual factors. The overall anticoagulant effect is generally seen between 24 and 48 hours after drug administration. However, the peak anticoagulant effect may be delayed 72–96 hours. Regular monitoring of warfarin therapy is performed to improve both the safety and efﬁcacy of this drug. The prothrombin time international normalized ratio (INR) is a clot-based assay that directly correlates with the clotting factor activity. Therapeutic warfarin for most indications is associated with INR values between 2 and 3. Warfarin has a narrow therapeutic range, with the risk of major hemorrhage increasing substantially when INR values exceed 5. For INR levels below 1.5, antithrombotic efﬁcacy is lost. Warfarin therapy may be affected by factors such as other drugs and dietary vitamin K, such that dosage should be adjusted by periodic determinations of PT/INR. The initiation of warfarin treatment is problematic because of variations in dose response. Physiologic and pharmacologic factors, such as interacting drugs or illnesses that affect the pharmacokinetics or pharmacodynamics of warfarin, dietary or GI factors that affect the availability of vitamin K, or physiologic factors that affect the synthetic or metabolic fate of the vitamin Kdependent coagulation factors can affect the warfarin therapy.37 The bleeding rate (including fatal, major, and minor bleeding events) of warfarin therapy is 7.6–16.5 per hundred patient–years. Major or life-threatening bleeds occur at a rate of 1.3 to 2.7 per hundred patient–years.38–40 Although major bleeding can occur at therapeutic levels, the risk of bleeding rises with increasing intensity of anticoagulation.

Direct thrombin inhibitors There are currently three direct thrombin inhibitors (DTIs) available for clinical use. Two of these inhibitors, lepirudin and bivalirudin, are based on the thrombin inhibitor, hirudin, which was originally derived from the saliva of medicinal leeches (Hirudo medicinalis). The third DTI, argatroban, is a small-molecular-weight arginine derivative which takes advantage of the speciﬁcity of thrombin for cleaving at arginine sites on substrate. The DTIs are only very rarely used for VTE prophylaxis.

Prophylaxis recommendations

Lepirudin

PROPHYLAXIS RECOMMENDATIONS

Lepirudin (recombinant hirudin) is a speciﬁc and irreversible thrombin inhibitor.41 Its amino terminal domain interacts with the active site of thrombin and its carboxy terminal tail binds to exosite.41,42 The terminal half-life of hirudin is 60 minutes after intravenous injection and 120 minutes after subcutaneous injection.43 Clot-bound thrombin, an important thrombotic risk factor inaccessible to ATIII-heparin, is effectively inhibited by hirudin. Hirudin therapy is monitored using standard aPTT assay. Subcutaneous lepirudin has been evaluated in two large phase III trials of DVT prophylaxis in patients undergoing total hip arthroplasty.44,45 In the ﬁrst trial, lepirudin was compared with subcutaneous UFH and in the second, with the LMWH enoxaparin. Lepirudin signiﬁcantly reduced venous thrombotic events assessed by venography in both trials. Nonetheless, current FDA approval is limited to the use of lepirudin for patients with HIT.

General surgery

Bivalirudin Bivalirudin, a 20 amino acid synthetic polypeptide analog of hirudin, has a terminal half-life of 25 minutes after intravenous injection and only a fraction is excreted via the kidneys. It has been evaluated primarily in patients undergoing percutaneous coronary intervention for coronary artery disease and this is its current FDA approval. In a phase 2, dose-escalating trial of 222 patients undergoing total hip and knee replacement surgery, hirulog (1.0 mg/kg every 8 hours) provided the very low rates of total DVT (17%) and proximal DVT (2%) with bleeding rates < 5%.46

Argatroban Argatroban is a peptidomimetic arginine derivative that binds non-covalently to the active site of thrombin to form a reversible complex. The plasma half-life of argatroban is 45 minutes and the drug is metabolized in the liver in a process that generates several active intermediates. Although this drug is safely used in patients with renal insufﬁciently, it should be used very cautiously (if at all) in those with hepatic insufﬁciency. Like lepirudin, the FDA approval for this drug is for the indication of HIT.

Aspirin Aspirin is either ineffective or inferior to other forms of VTE prophylaxis. Its use provides modest beneﬁt at best and is therefore not recommended as a lone prophylaxis strategy (Grade 1A).

283

The risk of venous thrombosis following general surgery varies depending on the extent and nature of the procedure and the presence of the patient-speciﬁc risk factors previously discussed (Box 23.1). Patients are thus stratiﬁed into low, moderate, high, and very high-risk groups (Box 23.2). For low-risk general surgery, the risk of VTE is sufﬁciently low such that early ambulation alone is satisfactory (Grade 1C). For moderate-risk patients, VTE prophylaxis may include low-dose UFH or prophylactic dose LMWH (< 3400 units/day; Grade 1A). For high-risk general surgery patients, elastic compression stockings should be combined with either low-dose heparin (5000 units tid) or LMWH (> 3400 units/day; Grade 1A). In very high-risk general surgical patients with multiple concomitant risk factors, the use of either UFH (5000 units tid), LMWH (> 3400 units/day) or fondaparinux is appropriate (Grade 1A) and should be combined with mechanical prophylaxis (Grade 1C). Unfractionated heparin (5000 units tid) has not been shown to be inferior to LMWH for this indication.47 Mechanical prophylaxis with elastic compression stockings and IPC may further reduce the risk of VTE when added to pharmacologic prophylaxis in these high-risk and very high-risk patients.4 Colorectal surgery particularly for the indication of malignancy resection is associated with an increased risk of postoperative VTE. In the ENOXACAN study, 631 patients undergoing colorectal surgery for malignancy were randomized to receive either low-dose UFH (5000 units tid) or enoxaparin (40 mg qd).48 All thrombotic events were conﬁrmed by either venography or pulmonary

BOX 23.2 Risk stratification in surgical patients Low risk Minor surgery, age <40 years, no additional risk Moderate risk Major surgery, age >40 years, no additional risk High risk Major surgery, age >40 years, with additional risk of MI Very high risk Major surgery, >40 years, with additional risk ● Prior venous thromboembolism ● Cancer ● Molecular hypercoagulable state ● Hip or knee arthroplasty ● Hip fracture surgery ● Major trauma ● Spinal cord injury

284

Current recommendations for prevention of deep venous thrombosis

scintigraphy. Patients were followed for 3 months. Venous thrombosis rates were equivalent for both groups (UFH 18.2% vs LMWH 14.7%). Major hemorrhage was also equivalent (UFH 2.9% vs LMWH 4.1%). Similar results were noted in the Canadian Colorectal DVT Prophylaxis Trial in which 936 patients underwent colorectal surgery for malignancy (n = 475) or IBD (n = 584).49 Venous thromboembolism rates (9.4% for both) and major hemorrhage rates (1.5% vs 2.7%) were nearly identical for the low-dose UFH and enoxaparin groups. The FX140 investigators compared two LMWHs in patients undergoing colorectal surgery for cancer.50 In this study, 1271 patients were randomized to either nadroparin (2850 IU/day) or enoxaparin (40 mg/day). Although VTE rates were similar between groups, bleeding complications were more common in enoxaparin-treated patients. In summary, the rates of VTE following colorectal surgery are high and mandate aggressive prophylaxis. Unfractionated heparin (5000 units tid) and LMWH (> 3400 units/day) have similar efﬁcacies and are both acceptable for this indication (Grade 1B).

Vascular surgery Patients undergoing vascular surgery may have less risk than those undergoing other surgeries. This may reﬂect the intraoperative use of heparin. The risk of VTE in patients undergoing vascular surgery is directly related to patient age, abdominal vascular procedures, limb salvage procedures, surgical duration, and operative venous trauma. Risk categorization is otherwise similar to that of general surgery (Box 23.2). For patients not receiving prophylaxis, the rates of DVT can be substantial. For example, in those patients assessed by venography, the rates vary from 18% to 42%.51,52 In a cohort of 50 patients undergoing vascular surgery, the VTE rates were assessed by serial ultrasound performed preoperatively and again prior to hospital discharge. Thrombotic event rates were highest following an abdominal procedure (41%) and lowest in those undergoing peripheral bypass procedures (18%).52 Calf vein DVTs were four times more common than more proximal thrombotic events. The VTE prophylaxis recommendations for general surgery can be extrapolated to the patient undergoing vascular surgery. By deﬁnition, most vascular patients carry considerable medical comorbidities including extensive coronary disease, myocardial dysfunction, and obstructive pulmonary disease, which increase the risk of venous thrombosis and enhance the mortality rate of patients suffering a PE. Vascular patients are furthermore unique in that they frequently receive systemic heparin anticoagulation during the course of their surgery. Consequently, preoperative low-dose heparin or intraoperative IPC are unwarranted. Nevertheless, patients undergoing thoracic or thoracoabdominal aortic

reconstructions or other complicated vascular surgery (i.e., ruptured aortic aneurysm repair, major vascular amputations, major venous reconstructions) frequently require extended intensive care unit (ICU) support. The mobility of these patients is limited and they often suffer multi-organ system failure. Although there are no vascular surgery-speciﬁc data, extrapolation from other ICU patients suggests that the VTE risk is high and warrants prophylaxis. For patients in whom the risk of bleeding is high, IPC combined with elastic compression stockings is an excellent prophylaxis choice (Grade 2B). Elastic compression stockings combined with either low-dose heparin or LMWH are appropriate pharmacologic prophylaxis strategies (Grade 1C).

Orthopedic surgery TOTAL HIP REPLACEMENT

As our population ages and becomes increasingly obese, the need for total joint replacement is only anticipated to increase. Prevention of VTE in these elderly, obese and sometime frail patients is therefore paramount. Vitamin K antagonists are widely used for this purpose in total hip arthroplasty. The advantages of warfarin in this setting include proven efﬁcacy, a delayed onset of action, titratable response, acceptable bleeding risk, wide availability and familiarity.4 The goal INR should be adjusted to values between 2.0 and 3.0. Whether initiated pre- or postoperatively, the efﬁcacy of warfarin therapy is maintained. Multiple trials have shown that LMWH is safe and effective prophylaxis after total hip replacement. Vitamin K antagonists have been compared with LMWH in several trials with mixed results. Two trials showed an advantage of LMWH over warfarin,53,54 whereas three additional trials showed no difference.55–57 Fondaparinux is an acceptable alternative agent that appears to be at least as effective as the LMWH enoxaparin for this indication.58,59 Postoperative bleeding rates were similar in these two trials. In summary, either LMWH, fondaparinux (2.5 mg/day), or vitamin K antagonism with warfarin (goal INR 2.0–3.0) are acceptable prophylactic regimens for this indication (Grade 1A). TOTAL KNEE REPLACEMENT

Total knee replacement surgery appears to carry a greater risk of VTE than total hip replacement surgery. Although the rate of venographic-conﬁrmed DVT in patients undergoing this procedure is as high as 50%, the rate of symptomatic DVT is much lower, particularly if appropriate prophylaxis is used. Adjusted-dose vitamin K antagonists provide effective prophylaxis in patients undergoing total knee replacement surgery with symptomatic VTE occurring in 1.0–1.3% of patients.60,61 A

Prophylaxis recommendations

number of trials have compared coumarin derivatives with LMWH, and it has been consistently more effective than warfarin in the reduction of VTE but results in a higher bleeding rate.55,62–64 Consequently, the choice of LMWH or adjusted-dose warfarin depends on the estimated VTE and bleeding risks. Intermittent pneumatic compression provides effective adjunctive non-pharmacological prophylaxis for total knee replacement patients. Fondaparinux is an acceptable alternative agent with approximately equal efﬁcacy compared with enoxaparin.65,66 In summary, either LMWH, fondaparinux (2.5 mg/day), or vitamin K antagonism with warfarin (goal INR 2.0–3.0) are acceptable prophylactic regimens for this indication (Grade 1A).

HIP FRACTURE SURGERY

Hip fracture surgery is associated with a very high risk of postoperative VTE, with venographic rates approaching 50%.4 Symptomatic proximal DVT rates are approximately 25% and fatal PE occurs between 1.4% and 7.5%. Prophylaxis of hip fracture patients remains a major challenge because of the risk of bleeding associated with recent trauma. The risk of DVT is increased if hospital admission is delayed for more than 2 days after hip fracture. Moreover, the risk of fatal PE is reduced if hip fracture patients are operated within 24 hours of their injury. Either adjusted-dose warfarin or LMWH prophylaxis is recommended and should be administered as soon as the patient is clinically stable. Fondaparinux may be the preferred prophylactic agent for this indication. Compared with LMWH, fondaparinux reduced the rate of proximal DVT (0.9% vs 4.3%) with an equivalent rate of major hemorrhage (2.2% for both groups).67 In summary, fondaparinux (Grade 1A), LMWH (Grade 1C), or vitamin K antagonism with warfarin (Grade 2B) are acceptable prophylactic regimens for this indication.

KNEE ARTHROSCOPY

Arthroscopic knee surgery is the most common orthopedic procedure performed in the USA.4 The rate of symptomatic venous thrombosis following this procedure is extremely low, with published rates less than 0.005%. The recommendations for VTE prophylaxis following knee arthroscopy is therefore limited to early ambulation for the most patients (Grade 2B). OPTIMAL DURATION OF PROPHYLAXIS

The optimal duration of prophylaxis following orthopedic surgery remains uncertain and is a topic of ongoing debate.68–70 Although VTE prophylaxis is typically stopped at hospital discharge, two-thirds of venous thrombotic

285

events occur after hospital discharge.68 The risk of VTE may persist for up to 3 months following surgery. Most trials continued prophylaxis for at least 7–10 days. However, the current duration of postoperative hospitalization is often 4 days or less, which may provide an inadequate duration of prophylaxis. In a meta-analysis of nine trials of extended-duration prophylaxis (30–42 days), the odds ratio of VTE rates was signiﬁcantly reduced (OR 0.38, 95% CI 0.24–0.61).69 This risk reduction was greater for patients undergoing total hip replacement than for total knee replacement. Extended-duration prophylaxis was not associated with an excessive rate of major hemorrhage. Based on these combined data, the current ACCP guidelines include a ﬁrm recommendation that all patients receive 10 days of appropriate VTE prophylaxis following total joint replacement or hip fracture surgery (Grade 1A). For patients undergoing total hip arthroplasty or hip fracture surgery, prophylaxis should be continued for 4 weeks, particularly in patients with continuing VTE risk factors (e.g., a previous history of VTE, obesity, continued immobilization, bilateral simultaneous total knee replacement; Grade 1A).4

Neurosurgery The risk for VTE following neurosurgery is increased with intracranial procedures, malignancy, long surgical duration, limb paresis, and advanced age.4 Rates of symptomatic VTE range from 3.7% to 19% depending on the presence of these variables.71–73 Intermittent pneumatic compression, with or without elastic compression stockings, has been the prophylaxis of choice for elective neurosurgery patients, since even minimal bleeding could be catastrophic (Grade 1A). Low-dose UFH (Grade 2B) or LMWH (Grade 2A) are acceptable prophylactic agents for high-risk patients.73,74 In one study of 150 patients undergoing craniotomy for brain tumor resection, the use of either agent completely eliminated symptomatic DVT assessed by pre-discharge duplex ultrasonography.68 In another study of 100 patients undergoing craniotomy, there was no signiﬁcant difference in postoperative hemorrhage, or VTE between heparin and dalteparin groups.74

Acute spinal cord injury with leg paralysis Individuals suffering from spinal cord injury have the highest rates of VTE among all hospitalized patients.75–77 The incidence of asymptomatic VTE in patients suffering spinal cord injury is high with numbers ranging from 60% to 100%.78–82 Pulmonary embolism remains the third leading cause of death in these patients.83,84 Even with appropriate prophylaxis, the rates may be greater than 60%.77 Major risk factors for VTE in patients suffering

286

Current recommendations for prevention of deep venous thrombosis

spinal cord injury include increased age, lower extremity fracture and delayed use of prophylaxis. The period of greatest risk for VTE is the ﬁrst 2 weeks after injury, with symptomatic PE rarely occurring beyond 3 months. Consequently, the prophylaxis duration in the absence of other risk factors should be 3 months from the date of the injury. Based on the available evidence, LMWH provides effective prophylaxis for patients with acute spinal cord injury and paralysis (Grade 1B). These agents should be initiated once adequate hemostasis has been conﬁrmed.4 For those patients in whom pharmacologic prophylaxis cannot be safely used because of excessive bleeding risk, combined IPC and GCS should be employed (Grade 1C).

unselected trauma patients (Grade 1C). The advent of retrievable ﬁlters has been felt by many to be an attractive option for high-risk trauma patients. One study compared the rates of ﬁlter placement, ﬁlter-related complications, and PE before and after the introduction of retrievable ﬁlters at their institution.89 With the introduction of retrievable ﬁlters at their institution, the rate of ﬁlter placement tripled, yet there was no signiﬁcant difference in the rate of PE. Thus far, there are no randomized trials to show us the correct use of these ﬁlters in the setting of trauma.

Neuraxial anesthesia Multiple trauma Asymptomatic DVT is common in trauma patients [injury severity score (ISS) > 9]. Using venography, one study of 349 trauma patients found a high DVT prevalence after lower extremity fractures (69%), spinal cord injury (62%), or isolated injury to the face, chest, or abdomen (50%).85 None of these patients received prophylaxis. Other investigators using ultrasound found a 15.9% incidence of popliteal and calf vein DVT in 698 trauma patients.86 Importantly, 35.7% of these showed signs of propagation over time. Risk factors for propagation included high ISS scores, age < 62 years, ICU admission, and need for an operation. In a randomized trial of 344 trauma patients (ISS > 9), enoxaparin (30 mg bid) was compared with heparin (5000 units bid) for the prevention of VTE.87 Venographically conﬁrmed proximal DVT was signiﬁcantly lower in the enoxaparin group (6%) compared with the heparin group (15%). Major bleeding was not signiﬁcantly different (enoxaparin 3.9% vs heparin 0.7%). For these reasons, LMWH prophylaxis is recommended for trauma patients in whom it is safe from a hemostasis standpoint (Grade 1A). Intermittent pneumatic compression was compared with LMWH (enoxaparin 30 mg bid) in 442 trauma patients (ISS > 9).88 In this study, ultrasound was performed within 24 hours of admission to establish the presence of pre-existing DVT, and weekly thereafter or as indicated when DVT was suspected. Six patients who had IPC and one who received LMWH suffered a DVT (P = 0·122). There was one PE in each group. The combined incidence of major and minor bleeding did not differ signiﬁcantly between the intervention groups. Intermittent pneumatic compression is therefore recommended for multiple trauma patients for whom anticoagulant therapy is not feasible especially in the setting of active bleeding (Grade 1B). If IPC is not feasible because of leg trauma, prophylactic IVC ﬁlter placement may be appropriate in selected patients who cannot tolerate any of the other three recommended modalities.33 Inferior vena cava ﬁlter therapy is not recommended as primary prophylaxis for

Neuraxial anesthesia carries the rare but potentially devastating complication of perispinal hematoma in patients receiving prophylactic or therapeutic anticoagulation.90–92 This complication may result in paraplegia, as delicate neural tissues are compressed by bleeding within the conﬁned space of the spinal column. Signs and symptoms to look for include severe back pain with progressive lower extremity weakness or numbness, and bowel or bladder dysfunction. Diagnosis of this complication requires diligence with clinical scrutiny, as detection may be obscured by the anesthesia delivery (Grade 1C). Perispinal hematomata have been described following the use of either LMWH or UFH. The risk exists for both the insertion and removal of perispinal anesthesia delivery catheters. Risk factors for perispinal hematoma include advanced age, vertebral column malalignment, traumatic insertions, and a history of prior bleeding diathesis. Other factors suspected of predisposing patients to spinal hematoma include enoxaparin overdose, commencing enoxaparin prior to establishment of hemostasis, and use of concurrent medications known to increase bleeding. In general, it is best to wait 12 hours from the last LMWH injection (if bid dose) or 18 hours (if daily dose) before either insertion or retrieval. More than 2 hours should elapse from the time of catheter manipulation before reinitiation of anticoagulants. If the spinal access was traumatic, this time interval should be extended. In a review of neuraxial complications associated with concurrent LMWH or heparinoid prophylaxis and regional anesthesia or analgesia, the following recommendations were provided for patients receiving an initial LMWH dose before surgery: ●

●

regional anesthesia should be avoided in patients with a clinical bleeding disorder or in patients receiving other drugs which potentially may impair hemostasis (e.g., aspirin or non-steroidal anti-inﬂammatory drugs, platelet inhibitors, or other anticoagulants); insertion of the spinal needle should be delayed for 10–12 hours after the initial LMWH injection;

Prophylaxis recommendations

●

regional anesthesia should be avoided in patients with a hemorrhagic aspirate (e.g., “bloody tap”) during the initial spinal needle placement;

●

287

a single-dose spinal anesthetic is preferred over continuous epidural anesthesia;

Guidelines 3.7.0 of the American Venous Forum on current recommendations for prevention of deep vein thrombosis No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.7.1

When the risk of bleeding from pharmacologic agents is high, we 1 recommend using non-pharmacologic methods of venous thromboembolism prophylaxis including elastic compressive stockings, intermittent pneumatic compression devices, leg elevation and early ambulation. Each of these reduces venous thrombotic events by approximately 20%

C

3.7.2

For patients at very high risk for venous thromboembolism we suggest non-pharmacologic methods of venous thromboembolism prophylaxis in combination with pharmacologic agents

2

A

3.7.3

For patients with acute venous thromboembolism within 1 month, who undergo urgent/emergency surgery or if other circumstances prohibit anticoagulation we recommend placement of an inferior vena cava ﬁlter

1

C

3.7.4

An inferior vena cava ﬁlter may be suitable for prophylaxis for the multiple 2 trauma patient with bleeding risk precluding pharmacologic prophylaxis

C

3.7.5

The indications for temporary, retrievable, or optional inferior vena cava ﬁlters are the same as those for permanent inferior vena cava ﬁlters

1

C

3.7.6

Aspirin is either ineffective or inferior to other forms of venous thromboembolism prophylaxis. Its use provides modest beneﬁt at best and we do not recommend it alone for prophylaxis

1

A

3.7.7

For moderate-risk patients, venous thromboembolism prophylaxis may include low-dose unfractionated heparin or prophylactic dose low-molecular-weight heparin (< 3400 units/day)

1

A

3.7.8

For high-risk general surgery patients, elastic compression stockings should be combined with either low-dose heparin (5000 units tid) or low-molecular-weight heparin (> 3400 units/day)

1

A

3.7.9

In very high-risk general surgical patients with multiple concomitant risk factors, the use of either unfractionated heparin (5000 units tid), low-molecular-weight heparin (> 3400 units/day) or fondaparinux is appropriate and should be combined with mechanical prophylaxis

1

A

3.7.10 Following total joint replacement or hip fracture surgery we recommend appropriate venous thromboembolism prophylaxis for 10 days

1

A

3.7.11 For patients undergoing total hip arthroplasty or hip fracture surgery, prophylaxis should be continued for 4 weeks, particularly in patients with continuing venous thromboembolism risk factors (e.g., a previous history of VTE, obesity, continued immobilization, bilateral simultaneous total knee replacement)

1

A

3.7.12 Low-dose unfractionated heparin or low-molecular-weight heparin are acceptable prophylactic agents for high-risk patients in neurosurgery

2

B

3.7.13 Low-dose unfractionated heparin is safe and effective prophylaxis for hospitalized patients with other general medical conditions

1

A

288

●

●

Current recommendations for prevention of deep venous thrombosis

for patients receiving continuous anesthesia, the epidural catheter should be left indwelling overnight and removed the following day; LMWH should be delayed for at least 2 hours after spinal needle placement or catheter removal.

For patients in whom spinal hematoma is suspected, diagnostic imaging and deﬁnitive surgical therapy must be performed as rapidly as possible in order to avoid permanent paresis. In summary, all patients receiving neuraxial anesthesia and anticoagulant prophylaxis should be monitored carefully and frequently for early signs of cord compression (Grade 1C).

Acute stroke with lower extremity paralysis Low-dose heparin and LMWH are effective as prophylaxis after acute stroke with paresis or paralysis (Grade 1A). Intermittent pneumatic compression combined with lowdose heparin is more effective prophylaxis than low-dose heparin alone.93 In the patient with stroke associated with cerebral hemorrhage in whom anticoagulation is contraindicated, IPC is an appropriate alternative (Grade 1C).

Other medical conditions Low-dose unfractionated heparin is safe and effective prophylaxis for hospitalized patients with other general medical conditions (Grade 1A).94 For bleeding patients, IPC would be expected to provide similar prophylaxis efﬁcacy (Grade 1C). A recent clinical trial found LMWH to be more effective than placebo among hospitalized patients with acute medical illnesses.94 Whether LMWH is more effective than low-dose heparin is unknown. Extrapolating from other clinical trial data, combination prophylaxis with IPC, elastic compression stockings, and low-dose heparin, or LMWH prophylaxis is appropriate for patients with multiple concomitant risk factors.

CONCLUSIONS In summary, VTE is the most common preventable cause of death and suffering. Providing appropriate VTE prophylaxis is the highest ranked safety practice for patients at risk. Recognition of the patient at risk and delivery of appropriate prophylaxis is imperative in order to reduce the incidence of VTE (including fatal PE) in hospitalized patients.

REFERENCES 1. Silverstein MD. Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585–93.

2. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162: 1245–8. 3. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809–15. 4. Geerts WH, Pineo GF, Heit JA, et al. Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338S–400S. 5. US Bureau of the Census. Statistical Abstract of the United States: 2000, 120th edn. Washington, DC: US Bureau of the Census 2000. 6. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006; 166: 772–80. 7. Goldhaber SZ, Tapson VF. DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasoundconﬁrmed deep vein thrombosis. Am J Cardiol 2004; 93: 259–62. 8. Flordal PA, Bergqvist D, Burmark US, et al. Risk factors for major thromboembolism and bleeding tendency after elective general surgical operations. Eur J Surg 1996; 162: 783–789. 9. Hendolin H, Mattila MAK, Poikolainen E. The effect of lumbar epidural analgesia on the development of deep vein thrombosis of the legs after open prostatectomy. Acta Chir Scand 1981; 147: 425–29. 10. Fletcher JP, Batiste P. Incidence of deep vein thrombosis following vascular surgery. Int Angiol 1997; 16: 65–8. 11. Farkas JC, Chapuis C, Combe S, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing vascular surgery. Eur J Vasc Surg 1993; 7: 554–60. 12. Vandenbroucke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453–7. 13. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med 2000; 160: 49–52. 14. Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein Sdeﬁciency taking oral contraceptive medication: the GTH Study Group on Natural Inhibitors. Thromb Haemost 1994; 71: 548–52. 15. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Arch Intern Med 2004; 164: 1965–76.

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30. Prandoni P, Lensing AW, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128–33. 31. Ten Wolde M, Kraaijenhagen RA, Schiereck J, et al. Travel and the risk of symptomatic venous thromboembolism. Thromb Haemost 2003; 89: 499–505. 32. Lapostolle FK, Surget V, Borron SW, et al. Severe pulmonary embolism associated with air travel. N Engl J Med 2001; 345: 779–83. 33. Baglin TP, Brush J, Streiff M. British Committee for Standards in Haematology Writing Group. Guidelines on use of vena cava ﬁlters. Br J Haematol 2006; 134: 590–5. 34. Hirsh J. Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S–203S. 35. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S–37S. 36. Turpie AG, Eriksson BI, Lassen MR, Bauer KA. Fondaparinux, the ﬁrst selective factor Xa inhibitor. Curr Opin Hematol 2003; 10: 327–32. 37. Ansell J, Hirsh J, Poller L, et al. The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 204S–33S. 38. Van der Meer F, Rosendaal F, Vandenbroucke J. Briet E. Bleeding complications in oral anticoagulant therapy. Arch Intern Med 1993; 153: 1557–62. 39. Cannegieter S, Rosendaal F, Wintzen A, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11–7. 40. Palareti G, Leali N, Coccheri S, et al. on behalf of the Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423–8. 41. Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost 1996; 22: 185–96. 42. Toschi V, Lettino M, Gallo R, et al. Biochemistry and biology of hirudin. Coron Artery Dis 1996; 7: 420–8. 43. Lefevre G, Duval M, Gauron S, et al. Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin. Clin Pharmacol Ther 1997; 62: 50–9. 44. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efﬁcacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997; 79: 326–33. 45. Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecularweight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329–35.

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46. Ginsberg JS, Nurmohamed MT, Gent M, et al. Use of Hirulog in the prevention of venous thrombosis after major hip or knee surgery. Circulation 1994; 90: 2385–9. 47. Wolf H, Encke A, Haas S, Welzel D. Comparison of the efﬁcacy and safety of Sandoz low molecular weight heparin and unfractionated heparin: interim analysis of a multicenter trial. Sem Thromb Hemostas 1991; 17: 343–6. 48. Efﬁcacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group. Br J Surg 1997; 84: 1099–103. 49. McLeod RS, Geerts WH, Sniderman KW, et al. Canadian Colorectal Surgery DVT Prophylaxis Trial investigators. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the Canadian colorectal DVT prophylaxis trial: a randomized, double-blind trial. Ann Surg 2001; 233: 438–44. 50. Simonneau G, Laporte S, Mismetti P, et al. FX140 Study Investigators. A randomized study comparing the efﬁcacy and safety of nadroparin 2850 IU (0.3 mL) vs, enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. J Thromb Haemostas 2006; 4: 1693–700. 51. Olin JW, Graor RA, O’Hara P, Young JR, The incidence of deep venous thrombosis in patients undergoing abdominal aortic aneurysm resection. J Vasc Surg 1993; 18: 1037–41. 52. Hollyoak M. Woodruff P. Muller M. Daunt N. Weir P. Deep venous thrombosis in postoperative vascular surgical patients: a frequent ﬁnding without prophylaxis. J Vasc Surg 2001; 34: 656–60. 53. Francis CW, Pellegrini VD Jr, Totterman S, et al. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. J Bone Joint Surg Am 1997; 79: 1365–72. 54. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a doubleblind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2199–207. 55. RD Heparin Arthroplasty Group. RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg Am 1994; 76: 1174–85. 56. Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370–6. 57. Hamulyak K, Lensing AW, van der Meer J. et al. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group. Thromb Haemost 1995; 74: 1428–31.

58. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. PENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–6. 59. Lassen MR, Bauer KA, Eriksson BI, Turpie AG, European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715–20. 60. Robinson KS, Anderson DR, Gross M, et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the postarthroplasty screening study. A randomized, controlled trial. Ann Intern Med 1997; 127: 439–45. 61. Lieberman JR, Sung R, Dorey F, et al. Low-dose warfarin prophylaxis to prevent symptomatic pulmonary embolism after total knee arthroplasty. J Arthroplasty 1997; 12: 180–4. 62. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous lowmolecular-weight heparin vs warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective. Arch Intern Med 1997; 157: 298–303. 63. Heit JA, Berkowitz SD, Bona R, et al. Efﬁcacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group. Thromb Haemost 1997; 77: 32–8. 64. Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370–6. 65. Colwell CW Jr, Kwong LM, Turpie AG, Davidson BL, Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopaedic surgery. J Arthroplasty 2006; 21: 36–45. 66. Turpie AG, Bauer KA, Eriksson BI, Lassen MR, Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a metaanalysis of 4 randomized double-blind studies. Arch Intern Med 2002; 162: 1833–40. 67. Eriksson BI, Bauer KA, Lassen MR, Turpie AG. Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298–304. 68. Douketis JD, Eikelboom JW, Quinlan DJ, et al. Shortduration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002; 162: 1465–71.

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81. Petaja J, Myllynen P, Rokkanen P, Nokelainen M. Fibrinolysis and spinal injury: relationship to posttraumatic deep vein thrombosis. Acta Chir Scand 1989; 155: 241–6. 82. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331: 1601–6. 83. Waring WP, Karunas RS. Acute spinal cord injuries and the incidence of clinically occurring thromboembolic disease. Paraplegia 1991; 29: 8–16. 84. DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil 1999; 80: 1411–19. 85. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331: 1601–6. 86. Iskander GA, Nelson RS, Morehouse DL, et al. Incidence and propagation of infrageniculate deep venous thrombosis in trauma patients. J Trauma 2006; 61: 695–700. 87. Geerts WH, Jay RM, Code KI, et al. A comparison of lowdose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335: 701–707. 88. Ginzburg E. Cohn SM, Lopez J, et al. Miami Deep Vein Thrombosis Study Group. Randomized clinical trial of intermittent pneumatic compression and low molecular weight heparin in trauma. Br J Surg 2003; 90: 1338–44. 89. Antevil JL, Sise MJ, Sack DI, et al. Retrievable vena cava ﬁlters for preventing pulmonary embolism in trauma patients: a cautionary tale. J Trauma 2006; 60: 35–40. 90. Vandermeulen EP, Van Aken H. Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994; 79: 1165–77. 91. Horlocker TT, Heit JA. Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg 1997; 85: 874–85. 92. Wysowski DK, Talarico L, Bacsanyi J, Botstein P. Spinal and epidural hematoma and low-molecular-weight heparin. N Engl J Med 1998; 338: 1774–5. 93. Kamran SI, Downey D. Ruff RL. Pneumatic sequential compression reduces the risk of deep vein thrombosis in stroke patients. Neurology 1998; 50: 1683–8. 94. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793–800.

24 The management of axillo–subclavian venous thrombosis in the setting of thoracic outlet syndrome RICHARD M. GREEN AND ROBERT ROSEN Introduction Thrombolysis Management after thrombolysis

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INTRODUCTION

THROMBOLYSIS

With increasing awareness of axillo–subclavian vein thrombosis, early diagnosis and treatment have become the standard of care. No treatment or treatment with anticoagulant therapy alone is suboptimal, resulting in some degree of chronic disability and persistent symptoms of upper extremity venous obstruction in anywhere from 25% to 75% of affected patients.1,2 There is little controversy regarding catheter-directed thrombolytic therapy as the best chance for complete clot dissolution when administered early.3 There are disagreements regarding what to do following thrombolysis and opinions vary between immediate and delayed intervention, anterior versus transaxillary rib resection, and operative versus percutaneous venous reconstruction. Although the pioneering work of Machleder et al.4 indicated that a period of time approaching 6 weeks should elapse between thrombolysis and rib removal, the prevailing current opinion is that thrombolytic therapy should be followed by operative ﬁrst-rib resection and catheter-based intervention of any underlying venous abnormality at the costoclavicular space uncovered during thrombolysis. The potential advantages of such an aggressive strategy are that the risk for recurrent thrombosis is reduced and the patients are more likely to escape the consequences of major venous obstruction on the affected arm.5

The results of catheter-directed thrombolytic therapy for axillo-subclavian venous thrombosis, regardless of etiology, are mostly dependent on the chronicity of the thrombus. Most contemporary series report rates of nearcomplete thrombus clearance when prompt treatment is initiated. The previous chapter discussed the details of thrombolysis. We would like to emphasize the importance of cannulation of the median antecubital vein. Working through the cephalic vein is a mistake and will result in the guide wire entering the subclavian vein central to the thrombus. Fig. 24.1 depicts a case where a delayed diagnosis was made. The patient, a 36 year old woman, developed a swollen blue arm after a strenuous upper body work-out with weights. She went to a local emergency room immediately and an ultrasound was carried out that was interpreted as consistent with an acute axillo– subclavian vein thrombosis. She was anticoagulated with heparin and taken to the interventional radiology suite where a venogram was interpreted as normal. Two weeks later she was referred to us, and another venogram was performed through the femoral vein and an occluded subclavian vein was traversed with a wire (Fig. 24.1). The delay in diagnosis and missed opportunity were likely due to an initial study via the cephalic vein. We often use access

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well with complete relief of her arm swelling during normal activities and some mild swelling with her upper extremity weight lifting. A duplex scan performed 18 months after her treatment (Fig. 24.3) shows excellent ﬂow through the axillo–subclavian vein with some chronic changes consistent with an old deep venous thrombosis. We are reluctant however to continue thrombolytic therapy when no immediate beneﬁt is achieved and almost always stop treatment after 24 hours. Rarely, thrombolysis will not be effective either physiologically or anatomically even when the thrombus can be crossed with a wire and catheter-directed drug administration is possible. The venogram in Fig. 24.4 shows a left subclavian vein

Figure 24.1 Wire is seen in an occluded right subclavian vein. The diagnosis of subclavian vein thrombosis was initially missed when a venogram was performed through the arm and probably through the cephalic vein. When access may be difﬁcult we use the retrograde approach from the femoral vein.

from a femoral vein when the arm is swollen and the basilic vein is obscured or when chronic occlusions necessitate complex recanalization maneuvers. Once our wire was in the occluded axillo-subclavian vein, thrombolysis was initiated. There was clinical improvement over the next 24 hours and a transaxillary right ﬁrst rib resection was performed. A follow-up venogram carried out 2 days after the operation showed some recanalization of the previously occluded vein (Fig. 24.2) and no further intervention was performed This patient has done very

Figure 24.3 Duplex ultrasound at 18 months showing venous patency with chronic changes consistent with prior thrombosis. The patient is much improved with mild swelling after strenuous activity.

Figure 24.2 The result in the patient in Fig 24.1 after 24 hours of thrombolysis and subsequent ﬁrst rib resection. The patient improved clinically and the venogram demonstrates some ﬂow in the previously occluded subclavian vein.

Figure 24.4 Patient with a 2 week history of swelling and pain in his left arm presented with subclavian vein occlusion. Venogram shows signiﬁcant development of collateral veins. We were able to cross the occluded vein with a wire and instituted thrombolytic therapy without any effect after 24 hours.

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Figure 24.5 The patient in Fig 24.4 could not undergo immediate rib resection but because of severe symptoms requested recanalization with a stent. This is not our routine order of care and patient returned for deﬁnitive operation within 1 month. The vein remained patent.

occlusion in an international traveler who sought attention 2 weeks after symptoms began. We were able to cross the occlusion but were not able to achieve recanalization or symptomatic relief. The patient could not stay in New York City for sufﬁcient time to undergo ﬁrst rib removal and therefore requested the vein be opened by any means possible. Reluctantly, we agreed to recanalize the occluded vein with a self-expanding stent (Fig. 24.5). Stent placement prior to operative decompression is not a long-term solution as the stents are subject to compression between the clavicle and ﬁrst rib, fracture, and recurrent thrombosis.6 This patient did return for operative decompression of the thoracic outlet within a month and the vein remains patent at 1 year.

MANAGEMENT AFTER THROMBOLYSIS There is a short-term recurrence rate approaching 30% when the underlying condition responsible for the venous occlusion is neglected.7 Although it was once acceptable to delay therapy after thrombolysis in order to assess the residual venous abnormality and the effect it has on the patient, the treatment algorithm has clearly changed to earlier intervention in young, active patients. Some patients, particularly those who are elderly or sedentary, will remain asymptomatic even if their vein re-occludes and no further intervention is often a reasonable choice. Our preferred approach at this time is to recommend ﬁrst rib resection in the same hospital immediately after thrombolysis. Our preference for these patients is the transaxillary approach as it offers direct visualization and exposure of the costoclavicular space and the site of

venous compression. It also allows the operator to perform an external venolysis when necessary in the presence of extrinsic venous compression. However, if more than venolysis of the subclavian vein is necessary, the anterior approach to the subclavian vein is necessary. Urschel and Kourlis8 challenged the wisdom of waiting to remove the rib and divided a group of patients with subclavian vein thrombosis into those treated with anticoagulation following thrombolysis and those treated with immediate operative decompression of the thoracic outlet. Almost two-thirds of the non-operative group developed recurrent symptoms during a 6 week period of follow-up. In contrast, 89% of those treated with immediate ﬁrst rib decompression following thrombolysis were able to return to work free of symptoms but the follow-up period was only 6 weeks. We have had anecdotal experience with stopping the heparin prior to rib resection and having the vein rethrombose in the post-operative period. The venogram seen in Fig. 24.6 is the result of 24 hours of catheterdirected thrombolysis in a 20 year old baseball player. Two days later he underwent a transaxillary ﬁrst rib resection after his heparin had been stopped. His arm became swollen on the following day and a venogram was performed that showed re-thrombosis of the axillosubclavian vein (Fig. 24.7). The patient was successfully treated with mechanical thrombolysis and stenting as well as re-anticoagulation. We now perform this operation while the patient is fully heparinized, typically place a large suction drain in the axillary space and have not had to reoperate for hematoma. Once the rib is removed, we proceed with another venogram in the neutral and shoulder abducted position. A few patients will have no abnormalities of the subclavian vein in either position and they should be treated with a 3–6 month course of oral anticoagulation. Any extrinsic compressive lesion should have been eliminated by the operative procedure but the majority of patients will have an intrinsic lesion of the subclavian vein in the costoclavicular space. The pivotal question that must be addressed in patients with intrinsic lesions is whether the subclavian vein needs to be treated. We try to individualize

Figure 24.6 Venogram in a 20 year old baseball player showing some recanalization of a completed occluded subclavian vein after 24 hours of catheter-directed thrombolysis. He underwent ﬁrst rib resection 2 days later after heparin was discontinued.

Operative reconstruction of the axillo-subclavian vein

295

Figure 24.7 The patient in Fig. 24.6 developed recurrent arm swelling 2 days after ﬁrst rib resection. The subclavian vein has reoccluded and the patient was successfully treated with mechanical thrombolysis and stenting. The vein has remained patent at 3 years and the patient continues his athletic activities.

our recommendations and those patients with persistent signs of venous obstruction, active life styles and physically demanding vocations should have venous intervention after successful thrombolysis. There are no studies comparing the long-term results of these procedures with less aggressive therapies however. The available options for treating intrinsic subclavian vein lesions include percutaneous transluminal angioplasty (PTA) with or without stent placement postoperatively, open patch angioplasty, or venous bypass at the time of thoracic outlet decompression. Fibrotic lesions at the costoclavicular space are very resistant to balloon angioplasty, often requiring inﬂations in excess of 10 atmospheres. This procedure can be quite painful and we recommend general anesthesia in this setting. The venogram in Fig. 24.8 depicts a patient with signiﬁcant clinical obstruction after thrombolysis and ﬁrst rib resection who underwent percutaneous balloon angioplasty with moderate symptomatic improvement. One year later, this patient returned with more severe venous obstructive symptoms and she was treated with stenting (Fig. 24.9). The image shows the stent prior to balloon expansion. The topic of stenting is covered more fully in the preceding chapter but our feeling is that self-expanding nitinol stents have a deﬁnite place in the treatment of these patients once the bony compression is relieved.

Figure 24.8 Venogram in a patient after thrombolysis and ﬁrst rib resection showing intrinsic obstruction of the subclavian vein. She was treated with balloon angioplasty with some relief of her obstructive symptoms.

Figure 24.9 The patient in Fig 24.8 returned 1 year later with more severe symptoms of obstruction and was treated with stenting. The image shows the stent prior to balloon expansion.

OPERATIVE RECONSTRUCTION OF THE AXILLO–SUBCLAVIAN VEIN The need for operative repair of the axillo–subclavian vein has been reduced signiﬁcantly by catheter-based therapies performed immediately after thrombolysis and ﬁrst rib

resection. We now reserve operative repair for those patients with disabling symptoms that have failed percutaneous therapies. This approach of delaying operative repair makes the reconstructive procedure more

296

The management of axillo–subclavian venous thrombosis in the setting of thoracic outlet syndrome

difﬁcult because these patients will have already had bony decompression of the thoracic outlet. Exposure of the subclavian vein with the intent of repair requires an anterior approach. The likelihood that the subclavian vein has been stented in the past is high and that means that some sort of venous bypass will be necessary. In the unlikely situation that a stent has not been placed a patch angioplasty is sometimes possible. The operative photograph in Fig. 24.10 demonstrates the exposure of the subclavian vein after a medial claviculectomy. The subclavian vein has been opened longitudinally, the post-thrombotic web will be excised, and a saphenous vein patch will be applied.

Figure 24.10 Operative exposure of the subclavian vein. The medial third of the clavicle has been excised. The vein has been opened longitudinally and the obstructing post-phlebitic web can be seen. A saphenous vein patch was applied with an excellent long-term result.

Figure 24.11 Venogram performed 2 years after a jugular venous turndown and medial claviculectomy in a 36 year auto mechanic. The patient describes no symptoms in his dominant right arm and reports that he can perform his physical job requirements without difﬁculty.

Excision of the medial clavicle when direct venous access is required allows for disarticulation of the sternoclavicular joint and easy access to the involved venous structures.9,10 This approach is particularly useful when an internal jugular vein to axillary vein bypass is planned. If one mobilizes the internal jugular vein up to the base of the skull there is enough length to turn down in the neck to the supraclavicular portion of the axillary vein. The venogram in Fig. 24.11 demonstrates the appearance of this bypass after 2 years. If more conduit length is necessary, the venous reconstruction can be performed using a spiraled saphenous vein (Fig. 24.12) This procedure can be performed without a medial claviculectomy but we prefer to use one to lessen the chance of bony compression of the bypass with shoulder abduction. We are aware of the cosmetic problems and occasional discomfort that can occur in some patients after medial claviculectomy. In some cases there is a minor loss of power in the affected extremity. Nonetheless, for properly selected patients (signiﬁcant arm swelling, signiﬁcant aching after modest arm use, highly active individual) with signiﬁcant subclavian venous obstruction after thrombolysis, medial claviculectomy and venous reconstruction provide excellent long-term patency with relatively few side-effects.11 An alternative approach to the repair of the subclavian vein and decompression of the outlet was proposed by Molina.12 After removal of the ﬁrst rib and the scalene muscles through an anterior subclavicular approach, the incision is continued into the sternum and then upward into the sternal notch. The mediastinal tissues are dissected away, and the innominate and subclavian veins are easily exposed. Although this approach leaves the sternoclavicular joint intact and may reduce some of the minor postoperative complaints after claviculectomy, it does not provide sufﬁcient access to the jugular vein for a

Figure 24.12 Use of a spiraled saphenous vein for a long venous repair to the infraclavicular portion of the axillary vein. The vein was constructed over a 14F chest tube. This approach does not require a medial claviculectomy.

The editor’s comments

transposition. We believe that this approach is useful when venous reconstruction of the innominate vein is required. We have steadily moved from a treatment algorithm of venous repair only after failure of thrombolysis and bony decompression to immediate percutaneous therapy following bony decompression. A single-staged procedure is appealing because waiting to solve the venous obstruction may preclude the only chance these patients have to be cured before severe ﬁbrosis takes place in the affected vein. Nonetheless, this transition has been accomplished largely on anecdotal information as the long-term behavior of venous stents in the subclavian vein remains an unknown and some early reports raise caution about the durability.13 In conclusion, the treatment of subclavian venous thrombosis due to thoracic outlet compression has gone through a major change with the advent of percutaneous therapies. We currently believe that the combination treatment of venous thrombolysis followed by thoracic outlet decompression is safe and effective. Although we may in the immediate postoperative period elect to perform a balloon angioplasty for a severe intrinsic lesion and persistent arm swelling, we feel that stent placement is rarely indicated. If symptoms persist or recur we give patients two options: stent placement or direct venous repair. In this era most patients opt for stenting. If the stent fails, operative repair of the vein is indicated. If a stent is placed it will make operative repair of the vein more complicated, likely requiring the use of a spiral vein graft.

THE EDITOR’S COMMENTS In this excellent chapter Drs Green and Rosen summarize a large number of examples of endovascular and open surgical treatment of axillary–subclavian venous thrombosis and provide a useful and proven algorithm for management. A slightly different approach accepted by the editor’s group and by several members of the American Venous Forum deserves to be mentioned. Molina14 recently reported results of 114 patients treated for effort thrombosis of the subclavian vein. There was 100% success in re-establishing the ﬂow and normal caliber of the subclavian vein in the 97 patients who presented early after thrombosis and had thrombolysis followed by immediate open surgery, which included resection of the medial portion of the ﬁrst rib, with, or, in most patients, without partial median sternotomy. Venous reconstruction was usually performed with vein patch angioplasty. Seven patients required balloon angioplasty and stenting. Early primary assisted patency was 100%. Only 29% of the patients had successful surgery if surgery was delayed. We agree with the authors that an emergent approach to treat effort-related subclavian vein thrombosis seems to be effective in re-establishing venous ﬂow in the subclavian vein and that thrombolysis with early open surgery to treat the underlying venous pathology gives the best long-term results.

Guidelines 3.8.0 of the American Venous Forum on the management of axillo–subclavian venous thrombosis in the setting of thoracic outlet syndrome No.

297

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.8.1 For axillary–subclavian venous thrombosis in patients with thoracic outlet syndrome we recommend venous thrombolysis followed by thoracic outlet decompression. This combination is safe and effective

1

B

3.8.2 We do not recommend subclavian vein stenting in the immediate postoperative period following thrombolysis and surgical decompression for subclavian vein thrombosis in the setting of thoracic outlet syndrome

1

B

3.8.3 For patients with residual stenosis following thrombolysis for subclavian vein thrombosis in the setting of thoracic outlet syndrome we suggest early surgical decompression and direct open surgical repair, or alternatively, stent placement

2

C

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The management of axillo–subclavian venous thrombosis in the setting of thoracic outlet syndrome

REFERENCES 1. Hughes ESR. Venous obstruction in the upper extremity (Paget-Schroetter’s syndrome): a review of 320 cases. Int Abstract Surg 1949; 88: 89–127. 2. Tilney NL, Grifﬁths HJG, Edwards EA. Natural history of major venous thrombosis of the upper extremity. Arch Surg 1970; 101: 792–6. 3. Druy EM, Trout HH III, Giordano JM, Hix WR. Lytic therapy in the treatment of axillary and subclavian vein thrombosis. J Vasc Surg 1985; 2: 821–7. 4. Machleder HI. Upper extremity venous occlusion. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery, 3rd edn. St Louis, MO: Mosby-Year Book, 1995: 958–63. 5. Lee C, Grassi J, Belkin M, et al. Early operative intervention after thrombolytic therapy for primary subclavian vein thrombosis: an effective treatment approach. J Vasc Surg 1998; 27: 1101–8. 6. Lee J, Karwowski J, Harris EJ, et al. Long-term thrombotic recurrence after nonoperative management of PagetSchroetter syndrome. J Vasc Surg 2006; 43: 1236–43. 7. Stange-Vognsen HH III, Hauch O, Anderson J, Struckmann J. Resection of the ﬁrst rib following deep arm vein

8.

9. 10.

11.

12. 13.

14.

thrombolysis in patients with thoracic outlet syndrome. J Cardiovasc Surg 1989; 30: 430–3. Urschel HC, Kourlis H. Thoracic outlet syndrome: a 50-year experience at Baylor University Medical Center. Proc Bayl Univ Med Cent 2007; 2: 125–35. DeWeese JA, Adams JT, Gaiser DL. Subclavian venous thrombectomy. Circulation 1970; 42 (Suppl): 158–64. Aziz S, Straehley CJ, Whelan TJ. Effort-related axillosubclavian vein thrombosis. Am J Surg 1986; 152: 57–61. Green RM, Waldman D, Ouriel K, et al. Claviculectomy for subclavian venous repair: Long-term functional results: J Vasc Surg 2000; 32: 315–21. Molina, JE. A new surgical approach to the innominate and subclavian vein. J Vasc Surg 1998; 27: 576–81. Kreienberg PB, Chang BB, Darling RC 3rd, et al. Long-term results in patients treated with thrombolysis, thoracic inlet decompression, and subclavian vein stenting for PagetSchroetter syndrome. J Vasc Surg 2001; 33 (2 Suppl): S100–5. Molina JE, Hunter DW, Dietz CA. Paget-Schroetter syndrome treated with thrombolytics and immediate surgery. J Vasc Surg 2007; 45: 328–34.

25 Indications, techniques, and results of inferior vena cava filters VENKATARAMU N. KRISHNAMURTHY, LAZAR J. GREENFIELD, MARY C. PROCTOR AND JOHN E. RECTENWALD Introduction Background Indications for inferior vena cava ﬁlter placement Contraindications to inferior vena cava ﬁlter placement Filter characteristics: which one is an ideal ﬁlter? Types of inferior vena cava ﬁlters Techniques of inferior vena cava ﬁlter placement Venous access Inferior venacavogram Intravascular ultrasound and transabdominal duplex ultrasound-guided placement of IVC ﬁlters

299 299 300 301 302 302 306 306 306 307

Transabdominal duplex ultrasound technique Intravascular ultrasound technique Follow-up of inferior vena cava ﬁlters Complications of inferior vena cava ﬁlters Comparison of performance between inferior vena cava ﬁlters Suprarenal inferior vena cava and superior vena cava ﬁlters Conclusion References

307 308 308 308 309 310 310 312

INTRODUCTION

BACKGROUND

The majority of pulmonary emboli (PEs) arise from thrombosis in the deep veins of legs and pelvis. The treatment of choice for venous thromboembolism (VTE) is anticoagulation. Unfortunately, many patients cannot be adequately treated with anticoagulation alone, or have signiﬁcant contraindications to anticoagulation. This subset of patients requires placement of venous ﬁlter devices that provide partial interruption of the inferior vena cava (IVC) to prevent PE. The goal of IVC ﬁlter placement is to trap clinically signiﬁcant thromboemboli without causing complete occlusion of the IVC. Pulmonary embolism due to thrombi arising from upper extremity veins is controversial although thrombosis in these veins has increased in frequency because of increased use of these veins for the placement of central venous catheters for the administration of medication and hemodialysis access. The recent advent of removable or “optional retrievable” IVC ﬁlters has broadened the indications for the use of IVC ﬁlters to include prophylactic placement, although this is currently controversial. In this chapter, we discuss the indications, clinical use, efﬁcacy, insertion techniques, and complications of IVC ﬁlters.

John Hunter introduced one of the earliest techniques for prevention of PE when he ligated the femoral vein at the level of the thrombus. Later Homans addressed the problem by ligating both of the femoral veins. When these techniques failed to prevent recurrent PE, ligation of IVC was performed. Inferior vena cava ligation involved a laparotomy under general anesthesia in patients with signiﬁcant pulmonary hypertension, right heart failure and associated oxygenation deﬁcits, and was associated with signiﬁcant morbidity from lower extremity edema, stasis ulceration, and post-thrombotic syndrome. Moreover, ligation of the IVC was associated with a recurrent PE rate of up to 15% from the development of collateral vessels around the ligated segment. Mortality following ligation was unacceptably high ranging from 4% in low-risk patients to 39% in patients with signiﬁcant cardiac disease.1 Improvements in surgical vena caval interruption techniques involved suture or staple grids and external caval clips in an effort to preserve channels for blood ﬂow while preventing PE. These procedures, although an improvement on IVC ligation, were also fraught with complications. Today, ligation and placation of the IVC are mainly of historical interest.

300

Indications, techniques, and results of inferior vena cava ﬁlters

In the late 1960s, the Mobin–Uddin umbrella was introduced and became widely utilized because of its efﬁcacy and ease of placement compared with the contemporary surgical treatment options. Although it effectively prevented pulmonary embolism, it did so at the expense of caval patency and was associated with an IVC occlusion rate reported to be as high as 65%.2 In addition, there were signiﬁcant problems with caval ﬁxation that resulted in frequent migration of the device into the right heart or pulmonary artery. As a result, it was later withdrawn from the market. The Greenﬁeld ﬁlter was ﬁrst used in 1972 to provide protection against PE and is the benchmark to which all other ﬁlters are currently compared. As a result of its then unique conical design, the long-term patency rate has been above 95% over the past 27 years.3 Mathematical modeling and in vitro studies have proved that the unique design allows up to 70% of the cone volume to be ﬁlled with thrombus, resulting in 50% of IVC obstruction before signiﬁcant reduction in blood ﬂow occurs. The original 24 French (Fr) stainless steel ﬁlter was developed for operative insertion via a femoral or internal jugular venotomy under local anesthesia. The operative procedure was preceded by a venacavogram to determine the shape and size of the vena cava to rule out caval anomalies and to allow identiﬁcation of the appropriate site for placement. The use of the Seldinger technique for access to the vascular system and percutaneous placement of the 24Fr Greenﬁeld ﬁlter naturally evolved, but a high rate of insertion site thrombosis secondary to the large 28Fr access sheath was noted.4,5 As a result of these concerns, devices with smaller delivery systems were developed that allowed for safer percutaneous delivery. By eliminating the need for the operative venous exposure and the surgical operating room, the cost of the procedure could be reduced. With the new-found ease of insertion and reduced procedural cost, the use of vena caval ﬁlters increased signiﬁcantly to the rate of 100 000 ﬁlter placements per year seen in 2003, with an industry estimated increase of 16% per year.6

INDICATIONS FOR INFERIOR VENA CAVA FILTER PLACEMENT The indications for IVC ﬁlter placement are well established. These indications include the presence of deep vein thrombosis (DVT) and/or PE and patients with a baseline contraindication to anticoagulation, those who suffer a complication from anticoagulation or who develop recurrent DVT or PE despite adequate (therapeutic) anticoagulation, and patients who previously have had a massive PE and cannot tolerate the further cardiopulmonary insult that would be associated with an additional PE. Other accepted, but more controversial, indications for IVC ﬁlter placement include the presence of a free-ﬂoating thrombus greater than 5 cm in length

BOX 25.1 Indications for inferior vena cava (IVC) filter placement Common indications ● Contraindication to anticoagulation in patients with pulmonary embolism (PE)/deep vein thrombosis (DVT) ● Complications of anticoagulation ● Failure of anticoagulation due to progression of DVT, recurrent PE, or noncompliance ● Massive, life-threatening PE with residual DVT despite anticoagulation ● Free-ﬂoating thrombus in IVC, iliac or pelvic veins ● Chronic, recurrent PE with pulmonary hypertension and cor pulmonale Indications speciﬁcally for prophylactic IVC ﬁlter Patients with prior PE with signiﬁcantly increased risk for second PE or those with poor cardiopulmonary reserve ● Patients with a signiﬁcant burden of proximal DVT or free-ﬂoating thrombus ● Patients at high risk for complications of thromboembolism (malignancies and major/multiple trauma) ● Patients who cannot receive anticoagulants (internal organ injury, active internal bleeding) ● Multiple risk factors for DVT in a preoperative patient ●

within an iliac vein or the IVC (Box 25.1). These indications for ﬁlter placement are discussed in detail below. The most generally accepted indications for prophylactic IVC ﬁlter placement are the presence of risk factors that simultaneously predispose the patient to a high risk of PE and a contraindication to standard DVT prophylaxis agents.

Contraindications to anticoagulation This is the most frequently cited reason for selecting IVC ﬁlter placement over standard anticoagulation therapy. Major contraindications to anticoagulation are serious active bleeding, recent spinal cord or brain injury, recent stroke, surgery, or trauma. Advanced age and pregnancy are also considered as relative contraindications to anticoagulation but remain controversial. Many contraindications to anticoagulation therapy are self-limited or are reversed over time, allowing anticoagulation to be started at a later time. This advocates the increased use of retrievable IVC ﬁlters. Malignancy has long been known to carry a signiﬁcantly increased risk of VTE. The reported incidence of PE in the literature is somewhere between 7–50% in patients with malignancy.7 Two studies have estimated the risks of PE in cancer patients to be approximately 3.6-fold

Contraindications to inferior vena cava ﬁlter placement

higher than in patients without malignancy.8,9 These same patients that are at increased risk for VTE also appear to be at increased risk of bleeding while receiving anticoagulation therapy.8,10,11 Debate regarding the use of IVC ﬁlters in the setting of malignancy has persisted since the 1990s. Despite frequent use for this indication and continued attempts to clarify their role, the proper use of IVC ﬁlters in the setting of malignancy remains a point of contention. In such a complex issue, there is no simple and straightforward answer. Undoubtedly there is a subset of cancer patients, even some with metastatic disease, who will beneﬁt from IVC ﬁlter placement. There is also a large group with advanced disease and short life expectancy who are unlikely to derive any clinical beneﬁt from ﬁlter placement. However, patients with cancer who have standard indications for an IVC ﬁlter should not be denied the procedure on a purely ﬁscal basis.

Complications of anticoagulation The major complication associated with anticoagulation is bleeding. Five to 10% of patients treated with intravenous heparin will develop a bleeding complication during therapy. The severity of bleeding is variable. The risk of bleeding while on heparin appears to be dose dependent and varies with the patient’s inherent risk, i.e., prior surgery or trauma, predisposing clinical factors or underlying haemostatic conditions.12,13 In addition to bleeding complications, heparin-induced thrombocytopenia develops in 1.1–2.9% of patients receiving unfractionated heparin.14 Should this occur, all heparin must be discontinued, even that used for ﬂushing lines and catheters as the condition responds to cessation of therapy. Rarely, patients may develop sensitivity to heparin with development of a cutaneous rash or anaphylaxis. The incidence of these complications is much lower with the use of low-molecular-weight heparins. Osteoporosis has also been found in a small number of patients and may develop when prolonged heparin therapy is used during pregnancy.15 Bleeding may also occur in up to 10% of patients treated with warfarin (Coumadin). The degree of bleeding is most often associated with the inactivation of the clotting cascade as indicated by the international normalized ratio (INR). Patients with a signiﬁcantly elevated INR are more likely to develop major hemorrhagic complications than those with mildly elevated levels.16 Routine monitoring and dietary counseling will help to prevent such complications. Monitoring should also be undertaken when there has been a change in concomitant medications. Several drugs have either a synergistic or antagonistic interaction with warfarin, resulting in decreased efﬁcacy or increased risk of adverse events. In addition to bleeding complications, a small number of patients develop warfarin-associated skin necrosis, which usually is seen early and in the absence of adequate

301

concurrent heparin treatment. It is most likely to occur in areas of increased subcutaneous fat and may also be associated with the “blue toe” syndrome. Should this develop, the drug must be promptly discontinued.17

Failure of anticoagulation Failure of anticoagulation to prevent recurrent thromboembolic events is another common indication for ﬁlter placement. Prior to determining that anticoagulation has failed, it should be established that the patient was adequately anticoagulated to begin with. Many times, failures of anticoagulation are failures to reach therapeutic drug levels. The patient who develops recurrence or extension of thromboembolism while anticoagulated may, in fact, not be adequately anticoagulated or simply noncompliant. In order to reduce this risk, patients should be monitored closely during the initiation of therapy with heparin to assure they are therapeutic within the ﬁrst 24 hours. For low-molecular-weight heparin, patients become therapeutic with an appropriate weight-based dose. Nomograms have been developed to insure that this takes place.18,19 Recurrent PE in the face of adequate anticoagulation or severe cor pulmonale is a standard indication for ﬁlter placement.20 The risk from further embolism is considered sufﬁcient to warrant ﬁlter placement.

Indications for prophylactic inferior vena cava filter placement Indications for IVC ﬁlter as a prophylactic measure are listed in Box 25.1. More recently prophylactic ﬁlters have been used in patients who do not yet have DVT or PE but, because of their associated medical conditions (malignancies and traumatic injuries), are at great risk of experiencing such events.21 The constellation of traumatic injuries that constitutes high risk includes brain injury, spinal cord injury, and pelvic and lower extremity long bone fractures. There is a 50-fold increase in thromboembolic complications compared with other trauma patients.22 The use of IVC ﬁlters in these patients has been criticized. By itself, the ﬁlter protects against PE, but does nothing to prevent additional episodes of thrombosis or treat existing DVT. There are also concerns about increased healthcare costs and procedural morbidity/ mortality.22–27 It is possible that, as optional retrievable ﬁlters become more widespread and better studied, they may become more widely accepted in such cases.

CONTRAINDICATIONS TO INFERIOR VENA CAVA FILTER PLACEMENT The only absolute contraindications to IVC ﬁlter insertion are complete thrombosis of the IVC and inability to gain

302

Indications, techniques, and results of inferior vena cava ﬁlters

access to the IVC because of severe venous obstruction. Another contraindication is uncorrectable, severe coagulopathy or thrombocytopenia, in which cases surgical venotomy and surgical placement may be safer, although IVC ﬁlters with low-proﬁle delivery devices may be useful in these cases. Careful evaluation of the risks versus beneﬁts of ﬁlter placement should be done in such patients. Special situations requiring caution prior to ﬁlter placement include patients with untreated or uncontrolled bacteremia who should be treated with immediate and appropriate antibiotic treatment, and ﬁlter placement in pediatric patients and pregnant women because of uncertain long-term effects and durability of the ﬁlters. Again, retrievable ﬁlters may have a role in these patients depending on the speciﬁcs of these cases. If an IVC ﬁlter must be placed in a pregnant woman or woman of childbearing age, placement of the ﬁlter in the suprarenal position should be considered to avoid the potential complication of compression of the ﬁlter by the enlarging uterus.

FILTER CHARACTERISTICS: WHICH ONE IS AN IDEAL FILTER? Several designs of ﬁlters in various size and shapes are available for clinical use. Availability of such wide range of ﬁlters by itself suggests that not one type by itself is ideal. Characteristics of an ideal ﬁlter are described in Box 25.2. The most important desirable factors are high ﬁltering efﬁciency (large and small emboli) without impedance of blood ﬂow, stability of positioning and structure, and a low rate of associated morbidity.

BOX 25.2 Characteristics of an ideal filter 1 High ﬁltering efﬁciency for both large and small emboli without impedance of blood ﬂow 2 Stability of position / ﬁxation and structural integrity 3 Low procedural morbidity; no mortality; low cost 4 Ideal biomechanical property: biocompatible, nonthrombogenic, MRI compatible 5 Ideal delivery system: small caliber, easy deployment with ability to reposition 6 Safe retrievability when no longer needed

TYPES OF INFERIOR VENA CAVA FILTERS The Greenﬁeld ﬁlter was originally introduced in 1972 (Fig. 25.1). It is constructed of stainless steel and it was intended for open surgical placement via a 28 Fr sheath. It has been discontinued from clinical use and replaced with

Figure 25.1 The original stainless steel Greenﬁeld ﬁlter ﬁrst used in 1972. Used with permission from Vascular Surgery, 4th edn, Rutherford RB, ed. Philadelphia, PA: W.B. Saunders Company, 1995.

a lower proﬁle system. In addition to the Greenﬁeld ﬁlter, several new IVC ﬁlters are available for clinical use. Currently there are 10 FDA-approved IVC ﬁlters available for use in the USA (Table 25.1). Most of the ﬁlters are permanent devices and a brief description of these devices follows.

Titanium Greenfield filter The titanium version of the Greenﬁeld ﬁlter has a conical conﬁguration consisting of six struts that are compressed into a 12 Fr carrier (14.3 Fr outer diameter sheath). The sheath is inserted with a guide wire, but actual ﬁlter deployment occurs without the use of a guide wire, unlike the original and stainless steel over-the-wire design. The ﬁlter is designed for IVC diameters smaller than 28 mm. The ﬁlter comes in femoral and jugular versions.

Stainless steel over-the-wire Greenfield filter The ﬁlter has six stainless steel struts that are press-ﬁtted into a cylindrical cap with a hole that the guide wire can pass through. This ﬁlter is placed over a centering guide wire to address frequently encountered instances of ﬁlter tilting and asymmetry with the titanium version. The hooks of four of the legs point superiorly, and two opposite hooks point inferiorly to prevent migration. The hooks are also “recurved” forming a complete circle before protruding to decrease the degree of hook penetration. There are separate femoral and jugular versions of this ﬁlter. The ﬁlter is safe for magnetic resonance imaging (MRI) but causes a signiﬁcant amount of artifact (Fig. 25.2a).

Types of inferior vena cava ﬁlters

303

Table 25.1 Permanent inferior vena cava ﬁlters Name

Titanium Greenﬁeld Over-the-WireStainless steel Greenﬁeld VenaTech/LGM Low Proﬁle VenaTech Simon Nitinol TrapEase Bird’s Nest

Manufacturer

Year introduced

FDA approval

Delivery system size

Maximum diameter (mm)

Length (mm)

Material

MRI compatibility

Boston Scientiﬁc/ Medi-tech, Natick, MA Boston Scientiﬁc/ Medi-tech, Natick, MA

1988

1989

14.3 Fr

38

47

Titanium

Compatible

1994

1995

15 Fr

32

49

Stainless steel

Not compatible

1986

1989

14.6 Fr

30

38

Phynox

Compatible

2000

2001

9 Fr

40

43

Phynox

Compatible

1988 1998 1982

1990 2000 1989

9 Fr 8 Fr 14 Fr

28 35 40

45 50–65 70–110

Nitinol Nitinol Stainless steel

Compatible Compatible Not compatibleCreates large artifacts

B Braun Medical, Evanston, IL B. Braun, Boulogne, France Bard, Covington, GA Cordis, Miami, FL Cook, Bloomington, IN

LGM or VenaTech filter This ﬁlter has a six-strut conical conﬁguration with side rails containing hooklets that provide caval centering and ﬁxation, respectively. The ﬁlter is designed for IVC diameters of 28 mm or less. The ﬁlter comes loaded in an injection syringe, with the orientation of ﬁlter injection into the sheath determined by the access route (femoral or jugular) (Figure 25.2d).

VenaTech low-profile filter

two levels of ﬁltration. The ﬁlter daisy wheel has seven overlapping loops. The ﬁlter is manufactured from Nitinol (an alloy of nickel and titanium), which has unique thermal–mechanical memory properties, which allow the ﬁlter to exist in the straightened but ﬂexible form at room temperatures (< 27°C) within the 6 Fr delivery carrier and reform into a predetermined designed ﬁlter shape at body temperatures. The ﬁlter is designed for IVC diameters of 28 mm and smaller. The ﬁlter can be deployed from femoral or jugular and antecubital routes (Fig. 25.2c).

TrapEase filter

Instead of six side struts as with the original VenaTech ﬁlter, this design uses eight Phynox wires formed in a conventional conical conﬁguration with welded hooks, some oriented superiorly and others inferiorly. The lateral, side-rail conﬁguration of these wires allows for caval centering and stabilizing. The ﬁlter is approved for use in IVC diameters as large as 35 mm. The low-proﬁle ﬁlter can be deployed from femoral or jugular and antecubital routes. The low-proﬁle design uses a similar syringe injection system to properly orient the ﬁlter for femoral or jugular uses (Figure 25.2e).

The TrapEase ﬁlter is a signiﬁcant departure from the conical design introduced by Greenﬁeld. It has a doublebasket symmetric conﬁguration with cephalad and caudad baskets in a six-diamond or trapezoidal shape. The baskets are connected by six straight struts, which contain proximal and distal hooks for ﬁxation within the IVC. The ﬁlter can be inserted by femoral, jugular, or antecubital approaches. The TrapEase IVC ﬁlter can be used in patients with IVC diameters 30 mm and smaller (Fig. 25.2g).

Simon Nitinol filter

Bird’s nest filter

The conﬁguration of the ﬁlter uses a conical array of six struts with hooks at the base, with a daisy-wheel conﬁguration of wires at the ﬁlter apex, in effect providing

This ﬁlter consists of four stainless-steel wires (25 cm × 0.18 mm) attached to two V-shaped struts. The V-shaped struts have small barbs at the two ends to engage the IVC

304

Indications, techniques, and results of inferior vena cava ﬁlters

(a)

(b)

(e)

(f)

(c)

(d)

(g)

(i)

wall. During insertion, the four wires are extruded from the delivery system in a random distribution, simulating a bird’s nest. The ﬁlter is approximately 7 cm long but, in practice, the deployed length varies by the amount of overlap of the “V” struts. It can be placed in IVC with diameters as large as 40 mm. It can be placed by femoral or jugular routes. The ﬁlter generates the largest MRI artifact of all the ﬁlter devices because of the stainless-steel construction (Fig. 25.2i).

(h)

Figure 25.2 Various available ﬁlters. (a) Stainless steel Greenﬁeld (Boston Scientiﬁc/Meditech); (b) Günther Tulip MREye* (Cook); (c) Simon Nitinol (Bard); (d) Venatech LGM (B. Braun); (e) Venatech LP (B. Braun); (f) OptEase* (Cordis); (g) TrapEase (Cordis); (h) G2 Filter (Bard); (i) Bird’s Nest (Cook). Reprinted with permission from Getzen TM, Rectenwald JE. Inferior vena cava ﬁlters in the cancer patient: current use and indications. J Natl Compr Canc Netw 2006; 4: 881–8.

Temporary and optional retrievable filters The temporary and retrievable ﬁlters provide the opportunity for removal of the ﬁlter after the risk for major PE is over and/or safe anticoagulation can be restarted. There is an increasing trend for ﬁlters for temporary use primarily based on the ﬁndings of the PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) study.28,29 The PREPIC study is the

Types of inferior vena cava ﬁlters

305

FDA for use as a retrievable ﬁlter. The time of retrieval for these ﬁlters varies with device and there are multiple case reports of ﬁlter retrieval several months to a year after placement. In general, retrieval of ﬁlters must be performed as soon after placement as clinically possible because endothelialization of the ﬁlter struts to the IVC wall has been described to occur as soon as 12 days after ﬁlter placement.32

only prospective, randomized clinical trial evaluating efﬁcacy of inferior vena cava ﬁlters in the prevention of pulmonary embolus. Follow-up data at 2 years, and more recently at 8 years, show signiﬁcant long-term protection against recurrent pulmonary embolism (symptomatic PE in 6.2 % within the patients randomized to the IVC ﬁlter group vs 15.1% randomized to the anticoagulation group) but patients who had inferior vena cava ﬁlters placed had a higher incidence of recurrent DVT (35.7% in the ﬁlter group compared with 27.5% in the group without ﬁlters, P = 0.042). These data on the higher rate of recurrent DVT in patients with ﬁlters in place have fueled the surge in development and use of optional retrievable ﬁlters. Temporary ﬁlters, by deﬁnition, remain attached to the delivery system. This facilitates retrieval but the external portion increases the risk of infection. Temporary ﬁlters are not clinically available in the USA and are associated with poor outcome in small European studies.30,31 Two of the earliest caval interruption devices were designed for temporary use. These include the Eichelter sieve and the Moser balloon. These were soon abandoned in response to concern for the fate of the trapped embolus.1 In contrast to temporary ﬁlters, with optional retrievable IVC ﬁlters the delivery system is completely removed and the venous system is re-accessed at a later date for retrieval of the ﬁlter if desired. The ﬁrst retrievable ﬁlter commercially available was the Amplatz device but this ﬁlter was removed from the market because of the high rate of IVC occlusion. Table 25.2 lists the commercially available retrievable IVC ﬁlters in the USA. These are approved by the FDA and include the Günther Tulip, the OptEase, and the Recovery Nitinol ﬁlter. These ﬁlters are FDA approved for permanent placement as well. The Recovery Nitinol ﬁlter, although it has been withdrawn from the market secondary to problems with strut fractures and ﬁlter migration, is included in this discussion as thousands of these ﬁlters have been placed and are frequently seen clinically. The Recovery Nitinol ﬁlter has been replaced by the Generation 2 (G2) ﬁlter. The G2 ﬁlter has been FDA approved for permanent placement and is currently in the process of being evaluated by the

Günther Tulip filter This ﬁlter consists of four main struts conﬁgured as a cross with 1 mm long hooks at the inferior end for IVC ﬁxation. Each strut has an elongated wire loop that extends inferiorly three-quarters of the length from the apex to the hooked end of the four main cross struts. The ﬁlter is 30 mm in diameter and 45 mm long in the fully expanded state. Whereas the ﬁlter can be placed from either femoral or jugular access sites, retrieval is performed from the right jugular site with use of a retrieval snare and a 12 Fr sheath. It is recommended by the manufacturer that the ﬁlter removal be carried out within 14 days of implantation, but “conventional wisdom” suggests that removal up to 8 weeks is possible. Data suggest that the Günther Tulip may be safely removed at 30 days with minimal, if any, complications,33 and removal 126 days after placement has been reported (Fig. 25.2b).34

Recovery filter and Generation 2 filters Both the discontinued Recovery and the currently available G2 ﬁlters have two levels of ﬁltration similar to the Simon Nitinol ﬁlter. These ﬁlters have six arms and six legs (upper and lower ﬁltering elements, respectively). The Recovery ﬁlter can be retrieved from the right jugular vein approach with a retrieval cone that is fabricated from nine metal claws covered with urethane material. As stated previously, the Recovery ﬁlter has recently been withdrawn from the market secondary to concerns over

Table 25.2 Retrievable inferior vena cava ﬁlters Name

Manufacturer

Year introduced

Delivery System size

Material

MR compatibility

Recommended time for retrieval

FDA approval for retrievable use

Günther Tulip

Cook

8.5 Fr

Elgiloy

Compatible

14 days

Approved

G2

Bard

1992 (Available in US since 2001) 2000

7.0 Fr

Nitinol

Compatible

60 days

OptEase

Cordis

2003

6.0 Fr

Nitinol

Compatible

23 days

Currently permanent use only Approved

306

Indications, techniques, and results of inferior vena cava ﬁlters

migration and fragmentation of the ﬁlter over time. The Recovery ﬁlter has been modiﬁed by increasing its resting diameter, changing the angulation of the wires forming the upper ﬁltering elements, and changing the metallic composition of the hooks attached to the lower ﬁltering elements. This modiﬁed Recovery ﬁlter has been renamed the G2 ﬁlter. The G2 ﬁlter is currently only FDA approved for permanent use, although approval for use as an optional retrievable ﬁlter is expected (Fig. 25.2h).

OptEase filter The OptEase ﬁlter is a dual cone (symmetrical) design nearly identical to the TrapEase. The OptEase ﬁlter has been modiﬁed with the placement of unidirectional barbs and an apical hook for removal, and can be inserted from jugular or femoral routes with the same 6 Fr introducer sheath (by reorienting the ﬁlter). This ﬁlter is retrieved from the femoral vein only, by snaring a small hook at the caudal end of the ﬁlter (Fig. 25.2f).

TECHNIQUES OF INFERIOR VENA CAVA FILTER PLACEMENT Placement techniques for each of the ﬁlters differ and the most appropriate step-by-step guide for placement can be found in the operator’s instructions provided by the manufacturers. These directions should be reviewed prior to placement and followed carefully to insure the safety of the patient. Usual steps involved in percutaneous ﬁlter placement are described in Box 25.3.

BOX 25.3 Steps involved in radiological inferior vena cava filter (IVC) placement 1 Preprocedural evaluation ● Review indication and risk versus beneﬁts of IVC ﬁlter placement including the duration for which the ﬁlter is likely to be needed ● Review available Duplex US/CT/MRI to evaluate presence of IVC, iliac or femoral vein thrombus ● Evaluate coagulation status 2 Preparation for ﬁlter placement ● Choose access based on the above evaluation ● Perform inferior venacavogram – evaluate for IVC thrombus; Identify level of renal veins; Measure IVC diameter; Detect venous anomalies 3 Choose appropriate ﬁlter and deploy according to operator’s manual instructions provided by the manufacturer 4 Perform post-deployment radiographs 5 Follow-up recommendations

VENOUS ACCESS The choice depends on the patency of the vein access site and sometimes operator preference. The right common femoral vein is the most common access site and affords a relatively straight course to the IVC. This is the preferred access site unless there is evidence for a clot in the right femoral or iliac veins. The right jugular vein is another common access site through which most of the available ﬁlters can be deployed. The left femoral, jugular, and antecubital veins have all been used depending on the anatomy and type of the ﬁlter that is planned to be deployed. Placement of IVC ﬁlters through the left femoral and jugular approaches have been associated with a greater incidence of ﬁlter “tilt” with respect to the course of the IVC. Filters with low-proﬁle delivery systems such as the TrapEase and Simon Nitinol ﬁlters (6 Fr) can be placed via the antecubital vein.35 Alternative access sites have been described and are limited only by the ingenuity of the surgeon or interventionalist. For example, the authors have successfully placed Simon Nitinol ﬁlters through the right great saphenous vein in morbidly obese patients and Günther Tulip ﬁlters through a brachial approach in patients with bilateral femoral and jugular thrombosis.

INFERIOR VENACAVOGRAM Either iodine-based contrast or carbon dioxide is used to obtain a venogram via a marking pigtail catheter (Fig. 25.3). The venacavogram is used to identify venous anomalies, measure caval diameter, exclude thrombus in the IVC, and identify the level of the renal veins. The opaciﬁcation of the renal veins may be enhanced by the Valsalva maneuver. Except for the Bird’s nest and the Venatech LP ﬁlters, which can be placed in an IVC measuring up to 40 mm, most of the commercially available ﬁlters are recommended for IVC diameters of 28 mm or less. When placing a ﬁlter in a patient with a megacava, two options for treatment exist: placement of a Bird’s Nest or other ﬁlter type approved for large vena cava or placement of bilateral common iliac vein ﬁlters with devices approved for cava 28 mm in diameter or less. Three major venous anomalies are of particular interest when placing an IVC ﬁlter. These are duplication of the IVC, circumaortic left renal vein, and left-sided IVC. These anomalies must be assessed prior to placing an IVC ﬁlter. Duplication of the IVC is seen in 0.2–3.8% of population and occurs because of persistence of both right and left cardinal veins. The cavae may be of equal size although the right cava is usually larger. The left cava joins the right at the level of the left renal vein. This IVC variant can be safely excluded if contrast ﬁlls the left iliac vein on the cavogram. If the left iliac vein is not seen on the venogram and the left renal vein appears prominent, then a duplicated IVC should be actively ruled out prior to ﬁlter

Transabdominal duplex ultrasound technique 307

(a)

(b)

(c)

Figure 25.3 Inferior venacavogram performed prior to inferior vena cava (IVC) ﬁlter placement shows normal caliber of the IVC and location of renal veins. (a, b) Inferior venacavogram using iodinated contrast media in digital subtraction mode and with bone landmarks to facilitate inferior vena cava ﬁlter placement. (c) Inferior venacavogram using carbon dioxide as contrast medium in a patient with renal insufﬁciency.

placement. If a duplicated cava is identiﬁed, then two options exist. Two ﬁlters may be placed in both cavae or a suprarenal ﬁlter can be placed. A circumaortic renal vein occurs in 8.7% of the population and the posterior component of the left renal vein is usually lower than the anterior one. The ﬁlter should be placed below the entry of all renal vein branches. A left-sided IVC is rare, with a prevalence of 0.2–0.5%. The left cava crosses at the level of the renal vein to right side and the ﬁlter is deployed in an infrarenal location in such patients.

INTRAVASCULAR ULTRASOUND AND TRANSABDOMINAL DUPLEX ULTRASOUNDGUIDED PLACEMENT OF IVC FILTERS Bedsides placement of inferior vena cava ﬁlters by using either transabdominal duplex or intravascular ultrasound (IVUS) guidance has been shown to be safe and effective.36,37 These techniques are preferred and are especially useful in critically ill patients, those who are pregnant, those who have a contraindication to iodinated contrast media and CO2 is not available, or in obese patients who exceed the safe weight limits of standard radiographic equipment.

TRANSABDOMINAL DUPLEX ULTRASOUND TECHNIQUE Transabdominal duplex ultrasonography is performed to determine the technical feasibility of bedside ﬁlter placement. Important ﬁndings to be noted on preprocedural ultrasound include the IVC diameter, the absence of venous thrombosis, the absence of venous anomalies, and the patency of the intended femoral vein access site. The IVC must be adequately visualized at the renal vein junction in both the transverse and the longitudinal axes. Identiﬁcation of the right renal vein is critical because this usually represents the lowest renal vein. If venous anomalies or iliofemoral venous thrombosis is suspected, contrast venography is preferred to more precisely deﬁne the venous anatomy before ﬁlter placement. The procedure is usually performed under local anesthesia. The femoral vein access is obtained and a 0.1 cm guide wire is advanced into the IVC. The ﬁlter introducer sheath is advanced over this wire to just above the renal vein conﬂuence. The guide wire is removed to enable adequate visualization of the tip of the delivery catheter. The lowest renal vein/IVC junction is visualized transversely as the ﬁlter delivery catheter and sheath are slowly pulled back. When the tip of the ﬁlter delivery

308

Indications, techniques, and results of inferior vena cava ﬁlters

catheter disappears from the ultrasound view, the intended deployment position has been reached. This is directly visualized on the longitudinal view and the ﬁlter is deployed. Full deployment is conﬁrmed with dedicated duplex imaging and plain abdominal radiographs.

INTRAVASCULAR ULTRASOUND TECHNIQUE Under local anesthesia, femoral vein access is obtained and a 9F (longer than 25 cm) sheath is placed into the IVC over a 0.1 cm guide wire. An IVUS probe (15 MHz) is inserted over the guide wire to the level of the right atrium. Using the pullback technique, the level of the renal veins, caval diameter, caval anomalies, caval thrombosis, and conﬂuence of the iliac veins is identiﬁed. If the conﬂuence of the iliac veins is not clear, contralateral femoral vein access is obtained and IVUS is performed again to identify the above venous landmarks. Single or dual venous access techniques can be used for ﬁlter placement. In the dual venous access technique, the IVUS probe is positioned just below the renal veins. Filter deployment is performed through separate venous access, preferably through the contralateral femoral vein to reduce the incidence of access site thrombosis by dual puncture at a single common femoral vein. The ﬁlter delivery catheter and sheath are inserted to a level above the renal veins and pulled back to just below the renal veins. Correct placement is then conﬁrmed by IVUS. Once the position is conﬁrmed, the IVUS probe is pulled back and the ﬁlter is deployed. In the single vein, single puncture technique the IVUS probe is removed after the vein anatomy is interrogated. The length of the IVUS probe is then premeasured against the length of the ﬁlter delivery catheter that corresponds to the position of the ﬁlter delivery catheter when fully loaded in the sheath. Measurement guides on the IVUS probe marks this distance. The IVUS probe is then inserted into the sheath up to this premeasured length, which represents the distance that the ﬁlter delivery catheter extends beyond the length of the sheath. The IVUS probe and sheath are pulled back together to the level just below the lowest renal vein as visualized by IVUS. In this regard, IVUS is guiding sheath positioning, which, because of the premeasured length, indirectly guides the intended ﬁlter position. The IVUS probe is removed, the ﬁlter delivery catheter is loaded into the sheath, and the IVC ﬁlter is deployed. Postprocedure abdominal radiographs are obtained to conﬁrm the placement, position, and alignment of the ﬁlter.

FOLLOW-UP OF INFERIOR VENA CAVA FILTERS Patients with vena cava ﬁlters should undergo follow-up on an annual basis. The purpose of the examination is to

evaluate the mechanical stability of the ﬁlter. In addition, the condition of the lower extremities is evaluated to monitor the on-going risk for recurrent thrombosis. Because so many of these devices are placed by radiologists it is important that the information about ﬁlter placement is passed along to the patient’s local physician so that arrangements for the appropriate studies can be made. Traditionally, follow-up after IVC ﬁlter placement has included physical examination of the lower extremities to observe for edema, hyperpigmentation, skin ulceration, and other signs and essentially treatment of the postthrombotic syndrome. In the past, anteroposterior and lateral radiographs of the ﬁlter have been obtained at intervals and compared with previous studies for IVC ﬁlter follow-up as well to demonstrate the mechanical stability and physical integrity of the device. This practice is currently controversial as the long-term complications of established IVC ﬁlters are low. Newer ﬁlters, with less long-term data on fracture and migration rates, may be candidates for this more rigorous follow-up until these issues are ﬁrmly resolved. Emergent follow-up should be obtained if the patient develops new bilateral lower extremity edema. Should this occur, a duplex scan of the vena cava is performed to look for the thrombus in the ﬁlter or IVC. If the results of the ultrasound study are indeterminate, the patient should undergo a venacavogram to evaluate for caval obstruction. If occlusion is documented and felt to be of recent origin (less than 7 days), and the patient’s medical condition allows, thrombolytic therapy may be attempted in order to treat current symptoms and prevent later post-thrombotic syndrome. Patients who present with signs or symptoms of PE should also undergo venacavography to determine the patency of the ﬁlter and the presence of trapped or propagating emboli. Rare propagation of the thrombus above the level of the ﬁlter may be an indication for a second (suprarenal) ﬁlter rather than thrombolytic therapy.

COMPLICATIONS OF INFERIOR VENA CAVA FILTERS Complications of IVC ﬁlter placement include those related directly to the procedure for placement or removal and those related to length of time the ﬁlter stays inside the IVC.38,39 The incidence of complications varies and depends not only on ﬁlter type, but more importantly on the methods used to assess complications and the duration of follow up. Table 25.3 lists the common complications associated with IVC ﬁlter placement. Fortunately, most of the complications associated with IVC ﬁlters are minor or infrequent. Access site thrombosis is the most common complication. With newer and smaller delivery systems, the incidence of occlusive thrombosis of the access vein is low (2–10%), although a non-occlusive femoral vein thrombus is seen more often (25%). Inferior vena cava

Comparison of performance between inferior vena cava ﬁlters 309

Table 25.3 Complications of inferior vena cava (IVC) ﬁlter placement Incidence (%) 1. Procedure-related complications Puncture site complications: bleeding, infection, thrombosis, air embolism Delivery system complications, Filter malposition, tilting, or incomplete opening IVC wall penetration Death 2. Filter migration – to renal vein, heart or pulmonary artery 3. Filter fracture 4. New or worsened DVT 5. IVC thrombosis 6. Recurrent PE / Fatal PE 7. Venous insufﬁciency

4–11

3–69 <1% 6–30 6–30 2–5 10–30

thrombosis is a serious and potentially fatal complication requiring emergent diagnosis and treatment. The thrombus may extend above the level of the ﬁlter causing major PE necessitating the placement of an additional ﬁlter in the suprarenal IVC. The IVC thrombosis may also cause phlegmasia cerulea dolens, a limb-threatening condition. Whereas a small clot burden may be treated with anticoagulation, large to complete caval thrombosis causing symptoms may need thrombolysis or stent placement in the IVC to restore patency and treat associated phlegmasia. Minor degrees of ﬁlter migration are of little concern. However, ﬁlter migration to the heart or pulmonary artery may be fatal because of the development of associated arrhythmias, acute myocardial infarction, pericardial tamponade, and cardiac valvular injury. Percutaneous retrieval or repositioning can be performed in these situations in an attempt to avoid emergent thoracotomy.

The inﬂuence of the IVC ﬁlter tilt and asymmetry on ﬁlter function is controversial, with some supporting40,41 and others questioning its clinical signiﬁcance.42 Earlier studies43 showed that, when centered, the original Greenﬁeld IVC ﬁlter allowed the passage of small clots, and eccentric positioning (> 14°) allowed small and large clots to pass through. In an experimental study, Greenﬁeld et al.44 showed that alignment became important only when the IVC diameter exceeded 22 mm. More recently Greenﬁeld et al.42 evaluated the clinical signiﬁcance of ﬁlter asymmetry (strut pattern in the cava and not the ﬁlter tilt) on recurrent PE and caval thromboses in patients with titanium Greenﬁeld IVC ﬁlters. A total of 738 ﬁlters were inserted and follow-up was available for 373 patients (65%). Inferior vena cava ﬁlter asymmetry was found in 42 cases (5%). With asymmetric ﬁlter placement, recurrent PE was seen in 8.6%, and IVC thrombosis was seen in 5.7% of patients. In comparison with symmetric ﬁlter placement, recurrent PE was seen in 3.3% and IVC thrombosis was seen in 1.7% of patients. The relative risk of recurrent PE with an asymmetric ﬁlter was 2.6 times that with a symmetric ﬁlter and the relative risk of IVC thrombosis was 3.4 versus patients with symmetric ﬁlters. These ﬁndings were statistically not signiﬁcant and the ﬁlter leg distribution did not appear to be associated with an increased incidence of recurrent PE or caval thrombosis.

COMPARISON OF PERFORMANCE BETWEEN INFERIOR VENA CAVA FILTERS Despite a large number of clinical studies describing the effectiveness and safety of IVC ﬁlters, there are no studies which prospectively compare different ﬁlter designs. There is a misconception that because the published data for vena caval ﬁlters are similar they are equivalent. Outcomes from a recent in vivo animal study demonstrated that this is not true. Fig. 25.4 shows that thrombus resolution in the Bird’s Nest, Simon Nitinol and VenaTech ﬁlters results in

Figure 25.4 Results of experimental thromboembolism to the Birds Nest (BN), Simon Nitinol (SN) and VenaTech (VT) ﬁlters in sheep allowing sufﬁcient time (30 days) for thrombus resolution. All ﬁlters show ﬁbrous webbing.

310

Indications, techniques, and results of inferior vena cava ﬁlters

Figure 25.5 Results of experimental thromboembolism to the experimental ﬁlter (NGF), the percutaneous stainless steel Greenﬁeld ﬁlter (PSGF) and the titanium Greenﬁeld ﬁlter (TGF) in sheep with the same protocol as in Fig. 25.3. All ﬁlters were clear of any residual ﬁbrous tissue.

heavy layers of ﬁbrin webbing, and Fig. 25.5 demonstrates the absence of webbing associated with the stainless-steel, titanium Greenﬁeld ﬁlters and an investigational device. Comparing different designs is difﬁcult due to variations in the population studied, evaluation criteria, associated treatment, and the type and duration of followup.45–48 Therefore, several guidelines have been published concerning reporting standards for ﬁlters.49,50 Metaanalyses have shown the efﬁcacy of ﬁlters in the prevention of PE irrespective of the ﬁlter design.51 Five major reports of objectively documented Greenﬁeld ﬁlter patient outcomes have been published.52–56 The follow-up included abdominal radiographs to determine the position of the ﬁlter and either venographic or ultrasound studies to determine the patency of the ﬁlter. In addition, reports on sub-groups of patients have also been published.57,58 These reports have covered 27 years of experience with the stainless-steel and the titanium Greenﬁeld ﬁlters. In all, the patency rate has remained at 96% and the rate of recurrent PE has been between 3% and 5%.1 The comparative efﬁcacy and complications of different IVC ﬁlters are detailed in Table 25.4.

SUPRARENAL INFERIOR VENA CAVA AND SUPERIOR VENA CAVA FILTERS Indications for suprarenal IVC ﬁlter placement are listed in Box 25.4. The efﬁcacy and safety of Greenﬁeld ﬁlters placed in a suprarenal position appears similar to that of ﬁlters placed conventionally in the infrarenal location.3,59–61 The role of the superior vena cava (SVC) ﬁlter in preventing PE is controversial. A few reports have described the beneﬁts of such ﬁlter placement.62–65 Superior vena cava thrombosis and guide wire entrapment during central line placement are potential complications of SVC ﬁlter placement.

CONCLUSION Vena caval ﬁlters provide protection against PE without the signiﬁcant morbidity and mortality associated with surgical interruption. They are intended for use in patients who are at risk of PE but where anticoagulation is contra-

Table 25.4 Performance of different inferior vena cava ﬁlters Filter

Stainless steel Greenﬁeld Titanium Greenﬁeld Stainless-steel over-thewire Greenﬁeld Simon Nitinol Bird’s Nest VenaTech/LGM Low proﬁle VenaTech TrapEase Gunther Tulip

Number

Mean follow up (months)

Recurrent pulmonary embolism (%)

DVT (%)

3184 511

18 5.8

2.6 3.1

5.9 22.7

599 319 1426 1050 30 65 83

26 16.9 14.2 12 2.3 6 4.5

2.6 3.8 2.9 3.4 0 0 3.6

7.3 8.9 6 32 10.3 45.7 Not reported

IVC thrombosis (%)

3.6 6.5 1.7 7.7 3.9 11.2 0 2.8 9.6

Post-thrombotic syndrome

19 14.4 2 12.9 14 41 Not reported Not reported Not reported

Conclusion

BOX 25.4 Indications for suprarenal inferior vena cava filter placement ●

● ●

Renal vein or infrarenal vena cava or ovarian vein thrombosis During pregnancy or in women anticipating pregnancy Thrombus propagating proximal to a previously placed ﬁlter in infrarenal location

indicated or thought to be insufﬁcient. Inferior vena cava ﬁlter placement is a technically straightforward and safe procedure with an associated low morbidity and mortality. Multiple studies have demonstrated the efﬁcacy of ﬁlters in preventing PE, although rarely IVC ﬁlters may cause

311

progression or recurrence of DVT in lower extremities and IVC thrombosis. The rate of these complications is device speciﬁc and it is important for physicians placing IVC ﬁlters to be familiar with the thrombosis, migration, and complication rates associated with the ﬁlter chosen for placement. There has been a recent surge in placement of retrievable ﬁlters for prophylaxis of PE in patients with time-limited contraindications to anticoagulation. The patient beneﬁt associated with this practice is largely theoretical and needs to be objectively studied. The type of ﬁlter used should be tailored to each patient, with particular attention to the indication and the long-term results associated with the IVC ﬁlter chosen. The recent increase in the use of retrievable IVC ﬁlters is notable and additional studies are required to document their safety and efﬁcacy.

Guidelines 3.9.0 of the American Venous Forum on indications, techniques, and results of inferior vena cava ﬁlters No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.9.1 We recommend placement of inferior vena cava ﬁlters in patients with deep vein thrombosis and/or pulmonary embolism and a baseline contraindication to anticoagulation; in patients who suffer a complication from anticoagulation; in patients that develop recurrent deep vein thrombosis or pulmonary embolism despite adequate anticoagulation; and in patients who previously have had a massive pulmonary embolism and cannot tolerate further cardiopulmonary insult that would be associated with an additional pulmonary embolism

1

A

3.9.2 We recommend placement of an inferior vena cava ﬁlter in patients with a free ﬂoating thrombus greater than 5 cm in length within an iliac vein or the inferior vena cava

1

B

3.9.3 We recommend prophylactic ﬁlters to patients if their associated medical conditions (malignancy or traumatic injuries) predispose to deep vein thrombosis or pulmonary embolism

1

B

3.9.4 We suggest caution in special situations prior to ﬁlter placement for patients with untreated or uncontrolled bacteremia, and pediatric patients and pregnant women because of the uncertain long-term effects and durability of the ﬁlters

2

C

3.9.5 We suggest bedside placement of inferior vena cava ﬁlters by using either transabdominal duplex or intravascular ultrasound guidance; both have been shown to be safe and effective

2

B

3.9.6 We suggest performing additional studies to document the safety and efﬁcacy of the placement of retrievable ﬁlters in patients with time-limited contraindications to anticoagulation

2

B

3.9.7 We suggest a follow-up examination annually to patients with vena caval ﬁlters to evaluate the mechanical stability of the ﬁlter; in addition, the condition of the lower extremities is evaluated to monitor the ongoing risk for recurrent thrombosis

2

B

312

Indications, techniques, and results of inferior vena cava ﬁlters

As improved techniques for delivery of these devices and new materials and designs are developed, it is essential to keep in focus the indications and appropriate use of these devices, including retrievable ﬁlters. Rather than focusing on the differences among the various devices (which will sort itself out over time) the major effort ought to be directed toward identifying those patients who are at highest risk for signiﬁcant pulmonary embolism. Efforts must also continue to be directed to improve methods of thromboprophylaxis since no ﬁlter can inﬂuence the development or course of the underlying disorder. This is clearly a case where a well-planned offense is the best defense against this unnecessary source of morbidity and mortality.

REFERENCES 1. Greenﬁeld LJ, Wakeﬁeld T. Prevention of venous thrombosis and pulmonary embolism. In: Tompkins R, Cameron J, Langer B, eds. Advances in Surgery. Chicago: Year Book Medical Publishers, 1989; 301–23. 2. Mansour M, Chang AE, Sindelar WF. Interruption of the inferior vena cava for the prevention of recurrent pulmonary embolism. Am Surg 1985; 51: 375–80. 3. Greenﬁeld LJ, Proctor MC. Suprarenal ﬁlter placement. J Vasc Surg 1998; 28: 432–8. 4. Pias SO, Tobin KD. Percutaneous insertion of the Greenﬁeld Filter. Am J Roentgenol 1989; 152: 933–8. 5. Dorfman GS, Cronan JJ, Paolella LP, et al. Iatrogenic changes at the venotomy site after percutaneous placement of the Greenﬁeld ﬁlter. Radiology 1989; 173 (1): 159–62. 6. Peterson L. Inferior vena cava ﬁlters. Trends Med 2003. 7. Lin J, Proctor MC, Varma M, et al. Factors associated with recurrent venous thromboembolism in patients with malignant disease. J Vasc Surg 2003; 37:976–983. 8. Gitter MJ, Jaeger TM, Petterson TM, et al. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc 1995; 70:725–733. 9. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. 10. Ihnat DM, Mills JL, Hughes JD, et al. Treatment of patients with venous thromboembolism and malignant disease: should vena cava ﬁlter placement be routine? J Vasc Surg 1998; 28: 800–807. 11. Krauth D, Holden A, Knapic N, et al. Safety and efﬁcacy of long-term oral anticoagulation in cancer patients. Cancer 1987; 59: 983–5. 12. Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865–75. 13. Harrington R, Ansell J. Risk-beneﬁt assessment of anticoagulant therapy. Drug Safety 1991; 6 (1): 54–69.

14. Schmitt BP, Adelman B. Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci 1993; 305: 208–15. 15. Greaves M. Anticoagulants in pregnancy. Pharmacol Ther 1993; 59: 311–27. 16. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: Clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315–28. 17. Eby CS. Warfarin-induced skin necrosis. Hemato Oncol Clin North Am 1993; 7: 1291–300. 18. Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. Arch Intern Med 1997; 137: 2317–21. 19. Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992; 152: 1589–95. 20. Greenﬁeld LJ. Intraluminal techniques for vena caval interruption and pulmonary embolectomy. World J Surg 1978; 2: 45–59. 21. Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Intl J Hematol 2001; 73: 137–44. 22. Pasquale M, Fabian TC, and the EAST Ad Hoc Committee on Practice Management Guideline Development. Practice management guidelines for trauma from the Eastern Association of Trauma. J Trauma 1998; 44: 941–56. 23. Rosen MP, Porter DH, Kim D. Reassessment of vena caval ﬁlter use in patients with cancer. J Vasc Interv Radiol 1994; 5: 501–6. 24. Shackford SR, Davis JW, Hollingsworth-Fridlung P, et al. Venous thromboembolism in patients with major trauma. Am J Surg 1990; 159: 365–9. 25. Khansarinia S, Dennis JW, Veldenz HC, et al. Prophylactic Greenﬁeld ﬁlter placement in selected high-risk trauma patients. J Vasc Surg 1995; 22: 231–6. 26. Rogers FB, Strindberg G, Shackford SR, et al. Five-year follow-up of prophylactic vena cava ﬁlters in high-risk trauma patients. Arch Surg 1998; 133: 406–12. 27. McMurty AL, Owings JT, Anderson JT, et al. Increased use of prophylactic vena cava ﬁlters in trauma patients failed to decrease overall incidence of pulmonary embolism. J Am Coll Surg 1999; 189: 314–20. 28. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval ﬁlters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Eng J Med 1998; 338: 409–15. 29. The PREPIC Study Group. Eight year follow-up of patients with permanent vena cava ﬁlters in the prevention of pulmonary embolism: The PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation 2005; 112: 416–22. 30. Lorch H, Welger D, Wagner V, et al. Current practice of temporary vena cava ﬁlter insertion: a multicenter registry. J Vasc Interv Radiol 2000; 11: 83–8.

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31. Yamagami T, Kato T, Lida S, et al. Retrievable vena cava ﬁlter placement during treatment for deep venous thrombosis. Br J Radiol 2003; 76:712–718. 32. Burbridge BE, Walker DR, Millward SF. Incorporation of the Günther temporary inferior vena cava ﬁlter into the caval wall. J Vasc Interv Radiol 1996; 7: 289–90. 33. De Gregorio MA, Gamboa P, Bonilla DL, et al. Retrieval of Günther Tulip optional vena cava ﬁlters 30 days after implantation: a prospective trial. J Vasc Interv Radiol 2006; 11: 1781–9. 34. Terhaar OA, Lyon SM, Given MF, et al. Extended retrieval of the Günther Tulip ﬁlter. J. Vasc Interv Radiol 2004; 15:1257–62. 35. Kim D, Schlam B, Porter DH, Simon M. Insertion of the Simon Nitinol caval ﬁlter: Value of the antecubital vein approach. Am J Roentgenol 1991; 157: 521–2. 36. Passman MA, Dattilo JB, Guzman RJ, Naslund TC. Bedside placement of inferior vena cava ﬁlters by using transabdominal duplex ultrasonography and intravascular ultrasound imaging. J Vasc Surg 2005; 42: 1027–1032. 37. Corriere MA, Passman MA, Guzman RJ, et al. Comparison of bedside transabdominal ultrasound versus contrast venography for inferior vena cava ﬁlter placement: what is the best modality. Ann Vasc Surg 2005; 19 (2): 229–34. 38. Ray CE, Kaufman JA. Complications of inferior vena cava ﬁlters. Abdom Imaging 1996; 21: 368–74. 39. Ballew KA, Philbrick JT, Becker DM. Vena cava ﬁlter devices. Clin Chest Med 1995; 16: 295–305. 40. Kinney TB, Rose SC, Weingarten KW, et al. IVC ﬁlter tilt and asymmetry: comparison of the over-the-wire stainlesssteel and titanium Greenﬁeld IVC ﬁlters. J Vasc Interv Radiol 1997; 8: 1029–1037. 41. Kinney TB, Rose SC. Regarding “limb asymmetry in titanium Greenﬁeld ﬁlters.” J Vasc Surg 1998; 16: 436–44. 42. Greenﬁeld LJ, Proctor MC, Cho KJ, Wakeﬁeld TW. Limb asymmetry in titanium Greenﬁeld ﬁlters: clinically signiﬁcant? J Vasc Surg 1997; 26: 770–5. 43. Katsamouris AA, Waltman AC, Delichatsios MA, Athanasoulis CA. Inferior vena cava ﬁlters: in vitro comparison of clot trapping and ﬂow dynamics. Radiology 1988; 166: 361–6. 44. Greenﬁeld LJ, Proctor MC. Experimental embolic capture by asymmetric Greenﬁeld ﬁlters. J Vasc Surg 1992; 16: 436–44. 45. Rousseau H, Perreault P, Otal P, et al. The 6-F Nitinol TrapEase inferior vena cava ﬁlter: results of a prospective multicenter trial. J Vasc Interv Radiol 2001; 12: 299–304. 46. Streiff MB. Vena caval ﬁlters: a comprehensive review. Blood 2000; 95: 3669–77. 47. Greenﬁeld LJ, Proctor MC. The percutaneous Greenﬁeld ﬁlter: outcomes and practice patterns. J Vasc Surg 2000; 32: 888–93. 48. Neuerburg JM, Günther RW, Vorwerk D, et al. Results of a multicenter study of the retrievable Tulip vena cava ﬁlter: early clinical experience. Cardiovasc Intervent Radiol 1997; 20: 10–16.

49. Greenﬁed LJ, Rutherford RB, and Participants in the vena caval ﬁlter consensus conference. Recommended reporting standards for vena caval ﬁlter placement and patient follow-up. J Vasc Surg 1999; 30: 573–9. 50. Grassi CJ, Swan TL, Cardella JF, et al. Quality improvement guidelines for percutaneous permanent inferior vena cava ﬁlter placement for the prevention of pulmonary embolism. J Vasc Interv Radiol 2001; 12: 137–41. 51. Becker DM, Philbrick JT, Selby JB. Inferior vena cava ﬁlters: indications, safety, effectiveness. Arch Intern Med 1992; 152: 1985–94. 52. Greenﬁeld LJ, Proctor MC. Current treatment and prevention of pulmonary embolus with the Greenﬁeld Filter. In: Braverman, MH, Tawes RL, eds. Surgical Technology II. San Francisco: Surgical Technology International, 1993; 289–91. 53. Greenﬁeld LJ, Michna BA. Twelve-year clinical experience with the Greenﬁeld vena caval ﬁlter. Surg 1988; 104: 706–12. 54. Greenﬁeld LJ. Current indications for and results of Greenﬁeld ﬁlter placement. J Vasc Surg 1984; 1: 502–504. 55. Greenﬁeld LJ, Peyton R, Crute S, Barnes RW. Greenﬁeld vena caval ﬁlter experience: Late results in 156 patients. Arch Surg 1981; 116: 1451–5. 56. Greenﬁeld LJ, Zocco J, Wilk J, et al. Clinical experience with the Kim-Ray Greenﬁeld vena caval ﬁlter. Ann Surg 1977; 185: 692–8. 57. Jarrell B, Szentpetery S, Mendez-Picon G, et al. Greenﬁeld ﬁlter in renal transplant patients. Arch Surg 1981; 116: 930–2. 58. Hux C, Wapner R, Chayen B, et al. Use of the Greenﬁeld ﬁlter for thromboembolic disease in pregnancy. Am J Obstet Gynecol 1986; 155: 734–7. 59. Athanasoulis CA, Kaufman JA, Halpern EF, et al. Inferior vena caval ﬁlters: review of a 26-year single-center clinical experience. Radiology 2000; 216: 54–66. 60. David W, Gross WS, Colaiuta E, et al. Pulmonary embolus after vena cava ﬁlter placement. Am Surg 1999; 65: 341–6. 61. Matchett WJ, Jones MP, McFarland DR, Ferris EJ. Suprarenal vena caval ﬁlter placement: follow-up of four ﬁlter types in 22 patients. J Vasc Interv Radiol 1998; 9: 588–93. 62. Hoffman MJ, Greenﬁeld LJ. Central venous septic thrombosis managed by superior vena cava Greenﬁeld ﬁlter and venous thrombectomy: a case report. J Vasc Surg 1986; 4: 606–11. 63. Pais SO, Orchis DF, Mirvis SE. Superior vena caval placement of Kimray-Greenﬁeld ﬁlters. Radiology 1987; 165: 385–6. 64. Owen EWJ, Schoettle GPJ, Harrington OB. Placement of a Greenﬁeld ﬁlter in the superior vena cava. Ann Thorac Surg 1992; 53: 896–7. 65. Ascher E, Hingorani A, Tsemekhin, et al. Lessons learned from a 6-year clinical experience with superior vena cava Greenﬁeld ﬁlters. J Vasc Surg 2000; 32: 881–7.

26 Superficial venous thrombophlebitis ANIL HINGORANI AND ENRICO ASCHER Introduction Clinical presentation Etiology Pathology Trauma Suppurative Migratory

314 314 314 315 315 315 315

INTRODUCTION Although superﬁcial venous thrombophlebitis (SVT) is a relatively common disorder with a signiﬁcant incidence of recurrence and has potential morbidity from extension and pulmonary embolism (PE), it has been considered the stepchild of deep vein thrombosis (DVT) and received limited attention in the literature. It has been reported that acute SVT occurs in approximately 125 000 people in the USA per year.1 However, the actual incidence of SVT is most likely far greater, for these reported statistics may be outdated and many cases go unreported. Traditional teaching suggests that SVT is a self-limiting process of little consequence and small risk, leading some physicians to dismiss these patients with the clinical diagnosis of SVT and to treat them with “benign neglect.” In an attempt to dispel this misconception, this chapter will examine the more current data regarding SVT and its treatment.

CLINICAL PRESENTATION Approximately 35–46% of patients diagnosed with SVT are men with an average age of 54 years, whereas the average age for women is about 58 years old.2,3 The most frequent predisposing risk factor for SVT is the presence of varicose veins, which occurs in 62% of patients. Others factors associated with SVT include age > 60 years old, obesity, tobacco use, and history of DVT or SVT. Factors associated with extension of SVT include age > 60 years old, male sex and history of DVT. The physical diagnosis of superﬁcial thrombophlebitis is based on the presence of erythema and tenderness in the

Mondor’s disease Small saphenous superﬁcial vein thrombosis Superﬁcial thrombophlebitis with varicose veins Upper extremity superﬁcial venous thrombosis Diagnosis Treatment References

315 315 315 316 316 316 318

distribution of the superﬁcial veins, with the thrombosis identiﬁed by a palpable cord. Pain and warmth are clinically evident and signiﬁcant swelling may be present even without DVT. From time to time, a patient may present with erythema, pain, and tenderness as a streak along the leg. A duplex ultrasound scan reveals no DVT or SVT. In these patients, the diagnosis of cellulitis or lymphangitis needs to be considered.

ETIOLOGY The tenet is that hypercoaguable states, changes in the vessel walls and changes in the characteristics of the ﬂow of blood, as cited by Virchow over 100 years ago, are recognized to play a role in the etiology of thrombosis. Although stasis and trauma of the endothelium have been cited as a cause of SVT, a hypercoaguable state associated with SVT has largely been unexplored. Furthermore, since the DVT which occurs in association with SVT is often found to be non-contiguous with the SVT,2,3 the presumed mechanism of DVT by direct extension of thrombosis from the superﬁcial venous system to the deep venous system needs to be questioned, and systemic factors in the pathophysiology of SVT should be explored. To determine whether a hypercoaguable state contributes to the development of SVT, the prevalence of deﬁcient levels of anticoagulants were measured in a population of patients with acute SVT.4 Twenty-nine patients with SVT were entered into the study. All patients had duplex ultrasound scans performed on both the superﬁcial and deep venous systems. Patients solely with SVT were treated with non-steroidal anti-inﬂammatory

Superﬁcial thrombophlebitis with varicose veins 315

drugs and those with DVT were treated with heparin and warfarin. All patients had a coagulation proﬁle performed that included (a) protein C antigen and activity, (b) activated protein C (APC) resistance, (c) protein S antigen and activity, (d) antithrombin III (AT III) and (e) lupustype anticoagulant. Twelve patients (41%) were found to have abnormal results consistent with a hypercoaguable state. Five of the patients (38%) with combined SVT and DVT and seven of the patients (44%) with SVT alone were found to be hypercoaguable. Four patients had decreased levels of AT III only and four patients had APC resistance identiﬁed. One patient had decreased protein C and protein S, and three patients had deﬁciencies of AT III, protein C and protein S. The most prevalent anticoagulant deﬁciency was AT III. Furthermore, in a subsequent separate set of data examining patients with recurrent SVT, anticardiolipin antibodies were detected in 33% of patients.5 These ﬁndings suggest that patients with SVT are at an increased risk of having an underlying hypercoaguable state.6

MIGRATORY Migratory thrombophlebitis was ﬁrst described by Jadioux in 18458 as an entity characterized by repeated thrombosis developing in superﬁcial veins at varying sites, but most commonly in the lower extremity. This entity may be associated with carcinoma and may precede diagnosis of the carcinoma by several years. Consequently, a work-up for occult malignancy may, in fact, be warranted when the diagnosis of migratory thrombophlebitis is made.

MONDOR’S DISEASE Mondor’s disease is deﬁned as thrombophlebitis of the thoracoepigastric vein of the breast and chest wall. It is thought to be associated with breast carcinoma or hypercoaguable state although cases have been reported with no identiﬁable cause.9 Recently, the term has also been applied to SVT of the dorsal vein of the penis.10 Treatment consists of conservative measures with warm compresses and non-steroidal anti-inﬂammatories.

PATHOLOGY Although a great deal of literature exists describing the various changes that take place in the leukocyte–vessel wall interactions, cytokines/chemokines and various other factors involved with the development and resolution of DVT, data investigating the changes involved with SVT were not identiﬁed. Although some authors have alluded that the underlying pathology of SVT with DVT may be analogous, to date, this viewpoint remains mostly unsupported.

TRAUMA The most common source of trauma associated with SVT is an intravenous cannula. This SVT may result in erythema, warmth, and tenderness along its course. Treatment starts with removal of the cannula and warm compresses. The resultant lump may persist for months notwithstanding this treatment.

SUPPURATIVE Suppurative SVT (SSVT) is also associated with the use of an intravenous cannula; however, SSVT may be lethal because its association with septicemia. The associated signs and symptoms of SSVT include pus at an intravenous site, fever, leukocytosis, and local intense pain.7 Treatment begins with removal of the foreign body and intravenous antibiotics. Excision of the vein is rarely needed to clear the infection.

SMALL SAPHENOUS SUPERFICIAL VEIN THROMBOSIS Although the bulk of attention has been focused on SVT of the great saphenous vein (GSV), SVT of the small saphenous vein (SSV) is also of clinical import. Small saphenous vein SVT may progress into popliteal DVT. In a group of 56 patients with SSV SVT, 16% suffered from PE or DVT.2 Therefore, it is crucial that patients with SSV SVT be treated similarly to those diagnosed with GSV SVT, employing the same careful duplex examination, follow-up, and anticoagulation or ligation if the SVT approaches the popliteal vein.

SUPERFICIAL THROMBOPHLEBITIS WITH VARICOSE VEINS It has been reported that only 3–20% of SVT patients with varicose veins will develop DVT, compared with 44–60% without varicose veins.11–13 Therefore, it appears that patients with varicose veins may have a different pathophysiology from those without varicose veins. However, in a more recent study, no increased incidence of DVT or PE was noted when comparing patients with and without varicose veins in the 186 SVT patients identiﬁed.2 Consequently, the question of whether the SVT patients with and without associated varicose veins should be thought of as separate classiﬁcations remains ambiguous.14 Conversely, addressing those patients with SVT involving varicose veins only is essential. This type of SVT may remain localized to the cluster of tributary varicosities

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or may, from time to time, extend into GSV.2 Superﬁcial venous thrombosis of varicose veins themselves may occur without antecedent trauma. Superﬁcial venous thrombosis is frequently found in varicose veins surrounding venous stasis ulcers. This diagnosis should be conﬁrmed by duplex ultrasound scan, as the degree of the SVT may be much greater than that based solely on clinical examination. Treatment consists of conservative therapy of warm compresses and non-steroidal anti-inﬂammatories.

UPPER EXTREMITY SUPERFICIAL VENOUS THROMBOSIS Although very little appears in the literature, upper extremity SVT is believed to be the result of intravenous cannulation and infusion of caustic substances that damage the endothelium. Interestingly, the extension of upper extremity SVT into upper extremity DVT or PE is a very rare occurrence compared with lower extremity SVT.15 Initial treatment of upper extremity SVT is catheter removal followed by conservative measures, such as warm compresses and non-steroidal anti-inﬂammatory medications.

DIAGNOSIS It is supposed by a few authors that SVT is a benign common process that requires no further work-up unless symptoms fail to resolve quickly on their own.16 This is despite the ﬁndings that indicate DVT associated with SVT may not be clinically apparent.2 Duplex ultrasound scanning has become the initial test of choice for the diagnosis of DVT and the evaluation of SVT since ﬁrst introduced by Talbot in 1982. The availability of reliable duplex ultrasonography of the deep and superﬁcial venous systems has made routine determination of the location and incidence of DVT in association with SVT accurate and practical. Furthermore, the extent of involvement of the deep and superﬁcial systems can be more accurately assessed utilizing this modality, for routine clinical examination may not be able to precisely evaluate the proximal extent of involvement of the deep or superﬁcial systems. Duplex ultrasound imaging also offers the advantage of being inexpensive, non-invasive, and can be repeated for follow-up examination. As venography may contribute to the onset of phlebitis and duplex imaging affords an accurate diagnosis, venography is not recommended. Duplex imaging of patients with SVT has revealed the concomitant DVT to range from 5% to 40%.2,17–20 It is important to note that up to 25% of these patients’ DVTs may not be contiguous with the SVT or may be even in the contralateral lower extremity.2

TREATMENT The location of the SVT determines the course of treatment.21 The therapy may be altered should the SVT involve tributaries of the GSV, distal GSV, or GSV of the proximal thigh. Traditional treatment for SVT localized in tributaries of the GSV and the distal GSV has consisted of ambulation, warm soaks and non-steroidal antiinﬂammatory agents.1,22,23 Surgical excision may play a role in the rare case of recurrent bouts of thrombophlebitis in spite of maximal medical management. However, this type of management does not address the possibilities of clot extension or attendant DVT associated with proximal GSV SVT. The progression of isolated SVT to DVT has been evaluated.13,20 In one study, patients with thrombosis isolated to the superﬁcial veins with no evidence of deep venous involvement by duplex ultrasound examination were assessed by follow-up duplex ultrasonography to determine the incidence of disease progression into the deep veins of the lower extremities. Initial and follow-up duplex scans evaluated the femoropopliteal and deep calf veins in their entirety with follow-up studies performed at an average of 6.3 days. Two hundred and sixty-three patients were identiﬁed with isolated superﬁcial venous thrombosis. Thirty (11%) patients had documented progression to deep venous involvement. The most common site of deep vein involvement was the progression of disease from the GSV in the thigh into the common femoral vein (21 patients), with 18 of these extensions noted to be non-occlusive and 12 having a free-ﬂoating component. Three patients had extended above-knee saphenous vein thrombi through thigh perforating veins to occlude the femoral vein in the thigh. Three patients had extended below-knee saphenous SVT into the popliteal vein, and three patients had extended below-knee thrombi into the tibioperoneal and calf perforating veins. At the time of the follow-up examination, all 30 patients were being treated without anticoagulation. As a result of this type of experience, we recommend repeat duplex scanning for SVT of the GSV or LSV after 48 hours to assess for progression.24 For SVT within 1 cm of the saphenofemoral junction, management with high saphenous ligation with or without saphenous vein stripping has been suggested to be the treatment of choice because of the recognized potential for extension into the deep system and embolization.25–28 In a series of 43 patients who underwent ligation of the saphenofemoral junction with and without local CFV thrombectomy and stripping of the GSV, only two patients were found with postoperative contralateral DVT, one of whom had a PE.3 Eighty-six percent of the patients were discharged within 3 days. Four patients developed a wound cellulitis that was treated with antibiotics. One patient had a wound hematoma requiring no treatment. Although satisfactory results were noted in these instances, several issues still remain unresolved. The question of

Diagnosis

whether or not to strip the GSV in addition to high ligation is not clearly addressed, although these patients do seem to experience less pain once the SVT is removed. Ligation was initially proposed to avert the development of deep venous thrombosis by preventing extension via the saphenofemoral junction. Since issues of non-contiguous DVT and post-ligation DVT with PE are not addressed by this therapy, alternative treatment options need to be explored. A prospective non-randomized study was conducted to evaluate the efﬁcacy of a non-operative approach of anticoagulation therapy to manage saphenofemoral junction thrombophlebitis (SFJT).22 Over a 2 year period between January 1993 and January 1995, 20 consecutive patients with SFJT were entered into the study. These patients were hospitalized and given a full course of heparin treatment. Duplex ultrasonography was performed before admission, both to establish the diagnosis and to evaluate the deep venous system. Two to 4 days after admission, a follow-up duplex ultrasound scan was performed to assess resolution of SFJT and to reexamine the deep venous system. Patients with SFJT alone and resolution of SFJT as documented by duplex ultrasound scans were maintained on warfarin for 6 weeks. Those patients with SFJT and DVT were maintained on warfarin for 6 months. The incidence of concurrent DVT and its location were noted. The efﬁcacy of anticoagulation therapy was evaluated by measuring SFJT resolution, recurrent episodes of SFJT, and occurrence of PE. A 40% incidence (eight of 20 patients) of concurrent DVT with SFJT was found. Of these eight patients, four had unilateral DVT, two had bilateral DVT, and two had development of DVT with anticoagulation. Deep vein thrombosis was contiguous with SFJT in ﬁve patients and non-contiguous in three patients. Seven out of 13 duplex ultrasound scans obtained at 2–8 months’ follow-up demonstrated partial resolution of SFJT, ﬁve had complete resolution, and one demonstrated no resolution. There were no episodes of PE, zero recurrences, and no anticoagulation complications at maximum follow-up of 14 months. Anticoagulation therapy to manage SFJT was effective in achieving resolution, preventing recurrence and preventing PE within the follow-up period. The high incidence of DVT associated with SFJT suggests that careful evaluation of the deep venous system during the course of management is necessary.29 It should be noted that the short-term effect of anticoagulation on progression to DVT or the long-term effect on local recurrence of SVT has not been evaluated. When comparing these two types of therapy, one group suggested that high ligation for SFJT would be more costeffective than systemic anticoagulation for 6 months.3 The question of whether patients with SVT need to be treated for a 6 month period remains uncertain. Our treatment course of anticoagulation spans a period of 6 weeks and, over the last 10 years, we have noted no incidence of PE or complications of anticoagulation. Furthermore, signiﬁcant cost savings could be realized if the low-molecular-weight

317

heparins (LMWHs) are used in an outpatient setting instead of unfractionated intravenous heparin.30 In addition, since the surgical options do not address the hypercoaguable state of these patients and may create injury to the endothelium at the saphenofemoral junction, the surgical options seem to be less appealing, at least on a theoretical basis. This issue of anticoagulation versus surgical therapy was addressed in a prospective study consisting of 444 patients randomized to six different treatment plans (compression only, early surgery with and without stripping, low-dose subcutaneous heparin, LMWH, and oral anticoagulant treatment) in the management of superﬁcial thrombophlebitis.31 Patients presenting with SVT and large varicose veins without any suspected/ documented systemic disorder were included in this study. The criteria for inclusion were as follows: venous incompetence (by duplex); a tender, indurated cord along a superﬁcial vein; and redness and heat in the affected area. Exclusion criteria were obesity, cardiovascular or neoplastic diseases, non-ambulatory status, bone/joint disease, problems requiring immobilization, age > 70 years, and patients with superﬁcial thrombophlebitis without varicose veins. Color duplex ultrasound scans were used to detect concomitant DVT and to evaluate the extension or reduction of SVT at 3 and 6 months. The incidence of SVT extension was higher in the elastic compression and in the saphenous ligation groups (P < 0.05) after 3 and 6 months. There was no signiﬁcant difference in DVT incidence at 3 months among the treatment groups. Stripping of the affected veins was associated with the lowest incidence of thrombus extension. The cost for compression solely was found to be the lowest, and the treatment arm including LMWH was found to be the most expensive. The highest social cost (lost working days, inactivity) was observed in subjects treated with stockings alone. However, careful examination reveals that the results of this study are difﬁcult to evaluate, as the details of the treatment protocols were not speciﬁcally identiﬁed. Furthermore, the exclusion criteria would eliminate many of the patients diagnosed with SVT in a clinical practice and the inclusion of almost any patient presenting with SVT, regardless of its location, makes the remaining groups quite variable. Furthermore, in a double-blind trial, 427 patients with documented acute symptomatic superﬁcial vein thrombosis of the legs were randomly assigned to receive subcutaneous enoxaparin sodium, 40 mg; subcutaneous enoxaparin, 1.5 mg/kg; oral tenoxicam; or placebo, once daily for 8–12 days.32,33 The primary outcome was deep venous thromboembolism between days 1 and 12, deﬁned as DVT detected by ultrasonography between days 8 and 12 or earlier if clinically indicated, or documented symptomatic pulmonary embolism. For the secondary outcomes, superﬁcial vein thrombosis recurrence or extension was also considered. The incidence of deep

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Guidelines 3.10.0 of the American Venous Forum on superﬁcial venous thrombophlebitis No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.10.1 For saphenous vein thrombophlebitis within 1 cm of the saphenofemoral or saphenopopliteal junction, we suggest high saphenous vein ligation with or without saphenous vein stripping to avoid extension into the deep system and embolization. Anticoagulation is an acceptable alternative therapy

2

B

3.10.2 For thrombophlebitis localized in the distal segment or in tributaries of the great saphenous vein we suggest ambulation, warm soaks and nonsteroidal anti-inﬂammatory agents. We suggest surgical excision only in rare cases of recurrent bouts of thrombophlebitis in spite of maximal medical management

2

B

venous thromboembolism was not reduced in these groups compared with placebo by day 12. However, the incidence of deep and superﬁcial venous thromboembolism by day 12 was signiﬁcantly reduced in all active treatment groups, from 30.6% (34 of 111 patients) in the placebo group to 8.3% (9 of 109 patients), 6.9% (7 of 102 patients), and 14.9% (14 of 94 patients) in the 40 mg enoxaparin (P < 0.001), 1.5 mg/kg enoxaparin (P < 0.001), and tenoxicam (P < 0.01) groups, respectively. This group concluded further evaluation of treatment using NSAID or LMWH is warranted. However, again, signiﬁcant limitations of this study are noted. Since any SVT longer than 5 cm was included, the study group is quite variable, and this tends to dilute the speciﬁc treatment recommendations that can be drawn for each type of SVT. This study, which was supported by the pharmaceutical industry, still remains underpowered to answer some of the important questions and the data suggest that the patients may have been possibly undertreated with the short treatment duration. In an attempt to further clarify some of these issues, one group attempted to perform a meta-analysis of surgical versus medical therapy for isolated above-knee SVT. However, a formal meta-analysis was not possible because of the paucity of comparable data between the two groups. This review suggested that medical management with anticoagulants is somewhat superior for minimizing complications and preventing subsequent DVT and PE. Ligation with stripping allows superior symptomatic relief from pain.34 Based on these data, the authors suggest that anticoagulation is appropriate in patients without contraindication. Although proximal GSV SVT occurs not infrequently, the best treatment regimen based on its underlying pathophysiology and resolution rate remains contro-

versial. More recent investigations do offer some guidelines;35 however, care should be exercised by the physician in diagnosing SVT to avoid the complications that may ensue because of the nature of the SVT. Further examination of the unresolved issues involving SVT is fundamental.36

REFERENCES ●

= Key primary paper 1. DeWeese MS. Nonoperative treatment of acute superﬁcial thrombophlebitis and deep femoral venous thrombosis. In: Ernst CB, Stanley JC, eds. Current therapy in vascular surgery. Philadelphia: BC Decker, 1991; 952–60. 2. Lutter KS, Kerr TM, Roedersheimer LR, et al. Superﬁcial thrombophlebitis diagnosed by duplex scanning. Surgery 1991; 110: 42–6. 3. Lohr JM, McDevitt DT, Lutter KS, et al. Operative management of greater saphenous thrombophlebitis involving the saphenofemoral junction. Am J Surg 1992; 164: 269–75. 4. Hanson JN, Ascher E, DePippo P, et al. Saphenous vein thrombophlebitis (SVT): a deceptively benign disease. J Vasc Surg 1998; 27: 677–80. 5. de Godoy JM, Batigalia F, Braile DM. Superﬁcial thrombophlebitis and anticardiolipin antibodies—report of association. Angiology 2001; 52: 127–9. 6. Leon LR Jr, Labropoulos N. Superﬁcial vein thrombosis and hypercoagulable states: the evidence. Perspect Vasc Surg Endovasc Ther 2005; 17 (1): 43–6. 7. Hammond JS, Varas R, Ward CG. Suppurative thrombophlebitis: a new look at a continuing problem. South Med J 1988; 81: 969–71.

References 319

8. Glasser ST. Principles of Peripheral Vascular Surgery. Philadelphia: FA Davis, 1959. 9. Mayor M, Buron I, de Mora JC, et al. Mondor’s disease. Int J Dermatol 2000; 39: 922–5. 10. Sasso F, Gulino G, Basar M, et al. Penile Mondors’ disease: an underestimated pathology. Br J Urol 1996; 77: 729–32. 11. Bergqvist D, Jaroszewski H. Deep vein thrombosis in patients with superﬁcial thrombophlebitis of the leg. BMJ 1986; 292: 658–9. 12. Prountjos P, Bastounis E, Hadjinikolaou L, et al. Superﬁcial venous thrombosis of the lower extremities co-existing with deep venous thrombosis. A phlebographic study on 57 cases. Int Angiol 1991; 10: 263–5. 13. Chengelis DL, Bendick PJ, Glover JL, et al. Progression of superﬁcial venous thrombosis to deep vein thrombosis. J Vasc Surg 1996; 24: 745–9. 14. Marchiori A, Mosena L, Prandoni P. Superﬁcial vein thrombosis: risk factors, diagnosis, and treatment. Semin Thromb Hemost 2006; 32: 737–43. 15. Sassu GP, Chisholm CD, Howell JM, Huang E. A rare etiology for pulmonary embolism: basilic vein thrombosis. J Emerg Med 1990; 8: 45–9. 16. William’s Manual of Obstetrics, Section XIII. Medical and Surgical Complication in Pregnancy, 20th edn. Sanford CT: Appleton & Lange, 1112. 17. Talbot SR. Use of real-time imaging in identifying deep venous obstruction: a preliminary report. Bruit 1982; 6: 41–2. 18. Skillman JJ, Kent KC, Porter DH, Kim D. Simultaneous occurrence of superﬁcial and deep thrombophlebitis in the lower extremity. J Vasc Surg 1990; 11: 818–23. 19. Jorgensen JO, Hanel KC, Morgan AM, Hunt JM. The incidence of deep venous thrombosis in patients with superﬁcial thrombophlebitis of the lower limbs. J Vasc Surg 1993; 18: 70–3. 20. Schonauer V, Kyrle PA, Weltermann A, et al. Superﬁcial thrombophlebitis and risk for recurrent venous thromboembolism. J Vasc Surg 2003; 37: 834–8. 21. Leon L, Giannoukas AD, Dodd D, et al. Clinical signiﬁcance of superﬁcial vein thrombosis. Eur J Vasc Endovasc Surg 2005; 29 (1): 10–7. 22. Ludbrook J, Jamieson GG. Disorders of veins. In: Sabiston DC Jr, ed. Textbook of Surgery, 12th edn. Philadelphia, PA: WB Saunders, 1981: 1808–27. 23. Hobbs JT. Superﬁcial thrombophlebitis. In: Hobbs JT, ed. The Treatment of Venous Disorders. Philadelphia, PA: JB Lippincott, 1977: 414–27.

24. Blumenberg RM, Barton E, Gelfand ML, Skudder P, Brennan J. Occult deep venous thrombosis complicating superﬁcial thrombophlebitis. J Vasc Surg 1998; 27: 338–43. 25. Husni EA, Williams WA. Superﬁcial thrombophlebitis of lower limbs. Surgery 1982; 91: 70–3. 26. Lofgren EP, Lofgren KA. The surgical treatment of superﬁcial thrombophlebitis. Surgery 1981; 90: 49–54. 27. Gjores JE. Surgical therapy of ascending thrombophlebitis in the saphenous system. Angiology 1962; 13: 241–3. 28. Plate G, Eklof B, Jensen, Ohlin P. Deep venous thrombosis, pulmonary embolism and acute surgery in thrombophlebitis of the long saphenous vein. Acta Chir Scand 1985; 151: 241–4. 29. Ascer E, Lorensen E, Pollina RM, Gennaro M. Preliminary results of a nonoperative approach to saphenofemoral junction thrombophlebitis. J Vasc Surg 1995; 22: 616–21. 30. Prandoni P, Tormene D, Pesavento R; Vesalio Investigators Group. High vs. low doses of low-molecular-weight heparin for the treatment of superﬁcial vein thrombosis of the legs: a double-blind, randomized trial. J Thromb Haemost 2005; 3: 1152–7. 31. Belcaro G, Nicolaides AN, Errichi BM, et al. Superﬁcial thrombophlebitis of the legs: a randomized, controlled, follow-up study. Angiology 1999; 50: 523–9. 32. Superﬁcial Thrombophlebitis Treated By Enoxaparin Study Group. A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal antiinﬂammatory agent, and placebo in the treatment of superﬁcial vein thrombosis. Arch Intern Med 2003; 163: 1657–63. ●33. Quenet S, Laporte S, Decousus H, et al. STENOX Group. Factors predictive of venous thrombotic complications in patients with isolated superﬁcial vein thrombosis. J Vasc Surg 2003; 38: 944–9. 34. Sullivan V, Denk PM, Sonnad SS, et al. Ligation versus anticoagulation: treatment of above-knee superﬁcial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001; 193: 556–62. 35. Wichers IM, Di Nisio M, Buller HR, Middeldorp S. Treatment of superﬁcial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review. Haematologica 2005; 90: 672–7. 36. Kalodiki E, Nicolaides AN. Superﬁcial thrombophlebitis and low-molecular-weight heparins. Angiology 2002; 53: 659–63.

27 Mesenteric vein thrombosis WALDEMAR E. WYSOKINSKI AND ROBERT D. MCBANE Introduction Etiology Clinical presentation Diagnostic methods

320 320 321 321

INTRODUCTION Mesenteric vein thrombosis (MVT) was ﬁrst described by Elliot in 1895.1 Four decades later, Warren and Eberhard2 recognized this as a distinct clinical entity and an important cause of bowel infarction. Now, more than 100 years after the ﬁrst description, MVT remains a serious thrombotic disorder that is both difﬁcult to diagnose and treat.3 The incidence of MVT in the general population is poorly deﬁned, with estimates from autopsy and surgical series ranging from 0.01% to 1.5%.4 Kazmers5 noted that MVT may be found in as few as one in 1000 laparotomies. The age at presentation varies from 45 to 65 years and both genders are equally represented.3–10 Venous thrombosis may be limited to the mesenteric veins or may propagate to or from other regional vessels.5–7 MVT accounts for 5–15% of patients with intestinal ischemia.8–10 The clinical course and symptomatology is determined by both the aggression of the thrombotic process and the extent of venous segments involved. The superior mesenteric vein is much more frequently involved relative to the inferior mesenteric vein.11 The acuity of MVT clinical presentation may vary considerably. Patients with acute MVT may note the sudden onset of abdominal pain that may quickly progress within hours to include signs of peritonitis with bowel infarction. Patients with subacute onset present primarily with abdominal pain that has developed over days to weeks.14 In these patients neither bowel infarction nor chronic complications (variceal hemorrhage) are likely. Rarely patients with prominent and persistent abdominal pain will develop intestinal infarction several days to weeks after the initial onset. Distinguishing between acute and subacute presentation however can be quite difﬁcult.5 It is for this reason that acute and subacute mesenteric venous

Treatment Outcomes Conclusions References

324 325 326 326

thromboses are often discussed together. Patients with chronic MVT have minimal if any symptoms. The diagnosis is often made as an incidental ﬁnding on crosssectional imaging studies when extensive venous collaterals are noted. Complications of portal vein or splenic vein thrombosis such as portal hypertension or esophageal variceal hemorrhage may also lead the clinician to MVT as the correct inciting etiology. This chapter will focus primarily on the acute form of MVT.

ETIOLOGY Mesenteric vein thrombosis can be classiﬁed as either primary or secondary based on our current understanding of congenital and acquired causative variables for this condition (Box 27.1). As our understanding of factors involved in the genesis of venous thrombosis evolves and as imaging modalities improve, the number of patients with primary, or unprovoked, MVT will continue to decline.3–5,6,12 Recent clinical series however continue to reveal that a speciﬁc underlying etiology cannot be ascertained in as many as 50% of patients.7,15 Predisposing conditions can be broadly divided into systemic or local factors. Local causes such as solid organ tumor or other organ pathology, infection, abdominal or pelvic surgery, or local trauma are prevalent relative to systemic inherited or acquired thrombophilias. Organ pathology involving the liver (cancer, cirrhosis, hepatitis), pancreas (pancreatitis, cancer), and spleen (splenomegaly of different causes, splenectomy) are particularly relevant.3,4,7,12,15–18 Dividing causes into systemic or local factors therefore provides a nice conceptual framework to organize causative factors. Distinguishing between permanent and temporary factors however appears to have

Diagnostic methods 321

BOX 27.1 Thrombophilia risk factors for mesenteric venous thrombosis Primary or familial thrombophilia Antithrombin deﬁciency Protein C deﬁciency Protein S deﬁciency Activated protein C resistance and factor V Leiden mutation Prothrombin G20210A mutation Elevated factor VIII Hyperhomocysteinemia Acquired or secondary thrombophilia Heparin-induced thrombocytopenia Disseminated intravascular coagulation Lupus anticoagulant and antiphospholipid antibody syndrome

important therapeutic implications particularly for the duration of treatment with anticoagulant. Although there is a general acceptance that inherited or acquired thrombophilias either cause or contribute to MVT cases,3–5,19 the precise role of these conditions remains unclear. Most studies have been retrospective in nature with incomplete coagulation assessment and limited by referral bias. Furthermore, in those patients where an underlying local etiology has been identiﬁed, coagulation testing is infrequently performed. Lastly, coagulation testing may be limited by timing of assay acquisition and thus result in over or underestimation of coagulation defects. Test interpretation may be affected by the thrombus itself, hepatic ischemia secondary to the thrombus, or treatment with heparinoids or vitamin K antagonists. Genetic studies suffer similar limitations of referral bias for speciﬁc testing. Therefore, the prevalence of factor V Leiden and prothrombin G20210A mutations reporting has ranged from 0 to 25%7,12–19 and is not different from that reported in lower extremity venous thrombosis.20 A speciﬁc inherited or acquired thrombophilia does not appear to be over-represented in MVT patients relative to those with venous thrombi at other locations. Personal or family history of venous thromboembolic disease is reported in 10–50% of MVT patients.3,11,12,15,19

CLINICAL PRESENTATION The onset of progressive abdominal pain in the patient with disproportionally few physical ﬁndings should prompt the clinician to think about MVT as a possible diagnosis. Although the duration of symptoms vary, the majority of patients will have had symptoms for more than

48 hours before seeking medical attention.3 In those patients with ascites, MVT should be high in the differential diagnosis particularly if thrombotic risk factors (e.g., oral contraceptive use or known malignancy) or historical factors such as personal and/or family history of venous thromboembolic disease are present. The clinical manifestations depend largely on the extent of the thrombus, the size and number of vessels involved, the acuity of venous obstruction, and the extent of venous collateral development.6 In general, clinical signs and symptoms of intestinal ischemia due to MVT are nonspeciﬁc. The pathophysiology includes mesenteric venous outﬂow obstruction that may lead to profound congestion and capillary malperfusion. This results in mesenteric ischemia with abdominal pain that is out of proportion to the physical ﬁndings.3,4,7,9–19,21 The abdominal pain is often localized to the mid-abdomen and is described as “colicky,” suggesting a compromised small bowel. Nausea, anorexia, vomiting, and diarrhea are also common. Hematemesis, hematochezia, or melena occur in about 15% of patients,13 but occult blood is detectable in the stool in nearly 50%.22 Abdominal distention is found in more that half of patients.21 Peritoneal signs develop in one-third to two-thirds of patients, although the initial physical ﬁndings may be entirely normal.13 When fever, guarding, and rebound tenderness are found, intestinal infarction must be anticipated. Hemodynamic instability is a grave prognostic ﬁnding and may result from hypovolemia due to ﬂuid collection within the bowel lumen or development of ascites or septicemia.13 Fluid resuscitation, early diagnosis conﬁrmation, and prompt surgical attention are central to improving the outcome of these unstable patients.

DIAGNOSTIC METHODS Recent advances in imaging technology have increased the accuracy and frequency of MVT diagnosis and improved our understanding of underlying causes. None the less, this condition is frequently misdiagnosed initially, or diagnosed late, and the outcome is often unfavorable.12 In patients for whom the diagnosis of MVT is suspected, sensitive imaging modalities should be used early in the evaluation.

Computed tomography Contrast-enhanced computed tomography (CT) is considered by many as the test of choice for suspected cases of MVT.23–26 The mesenteric vessels are well seen and the extent of bowel involvement can be simultaneously evaluated. Furthermore, other causes of abdominal pain can be excluded at the same time. An acute venous thrombus is identiﬁed as a central ﬁlling defect within the mesenteric vein (Fig. 27.1). Engorgement of the superior

322

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thrombosis, and mesenteric edema. Metallic and nonmetallic synthetic graft artifacts are reduced and the organ anatomy is well depicted.

Magnetic resonance

(a)

Magnetic resonance imaging (MRI) also has excellent sensitivity and speciﬁcity for the diagnosis of MVT (Fig. 27.2).31 Several advantages deserve enumerating, including the use of non-nephrotoxic contrast, no exposure to ionizing radiation, and the ability to tailor the image acquisition to correspond with the desired vascular territory. The bowel and other organ integrity can be assessed at the same time. Limitations include signal degradation due to ﬂow turbulence and metallic artifact related to vascular stents and other vascular clips.34,35

(b) Figure 27.1 Computed tomography example of mesenteric vein thrombosis. Computed tomography with intravenous contrast shows thrombosis of a branch vessel of the superior mesenteric vein (SMV) (arrows) with non-occlusive thrombus projecting into the lumen of the SMV up to the level of the conﬂuence with the splenic vein.

mesenteric vein with varying degrees of wall enhancement may also be observed. Other CT ﬁndings are less speciﬁc and represent manifestation of accompanying bowel ischemia. These include thickening of the small bowel wall and peritoneal ﬂuid. If these non-speciﬁc signs are seen in the setting of MVT, bowel infarction should be strongly considered. The sensitivity of contrast-enhanced CT imaging for MVT may be as high as 90%.3,22,27 In those patients with early thrombosis involving small venous branches, the sensitivity is diminished. The new multi-row CT scanners offer the advantages of signiﬁcantly shorter acquisition times, three-dimensional reconstruction, and reduced artifact, thus improving the overall diagnostic accuracy.29–30 This technique provides detailed assessment of both intra- and extraluminal abnormalities, mural

(a)

(b) Figure 27.2 Magnetic resonance imaging (MRI) example of mesenteric vein thrombus. Contrast-enhanced MRI of the abdomen demonstrates an acute occlusive venous thrombus (arrows) involving the superior mesenteric vein (SMV) both by cross-sectional (a) and coronal (b) views. The SMV is distended with acute-appearing thrombus.

Diagnostic methods 323

(a)

(c)

(b)

(d)

Ultrasonography Duplex ultrasound provides a sensitive and speciﬁc assessment of mesenteric blood ﬂow in the evaluation of patients with suspected MVT.23,36,37 Thrombus visualization within the mesenteric venous system conﬁrms the diagnosis (Fig. 27.3a,b). The lack of residual mesenteric venous ﬂow by Doppler assessment is also quite speciﬁc for the diagnosis of MVT (Fig. 27.3b,c). Thickened bowel wall, free intraperitoneal ﬂuid, and biliary disease can also be demonstrated. Advantages include a non-invasive and inexpensive assessment that can be obtained urgently at the patients bedside. There is neither nephrotoxic contrast nor ionizing radiation exposure during image acquisition. Limitations of this modality include operator skill and expertise, appropriate equipment capable of assessing slow ﬂow states, and patient-speciﬁc variables, including unsuitable acoustic windows and overlying bowel gas. In addition, large periportal collateral vessels in portal venous thrombosis may be mistaken for a patent portal vein. Intravenous administration of US-compatible intravascular contrast agents, in conjunction with grayscale harmonic imaging may increase vessel interrogation.37 In experienced hands, duplex ultrasound is an invaluable technique for this purpose.

Venography Although more invasive than the cross-sectional imaging modalities described, the advantages of conventional

Figure 27.3 Duplex ultrasound example of mesenteric vein thrombosis. This duplex ultrasound example depicts acute-appearing nonocclusive thrombus (arrow) involving the superior mesenteric vein in cross-section (a) and longitudinal (b) views. Both color (c) and Doppler interrogation (d) of the venous segment reveal that the thrombus is incompletely obstructing mesenteric venous outﬂow.

venography include an accurate assessment of mesenteric venous patency and ﬂow direction, venous collaterals, and a comprehensive assessment of thrombus burden (Fig. 27.4). Pressure gradients can be measured directly and endovascular therapies can be readily accomplished.

IVC

Figure 27.4 Venogram example of transjugular intrahepatic portosystemic shunt (TIPS) procedure. Venogram example of TIPS procedure showing partially occlusive mesenteric venous thrombus (large white arrow). The stented communication (thin black arrows) with the inferior vena cava is readily apparent.

324

Mesenteric vein thrombosis

Selective mesenteric angiography demonstrates impaired ﬁlling of the accompanying veins, arterial spasm, and prolonged opaciﬁcation of the arterial arcades, all indirect evidence supporting the diagnosis.23,38 The limitations of venography include the requirement of experienced personnel with appropriate imaging hardware. The evaluation includes transfer of a potentially unstable patient to a ﬂuoroscopy suite for image acquisition; this is invasive and exposes the patient both to nephrotoxic contrast and ionizing radiation.

Abdominal radiographs Although abdominal radiographs are abnormal in the majority of patients, the ﬁndings are speciﬁc for neither bowel ischemia nor MVT.4 The most common ﬁndings include adynamic ileus with dilated, ﬂuid-ﬁlled loops of bowel. Focal thickening of the mucosa (“thumbprinting”) or mesentery, and intramural or venous gas suggest advanced intestinal ischemia.39 Barium contrast studies should be avoided in these patients. In summary, there are a number of imaging studies to choose from in the evaluation of patients with suspected MVT. The choice involves a careful clinical assessment of the patient to determine the likelihood of MVT versus other diagnoses (assessing the pretest probability of disease). For the stable patient with reasonable creatinine clearance, contrast-enhanced CT imaging will provide considerable clinical information. Contrast-enhanced MRI provides a excellent alternative for stable patients with renal insufﬁciency. For patients who are less stable, bedside duplex ultrasound will provide an assessment of mesenteric vascular patency. The ultimate choice of imaging will depend on the radiology expertise and machinery available at the institution caring for the patient. Discussion of the patient-speciﬁc variables with the attending radiologist prior to decision-making is a very valuable and fruitful place to start.

Blood tests Blood tests may be very helpful in the evaluation of patients with suspected MVT. The complete blood count with differential is important to assess both the hemoglobin and hematocrit to ensure that occult bleeding is not overlooked. Polycythemia rubra vera, essential thrombocythemia, leukemia, myeloproliferative disorders and other hematologic disorders which may predispose to venous thrombosis can also be screened for with this test. The white blood count and differential will alert the physician to infections related to bowel infarction or perforation. Elevated serum lactate levels and metabolic acidosis will help to identify those patients with severely ischemic or infarcted bowel.40 Transaminase elevation implies additional involvement of the portal or hepatic

venous system. This is particularly relevant for initiation of treatment with vitamin K antagonists. Fibrin D-dimer elevation may also be helpful in determining the timing of thrombosis. An acute thrombus is anticipated to be accompanied by signiﬁcant D-dimer elevations. In the subacute or chronic setting, thrombosis evolution may no longer be associated with D-dimer abnormalities. The timing of thrombophilia laboratory assessment may be a difﬁcult decision. Ideally, one would obtain these types of tests once the thrombus has been appropriately treated and the patient is no longer taking warfarin or heparin. Typically, this type of testing would be performed more than 2 weeks after warfarin has been discontinued to maximize the test sensitivity and speciﬁcity.

TREATMENT Medical management The appropriate treatment of patients with MVT involves multidisciplinary input from both medical and surgical services. Clinical observations suggest that immediate anticoagulation with heparin early in the course of the disease, even intraoperatively, improves survival, reduces thrombus propagation, and reduces the risk of recurrence.9 Gastrointestinal bleeding is not necessarily a contraindication to anticoagulant therapy, whereas the risk of bleeding must be weighed against the risk of bowel infarction. This decision requires careful and thorough patient evaluation including measures of bowel ischemia, thrombus burden and acuity, collateral circulation, and an assessment of bleeding risk. Although improved survival rates have been shown among patients receiving anticoagulant therapy (63% vs 44%) the need for chronic anticoagulant therapy in these patients is less clear.41 Observational studies suggest that chronic anticoagulant use reduces the incidence of recurrent venous thrombosis by one third.3,7,12,17,21 The efﬁcacy and optimal duration of anticoagulant therapy however has not been deﬁned by randomized trials. In general, anticoagulation should be continued until provoking factors have been eliminated if possible. In those patients whose MVT can be attributed to temporary risk factors, 6–12 months of anticoagulants is likely reasonable.5 Expert opinion would suggest that antibiotic therapy should be provided for patients with signs or symptoms of bowel compromise.

Endovascular intervention Endovascular therapies may be pursued for selected patients with acute MVT that is diagnosed early in the course of the disease before bowel infarction or peritonitis develops.42–44 Catheter-directed thrombolytic therapy has been performed successfully in a small subset of patients.

Outcomes 325

Candidates for this approach include those patients with acute and extensive mesenteric venous thrombosis with portal vein involvement for whom surgical thrombectomy or balloon embolectomy are not feasible options.42 Mechanical thrombectomy combined with catheterdirected thrombolysis may require gaining access by direct cannulation of the portal venous system via a percutaneous transhepatic or transjugular approach.42,45,46 Although this represents an attractive alternative to surgical intervention which appears safe and effective, prospective studies with adequate patient numbers are necessary for reliable assessment of this treatment method.

Surgical treatment The need for surgical intervention in patients with MVT is not universal and may be necessary for only a minority.3,17,21 Acute mesenteric ischemia accompanied by evidence of peritonitis or bowel infarction is an accepted indication for surgical intervention and resection of involved bowel. The key to successful surgery is to resect sufﬁcient bowel to assure proper anastomic healing and halt thrombus propagation while preserving as much viable intestine as possible. The decision-making may be complex and requires the technical skill and expertise of a surgeon who has familiarity with operations of this type. Management is dictated by the intraoperative ﬁndings, which range from segmental bowel ischemia to widespread mesenteric necrosis. Bowel perforation may or may be present. Often, the surgical procedure is staged with a repeat (“second-look”) laparotomy performed 1 day later.47 Postoperatively anticoagulants should be initiated as soon as hemostasis is adequately ensured. Under these circumstances, disease progression is uncommon.

Thrombectomy remains a potential treatment option for selected patients yet must be pursued quickly as thrombus maturation (beyond 3 days) reduces the success of this operation.48

OUTCOMES Reported mortality rates vary considerably and range from 2% to 50% within the follow-up range of 1 month to 5 years.3,7,9,13–17 These studies however are retrospective and heterogeneous in nature with varying proportions of acute and chronic, surgical, and non-surgical cases. Warren and Eberhardt2 compiled published reports of 75 cases of MVT to which they added two of their own. In this historic description, the overall mortality rate was 58.8%. Of the 55 patients who underwent surgical resection, the mortality rate was 45.4%. Of the remaining 20 who were treated medically, only one patient survived to hospital discharge. More recent reports have yielded more favorable results with declining mortality rates. Delay of diagnosis and intervention, post-surgical complications, and underlying malignancy carry a worse prognosis.12 The recurrence rate of venous thrombosis in these patients is not completely clear. Although rates are said to be increased, Kumar and Kamath7 reported only two recurrences among 30 patients with MVT limited to the superior mesenteric vein over a median follow-up of 18 months. Recurrent thrombosis was noted in 5 of 39 patients with combined porto-mesenteric-splenic thrombosis during median follow-up period of 27 months. These data suggest recurrence rates of 5–6% per year. Morasch et al.12 reported that all 22 long-term survivors of MVT (19 treated with warfarin) were thrombosis free at the last follow-up visit (mean 57.7 months period).

Guidelines 3.11.0 of the American Venous Forum on mesenteric vein thrombosis No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.11.1 We recommend computed tomography angiography and magnetic resonance angiography for the diagnosis of mesenteric venous thrombosis

1

B

3.11.2 We recommend immediate anticoagulation for treatment of mesenteric venous thrombosis to improve outcome

1

B

3.11.3 We recommend surgery to patients with mesenteric venous thrombosis if they have evidence of peritonitis or perforation

1

B

3.11.4 In patients with high-risk inherited thrombotic disorders or other permanent risk for thrombosis, we recommend lifelong anticoagulation

1

B

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CONCLUSIONS ●

●

●

●

●

●

●

●

Mesenteric vein thrombosis, although less common than arterial thrombosis, remains an important cause of mesenteric ischemia. Mesenteric vein thrombosis has lower morbidity and mortality than arterial mesenteric ischemia Both CT angiography and MR angiography are recommended tests for MVT diagnosis. There is still a considerable delay in the diagnosis because of a low degree of clinical suspicion and nonspeciﬁc clinical presentation. Immediate use of anticoagulation can improve the outcome. Surgery should be limited to patients with peritonitis or perforation, with the objective to conserve as much bowel as possible yet assuring viable margins. In patients with high-risk inherited thrombotic disorders or other permanent risk for thrombosis, lifelong anticoagulation is a reasonable option; when the predisposing cause is temporary, i.e., can be eliminated, at least 6 months of anticoagulation is recommended. The long-term prognosis of patients without cancer or other life-threatening conditions is generally good.

REFERENCES 1. Elliot JW. The operative relief of gangrene of intestine due to occlusion of the mesenteric vessels. Ann Surg 1895; 21: 9–23. 2. Warren S, Eberhard TP. Mesenteric venous thrombosis. Surg Gynecol Obstet 1935; 61: 102–21. 3. Rhee RY, Gloviczki P, Mendonca CT, et al. Mesenteric venous thrombosis: still a lethal disease in the 1990s. J Vasc Surg 1994; 20: 688–97. 4. Grendell JH, Ockner RK. Mesenteric venous thrombosis. Gastroenterology 1982; 82: 358–72. 5. Kazmers A. Mesenteric venous occlusion. In: Stanley JC, Ernst CB, eds. Current Therapy in Vascular Surgery. Philadelphia: BC Decker, 1987: 320–23. 6. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med 2001; 345: 1683–8. 7. Kumar S, Kamath PS. Acute superior mesenteric venous thrombosis: one disease or two? Am J Gastroenterol 2003; 98: 1299–304. 8. Reinus JF, Brandt LJ, Boley SJ. Ischemic diseases of the bowel. Gastroenterol Clin North Am 1990; 19: 319–43. 9. Abdu RA, Zakhour BJ, Dallas DJ. Mesenteric venous thrombosis 1911 to 1984. Surgery 1987; 101: 383–8. 10. Kirshner PA. Occlusion of the mesenteric arteries and veins with infarction of the bowel. Ann Mt Sinai Hosp 1955; 21: 307–17. 11. Naitove A, Weismann RE. Primary mesenteric venous thrombosis. Ann Surg 1965; 161: 516–523. 12. Morasch MD, Ebaugh JL, Chiou AC, et al. Mesenteric

13. 14. 15.

16.

17.

18.

19.

20.

21. 22. 23.

24.

25.

26.

27.

28.

29. 30.

31.

venous thrombosis: a changing clinical entity. J Vasc Surg 2001; 34: 680–4. Boley SJ, Kaleya RN, Brandt LJ. Mesenteric venous thrombosis. Surg Clin North Am 1992; 72: 183–201. Hassan HA, Raufman JP. Mesenteric venous thrombosis. South Med J 1999; 92: 558–62. Warshauer DM, Lee JK, Mauro MA, White GC 2nd. Superior mesenteric vein thrombosis with radiologically occult cause: a retrospective study of 43 cases. Am J Roentgenol 2001; 177: 837–41. Divino CM, Park IS, Angel LP, et al. A retrospective study of diagnosis and management of mesenteric vein thrombosis. Am J Surg 2001; 181: 20–3. Brunaud L, Antunes L, Collinet-Adler S, et al. Acute mesenteric venous thrombosis: case for nonoperative management. J Vasc Surg 2001; 34: 673–9. Grisham A, Lohr J, Guenther JM, Engel AM. Deciphering mesenteric venous thrombosis: imaging and treatment. Vasc Endovascular Surg 2005; 39: 473–9. Amitrano L, Brancaccio V, Guardascione MA, et al. High prevalence of thrombophilic genotypes in patients with acute mesenteric vein thrombosis. Am J Gastroenterol 2001; 96: 146–9. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 16: 1245–8. Rhee RY, Gloviczki P. Mesenteric venous thrombosis. Surg Clin North Am 1997; 77: 327–338. Harward TR, Green D, Bergan JJ, et al. Mesenteric venous thrombosis. J Vasc Surg 1989; 9: 328–33. Bradbury MS, Kavanagh PV, Bechtold RE, et al. Mesenteric venous thrombosis: diagnosis and noninvasive imaging. Radiographics 2002; 22: 527–41. Rosen A, Korobkin M, Silverman PM, et al. Mesenteric vein thrombosis: CT identiﬁcation. Am J Radiol 1984; 143: 84–6. Sommer A, Jaschke W, Georgi M. CT diagnosis of acute mesenteric vein thrombosis with intestinal infarction. Akt Radiol 1994; 4: 344–7. Kim JY, Byun JY, Lee JM, et al. Intestinal infarction secondary to mesenteric venous thrombosis: CT pathologic correlation. J Comput Assist Tomogr 1993; 17: 382–5. Vogelzang RL, Gore RM, Anschuetz SL, Blei AT. Thrombosis of the splanchnic veins: CT diagnosis. Am J Roentgenol 1988; 150: 93–6. Brink JA. Spiral CT angiography of the abdomen and pelvis: interventional applications. Abdom Imaging 1997; 22: 365–72. Hu H. Multi-slice helical CT: scan and reconstruction. Med Phys 1999; 26: 5–18. Rubin GD, Dake MD, Napel SA, et al. Three-dimensional spiral CT angiography of the abdomen: initial clinical experience. Radiology 1993; 186: 147–52. Haddad MC, Clark DC, Sharif HS, et al. MR, CT, and ultrasonography of splanchnic venous thrombosis. Gastrointest Radiol 1992; 17: 34–40.

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32. Leyendecker JR, Rivera E, Jr, Washburn WK, et al. MR angiography of the portal venous system: techniques, interpretation, and clinical applications. RadioGraphics 1997; 17: 1425–43. 33. Shirkhoda A, Konez O, Shetty AN, et al. Mesenteric circulation: three-dimensional MR angiography with a gadolinium-enhanced multiecho gradient-echo technique. Radiology 1997; 202: 257–61. 34. Prince MR, Grist TM, Debatin JF. 3D contrast MR Angiography. Berlin: Springer-Verlag, 1999. 35. Meaney JF, Prince MR, Nostrant TT, Stanley JC. Gadolinium-enhanced MR angiography of visceral arteries in patients with suspected chronic mesenteric ischemia. J Magn Reson Imaging 1997; 7: 171–6. 36. Abbitt PL. Portal vein thrombosis: imaging features and associated etiologies. Curr Probl Diagn Radiol 1992; 21: 115–47. 37. Verbanck JJ, Rutgeerts LJ, Haerens MH, et al. Partial splenoportal and superior mesenteric venous thrombosis. Early sonographic diagnosis and successful conservative management. Gastroenterology 1984; 86: 940–52. 38. Clark RA, Gallant TE. Acute mesenteric ischemia: angiographic spectrum. Am J Roentgenol 1984; 142: 555–62. 39. Tomchik FS, Wittenberg J, Ottinger LW. The roentgenographic spectrum of bowel infarction. Radiology 1970; 96: 249–60. 40. Lange H, Jackel R. Usefulness of plasma lactate concentration in the diagnosis of acute abdominal disease. Eur J Surg 1994; 160: 381–4.

41. Mathews JE, White RR. Primary mesenteric venous occlusive disease. Am J Surg 1971; 122: 579–83. 42. Poplausky MR, Kaufman JA, Geller SC, Waltman AC. Mesenteric venous thrombosis treated with urokinase via the superior mesenteric artery. Gastroenterology 1996; 110: 1633–5. 43. Yankes JR, Uglietta JP, Grant J, Braun SD. Percutaneous transhepatic recanalization and thrombolysis of the superior mesenteric vein. Am J Roentgenol 1991; 151: 289–90. 44. Rivitz SM, Geller SC, Hahn C, Waltman AC. Treatment of acute mesenteric venous thrombosis with transjugular intramesenteric urokinase infusion. J Vasc Interv Radiol 1995; 6: 219–28. 45. Train JS, Ross H, Weiss JD, et al. Mesenteric venous thrombosis: successful treatment by intraarterial lytic therapy. J Vasc Interv Radiol 1998; 9: 461–4. 46. Lopera JE, Correa G, Brazzini A, et al. Percutaneous transhepatic treatment of symptomatic mesenteric venous thrombosis. J Vasc Surg 2002; 36: 1058–61. 47. Pavel J, Levy MM, Krausz JM. The role of second-look procedure in improving survival time for patients with mesenteric vein thrombosis. Surg Gynecol Obstet 1990; 170: 287–91. 48. Inahara T. Acute superior mesenteric venous thrombosis: treatment by thrombectomy. Ann Surg 1971; 174: 956–61.

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PART

4

MANAGEMENT OF CHRONIC VENOUS DISORDERS Edited by Michael C. Dalsing and Bo Eklöf

28 Clinical presentation and assessment of patients with venous disease Andrew Bradbury and C. Vaughan Ruckley 29 Diagnostic algorithm for telangiectasias, varicose veins and venous ulcers: current guidelines Robert McLafferty and Andrew D. Lambert 30 Compression therapy for venous ulceration Gregory L. Moneta and Hugo Partsch 31 Drug treatment of varicose veins, venous edema and ulcers Philip D. Coleridge Smith 32 Sclerotherapy in the management of varicose veins of the extremities J. Leonel Villavicencio 33 Foam sclerotherapy Joshua I. Greenberg, Niren Angle and John J. Bergan 34 Percutaneous laser therapy of telangiectasia and varicose veins Thomas M. Proebstle and Jorge M. Trabal 35 Surgical treatment of the incompetent saphenous vein Adam Howard, Dominic P.J. Howard and Alun H. Davies 36 Radiofrequency treatment of the incompetent saphenous vein Robert F. Merchant and Robert L. Kistner 37 Laser treatment of the incompetent saphenous vein Nick Morrison 38 Phlebectomy Lowell D. Kabnick 39 Treatment algorithms for telangiectasia and varicose veins: current guidelines Jose I. Almeida and Jeffrey K. Raines 40 Recurrent varicose veins: etiology and management Michel Perrin 41 Local treatment of venous ulcers Thomas F. O’Donnell Jr 42 Surgical repair of deep vein valve incompetence Seshadri Raju

331 342 348 359 366 380 390 400 409 418 429 439 446 457 472

43 Artificial venous valves Michael C. Dalsing 44 Endovascular reconstruction for chronic iliofemoral vein obstruction Peter Neglén 45 Endovascular reconstruction of complex iliocaval venous occlusions Haraldur Bjarnason 46 Open surgical reconstructions for non-malignant occlusion of the inferior vena cava or iliofemoral veins Peter Gloviczki and Gustavo S. Oderich 47 The management of incompetent perforating veins with open and endoscopic surgery Jeffrey M. Rhodes, Manju Kalra and Peter Gloviczki 48 Percutaneous ablation of perforating veins Steve Elias 49 A treatment algorithm for venous ulcer: current guidelines Ralph G. DePalma

483 491 503 514 523 536 545

28 Clinical presentation and assessment of patients with venous disease ANDREW BRADBURY AND C. VAUGHAN RUCKLEY Introduction The upper limb

331 331

INTRODUCTION Most patients referred to vascular surgeons because of venous symptoms and signs undergo some form of further investigation, usually duplex ultrasound, in addition to clinical assessment. One interpretation of this observation would be that most practitioners believe history and examination alone to be unreliable, even misleading, in the assessment of venous pathology. Although there are circumstances where this is true, much useful information can be gleaned from a thorough clinical assessment based upon a sound understanding of the underlying anatomy and pathophysiology. There are important reasons why the technological improvements and ready availability of duplex and other investigative modalities should not be allowed to blunt our clinical skills. Clinical assessment is important to: 1. guide the choice of investigation(s) and enable questions posed to the technologist to be framed in a more clinically (and cost) effective manner; 2. allow a more meaningful interpretation of the results of investigations; 3. provide direction when further investigations are not obtainable; for example, in the emergency situation or in less well developed healthcare settings; 4. eliminate further investigation when it is not warranted.

THE UPPER LIMB The upper limb is less frequently involved with venous disease than the leg. However, such disease can have serious consequences for some patients for many reasons.

The lower limb References

334 341

In young and otherwise active patients, especially when the dominant arm is affected, the morbidity of chronic symptoms may be disabling. For increasing numbers of patients, ready access to and normal function of the veins of the upper limb offers the only prospect of long-term survival; for example, when hemodialysis, parenteral nutrition, long-term antibiotic administration, or chemotherapy must be provided. There is also an increased realization that the long-term patency of femorodistal bypass with prosthetic material may be unacceptably poor. That observation, together with an increase in graft infection (particularly methicillinresistant Staphylococcus aureus), has led many surgeons to more frequently use the arm veins for limb salvage. Knowledge of the anatomy of the arm veins is essential for performing a good physical examination. For venous anatomy the readers should consult Chapter 2.

Intermittent subclavian vein obstruction In the authors’ practice this is a rare presentation; most patients seem to seek medical attention only once the vein has thrombosed (see below). However, identiﬁcation of patients at the preocclusive stage may allow pre-emptive treatment to be considered.1 Patients typically complain of intermittent swelling; discomfort and tightness (not usually true pain) in the arm, which is relieved by rest; and abnormally prominent superﬁcial veins. These symptoms are aggravated in the erect position or when the arm is raised, for example, when typing, playing the piano, driving the car, standing to attention, playing the ﬂute or painting a ceiling. Patients with these symptoms should be evaluated with their shoulders in the neutral position (Fig. 28.1) and

332

Clinical presentation and assessment of patients with venous disease

Figure 28.1 The course of the subclavian vein. The subclavian vein begins at the lateral border of the ﬁrst rib and enters the costoclavicular space, which is bordered by the ﬁrst rib posteriorly and the clavicle with its underlying subclavius muscle and costocoracoid ligament anteriorly. The subclavian vein remains anterior to the anterior scalene muscle as opposed to the subclavian artery, which lies posterior to that muscle. Adapted from Adams et al.1

Figure 28.2 Compression of the subclavian vein in the military position. When the shoulder is retracted backward and downward the subclavian vein is narrowed by the scissoring action of the clavicle and ﬁrst rib. Adapted from Adams et al.1

Figure 28.3 Compression of the subclavian vein with hyperabduction of the arm. With hyperabduction and external rotation of the arm the clavicle rotates backward and downward and causes compression of the subclavian vein secondary to narrowing of the costoclavicular space. Adapted from Adams et al.1

braced in the military position (Fig. 28.2) or with their arms hyperabducted and externally rotated at the shoulder (Fig. 28.3 as this will result in the subclavian vein being compressed by the scissor-like closure of the costoclavicular space. Arm discomfort, swelling, and venous distension in this position suggest intermittent venous outﬂow obstruction. However, as with arterial

thoracic outlet obstruction, these ﬁndings can be reproduced in certain otherwise normal individuals at the extremes of movement. As subclavian vein thrombosis is a likely outcome of intermittent obstruction, active investigations with a view to surgical decompression are indicated.

The upper limb 333

Superficial venous thrombophlebitis Superﬁcial thrombophlebitis is characterized by localized pain, redness, and swelling over a segment of a superﬁcial vein. The great majority of cases are iatrogenic due to venous cannulation. Spontaneous thrombophlebitis, especially if recurrent, may be associated with malignant disease or thrombophilia. Palpation will reveal tenderness over an underlying thrombus in the vein with surrounding induration. If the thrombus in the vein is localized and not infected there will not be signiﬁcant distal swelling. Thrombus that propagates to involve the deep vein may, at least theoretically, lead to pulmonary embolus but is rare. A history of thrombophlebitis is important as it may have important consequences for venous access and the utility of an arm vein for arterial bypass.

Primary axillary–subclavian vein thrombosis Patients with this condition, once considered rare, are now increasingly presenting to the vascular surgeon for consideration of active intervention. Thrombosis originates in a chronically traumatized subclavian vein that has been repeatedly compressed by the costoclavicular scissors, and propagates for a variable distance both proximally and distally. There may be a prior history of intermittent obstruction. Patients present with arm swelling and discomfort, often following strenuous activity (hence the alternative term “effort thrombosis”)2 associated with either backward or downward traction on the shoulders, or hyperabduction of the arm. The pain, swelling, cyanosis, and venous distension may be quite severe. Associated arterial and neurological features of thoracic outlet compression are unusual. On examination the arm is obviously swollen, has a bluish discoloration with distended collateral veins over the shoulder. The treatment remains controversial but comprises various combinations of anticoagulation, thrombolysis, and surgical decompression.

external jugular vein as this complication is particularly common following direct subclavicular vein cannulation. A history of central venous cannulation is important to know in patients being considered for hemodialysis access and arterial reconstruction using an arm vein, for subclinical subclavian vein thrombosis or stenosis is common and may lead to unacceptable limb swelling postoperatively.

Phlegmasia cerulea dolens This typically occurs in patients with advanced malignancy, often being treated with chemotherapy via an indwelling central venous catheter. It is a variant of disseminated intravascular coagulation, as can easily be determined at surgery when not only the stem veins but also the macro- and micro-collateral channels will be found to contain thrombus. The diagnosis is obvious. It is associated with intense swelling, pain, and discoloration and it may progress to venous gangrene requiring amputation. Compartment syndrome may be present. Pulmonary embolus is relatively common.

Post-thrombotic syndrome Post-thrombotic symptoms are reported in 30–70% of patients following a primary subclavian vein thrombosis and comprise discomfort and swelling, particularly in positions that compress collaterals in the costoclavicular space (see above). However, the skin changes commonly found in the lower limb are extremely rare in the upper limb.

Arteriovenous malformations These are rare but can be misdiagnosed, especially in the lower limb, and will be considered in more detail below.

Secondary axillary–subclavian thrombosis Examination findings As the numbers of patients requiring central venous cannulation increases so does the incidence of this complication. Because the onset of venous stenosis and thrombosis is more gradual leading to the development of collaterals, and because other ouﬂow veins are less likely to be affected than in primary disease, the patient is often only mildly symptomatic or clearly asymptomatic. The ﬁrst presentation may be access line non-function, and duplex or a “linogram” shows the thrombosis. Treatment involves thrombolysis if the thrombus is extensive, or simply removal of the line and whatever anticoagulation may be feasible is provided. Lines should be placed if possible in the internal jugular vein, cephalic vein, or

INSPECTION

Most of the available clinical information can be gained by simply inspecting the arm and comparing it with the contralateral limb. The ability to answer yes to the following questions or examination points increases the change that venous thrombosis is present. In some instances, the examination is eliminating arterial or other disease as a concern. 1. Is the arm swollen? 2. Is the arm hypertrophied?

334

3. 4. 5. 6. 7.

Clinical presentation and assessment of patients with venous disease

Is the arm discolored? Are venous collaterals apparent? Are there scars and/or puncture sites? Is there evidence of previous trauma? Are there any indwelling lines or cannulae?

Superficial venous thrombophlebitis

PERCUSSION

Superﬁcial thrombophlebitis is an unfortunate term because it tends to be dissociated from deep vein thrombosis (DVT) when in fact the two commonly coexist. Two types of superﬁcial thrombophlebitis are recognized, differentiated by the vein afﬂicted: a normal vein or a diseased, usually varicose, vein. The former is usually iatrogenic, bacterial and is treated by removal of the line or cannula, with or without antibiotics. Occasionally, it can arise in association with known or occult malignancy and, in this circumstance, is often migratory. It may also be associated with thrombophilia. The latter usually complicates varicose veins (VV) and is particularly common in pregnancy. It is usually due to sterile thrombosis. There is intense pain and redness over the affected segment and, if a clot propagates through junctional and non-junctional perforators, there is a risk of PE. Systemic upset (pyrexia, tachycardia) and abscess formation are uncommon. Investigation of the deep veins, e.g., by duplex scan is generally indicated although symptoms of DVT are commonly absent. Treatment of this condition is discussed in detail in Chapter 26. On examination, there is rubor, calor, and dolor around the affected segment. Upon resolution, there is often a residual mass or cord (Fig. 28.4).

As in the leg, the course of superﬁcial veins can be outlined using the “tap” test (see below).

Deep vein thrombosis

PALPATION

1. Is the arm warmer? 2. Is there tenderness over an inﬂamed superﬁcial vein or in the supraclavicular fossa? 3. Is there evidence of obstructing pathology in the axilla and/or supraclavicular fossa; for example, enlarged lymph nodes, or a palpable cervical rib? 4. Are the veins hard and “cord-like” suggesting previous thrombophlebitis? 5. Are pulses present and are there any abnormal pulsations, either venous or arterial (arteriovenous ﬁstula, malformation)? 6. Are there any thrills? 7. Is there any edema and is it pitting? 8. Allen’s test to conﬁrm the arterial inﬂow to the hand and completeness of the palmar arch.

AUSCULTATION

The blood pressure should be measured in each arm. Are there any murmurs? ADDITIONAL STEPS

If the arm is swollen examination should include the axilla for adenopathy and the breast to exclude malignancy. If there is concern about the adequacy of the deep venous outﬂow (for example, if an AV ﬁstula or particularly a brachial vein transposition is being considered) then the arm can be observed for swelling after application of a light superﬁcial tourniquet around the upper arm. Obviously, symptoms of pulmonary embolism (PE) should prompt a full cardiorespiratory examination.

THE LOWER LIMB Venous disease of the lower limb is perhaps the commonest human afﬂiction. Indeed, it is so common that it may be considered an almost normal part of the aging process. Knowledge of the anatomy of the venous system of the leg is essential to perform a good physical examination. For detailed venous anatomy of the legs and pelvis, readers should consult Chapter 2.

Deep vein thrombosis, leading to PE, is the most common cause of potentially preventable death in adult patients. It is important to remember that most patients dying of PE in hospital have no symptoms or signs in their legs. Management, therefore, depends crucially upon prophylaxis, a high index of suspicion in “at risk” patients regardless of symptoms, and early recourse to deﬁnitive investigation. It is helpful to consider the development of DVT in two phases. In the early phase the thrombus is non-occlusive,

Figure 28.4 Superﬁcial venous thrombosis. Localized redness, tenderness, and swelling surround a palpably thrombosed superﬁcial vein. Adapted from DeWeese JA, Chapter 22. In: Schwartz SI, ed. Venous and Lymphatic Disease, Principles of Surgery, 4th edn. New York: McGrawHill, 1984.

The lower limb 335

may be free ﬂoating in a fast moving column of blood, and not yet organized and therefore not adherent to the vein wall. As a result, there is no swelling, inﬂammation (pain, heat, rubor, or tenderness), or distension of superﬁcial collateral veins. In other words, the leg may appear quite normal although the risk of embolism is high. In the late phase, the thrombus becomes occlusive and incites a phlebitis anchoring it to the vein wall; in addition, periphlebitis may give rise to inﬂammatory symptoms and signs. The patient develops all the “typical” clinical features of DVT. At this stage, however, the risk of PE is low. Even when “typical” symptoms and signs are present, studies show that less than half are due to DVT, the remainder being due to a range of other pathologies. So, the symptoms and signs of DVT are highly insensitive and non-speciﬁc. Homans’ sign is also unreliable, painful, and in patients with DVT may precipitate embolism; in the authors view it should not be performed. A scoring system, developed by Wells and colleagues,3 is currently used to determine the probability that a patient has deep vein thrombosis before tests are performed (Table 28.1). Patients with a score of 2 or more are considered likely to have deep vein thrombosis. Anatomically, it is useful to consider three patterns of disease (calf, femoral, and iliofemoral), although thrombosis is a dynamic process and proximal propagation is common (Fig. 28.5).

(a)

(b)

Table 28.1 Clinical model for predicting the pretest probability of deep vein thrombosis.* From Wells et al.3 Clinical characteristic Active cancer (patient receiving treatment for cancer within the previous 6 months or currently receiving palliative treatment) Paralysis, paresis, or recent plaster immobilization of the lower extremities Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or regional anesthesia Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling at least 3 cm larger than on the asymptomatic side (measured 10 cm below tibial tuberosity) Pitting edema conﬁned to the symptomatic leg Collateral superﬁcial veins (non-varicose) Previously documented deep vein thrombosis Alternative diagnosis at least as likely as deep vein thrombosis

Score 1

1 1

1 1 1

1 1 1 –2

*A score of two or higher indicates that the probability of deep vein thrombosis is likely; a score of less than two indicates that the probability of deep vein thrombosis is unlikely. In patients with symptoms in both legs, the more symptomatic leg is used.

(c)

Figure 28.5 (a) Calf vein thrombosis. The thrombosis is limited to the veins of the calf and the popliteal vein. There is minimal, if any, swelling at the level of the ankle. Tender deep cords may be palpable. Homans’ sign may be present. (b) Femoral vein thrombosis. There is thrombosis of the femoral vein, which is usually associated with thrombosis in the calf veins. Swelling is usually present and extends to just above the level of the knee. Popliteal tenderness and calf tenderness may be present. Homans’ sign may or may not be present. (c) Iliofemoral venous thrombosis. There is thrombosis of the iliac and proximal femoral vein and frequently calf veins are also involved. Edema is present from the foot to the level of the inguinal ligament. Tenderness is usually present in the groin and sometimes at the popliteal level and in the calf. Homans’ sign may or may not be present. Adapted from DeWeese JA, Chapter 22. In: Schwartz SI, ed. Venous and Lymphatic Disease, Principles of Surgery, 4th edn. New York: McGraw-Hill, 1984.

336

Clinical presentation and assessment of patients with venous disease

Calf vein thrombosis Calf vein thrombosis is usually localized to one or two of the three major veins of the lower leg. The thrombi are usually not completely obstructive and, since tibial and peroneal veins are paired, there is usually adequate venous drainage. Calf tenderness may be present but signiﬁcant swelling is nearly always absent, and, in fact, most patients have no symptoms or signs whatsoever. About 20% if untreated may propagate above the knee.

Femoral vein thrombosis Femoral vein thrombosis may propagate to the common femoral vein. As the great majority of lower limb DVTs arise in the calf veins, it is not surprising that thrombus is also present at that level in most patients. Tenderness is often present over the femoral vein. There is swelling at the ankle and calf of greater than 1 cm in most patients but it rarely extends above the patella unless outﬂow via the deep femoral vein is also compromised.

Iliofemoral thrombosis Iliofemoral venous thrombosis, since it commonly originates in the pelvic veins, does not involve the distal femoral or calf veins in over one-third of patients. Consequently, duplex scanning commonly fails to detect it. There is swelling of the thigh as well as the leg. If the cava is involved then the symptoms and signs are usually bilateral. This type of thrombosis frequently has a marked inﬂammatory component, especially when associated with pregnancy.

Phlegmasia cerulea dolens As described above with respect to the arm, extensive thrombosis may lead to phlegmasia, which in turn may precipitate venous gangrene. Phlegmasia of the lower limb sequesters a considerable proportion of the blood and body ﬂuids, especially if bilateral, with severe systemic effects which may include hypovolemic shock and renal failure.

TRUNK VARICES

These involve the main stem and/or major tributaries of the great saphenous vein (GSV) (80%) and/or the small saphenous vein (SSV) (20%); they are usually > 4 mm in diameter (and may be much larger), lie subcutaneously, are palpable, do not usually discolor the overlying skin, and are present in about a third of the adult population. Although ﬁve times more women than men present for treatment, the prevalence is roughly equal between the sexes. There appears to be a familial tendency and obesity, pregnancy, constipation, and prolonged standing may be aggravating factors. RETICULAR VARICES

These lie deep in the dermis, are < 4 mm in diameter, are impalpable, and may render the overlying skin dark blue. They may or may not be associated with trunk varices and are present in about 80% of the adult population. TELANGECTASIA

These are also termed spider or hyphen web veins. They lie superﬁcially in the dermis, are usually 1 mm or less in diameter, are impalpable, and render the overlying skin purple or bright red. Again, they may be associated with trunk and reticular varices and are present in 90% of adults. Like reticular veins, they are slightly commoner in women. SYMPTOMS

The great majority of individuals with VV are asymptomatic, or at least they do not seek treatment. Those who do attend the surgical clinic do so because they are unhappy about the appearance of their leg(s), and/or they associate lower limb symptoms with their VV, and/or they are concerned about developing complications. Many patients, especially young women, seek treatment because they consider their veins to be unsightly and want them removed. In general, the UK National Health Service does not fund minor cosmetic surgery. Patients are aware of this, and because they may also be embarrassed to admit that cosmesis is the main issue, they frequently complain of various lower limb symptoms as well. A wide variety of lower limb symptoms have been attributed to VV. These include:

Varicose veins EPIDEMIOLOGY

Varicose veins are so common that they could be considered a variant of normal. The prevalence of VV increases markedly with age and they are an almost universal ﬁnding in individuals over the age of 60 years.

1. 2. 3. 4. 5. 6. 7.

aching heaviness and tension a feeling of swelling tiredness restless legs nocturnal cramps itching.

The lower limb 337

Epidemiological studies4–6 show that: 1. such symptoms are present in about a half the adult population; 2. there is little or no relationship between these symptoms and the presence and severity of VV on clinical examination; 3. nor is there a good correlation between symptoms and the pattern and severity of reﬂux on duplex ultrasonography disease. Experience in the vascular clinic conﬁrms this to be the case and it can be difﬁcult to determine to what extent a patient’s symptoms are due to varicose veins. Surgeons are therefore cautioned against advising patients that surgery or sclerotherapy will necessarily abolish symptoms. Only a small proportion of patients with VV go on to develop the complications of chronic venous insufﬁciency, for example, lipodermatosclerosis, leg ulcers, hemorrhage, and thrombophlebitis. It is difﬁcult to predict which patients will progress, and there is no evidence that early VV surgery will prevent these complications from developing.

Chronic venous insufficiency Chronic venous insufﬁciency (CVI) may be deﬁned as the presence of skin damage including ulceration in the lower leg as a result of sustained ambulatory venous hypertension. For pathophysiology and epidemiology of CVI see Chapters 5, 6, 7 and 10. SYMPTOMS

All of the symptoms described above for VV may be associated with CVI, and there is a stronger relationship between such symptoms and the features of disease in this group. However, such patients are signiﬁcantly older and, as such, other comorbidities are much more common. In particular, arterial disease and musculoskeletal problems should not be overlooked and the symptoms falsely attributed to venous pathology. Unlike patients with simple VV where actual swelling is unusual, the majority of patients with CVI have a degree of edema. This is usually of mixed etiology: venous hypertension, right heart failure, and a degree of lymphedema, for example. Severe pain is unusual and suggests coexisting arterial disease and/or infection. HISTORY

This should include the history of the present and previous episodes of ulceration; previous thrombotic episodes; previous venous and non-venous surgery or other interventions to the leg, pelvis and abdomen; arterial

symptoms; diabetes; autoimmune disease; other medical conditions; locomotor problems; current medications and allergies.

EXAMINATION FINDINGS

Position The patient should be examined standing in a good light in a warm room and, in these circumstances, signiﬁcant VV soon become apparent. Patients often feel faint and some form of support should be available. The examiner can sit on the ﬂoor. Better still, the patient can be provided with a platform with a handrail while the examiner sits on a low chair. Inspection The cardinal features of VV are that they are dilated, elongated, tortuous, and sacculated. These features only arise when there is reverse ﬂow (reﬂux) and are commonly seen below an incompetent valve. The main trunks themselves may be dilated and may exhibit sacculation but they are rarely, if ever, tortuous or elongated because they are supported by the deep fascia. The distribution of varices will usually indicate whether they are tributaries of the great or small saphenous system or both. However, in an obese patient, or one who has undergone previous surgery, the anatomical connections may be obscure.7,8 In thin, particularly athletic, patients there may be highly visible and enlarged veins and these may be erroneously considered to be pathological when they are physiological. Such veins are dilated uniformly and do not exhibit elongation, tortuosity, or sacculation. The signs of chronic venous insufﬁciency include corona phlebectatica, lipodermatosclerosis, and open ulceration. Corona phlebectatica comprises a fan-shaped ﬂare of small intradermal varices on the medial aspect of the ankle and foot. The apex of the ﬂare is in the region of the one or more incompetent perforators which give rise to it, and it fans out towards the sole of the foot. Lipodermatosclerosis may be acute or chronic. In the acute phase, it is an inﬂammatory reaction that may be mistaken for cellulitis or phlebitis. It will overlie an area of perforator incompetence and the heat of a bacterial reaction will be absent as will any of the systemic features of infection such as lymphadenopathy, pyrexia, or leukocytosis. In the chronic phase, the skin of the mid to lower calf is pigmented. It is shiny and hard and ﬁxed to the underlying chronically inﬂamed and contracted subcutaneous tissue. Surrounding dermatitis is common, due usually to sensitivity reaction to medicaments applied to the area. White scar tissue (atrophie blanche) is often present. The site of lipodermatosclerosis relates to maximum ambulatory pressure and is communicated, usually by incompetent perforators, to the local venous system. The same applies to the site of open ulceration, although as ulcers increase in size this association becomes

338

Clinical presentation and assessment of patients with venous disease

Table 28.2 Differential diagnosis of leg ulceration Clinical features

Arterial ulcer

Venous ulcer

Gender Age

Men > women Usually presents > 60 years

Risk factors

Smoking, diabetes, hyperlipidemia and hypertension Most have a clear history of peripheral, coronary and cerebrovascular disease

Women > men Typically develops 40–60 years but patient may not present for medical attention until much older, multiple recurrences are the norm Previous DVT, thrombophilia, varicose veins

Past medical history

Symptoms Site

Edge Base

Severe pain is present unless there is (diabetic) neuropathy, pain maybe relieved by dependency Normal and abnormal (diabetics) pressure areas (malleoli, heel, metatarsal heads, ﬁfth metatarsal base) Regular, “punched-out”, indolent

Surrounding skin

Deep, green (sloughy) or black (necrotic) with no granulation tissue, may comprise major tendon, bone and joint Features of chronic ischemia

Veins Swelling

Empty, “guttering” on elevation Usually absent

More than 20% have clear history of DVT, many more have a history suggestive of occult DVT, i.e., leg swelling after childbirth, hip/knee replacement or long bone fracture About a third have pain but it is not usually severe and may be relieved on elevation Medial (70%), lateral (20%) or both malleoli and gaiter area Irregular, with neo-epithelium (whiter than mature skin) Pink and granulating but may be covered in yellowgreen slough Lipodermatosclerosis (pigmentation, induration, varicose dermatitis, atrophie blanche) Full, usually varicose Usually present

DVT, deep vein thrombosis.

blurred. An ulcer whose site or shape points to causative pressure damage is an important pointer to coexisting arterial disease (see Table 28.2).

Part 2 The compression is then released. The superﬁcial veins are then carefully observed for increased ﬁlling with blood.

Palpation

There are four possible results of the ﬁndings:

Percussion over a varix while palpating with the other hand at a higher or lower level will help trace out the pattern (the “tap” test of Chevrier). This is particularly helpful in the obese. There may be a cough impulse, even a thrill over a large varix, particularly a saphena varix in the groin.

●

Trendelenburg test The purpose of this test is to identify the level and location of deep to superﬁcial reﬂux. It is mainly of value in circumstances in which duplex scanning is not readily available. The test (Fig. 28.6) comprises two parts.

●

Part 1 With the patient lying down the leg is elevated to 45° and a tourniquet or the examiner’s hand compresses the GSV in the high thigh. With compression in place, the patient stands in a well-lit room. Previously noted superﬁcial veins are then carefully observed for ﬁlling with blood.

●

Negative-negative (Fig. 28.6a). Part 1 is negative when there is only gradual ﬁlling of normal veins from arterial inﬂow in the distal one third of the lower leg, indicating the valves in the perforating veins are normal. Part 2 is negative when following the release of the compression there is only continued gradual ﬁlling of the veins, indicating the valves in the GSVs are normal. Negative-positive (Fig. 28.6b) Part 1 is negative because the perforating veins have competent valves. Part 2 is positive when the release of compression results in sudden ﬁlling of all the superﬁcial veins, indicating the valves in the GSVs are incompetent. Positive-negative (Fig. 28.6c) Part 1 is positive when there is rapid ﬁlling of the veins in the lower leg, indicating there are incompetent valves in the deep and perforating veins. Part 2 is negative if there is only continued slow ﬁlling of the GSV, indicating there are competent valves in the GSV.

The lower limb 339

(b)

(a)

Negative

Negative

Negative

Positive

(d)

(c)

Positive

Negative

Positive

Positive

Figure 28.6 Trendelenburg test. Initially the patient is lying down with the leg elevated and then stands up with compression over the saphenofemoral junction with the hand or tourniquet. (a) Negative-negative response: there is gradual ﬁlling of the veins at the ankle over a 30 second period and there is continued slow ﬁlling after release of the hand. (b) Negative-positive response: on standing there is again only gradual ﬁlling of the distal vein but on release of compression there is a rapid retrograde ﬁlling of the saphenous vein. (c) Positivenegative response: with the saphenous vein compressed there is rapid ﬁlling of the superﬁcial veins through incompetent perforating veins. With release of compression there is further slow ﬁlling of all the veins. (d) Positive-positive response: on standing with the saphenous vein compressed there is again rapid ﬁlling of varices through incompetent perforating veins. On release of compression there is additional rapid ﬁlling of the saphenous vein through incompetent valves. Adapted from DeWeese JA, Chapter 22. In: Schwartz SI, ed. Venous and Lymphatic Disease, Principles of Surgery, 4th edn. New York: McGraw-Hill, 1984.

●

Positive-positive (Fig. 28.6d) Part 1 is positive, indicating there are incompetent valves in the deep and perforating veins. Part 2 is positive when the GSV shows rapidly increased ﬁlling following release of its compression, indicating the valves in the GSV are incompetent.

A more effective way to demonstrate reﬂux is to insonate over the site of incompetence and reﬂux with a portable continuous wave Doppler ultrasound probe. This is particularly valuable in obese patients or those with recurrent VV, where the anatomy may be obscure.

340

Clinical presentation and assessment of patients with venous disease

Ulcer assessment This should include Figure 28.7 Postthrombotic leg. There is visible swelling and secondary varicosities. There is brownish discoloration and brawny induration at the ankle level and ulceration is present over the site of an incompetent perforating vein just posterior and superior to the medial malleolus.

1. a description of the ulcer, concentrating on the features outlined in Table 28.1 (Fig. 28.7) 2. pulse status and ankle–brachial index 3. gait and, in particular, ankle mobility 4. general physical examination

Guidelines 4.1.0 of the American Venous Forum on clinical presentation and assessment of patients with venous disease No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.1.1 For clinical examination of the upper limb we recommend inspection with comparison with the contralateral limb, palpation, auscultation, and examination of the axilla for adenopathy. In patients with adenopathy or swollen arms we recommend examination of the breast to exclude malignancy

1

B

4.1.2 For clinical examination of the lower limbs in patients with suspected acute deep vein thrombosis we recommend inspection (edema, cyanosis, varicosity), palpation (tenderness, pitting edema), auscultation (arterial bruit, heart and lung examination) and examination of the deep and superﬁcial veins and calf muscles (tenderness or palpation of a cord)

1

B

4.1.3 We suggest the use of the clinical scoring system of Wells to predict the pretest probability of deep vein thrombosis

2

B

4.1.4 For clinical examination of the lower limbs for varicosity and chronic venous insufﬁciency we recommend inspection (varicosity, edema, skin discoloration, corona phlebectatica, ulcer, lipodermatosclerosis) palpation (cord, varicosity, tenderness, induration, reﬂux, pulses, thrill) auscultation (bruit) and examination of the groins and abdomen (masses, collateral veins or lymphadenopathy) and ankle mobility

1

B

4.1.5 Clinical presentation of patients with varicose veins may include symptoms like aching, heaviness and tension, sensation of swelling, tiredness, restless legs, nocturnal cramps and itching. We suggest that there is little or no relationship between these symptoms and the presence and severity of varicose veins or the pattern and severity of reﬂux

2

B

References 341

REFERENCES 1. Adams JT, DeWeese JA, Mahoney EB, et al. Intermittent subclavian vein obstruction without thrombosis. Surgery 1968; 63: 147–65. 2. Adams JT, DeWeese JS. “Effort” thrombosis of the axillary and subclavian veins. J Trauma 1971; 11: 923–30. 3. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795–8. 4. Bradbury AW, Ruckley CV. Venous symptoms and signs and the results of duplex ultrasound: do they agree? In: Ruckley CV, Fowkes FGR, Bradbury AW, eds. The Epidemiology and Management of Venous Disease. London: Springer-Verlag, 1998.

5. Bradbury AW, Ruckley CV. Venous reﬂux and chronic venous insufﬁciency. In: Yao JST, Pearce WH, eds. Practical Vascular Surgery. Stamford: Appleton and Lange, 1998: 475–89. 6. Bradbury AW, Evans CJ, Allan PL, et al. What are the symptoms of varicose veins ? Edinburgh vein study cross sectional population survey. BMJ 1999; 318: 353–6. 7. Bradbury AW, Stonebridge PA, Ruckley CV, Beggs I. Recurrent varicose veins: correlation between preoperative clinical and hand-held Doppler ultrasonographic examination, and anatomical ﬁndings at surgery. Br J Surg 1993; 80: 849–51. 8. Bradbury AW, Stonebridge PA, Callam M, et al. Recurrent varicose veins: assessment of the saphenofemoral junction. Br J Surg 1994; 81: 373–5.

29 Diagnostic algorithm for telangiectasias, varicose veins and venous ulcers: current guidelines ROBERT B. MCLAFFERTY AND ANDREW D. LAMBERT Introduction History Physical examination Laboratory examination Diagnostic vascular laboratory

342 342 343 343 343

Indirect non-invasive tests Direct non-invasive tests Radiologic imaging Invasive imaging References

344 344 344 345 346

INTRODUCTION

HISTORY

Chronic venous disease (CVD) is a common afﬂiction, with telangiectasia found in the large majority of people who are over 60 years old.1 The diagnosis of telangiectasias, varicose veins, and venous ulcers starts with a well-rooted understanding of venous anatomy and pathophysiology as outlined in previous chapters. Although advances in physiologic testing, duplex, and radiologic imaging continue to be made in the ﬁeld of CVD, a thorough and directed history and physical examination can lead the physician to the proper clinical assessment with supplementary tests as needed. This chapter describes an orderly process of making a diagnosis for a patient with CVD. Although simple problems can be diagnosed in a straightforward manner with little more than reliance on a thorough history and physical examination, subtle more serious disease may be present. Patients with intermediate to complex CVD may require more extensive diagnostic testing to better deﬁne the pathophysiology responsible for signs and symptoms. Herein, guidelines are presented in order to put history, physical examination, physiologic venous testing, duplex, and radiologic imaging into an orderly process for the practitioner. As a reminder, the diagnosis of CVD should be stratiﬁed according to clinical class, etiology, anatomic distribution, and pathophysiology (CEAP classiﬁcation system) (see Chapter 4).2 This chapter will primarily focus on telangiectasia (clinical class 1), varicose veins (clinical class 2), and venous ulcers (clinical class 6).

In taking a complete history for CVD, the use of openended questions remains paramount to retrieving valid information about symptoms. This dictum may be even more useful for patients with telangiectasia and varicose veins. Excluding the more severe signs of CVD that can be readily evident as contributing to the patient’s symptom complex, there can be a wide array of symptoms from patients with lesser degrees of CVD. By using simple questions such as “Can you describe what bothers you about your legs?” or even “What brings you to see me today?” one can start the cascade of allowing the patient to reveal subtle symptoms that previous practitioners may not have recognized. After allowing the patient to describe any symptoms in an uninterrupted fashion, the physician can ask the patient to be more speciﬁc about certain aspects of the history. Finally, when open-ended questions yield no more additional information, the physician can then proceed with directed questions and further obtain unmentioned details and pertinent negatives. Symptoms from varicose veins are often vague. Although some patients may be completely asymptomatic, many have symptoms revealed with careful open-ended questioning. These include dull pain, heaviness, tiredness, restlessness, itching, burning, tension of the skin, cramping, and mild edema. More severe symptoms such as marked edema, dermatitis, hyperpigmentation, lipodermatosclerosis, ulceration, and skin erosion with hemorrhage can be present solely with superﬁcial venous

Diagnostic vascular laboratory

valvular incompetence, but often are seen with concomitant deep valvular insufﬁciency. Although telangiectasias are often assumed to be asymptomatic, their presence can elicit symptoms similar to varicose veins. Furthermore, their presence with correlative symptoms, in the absence of varicose veins by inspection, still might indicate more severe underlying CVD only found by further physiologic testing. The severity and duration of symptoms are important for the history, following the detection of any symptoms of telangiectasias and varicose veins include. Other necessary questions include ascertaining information about a history of deep venous thrombosis, family history of venous diseases, occupation with regards to long duration of standing, previous venous surgery, presence of obesity, history of constipation, history of trauma to the lower extremities, previous orthopedic surgeries, periods of prolonged bed rest, and the past use of compression hosiery. In women, pain can worsen during the menstrual cycle or pregnancy secondary to increased total body ﬂuid volume and/or higher circulating levels of estrogen. Patients should also be asked if any problems occur when walking. Rarely, patients will have concomitant peripheral arterial disease and exhibit symptoms of claudication. Occasionally, patients may have symptoms of severe venous ambulatory hypertension. With this diagnosis, patients typically complain of a bursting pain in the calf muscles that is slow to abate with cessation of walking. Patients presenting with venous ulcer should be questioned in a similar manner. Other pertinent questions relevant to a patient with a venous ulcer include location, size, appearance, and whether there are signs and symptoms of infection present. Past and current treatment regimens are also very important.

PHYSICAL EXAMINATION The physical examination should take place in a warm, well-illuminated room with the patient in the standing position. With the patient’s legs completely disrobed, careful inspection is carried out and patterns of telangiectasia, reticular veins, and varicose veins are noted. Clusters of telangiectasia can appear as skin blemishes or venous lakes. Often they are present in the lateral and posterior thigh. Calf and thigh measurements should be performed. These help reveal more subtle problems with edema that may not be detected with simple visual assessment. Additionally, inspection for other more serious signs of CVD in the gaiter area is performed. These include dermatitis, hyperpigmentation, lipodermatosclerosis, cellulitis, and evidence of healed or active ulceration. Location, size, depth, color, and number of ulcerations should be noted. The presence of an underlying congenital arteriovenous or venous malformation may be revealed by the presence of a well-demarcated purplish pigmented area of the skin (port wine stain) or

343

limb hypertrophy. Inspection should also concentrate on the presence of scars, particularly in the distribution of previous vein stripping and phlebectomy. Occasionally auscultation in the vicinity of varicose veins may reveal a bruit. Patients with a previous history of trauma to the lower extremity may have an arteriovenous ﬁstula leading to varicose veins. A congenital arteriovenous or venous malformation can appear as a large isolated grape-like cluster of veins or as a moderate to large cluster of smaller vessels appearing with a reddish-bluish hue that penetrate more deeply into fatty and muscular layers of the limb. A bruit is not necessarily present. Palpation to aid in deﬁning the extent and pattern of CVD is extremely important. Often, when in the standing position, other dilated veins that are incompetent and not readily visualized can be palpated. This may be true when only telangiectasia or a venous ulcer is present by inspection. Palpation can also help deﬁne a more complete outline of varicose veins, particularly in the thigh region of obese patients. A thrill can be palpated in some patients with a traumatic arteriovenous ﬁstula. Careful palpation can also help ascertain more serious signs of infection by detecting the extent of dolor, tenderness, and induration. Outlining the extent of lipodermatosclerosis by palpation may also guide the physician to which area to avoid when performing phlebectomy or to focus on for subendoscopic perforator surgery. Patients should also be examined in the supine position. A complete abdominal exam may indicate a mass with venous obstruction. Varicose veins that continue to be visualized or are slow to dissipate may also indicate the presence of signiﬁcant venous obstruction. Pulse examination of the femoral, popliteal, dorsal pedal, and posterior tibial arteries should be performed.

LABORATORY EXAMINATION Patients with CVD should have blood and/or urine testing depending on their history, physical examination, and treatment plan. Patients with a personal or family history of thrombophilia may require complete screening for hypercoagulability (see Chapter 11). Patients with longstanding venous stasis ulcers may require a complete blood count and metabolic panel. The need for general anesthesia for the treatment of CVD often necessitates a need for baseline laboratory examination.

DIAGNOSTIC VASCULAR LABORATORY Although history and physical examination play a major role in making the diagnosis of CVD, it provides little information regarding the pathophysiology of CVD. Indirect and direct non-invasive testing for CVD performed in the vascular laboratory by an experienced

344

Diagnostic algorithm for telangiectasias, varicose veins and venous ulcers: current guidelines

technologist can be of great assistance in expanding the diagnosis of the patient according to the CEAP classiﬁcation. Delineation of venous reﬂux, obstruction, and calf muscle pump dysfunction are important to a diagnostic algorithm, particularly in the presence of varicose veins and venous ulcer.

INDIRECT NON-INVASIVE TESTS There are a number of indirect non-invasive venous vascular laboratory tests of which the majority utilize some form of plethysmography (see Chapter 14) to help deﬁne the presence and distribution of reﬂux, obstruction, and calf muscle pump dysfunction.3–5 Many vascular laboratories have the capacity to measure venous reﬁll time and/or venous outﬂow. Typically, venous reﬁll times are determined using photoplethysmography.6,7 Following 10 consecutive plantar ﬂexions of the ankle, blood is evacuated from the lower extremity and the venous pressure falls. If the valves are competent, reﬁll to the baseline pressure through the arterial circuit takes longer than 23 seconds. Reaching the baseline plateau in 20 seconds or less indicates venous valvular reﬂux. Although touted as imprecise, a thigh cuff can be placed and inﬂated to a pressure to occlude the great saphenous vein (~40 mmHg). This maneuver may further delineate whether the deep venous valves are incompetent. Venous outﬂow is typically measured with impedance and strain gauge plethysmography.8,9 With the patient in the supine position and the legs elevated 15–20°, thigh cuffs are inﬂated to 50–80 mmHg to occlude venous outﬂow. When the venous capacitance pressure equalizes to the occluding pressure from the arterial inﬂow of blood, the cuffs are rapidly deﬂated. Just prior to cuff deﬂation, total venous capacitance is compared between the limbs. Limbs with acute or chronic thrombus may have less venous capacitance. The rate of decline over 3 seconds compared with the baseline capacitance also tests for venous outﬂow obstruction. A leg that is slow to empty could have a thrombus more proximally. The presence of developed collateral venous circulation or venous duplicity can lead to a false-negative test. Increasingly, air plethysmography is being used for its ability to diagnose calf muscle pump dysfunction.10–12 Using an air-ﬁlled plastic bladder that surrounds the lower extremity, the system is calibrated with a known volume of air. Changes in air pressure within the bladder are recorded as maneuvers are made to change venous capacitance and limb calf diameter. In someone with calf muscle pump failure, minimal blood ejects from the limb with each ankle dorsiﬂexion yielding a markedly reduced ejection fraction and a high residual volume. Air plethysmography also tests other important physiologic parameters including venous volume, venous ﬁlling index, and residual volume fraction (see Chapter 14).

DIRECT NON-INVASIVE TESTS One of the most common direct non-invasive tests used to assess for venous valvular incompetence is described by van Bemmelen.13–15 Venous segments typically insonated for examination include common femoral, femoral, popliteal, posterior tibial, great and small saphenous veins. With the patient using a handrail and dangling the leg in the standing position, duplex insonates the aforementioned venous segment with an appropriately sized cuff placed approximately 5 cm below the probe. Depending on the cuff position, inﬂation pressures from 80 mmHg (thigh) to 120 mmHg (foot) are needed to overcome venous hydrostatic pressure and ensure complete venous evacuation. After maintaining an inﬂation of 3 seconds, the cuff is rapidly deﬂated within 0.3 seconds or less. Normal valves respond rapidly with cuff deﬂation, with 95% demonstrating complete cessation of reverse ﬂow within 0.3 seconds. Therefore, reversal of ﬂow that is greater than 0.5 seconds is considered abnormal. Typically, median reversal of ﬂow times for incompetent valves is 3–4 seconds. Identiﬁcation of perforating veins may also be a valid need of the diagnostic evaluation.16–18 With the legs in an exaggerated reverse Trendelenburg or sitting position, the duplex can be used to visualize perforating veins along the medial calf. With calf compression or ﬂexion, outward ﬂow from the deep to the superﬁcial venous system indicates incompetence. With the exception of identifying the location of perforating veins, this test is fraught with inaccuracy as 21% of normal individuals have reversal of ﬂow.

RADIOLOGIC IMAGING Depending on the clinical scenario, venous obstruction can play a major role in contributing to the pathophysiology of venous ulceration. Increased resistance to venous outﬂow in combination with valvular incompetence can be responsible for the more recalcitrant ulcer. Computed tomography or magnetic resonance imaging (MRI) can provide imaging to help make possible the diagnosis of venous obstruction.19–21 Intravenous contrast is usually necessary for optimal evaluation of venous disorders when using computed tomography. Large zones of the body can be imaged over a very short period of time. However, ﬂow artifacts can occur if homogeneous mixing does not occur between blood and contrast. This is less true for the lower extremities than the large central veins in the thorax. Magnetic resonance imaging has the beneﬁt of allowing for multiple views (e.g., axial, sagittal, coronal). This imaging modality can be useful in making the diagnosis of iliac vein compression (May–Thurner) syndrome. Magnetic resonance imaging can provide accurate measurements of the degree of left common iliac vein

Invasive imaging 345

compression by the right common iliac artery and further reveal other causes of compression such as pelvic masses, bone spurs, iliac artery aneurysms, retroperitoneal ﬁbrosis, and inﬂammatory processes can be identiﬁed. Magnetic resonance imaging has also been useful in making the diagnosis of acute venous thrombosis. It can provide an accurate picture of the overall clot burden, particularly in certain circumstances when the duplex examination is limited, such as in the presence of orthopedic hardware, large wounds, morbid obesity, and marked interstitial edema.

INVASIVE IMAGING Contrast venography When ﬁnalizing a diagnosis and contemplating either endovascular or operative treatment of venous pathology, particularly that responsible for a recalcitrant venous ulcer, contrast venography remains vital to providing the correct information about venous anatomy, reﬂux, and obstruction. Although a detailed description of ascending and descending venography are beyond the scope of this discussion, the techniques described by Rabinov and Paulin22 and Kistner et al.23 serve as thorough overviews, respectively. Ascending venography remains a primary technique to deﬁne venous outﬂow obstruction. Depending on other previous diagnostic imaging studies such as MRI and possible simultaneous endovascular treatments to be performed, this technique may involve puncture of a foot vein, popliteal vein, femoral vein, or common femoral vein. The use of a tourniquet on the calf can assist in ﬁlling the deep veins of the lower extremity if performing ascending venography from injection of a foot vein. Descending venography remains the primary technique to anatomically deﬁne valvular reﬂux and function. To maximize visualization of the deep veins using this technique, a tilt-table, the Valsalva maneuver, and manual compression of the thigh may be helpful. Manual injection of 10–20 ml boluses of contrast are preferred rather than use of a high-powered injector. Contrast that freely travels retrograde with no valves visualized can be very helpful when contemplating possible treatment such as valve reconstruction or auto-transplantion. Other salient points in maximizing the diagnostic potential of venography include using selective and superselective cannulation of venous tributaries to provide for better venous ﬁlling; maximizing valve closure by keeping the patient supine when performing retrograde cannulation (ipsilateral or contralateral); using larger amounts of contrast over longer periods of injection time. Multiple planar views at 90° obliquities (e.g., 45° left anterior oblique vs 45° right anterior oblique) can help further reveal a venous stenosis not appreciated fully on a typical anteroposterior image. When using a high-

powered contrast injector for larger vein visualization, venous trauma can be avoided by using multi-side hole catheters and decreasing injection pressure by approximately one-half that of arterial injections (14–28 bar).

Intravascular ultrasound In certain circumstances, venography even with different planar views may not be adequate in fully deﬁning the degree of venous obstruction. Whether it is iliac vein compression syndrome or obstruction from residual chronic thrombus, intravascular ultrasound (IVUS) remains the method of choice to provide an accurate cross-sectional representation of present pathology and may be more accurate than multiplanar venography to ﬁnitely deﬁne where lesions begin and end.24,25

Complaint of telangiectasia, varicose vein, and/or venous ulcer

Local symptoms Yes

No Limb symptoms

Yes

No History of venous diseases

Yes

No Review of systems

Yes

No Physical signs

Yes

No Laboratory testing (thrombophilia?)

Yes

No Indirect non-invasive tests (reflux?) and/or Direct non-invasive tests (reflux?)

Yes

No

Indirect non-invasive tests (outflow obstruction?) Yes

No Magnetic resonance venography and/or computed tomographic venography

Yes

No Contrast venography

Figure 29.1 Suggested algorithm for diagnosis of telangiectasias, varicose veins, and venous stasis ulcer may vary depending on presentation, history, and physical examination. Multiple diagnostic options and modalities exist and should follow this prescribed order depending on the initial constellation of signs and symptoms. Depending on ﬁndings, treatment can commence at any stage after complete history and physical examination.

346

Diagnostic algorithm for telangiectasias, varicose veins and venous ulcers: current guidelines

Guidelines 4.2.0 of the American Venous Forum on diagnostic algorithm for telangiectasias, varicose veins and venous ulcers No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.2.1 We recommend that in patients with telangiectasia, varicose veins and chronic venous insufﬁciency a complete history and detailed physical examination is complemented by duplex scanning of the deep, superﬁcial, and, selectively, the perforating veins, to evaluate valvular incompetence

1

B

4.2.2 We recommend that in patients with telangiectasia, varicose veins and chronic venous insufﬁciency laboratory examination is needed selectively for those with a personal or family history of thrombophilia (screening for hypercoagulability), in patients with long-standing venous stasis ulcers (blood count and metabolic panel) and in a case of general anesthesia for the treatment of chronic venous disease

1

B

4.2.3 We recommend in patients with telangiectasias, varicose veins, and chronic venous insufﬁciency selective use of plethysmography, computed tomography, magnetic resonance imaging, ascending and descending venography and intravascular ultrasound

1

B

Diagnostic algorithms From a practical standpoint for the clinician, patients typically come or are referred for evaluation because of the presence of spider veins (telangiectasia), varicose veins, or venous ulcer. Occasionally, chronic unilateral edema may be the sole complaint, but often other associated signs of chronic venous disease may be present. Thus far the discussion has provided a brief overview of the more common diagnostic tools that are typically available to help discern each aspect of CEAP in patients with these conditions. These many diagnostic tests and imaging studies help the physician in directing treatment, predicting prognosis, and providing a comparison with the baseline during follow-up. The algorithm presented (Fig. 29.1) is designed to help the healthcare professional provide complete care of these problems and further assure that more signiﬁcant underlying venous pathophysiology is addressed. Depending on a variety of treatment options that may be pursued for each particular constellation of symptoms, following the guidelines may vary from practitioner to practitioner. As prescribed in this chapter, the algorithm emphasizes diagnostic options in a logical order. Treatment options are outlined in other areas of this book and can occur at different stages of the algorithm, depending on the ﬁndings of diagnostic tests.

REFERENCES 1. Bradbury A, Ruckley CV. Clinical assessment of patients with venous disease. In: Gloviczki P, Yao SJT, eds. Handbook of Venous Disorders: Guidelines of the American Venous Forum, 2nd edn. London: Arnold, 2001: 71–82. 2. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. 3. Christopoulos D, Nicolaides AN. Noninvasive diagnosis and quantitation of popliteal reﬂux in the swollen and ulcerated leg. J Cardiovasc Surg (Torino) 1988; 29: 535–9. 4. Kalodiki E, Calahoras LS, Delis KT, et al. Air plethysmography: the answer in detecting past deep venous thrombosis. J Vasc Surg 2001; 33: 715–20. 5. Delis KT, Bjarnason H, Wennberg PW, et al. Successful iliac vein and inferior vena cava stenting ameliorates venous claudication and improves venous outﬂow, calf muscle pump function, and clinical status in post-thrombotic syndrome. Ann Surg 2007; 245 (1): 130–9. 6. Abramowitz HB, Queral LA, Finn WR, et al. The use of photoplethysmography in the assessment of venous insufﬁciency: a comparison to venous pressure measurements. Surgery 1979; 86: 434–41. 7. Nicolaides AN, Miles C. Photoplethysmography in the assessment of venous insufﬁciency. J Vasc Surg 1987; 5: 405–12.

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8. Hirai M, Yoshinaga M, Nakayama R. Assessment of venous insufﬁciency using photoplethysmography: a comparison to strain gauge plethysmography. Angiology 1985; 36: 795–801. 9. Perhoniemi V, Salo JA, Haapiainen R, Salo H. Strain gauge plethysmography in the assessment of venous reﬂux after subfascial closure of perforating veins: a prospective study of twenty patients. J Vasc Surg 1990; 12: 34–7 . 10. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufﬁciency: a randomized trial. J Vasc Surg 2004; 39 (1): 79–87. 11. Ting AC, Cheng SW, Wu LL, Cheung GC. Air plethysmography in chronic venous insufﬁciency: clinical diagnosis and quantitative assessment. Angiology 1999; 50: 831–6 . 12. Araki CT, Back TL, Padberg FT, et al. The signiﬁcance of calf muscle pump function in venous ulceration. J Vasc Surg 1994; 20: 872–7 . 13. van Bemmelen PS, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reﬂux with duplex ultrasound scanning. J Vasc Surg 1989; 10: 425–31. 14. van Bemmelen PS, Beach K, Bedford G, Strandness DE Jr. The mechanism of venous valve closure. Its relationship to the velocity of reverse ﬂow. Arch Surg 1990; 125: 617–9 . 15. van Ramshorst B, van Bemmelen PS, et al. The development of valvular incompetence after deep vein thrombosis: a follow-up study with duplex scanning. J Vasc Surg 1994; 19: 1059–66. 16. Gohel MS, Barwell JR, Wakely C, et al. The inﬂuence of superﬁcial venous surgery and compression on

17.

18.

19.

20.

21.

22. 23.

24. 25.

incompetent calf perforators in chronic venous leg ulceration. Eur J Vasc Endovasc Surg 2005; 29: 78–82. Delis KT, Husmann M, Kalodiki E, et al. In situ hemodynamics of perforating veins in chronic venous insufﬁciency. J Vasc Surg 2001; 33 (4): 773–82. Delis KT, Ibegbuna V, Nicolaides AN, et al. Prevalence and distribution of incompetent perforating veins in chronic venous insufﬁciency. J Vasc Surg 1998; 28 (5): 815–25. Dupas B, el Kouri D, Curtet C, et al. Angiomagnetic resonance imaging of iliofemorocaval venous thrombosis. Lancet 1995; 346: 17–9. Carpenter JP, Holland GA, Baum RA, et al. Magnetic resonance venography for the detection of deep venous thrombosis: comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 1993; 18: 734–41. Chung JW, Yoon CJ, Jung SI, et al. Acute iliofemoral deep vein thrombosis: evaluation of underlying anatomic abnormalities by spiral CT venography. J Vasc Interv Radiol 2004; 15: 249–56. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134–44. Kistner RL, Ferris EB, Randhawa G, Kamida C. A method of performing descending venography. J Vasc Surg 1986; 4: 464–8 . Neglen P, Raju S. Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 2002; 35: 694–700 . Forauer AR, Gemmete JJ, Dasika NL, et al. Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 2002; 13: 523–7.

30 Compression therapy for venous ulceration GREGORY L. MONETA AND HUGO PARTSCH Rationale Mechanism Patient evaluation

348 348 350

Forms of compression therapy Comparison studies: surgery versus compression References

350 356 357

RATIONALE

MECHANISM

Compression therapy is standard ﬁrst-line treatment for chronic venous insufﬁciency and venous ulcer and remains so despite progress in both ablative and reconstructive venous surgery. The goal of compression therapy for venous leg ulcers is to facilitate ulcer healing, provide rapid ulcer healing, and prevent recurrence. Compression therapy is, in fact, really quite good at promoting ulcer healing in most cases. Healing is usually reasonably rapid (within 3 months). Unfortunately, not all patients heal rapidly or completely and recurrence of ulceration remains a major problem following compression therapy, but the same may be stated for operative therapy as well. Patients who are elderly, obese, have coexisting deep venous reﬂux or arterial insufﬁciency, have long-standing or large ulcers, or multiple recurrences of ulceration will not do as well with compression therapy. Most forms of compression therapy are designed to allow the patient to remain ambulatory during treatment. Ambulatory compression can be achieved using a variety of techniques, including elastic compression stockings, paste gauze boots (Unna’s boot), and multilayer wraps, dressings, and bandages. Pneumatic compression devices, applied primarily at night, are also employed in some patients. In recent years, compression therapy has moved from primarily undergoing evaluation in isolation to comparisons of compression therapy alone versus other modalities of treatment for venous ulceration. Studies are also beginning to focus on the mechanisms of beneﬁt of compression therapy.

Ambulatory venous hypertension appears to act through largely unknown mechanisms to facilitate the tissue damage characteristic of severe chronic venous disease. It is assumed the abnormal hemodynamics of ambulatory venous hypertension must be overcome for compression therapy to be effective. The optimal pressure required to achieve a therapeutic hemodynamic effect is a matter of debate. Gravity governs intravenous pressure, which changes depending on the body position, and it is this which must be counteracted. Physiologically, the intravenous pressure in a leg vein reﬂects the weight of the blood column between the site of measurement and the right atrium.1 In the supine position, the venous pressure will be between 10 and 20 mmHg. Using a sphygmomanometer cuff containing an ultrasound permeable window (Echo cuff, VNUS Medical Technologies, Sunnyvale, CA), it can be demonstrated that in this position lower leg veins will be narrowed by an external pressure of 10–20 mmHg and totally occluded by a pressure of 20–25 mmHg.2 Venous narrowing by such low external pressures may explain the effect of thromboprophylactic stockings used in a recumbent patient. These will exert a pressure between 15 mmHg and 20 mmHg and therefore enhance venous blood ﬂow velocity. During standing, the intravenous pressure in a lower leg vein will rise to around 60 mmHg, depending on the height of the individual. An external pressure of around 35–40 mmHg has been shown to narrow the veins, but a pressure of more than 60 mmHg is necessary to occlude the veins totally (Fig. 30.1).2

Mechanism 349

(a)

(c)

(b)

(d)

From these experiments it may be concluded that major hemodynamic effects of external compression in an upright subject may only be expected when the interface pressure of the compression device is higher than 35– 40 mmHg. A safe upper limit of 60 mmHg for externally applied sustained compression was proposed based on several microcirculatory investigations.3 Intermittent pressure peaks can considerably exceeded this upper limit.4 Several plethysmographic investigations have shown that compression improves venous pump function in patients with chronic venous insufﬁciency, (CVI) (CEAP C3–C6), depending on the interface pressure.5 Inelastic bandages that do not give way to changes of the leg circumference produce a more pronounced reduction of venous reﬂux measured by air plethysmography than elastic material applied with the same resting pressure.6 Inelastic bandages applied with a resting pressure over 50 mmHg were also demonstrated signiﬁcantly to decrease ambulatory venous pressure measured in patients with severe chronic venous insufﬁciency walking on a treadmill (Fig. 30.2).7

Figure 30.1 The effect of variable degrees of external compression on a leg vein is demonstrated by using a blood pressure cuff with an ultrasound permeable window as a model for an inelastic bandage (Echo cuff, a). The diameter of the small saphenous vein is measured by duplex in the standing position. (b) Cross-section of the vein without external compression. A cuff pressure of 40 mmHg leads to some narrowing of the vein (c), a pressure of 70 mmHg occludes the vein (d).

This effect may be explained by an intermittent occlusion of the leg veins exerted by the pressure peaks of 80 mmHg produced by an inelastic bandage during walking (Fig. 30.2). Such effects cannot be achieved with elastic stockings that increase the interface pressure during walking to values which are only 3–8 mmHg higher than the resting presure.8 The exact local physiologic and biochemical mechanisms by which compression therapy leads to healing of venous ulceration remains uncertain. The mechanism(s) of beneﬁt of compression therapy will likely remain unknown until the underlying pathophysiology of venous ulceration is more fully elucidated on anatomic, physiologic, microcirculatory, and biochemical levels. There are many possible local cutaneous mechanisms that beneﬁt from compression therapy. Improvements in skin and subcutaneous tissue microcirculatory hemodynamics are postulated. There also appears to be a direct and favorable effect on subcutaneous pressures with compression therapy.9,10 Supine perimalleolar subcutaneous pressure increases with elastic compression. Increased subcutaneous pressure should create a Starling gradient

350

Compression therapy for venous ulceration

Figure 30.2 Intravenous pressure measured in a dorsal foot vein in a patient with severe superﬁcial and deep venous incompetence and venous leg ulcers. During walking on a tread mill (curves should be read from the right to the left side) the pressure does not fall and the systolic peaks are higher than the resting pressure (left). An elastic bandage exerting a pressure of 40 mmHg does not reduce ambulatory venous hypertension (middle). With an inelastic multicomponent bandage exerting an interface pressure of 55 mmHg the systolic pressure peaks during walking are getting lower than the standing pressure (right). The intravenous mean pressure given in the graph is calculated according to the formula: mean pressure = (2 × diastolic pressure + systolic pressure).

favoring resolution of edema by the movement of ﬂuid from the interstitial space to the lymphatic circulation. The increased subcutaneous pressure may also counteract transcapillary Starling forces favoring leakage of ﬂuid out of the capillary. These observations correlate with the obvious fact that elastic and non-elastic bandages reduce lower extremity edema in patients with CVI and venous ulceration. With edema reduction, the cutaneous and subcutaneous metabolism may improve because of enhanced diffusion of oxygen and other nutrients to the cellular elements of skin and subcutaneous tissues thereby promoting ulcer healing. A number of biochemical abnormalities have now been implicated in the etiology and chronicity of venous ulceration. The effects of compression therapy on these alterations in biochemistry remain largely unknown. Vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha (TNF-α) appear to participate in the tissue damage associated with chronic venous disease. Serum levels of both of these cytokines diminish in patients with venous ulcers treated with 4 weeks of compression therapy with four-layered bandaging. Reductions have correlated with ulcer healing as reﬂected by reduced ulcer size.11

PATIENT EVALUATION Compression therapy, like many other medical interventions, works best when patients understand their disease and the goals of therapy. Prior to the initiation of

compression therapy for venous ulceration, patients must be educated about their chronic disease and the need to comply with their treatment plan in order to heal ulcers and prevent recurrence. There are a large number of causes of chronic leg ulcers. Only about 70% of leg ulcers are venous in origin. A deﬁnitive diagnosis of venous ulceration must be made prior to undergoing treatment with compression therapy. A detailed history should be obtained including medications and associated medical conditions that may promote lower extremity ulceration. Venous insufﬁciency and or venous obstruction should be documented in the non-invasive vascular laboratory or by venography prior to initiation of compressive therapy. Possible arterial insufﬁciency is also assessed by physical examination and non-invasive studies prior to beginning compression therapy. Venous ulceration in the setting of coexisting arterial insufﬁciency, especially severe arterial insufﬁciency, is quite difﬁcult to heal and coexisting arterial insufﬁciency is a well recognized risk factor for non-healing of venous ulceration.12 Compression therapy is theoretically dangerous in the presence of signiﬁcant arterial insufﬁciency in that the already diminished skin perfusion pressure in patients with severe arterial insufﬁciency can be diminished further by compressive devices, resulting in an overall proulceragenic effect and even gangrene and limb loss.13 Compression therapy must be used with extreme caution in patients with arterial insufﬁciency and is essentially contraindicated in patients with an ankle brachial systolic blood pressure ratio < 0.5. Finally, systemic conditions that affect wound healing and leg edema such as diabetes mellitus, immunosuppression, and malnutrition should be sought and improved as much as possible prior to or during the course of compression therapy. Strong compression applied to both lower extremities may shift a considerable amount of blood volume towards the heart and is, therefore, contraindicated in patients with severe cardiac dysfunction.

FORMS OF COMPRESSION THERAPY Elastic stockings Compression therapy is most commonly delivered with gradient elastic compression stockings. Gradient elastic compression stockings, initially developed by Conrad Jobst in the 1950s, were made to simulate the gradient hydrostatic forces exerted by water in a swimming pool. Elastic compression stockings are available in various compositions, strengths, and lengths and can be customized for a particular patient. The beneﬁts of elastic compression stocking therapy for the treatment of CVI and healing of ulcerations have been well documented. In a retrospective review of 113 venous

Forms of compression therapy 351

ulcer patients, the use of below-knee, 30–40 mmHg elastic compression stockings, after ﬁrst resolving edema and cellulitis if present, resulted in 93% healing. Complete ulcer healing occurred in 99 of 102 (97%) patients who were compliant with stocking use versus 6 of 11 patients (55%) who were non-compliant (P < 0.0001). The mean time to ulcer healing was 5 months. Ulcer recurrence was less in patients who were compliant with their compression therapy. By life table analysis, ulcer recurrence was 29% at 5 years for compliant patients and 100% at 3 years for non-compliant patients.14 The patients in the study represented a cross-section of venous ulcer patients with a mean age of 59 years and 27% of ulcers were recurrent. Compliance with the use of stockings as instructed was very good. Not all centers, however, have had such favorable results with elastic compression stockings for healing venous ulcers. Older, less compliant patients and populations with a higher percentage of recurrent or long-standing ulcers will likely not do as well. In addition to promoting ulcer healing, elastic compression therapy can also improve quality of life in patients with CVI. In a recent prospective study, 112 patients with CVI documented by duplex ultrasound were administered a questionnaire to quantify the symptoms of swelling, pain, skin discoloration, cosmesis, activity tolerance, depression, and sleep alterations. Patients were treated with 30–40 mmHg elastic compression stockings. There were overall improvements in symptom severity scores at 1 month after initiation of treatment. Further improvements were noted at 16 months after treatment.15 Elastic stockings as a treatment for venous ulceration have the advantage that their effects, unlike compressive bandages, are operator independent. Once applied, their

effects are dependent on the strength of the stocking and independent of the patient as long as the patient wears them. Stockings are less bulky than other forms of compression therapy and therefore perhaps more comfortable. They can be worn with normal footwear and allow daily inspection of the wound. (Fig. 30.3) However, the stockings must be worn to be effective and they are easily removed or “forgotten” by the non-compliant patient. Patient compliance with compression therapy is crucial in treating venous leg ulcers. Patient compliance begins with patient education and reinforcement of that education at every visit to the ofﬁce and the clinic. Many patients are often initially intolerant of compression in areas of hypersensitivity adjacent to an active ulcer or at sites of previously healed ulcers. This intolerance of compression can sometimes be overcome by initially ﬁtting the patient with lower strength stockings followed by higher strength stockings over a period of several weeks. An obvious disadvantage is the added expense of the “introductory” stocking. Patients may also have difﬁculty applying elastic stockings. Many elderly, weak, or arthritic patients cannot apply elastic stockings. In one study of elderly (mean age 72 years) and predominately female patients (69%), 15% of patients were incapable of applying stockings and 26% could only put them on with signiﬁcant difﬁculty.16 Obese patients also frequently cannot reach their feet to apply an elastic stocking and are dependent on family members for application of the stocking. A number of aids have been developed to assist in the application of elastic stockings. With open-toe stockings, an inner silk sleeve can be placed over the patient’s forefoot to allow the stocking to slide smoothly during application. The sleeve is removed through the toe opening after the stocking has been placed. Another device allows the patient to load the stocking onto a wire frame. The patient then steps into the stocking and pulls the device upward, applying the stocking to the leg (Fig. 30.4a,b). Recurrence of ulceration after healing can be lessened by the use of elastic stockings after the ulcer has healed.14,16 However, in addition to all the other barriers to use of elastic stockings noted above, an additional problem after ulcer healing is the unwillingness of insurers to provide coverage for elastic stockings. This is in spite of good evidence demonstrating the cost-effectiveness of elastic stockings in preventing ulcer recurrence.17

Paste boots Figure 30.3 Gauze dressing with foam wedge overlying the ulcer to provide uniform compression. A short nylon stocking is then placed over the dressing and wedge to hold them in place. The nylon stocking also facilitates placement of the compression stocking. A zippered compression stocking is shown that may allow easier application of the elastic stocking.

Another method of compression was developed by the German dermatologist Paul Gerson Unna in 1896. Unna’s boot has been used for many years to treat venous ulcers and is available in many versions. Unna’s boot is basically a form of compression bandage. A typical Unna’s boot type dressing is a three or four-layer dressing and requires

352

Compression therapy for venous ulceration

(a)

changed weekly or sooner if the patient experiences signiﬁcant drainage from the ulcer bed. Once applied, Unna’s boot requires minimal patient involvement and provides continuous compression and topical therapy. However, the Unna’s boot has several disadvantages. It is uncomfortable to wear for some patients because of its bulkiness. This may affect patient compliance. In addition, the ulcer cannot be monitored after the boot is applied, the technique is labor intensive, and the degree of compression provided is operator dependent. Patients may also occasionally develop contact dermatitis to the components of Unna’s boot that may require discontinuation of therapy. In a 15 year review of 998 patients with one or more venous ulcers treated with Unna’s dressings, 73% of ulcers healed in patients who returned for more than one treatment. The median time to healing for individual ulcers was 9 weeks.18 Unna’s dressing has been compared with other forms of treatment. A randomized, prospective study comparing Unna’s boot to polyurethane foam dressing in 36 patients with venous ulcers demonstrated superior healing over 12 months in patients treated with Unna’s boot (94.7% vs 41.2%).19

Compressive bandages

(b) Figure 30.4 (a) Inner silk liner ﬁtted on the toe for easier stocking placement. (b) So-called “Butler” device, which holds the stocking open. The patient steps into the stocking and pulls the frame upward to apply the stocking.

The purported advantages of multilayered compressive dressings include maintenance of compression for a longer period of time, more even distribution of compression, and better absorption of wound exudates. The pressure delivered by a compressive bandage depends upon the radius of the limb to which it is applied, the number of layers applied, the elastic properties of the materials utilized in the bandage and the wrapping technique of the healthcare personnel who apply the bandages. There are, therefore, a wide variety of compression materials with different textures available, resulting in bandages whose elastic properties and applied pressure are quite variable. Pressure, layers, components, and elastic properties (P-LA-C-E) are the deciding features that have to be considered when compression bandages are applied.20 PRESSURE

application by trained personnel. A rolled gauze bandage impregnated with calamine, zinc oxide, glycerin, sorbitol, gelatin, and magnesium aluminum silicate is ﬁrst applied with graded compression from the forefoot to just below the knee. Additional layers consist of a continuous gauze dressing followed by an outer layer of elastic wrap, also applied with graded compression. The bandage becomes stiff after drying and the rigidity may aid in preventing edema formation. The resting pressure, measured on the distal lower leg immediately after application, may be 50–60 mmHg in the supine position. Unna’s boot is

The pressure developed beneath a bandage is governed by the tension in the fabric exerted by the bandager, the radius of curvature of the limb, and the number of layers applied. Several instruments are available to measure the interface pressure exerted by a compression device on an individual leg. In the supine position, pressure ranges in the gaiter area can be classiﬁed according to proposals from a recent consensus conference (Table 30.1).20 It must be stressed that the interface pressures exerted during standing and walking will increase in a manner that depends on the elastic property of the material. “Strong”

Forms of compression therapy 353

Table 30.1 Pressure ranges of compression bandages measured in the supine position at the medial aspect of the lower leg where the tendon changes into the muscular part of the gastrocnemius muscle Recommendation Mild Moderate Strong Very strong

mmHg < 20 20–40 40–60 > 60

and “very strong” bandages clearly produce higher interface pressure values than those obtained by compression stockings. LAYERS

Single-layer bandages will usually have an overlap of up to 50%. Multilayer bandages consist of several single layers. COMPONENTS

The components of a bandage are the different materials used for one compression bandage application. Besides their intended functions of padding, protection or retention, they exert varying effects on the interface pressure and on the stiffness of the ﬁnal bandage. Compression bandaging systems consist of at least two different bandaging materials applied over each other for the whole length of the bandage. ELASTIC PROPERTY

The usual differentiation between elastic and inelastic compression material is based on in vitro measurements using different extensometer devices, and assessing the relationship between the power exerted to distend the bandage and the resulting stretch. Table 30.2 shows a classiﬁcation for single-layer, single-component materials.20 Several layers of elastic bandages will create a bandage with increasingly inelastic properties. The same is true when two stockings are donned over each other or when

several components of different materials are applied. This is because of an increase in friction between the rough surfaces of different layers opposing the expansion of the leg in addition to the elastic strain of the ﬁbers. Typical examples of bandages with high friction are cohesive bandages that adhere to the underlying layer, and adhesive bandages that adhere to the skin (Fig. 30.2). Elasticity of the materials used in a compressive bandage (as well as the fabric used to make compression stockings) is determined with in vitro measurements that quantify the power required to distend or stretch the bandage and the resulting extension of the bandage: a socalled hysteresis curve.20,21 In general, an attempt is made to achieve a pressure of about 40 mmHg at the gaiter area. “Strong” bandage material will need to be stretched less than “weak” bandage material to achieve this pressure. Compressive bandages have varying degrees of stiffness with stiffness deﬁned as the increase in pressure applied per centimeter increase in leg circumference.21 A higher stiffness indicates relative inelasticity of the bandage. An inelastic bandage is deﬁned as having higher pressure increase moving from a supine to standing position whereas an elastic bandage is marked by a lower pressure increase going from supine to standing. These differences in sub-bandage pressures moving from supine to standing are reﬂected in a measurement termed the static stiffness index.22 Relatively high stiffness (inelasticity) bandages include the Pütter bandage which consists of two 5 meter long short-stretch bandages that are applied to the leg in opposite directions (e.g., Comprilan, Rosidal K, Pütter bandage). There are also inelastic kits. These kits consist of several components of padding foam material, short stretch bandages and a protecting hose-layer (Rosidal sys bandage). The main component of these bandages is cotton, which is permeable to air, is very well tolerated, and can be washed and reused (Comprilan, Rosidal). Applying several elastic layers over each other creates a bandage system with rather high stiffness (Four-layer bandage, Profore). The ﬁnal bandage, when applied according to the manufacturers’ instructions, will exert an interface pressure of about 40 mmHg on the distal lower leg in the resting position (Fig. 30.5). The Coban2 layer kit that was recently introduced consists of two layers with an adhesive surface. It is easy to apply and creates a stable, non-bulky bandage with high stiffness.

Table 30.2 Inelastic and elastic bandage materials Inelastic

Extensibility (%) Examples

Rigid

Short stretch

Elastic Long stretch

0–10 Zinc paste Velcro-band devices (CircAid)

10–100 Comprilan Rosidal K

> 100 Ace bandage Surepress

354

Compression therapy for venous ulceration

●

●

●

Figure 30.5 The Profore multilayer bandaging system. This is an example of a four-component relatively stiff elastic compression bandage. Compressive bandages with multiple layers provide better absorption and maintenance of compression strength than simple elastic wraps.

●

●

●

●

There are two main disadvantages of inelastic bandages. One is the loss of bandage pressure starting immediately after bandage application. After 1 hour, the initial resting pressure will already have dropped by about 25%, mainly due to an immediate decrease in the volume of the limb. The second disadvantage is the fact that a good inelastic compression bandage is not easy to apply. It is a skill that should be learned and trained. Bandages with inelastic material should be applied with much higher initial tension than elastic bandages because of the fast pressure drop. An inadequate bandaging technique is the main reason for the poor clinical outcome described in several studies.23 Examples of elastic bandages are Ace-bandage, Surepress, and Perfekta. Proguide is a kit consisting of a padding layer and a specially designed elastic bandage. Elongation of the bandage material leads to only a low pressure increase.3 Such bandages may exert a relatively high resting pressure which will increase only minimally during walking (“low working pressure”). The main advantage is that they are relatively easy to apply, whether by untrained staff or by the patients themselves. The main disadvantage is the high resting pressure and the uncomfortable feeling due to the constricting force of the elastic ﬁbers. This high resting pressure is also responsible for skin damage that may occur, particularly in patients with arterial occlusive disease, over highly exposed pressure sites such as over the dorsal ankle tendon. Several points should be considered when compressive bandages are applied. ●

Elastic bandages are easier to handle than inelastic bandages and may be applied by untrained staff or by patients themselves.

●

●

●

●

●

Inelastic material should be applied with much higher resting pressure, pressing the bandage roll towards the leg as if molding clay. The patient is encouraged to immediately walk for at least 30 minutes to decrease edema and thereby decrease the pressure being exerted under the bandage. In patients with a small ankle circumference, bandages should be applied with much less tension using amply amounts of orthopedic wool padding to protect the tendon. The initial turn may start at the base of the toes or be placed around the ankle or between the heel and the dorsal tendon to ﬁx the bandage. The ankle joint is always bandaged with maximal dorsal extension of the foot and the protruding tendon is carefully protected with cotton-wool. Overlapping can be carried out in a spiral fashion or with ﬁgures of eight. The proximal end of a knee-high bandage should cover the capitulum ﬁbulae. The bandage must be applied with no gaps so that each turn overlaps the previous turn by about 50%. Bandage materials must be non-allergenic to avoid the development of dermatitis. Pads can increase local pressure over ulcers or ﬁrm lipodermatosclerotic areas. Ask the patient to walk, and come back when the bandage is too tight. Pain may indicate arterial ischemia. In such cases, the bandage must be removed immediately. Bandaging of the lower leg is sufﬁcient for the majority of patients with chronic venous disorders. Walking exercises are essential to optimize the effect of compression therapy. However, compression is also able to reduce edema in immobile patients or in those with severely restricted mobility. Inelastic ﬁxed bandages are preferred for this indication because of the lower resting pressure. After some walking, the pressure will drop because of the immediate removal of edema. In the edematous phase, the bandage will loosen after a few days, and it should be renewed or over-wrapped with a short stretch bandage. The same is advisable when exudate from the ulcer penetrates the bandage. This may occur particularly during the initial treatment phase, and the patient should be informed to come back if this happens. If these conditions no longer exist, the bandage is changed every 7 days on average.

Stiffer, more inelastic, bandages may have greater effects on measurements of deep venous hemodynamics than less stiff bandages. A study using air plethysmographic measurements of venous volume and venous ﬁlling index in limbs with venous ulcers and treated with elastic long stretch versus inelastic, short stretch, bandages found greater improvement in the venous ﬁlling index with the short stretch, more inelastic, bandage.6

Forms of compression therapy 355

A clinical study of a relatively stiff bandaging system (multilayer wrap of orthopedic wool, crepe bandages and Coban bandages) reported results in 148 ulcerated limbs (126 patients) that were refractory to simple wraps. At 12 weeks, 74% of ulcers had healed and measurements of compression declined only 10% over 1 week.24 A direct comparison between a relatively elastic bandaging regimen and a relatively inelastic regimen has been performed. The authors randomized 112 venous ulcer patients to an elastic bandaging regimen (n = 57) or an inelastic regimen (n = 55). Larger ulcers took longer to heal with the elastic bandaging but complete healing at 26 weeks was no different; 58% of those treated with the more elastic bandage and 62% of those treated with the relatively inelastic system.25 Another study comparing multilayer bandaging versus relatively inelastic short-stretch bandaging for venous leg ulcers showed ulcers treated with multilayer bandaging healed more quickly.26 Authors from Serbia recently reported dramatic results in healing very large venous ulcers with a heelless open-toe elastic compression device knitted into a tubular conﬁguration. One hundred and thirty-eight patients with very large venous ulcers (20–210 cm2) were randomized to treatment with the tubular device plus a multilayer bandage system (n = 72) versus bandaging alone (n = 66). Cumulative healing was 93% in the group treated with the multilayered tubular dressing plus bandages and 51% in the group treated with bandaging alone.27 Clearly, multilayer compressive bandages can be effective in healing of venous ulcers. Stiffer, short stretch, bandages may have greater effects on deep venous hemodynamics and perhaps faster healing than more elastic bandages. Whether this provides overall increased clinical efﬁcacy remains to be determined. Direct comparisons between different multilayer bandaging systems and between multilayer bandaging systems and other methods of compression are needed.

(a)

(b) Figure 30.6 (a) The CircAid device consists of multiple nonelastic straps. (b) The device in place on a patient with the circumferential band being adjusted.

Pneumatic compression devices Legging orthosis Circ-Aid is a legging orthosis consisting of multiple pliable, rigid, adjustable compression bands.20 These bands wrap around the leg from the ankle to the knee and are held in place with Velcro. The device provides inelastic, rigid compression similar to an Unna boot with increased ease of application (Fig. 30.6a,b). Because the bands are adjustable, it can be tailored to the individual as limb edema decreases. The orthosis appears effective in promoting resolution of edema and is especially useful in patients who for various reasons are either unable or unwilling to wear compression stockings. This legging orthosis may be superior to elastic stockings in preventing limb swelling in patients with advanced venous insufﬁciency.28

External pneumatic compression devices can serve as an adjunctive in the treatment of lower extremity lymphedema, venous ulceration, or both. These devices may be particularly applicable to patients who have severe edema or morbid obesity. Relative contraindications to external pneumatic compression are arterial insufﬁciency and uncontrolled congestive heart failure. Pneumatic compression devices that provide sequential gradient intermittent pneumatic compression (IPC) have received the most attention. Results with these devices suggest improvement in ulcer healing, but this comment must be qualiﬁed by the fact that pump patients may also elevate their legs longer each day than non-pump patients. Despite the results of the few available studies indicating pneumatic compression may be useful in treatment of venous ulcers, especially those refractory to previous

356

Compression therapy for venous ulceration

ambulatory compression alone,29,30 the use of the adjuvant intermittent compression has not gained widespread acceptance.

COMPARISON STUDIES: SURGERY VERSUS COMPRESSION Current literature highlights the difﬁculties of comparing various forms of compression therapy for venous ulcer treatment with venous surgery. At least two major reviews have concluded that insufﬁcient evidence exists to favor one form of compression over another.31,32 In addition, there is insufﬁcient evidence to favor use of adjunctive dressings, such as hydrocolloid dressings, in addition to compression therapy to heal venous ulcers.32 Comparisons are hampered by a minimum of randomized controlled studies, different criteria for patient entry into studies, variable use of compression as an adjunct to surgical therapy, and potentially variable compliance with postoperative compression therapy. A recent study evaluated the hemodynamic effects of compression plus surgery versus compression alone in patients with venous ulceration. Legs with open or recently healed venous ulcers were treated with multilayer compression bandages or superﬁcial venous surgery plus compression. There were 112 legs randomized to compression and 102 to compression plus surgery. Venous reﬁll time, as measured by photoplethysmography, was the primary hemodynamic variable measured. Superﬁcial venous surgery provided increased hemodynamic beneﬁt versus compression alone. No clinical data were presented.33 There is now new material from the same group showing that surgical correction of superﬁcial venous reﬂux in addition to compression bandaging does

not improve ulcer healing but reduces ulcer recurrence at four years.33a In a study from Italy, Zamboni et al.34 randomized 80 consecutive patients with 87 venous leg ulcers to treatment with compression or minimally invasive surgery. Healing was remarkable in both groups, 100% at 31 days in the surgical group compared with 96% at 63 days in the compression group (P < 0.02). Follow-up was for 3 years and recurrence was 9% in the surgical group and 38% in the compression group (P < 0.05). Quality of life was also better in the surgical group. A British study randomized 76 patients with venous ulcer to treatment with a four-layer bandaging system or superﬁcial venous surgery and a four-layer bandaging system. Healing occurred in 64% of the compression group and 68% of the surgical group (P = 0.75) with no signiﬁcant difference in the time to ulcer healing and no differences in health-related quality of life.35 Why do these studies give such disparate results? The trials were similar in design, the patients nearly the same age, the mean ulcer sizes no different and yet the Italians concluded superﬁcial venous surgery works as an adjunct to treatment of venous ulcers whereas the English concluded superﬁcial surgery added nothing to compression therapy. Details of the two studies may explain the different conclusions. The Italians excluded ulcers > 12 cm, the English did not. The Italians excluded patients with secondary reﬂux or deep venous reﬂux. The English did not. The English patients had a mean of two previous episodes of venous ulceration. The Italian study did not provide information on previous episodes of venous ulceration. At this time, one is left to conclude that superﬁcial venous surgery may improve the results of compression therapy for venous ulceration in certain, more favorable, subgroups of patients with venous ulcers.

Guidelines 4.3.0 of the American Venous Forum on compression therapy for venous ulceration No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.3.1 Compression therapy is the primary treatment for venous ulceration

1

B

4.3.2 No one form of compression therapy is clearly superior to another. Compression devices should be individualized to the individual patient

1

B

4.3.3 Compliance is integral to initial success with compression therapy and we recommend long-term compression to reduce recurrence of ulceration

1

B

4.3.4 We suggest superﬁcial venous surgery in addition to compression therapy to reduce ulcer recurrence in certain classes of patients with venous ulceration

2

A

References 357

REFERENCES ● ◆

= Key primary paper = Major review article

1. Ludbrook J. Aspects of Venous Function in the Lower Limbs. Springﬁeld, IL: Charles Thomas, 1966 2. Partsch B, Partsch H. Calf compression pressure required to achieve venous closure from supine to standing positions. J Vasc Surg 2005; 42: 734–38. 3. Thomas S, Fram P. An evaluation of a new type of compression bandaging system. Available from: http://www.worldwidewounds.com. Accessed 23 June 2008. 4. Delis KT, Azizi ZA, Stevens RJ, et al. Optimum intermittent pneumatic compression stimulus for lower-limb venous emptying. Eur J Vasc Endovasc Surg 2000; 19: 261–9. 5. Abenhaim L, Clement D, Norgren L, et al. The management of chronic venous disorders of the leg: an evidence-based report of an international task force. Phlebology 1999; 14 (Suppl 1): 35–42. 6. Partsch H, Menzinger G, Mostbeck A. Inelastic leg compression is more effective to reduce deep venous reﬂuxes than elastic bandages. Dermatol Surg 1999; 25: 695–700. 7. Partsch H . Improvement of venous pumping function in chronic venous insufﬁciency by compression depending on pressure and material. Vasa 1984; 13: 58–64. ●8. Partsch H, Clark M, Bassez S, et al. Measurement of lower leg compression in vivo: Recommendations for the performance of measurements of interface pressure and stiffness. Dermatol Surg 2006; 32: 229–38. ●9. Nehler MR, Moneta GL, Woodard DM, et al. Perimalleolar subcutaneous tissue pressure effects of elastic compression stockings. J Vasc Surg 1993; 18: 783. 10. Nehler MR, Porter JM. The lower extremity venous system. Part II: The pathophysiology of chronic venous insufﬁciency. Perspect Vasc Surg 1992; 5: 81. 11. Murphy MA, Joyce WP, Condron C, et al. A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy. Eur J Vasc Endovasc Surg 2002; 23: 349–52. ●12. Humphreys ML, Stewart AHR, Gohel MS, et al. Management of mixed arterial and venous leg ulcers. Br J Surg 2007; 94: 1104–7. 13. Callum MJ, Ruckley CV, Dale JJ, Harper DR. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. BMJ 1987; 295: 1352. ●14. Mayberry JC, Moneta GL, Taylor LM Jr, et al. Fifteen-year results of ambulatory compression therapy for chronic venous ulcers. Surgery 1991; 109: 575. 15. Motykie GD, Caprini JA, Arcelus JI, et al. Evaluation of therapeutic compression stockings in the treatment of chronic venous insufﬁciency. Dermatol Surg 1999; 25: 116. 16. Franks PJ, Oldroyd MI, Dickson D, et al. Risk factors for leg ulcer recurrence: a randomized trial of two types of compression stockings. Age Aging 1994; 24: 490–94.

17. Korn P, Patel ST, Heller JA, et al. Why insurers should reimburse for compression stockings in patients with chronic venous stasis. J Vasc Surg 2002; 35: 950–7. 18. Lippmann HI, Fishman LM, Farrar RH, et al. Edema control in the management of disabling chronic venous insufﬁciency. Arch Phys Med Rehabil 1994; 75: 436. 19. Rubin JR, Alexander J, Plecha EJ, et al. Unna’s boot vs. polyurethane foam dressings for the treatment of venous ulceration. Arch Surg 1990; 125: 489–93. ●20. Partsch H, Clark M, Mosti G, et al. Classiﬁcation of compression bandages: practical aspects. Dermatol Surg 2008 May; 34 (5): 600–9. 21. Partsch H, Partsch B, Braun W. Interface pressure and stiffness of ready made compression stockings: comparison of in vivo and in vitro measurements. J Vasc Surg 2006; 44: 809–14. 22. Partsch H. The static stiffness index: a simple method to assess the elastic property of compression material in vivo. Dermatol Surg 2005; 31: 625–30. ◆23. Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2002; Issue 2, Art. No.: CD000265. ◆24. Blair SD, Wright DD, Backhouse LM, et al. Sustained compression and healing of chronic venous ulcers. BMJ 1988; 297: 1159–61. 25. Meyer FJ, Burnand KG, Lagattolla RF, et al. Randomized clinical trial comparing the efﬁcacy of two bandaging regimens in the treatment of venous leg ulcers. Br J Surg 2002; 89: 40–4. 26. Nelson EA, Iglesias CP, Cullum N, et al. Randomized clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I). Br J Surg 2004; 91: 1292–9. ●27. Milic DJ, Zivic SS, Bogdanovic DC, et al. A randomized trial of the Tubulcus multilayer bandaging system in the treatment of extensive venous ulcers. J Vasc Surg 2007; 46: 750–5. 28. Spence RK, Cahall E. Inelastic versus elastic compression in chronic venous insufﬁciency: a comparison of limb size and venous hemodynamics. J Vasc Surg 1996; 24: 783–7. 29. Pekanmaki K, Kolari PJ, Kiistala U. Intermittent pneumatic compression treatment for postthrombotic leg ulcers. Clin Exp Dermatol 1987; 12: 350–6. 30. Coleridge Smith P, Sarin S, Hasty J, et al. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surgery 1990; 108: 871–7. 31. Fletcher A, Cullum N, Sheldon TA. A systematic review of compression treatment for venous leg ulcers. BMJ 1997; 315: 576–80. 32. Palfreyman S, Nelson EA, Michaels JA. Dressings for venous leg ulcers: systematic review and meta-analysis. BMJ 2007; 335: 7613–17. 33. Gohel MS, Barwell JR, Earnshaw JJ, et al. Randomized trial of compression plus surgery versus compression alone in chronic venous ulceration (ESCHAR study) – haemodynamic and anatomical changes. Br J Surg 2005; 92: 291–7.

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33a. Gohel MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007 Jul 14; 335 (7610): 83. 34. Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs.

compression treatment: a randomized clinical trial. Eur J Vasc Endovasc Surg 2003; 25: 313–18. 35. Guest M, Smith JJ, Tripuraneni G, et al. Randomized clinical trial of varicose vein surgery with compression versus compression alone for the treatment of venous ulceration. Phlebology 2003; 18: 130–6.

31 Drug treatment of varicose veins, venous edema, and ulcers PHILIP D. COLERIDGE SMITH Introduction Varicose veins and edema Venous ulcers

359 359 360

INTRODUCTION Drugs are widely used in medicine today, but huge advances in the management of venous disease using drugs have not been reported. No drug will cure varicose veins, although some drugs beneﬁt venous edema and ulceration. The greatest expansion of drug treatment in the management of venous disease has been the use of foam sclerosants in the management of varicose veins. However, this is not the subject of this chapter. The most economically important ﬁeld of venous disease is leg ulceration. Presently available drugs have modest beneﬁt in this disease and cannot be recommended in every patient. I consider that by far the best approach to this problem would be a drug that addresses the underlying pathology of the disease.

VARICOSE VEINS AND EDEMA Varicose veins is a common problem affecting about 25% of the adult population in Westernized countries. This disease infrequently results in serious illness, although in a few patients severe skin changes (lipodermatosclerosis) and leg ulceration may develop. Varicose veins are associated with a wide range of symptoms (aching, pain, cramps, restless legs, feeling of heaviness, itching, feeling of swelling). The symptoms are commonly managed by elastic compression, sclerotherapy, surgery, or one of the modern methods of ablating the superﬁcial veins, which include laser and radiofrequency ablation as well as foam sclerotherapy. Is drug treatment useful in managing any of the consequences of varicose veins?

Summary Clinical practice guidelines References

363 363 364

In some countries, drugs are widely prescribed, but in others few drugs are used in the treatment of varicose veins. A range of phlebotonic drugs is used (Table 31.1). The origin of these is from plants or synthetic sources. A recent review of the efﬁcacy of these drugs has been published in the Cochrane database.2 In all, 110 studies were considered for inclusion in the analysis; however, valid methodology and data were present in only 44 studies covering a range of commonly prescribed drugs. The scope of this review included the following ﬂavonoids: rutoside, French maritime pine bark extract, grape seed extract, diosmin and hesperidin, disodium ﬂavodate and the saponide Centella asiatica. The synthetic products included were calcium dobesilate, naftazone, aminaftone and chromocarbe. The overall ﬁndings were that there appeared to be an effect on edema, but among the symptoms mentioned above only restless legs were moderated. For the more frequently prescribed drugs the following effects were observed: calcium dobesilate reduced cramps and restless legs; diosmin and hesperidin beneﬁted trophic disorders as well as cramps and swelling; and rutosides were found to beneﬁt edema. On the basis of their review, the authors concluded that there is insufﬁcient evidence to support the global use of phlebotonics in the management of the signs and symptoms described above. Fortunately, few side-effects of this treatment have been reported. Aescin (horse chestnut seed extract) is the subject of a separate Cochrane review.3 This assessed leg swelling, symptoms of chronic venous insufﬁciency, as described above, as well as adverse events. The study identiﬁed 29 randomized controlled trials, of which 17 were included; the remainder not being considered to be methodologically sound. The ﬁndings

360

Drug treatment of varicose veins, venous edema, and ulcers

Table 31.1 Classiﬁcation of the main venoactive drugs Group

Benzopyrones Alpha-benzopyrones Gamma-benzopyrones (ﬂavonoids)

Saponins

Substance

Origin

Dosage (mg/day)

Number of intakes/day

Coumarin

Melilot (Melilotus ofﬁcinalis L.) Woodruff (Asperula odorata L.) Citrus spp. Sophora japonica L.

90 combined with troxerutin (540) 300–600

3

1000

1 or 2

1000

1 or 2

120, then 60

3

2 or 3 tablets 116 100–300 300–360

2 or 3 2 1–3 3

2 sachets (extracts of Ginkgo, heptaminol and troxerutin) 1000–1500 400–600 30

2 2 or 3 2 or 3 1

Diosmin Micronized puriﬁed ﬂavonoid fraction Rutin and rutosides O-(β-hydroxyethyl)-rutosides (troxerutin, HR) Escin/Aescin

Ginkgo biloba

Sophora japonica L. Eucalyptus spp. Fagopyrum esculentum Moench Horse chestnut (Aesculus hippocastanum L.) Butcher’s broom (Ruscus aculeatus L.) Bilberry (Vaccinium myrtillus L.) Grape pips (Vitis vinifera) Maritime pine (Pinus maritima Lank) (Pycnogenol) Ginkgo biloba L.

Dobesilate Benzarone Naftazone

Synthetic Synthetic Synthetic

Ruscus extract Other plant extracts

Synthetic products

Anthocyanins Proanthocyanidines (oligomers)

1 or 2

Reproduced from Ramelet et al.1 HR, hydroxyrutosides.

showed that there were beneﬁts for the symptoms of edema, pain, and itching. In three studies (766 patients) in which compression stockings were used as a comparator treatment, no difference was found between aescin and compression stockings. A further Cochrane review identiﬁed three studies addressing edema and varicose veins of the lower limbs in pregnancy.4 One study (69 patients) showed that rutoside treatment reduced symptoms associated with varicose veins. A clinical trial (35 patients) addressing the use of stockings in pregnancy failed to reduced ankle edema. In summary, phlebotonic drugs have a modest effect on the symptoms of chronic venous disease including edema. These become less apparent or disappear when compression is used as a comparator treatment.

VENOUS ULCERS Venous ulceration is conventionally managed by compression treatment, which may be combined with surgery to varicose veins, perforating veins and much less

frequently with deep vein reconstruction. Compression treatments have been found to lead to acceleration of healing with a greater proportion of healed ulcers. A signiﬁcant problem remains the rate of recurrence of ulcers after healing with compression. Can this be reduced? Surgical ablation of incompetent superﬁcial veins apparently does not lead to more rapid healing, but does prevent recurrence of ulceration.5 This is certainly a very valuable adjunct to compression treatment. The costs of dressing a leg ulcer in the UK National Health Service are in the range of £6000–20 000 per year. This compares with the cost of surgical management of varicose veins of around £2000. Not all patients are prepared to undergo surgical treatment, especially the elderly. However, ultrasound-guided foam sclerotherapy has been reported to be effective in the management of venous ulceration.6 These are the standard methods of management but is there any advantage of drug treatment in this group? A small number of drugs have been studied in this respect, and some are of historical interest only. The mechanisms of pathogenesis of venous ulcers have been investigated at length by several authors, including me. Although many

Venous ulcers

factors have been found to be involved in the inﬂammatory process leading to leg ulceration, it has not been possible to identify a “crucial” step which could readily be inhibited by pharmacological means. I believe that it is too simplistic to consider that such an easy solution could be found. Instead, it may be better to modify a range of processes observed in developing leg ulcers. This may lead to useful therapeutic advance.

Drugs used in the management of venous ulcers Many drugs have been used in the management of leg ulcers. They may be given systemically or applied topically. In addition, a wide range of wound dressings have become available, some of which have “active” properties that might promote wound healing. Even honey has been applied to leg ulcers in the expectation that healing will be more rapid under the inﬂuence of this natural antibacterial compound.7 A recent review assessed the published data in 42 clinical trials in which hydrocolloid, foam, alginate, and hydrogel dressings were assessed.8 The authors concluded that there was no evidence that any of these accelerated wound healing when these were applied beneath compression. A further review has investigated published data concerning wound dressings and other topical applications.9 The authors considered 68 studies for inclusion in their analysis and eliminated all but 20, excluding the remainder on the basis of poor study design. Eight studies addressed the use of wound dressings but none showed conclusive advantage of one dressing over another in accelerating wound healing. A further seven studies addressed the subject of topical growth factor application. The list of compounds applied topically included platelet lysate, keratinocyte lysate, vasoactive intestinal peptide, granulocyte colony-stimulating factor (G-CSF), and becaplemin. Of these, only G-CSF improved ulcer healing signiﬁcantly, and these data were conﬁned to one clinical trial. In ﬁve studies, human skin equivalents were investigated. These included Dermagraft (Smith & Nephew, Hull, UK), cultured keratinocytes, Apligraf (Organogenesis, Canton, MA, USA), Epidex (Modex Therapeutics, Lausanne, Switzerland), and cultured epidermal allografts. Among these, evidence of improved healing was found in only one, which used Apligraf and involved 275 patients. In summary, wound dressings, growth factors, and human skin equivalents showed limited efﬁcacy in accelerating wound healing in the trials included. I conclude that, although wound dressings of modern design may facilitate management of leg ulcers, none has the power to heal ulcers above the effects of compression bandaging applied alone. Topical growth factors have no consistent effect and, of the skinequivalent dressings, only Apligraf has been shown to have beneﬁcial effects for venous ulcers.

361

Systemic drugs for wound healing Many drugs have been used in the hope of healing leg ulcers. I have included below those for which reasonable evidence has been accumulated. ZINC AND VITAMINS

Greaves and Skillen,10 in an old but widely quoted paper, reported complete healing in 13 of 18 patients with previously intractable ulceration after a 4-month course of 220 mg zinc sulfate three times daily. This might simply have reﬂected dietary inadequacy in this group. However, a systematic review of zinc supplements considered six small trials which constituted the only available evidence.11 No beneﬁcial effect of oral zinc treatment could be found in these studies. Adequate nutrition is as essential for leg ulcer healing as it is for wound healing of other types. A group of authors in the USA found deﬁciencies of vitamins A and E, carotenes, and zinc in patients being treated for venous leg ulcers.12 They speculated that this reﬂected compromised nutritional status which might inﬂuence leg ulcer healing rates. A further study found that the dietary intake of protein, vitamin C, and zinc may be inadequate in elderly patients with leg ulcers.13 This has led to renewal of the suggestion that dietary supplements should be given to elderly patients with leg ulcers;14 however, a broader approach than single vitamin supplements was used. FIBRINOLYTIC THERAPY

The concept of an oxygen diffusion barrier causing skin hypoxia was ﬁrst proposed by Browse and Burnand15 in 1982. This theory led to attempts to reverse the damaging cutaneous effects of venous hypertension by enhancing ﬁbrinolysis. The effect of stanozolol, an anabolic steroid with proﬁbrinolytic properties, was evaluated in 14 patients with longstanding lipodermatosclerosis (LDS) without active ulceration.16 After 3 months, all showed clinical improvement both subjectively and objectively (by mapping the area of LDS). Serum parameters of ﬁbrinolytic activity improved in all cases. Fibrinolytic treatment for venous ulceration has been evaluated in one trial of 75 patients.17 Patients were allocated to receive either stanozolol or placebo for up to 420 days, with conventional compression treatment utilized in all cases. In an interim report, the authors found complete healing in 26 of 40 ulcers in the stanozolol group and in 27 of 44 in the placebo group, indicating no beneﬁt from active over placebo treatment. No further study has appeared in the 20 years since this publication. Stanozolol has been withdrawn from clinical use in the UK. In a recent study, tissue plasminogen activator has been added as a topical treatment to leg ulcers as an ointment.18 The authors assessed the presence of pericapillary ﬁbrin on

362

Drug treatment of varicose veins, venous edema, and ulcers

skin biopsies before and after the treatment but found no difference. However, despite this, three of six ulcers studied healed during the 12 weeks of the investigation. Dermatan sulfate is a glycosaminoglycan which selectively catalyzes the inactivation of thrombin by heparin cofactor II without interacting with antithrombin III. Dermatan sulfate does not interact with other coagulation factors and, unlike heparin, is able to inactivate thrombin bound to ﬁbrin or to the surface of an injured vessel. Two dermatan sulfate-containing compounds, sulodexide and, particularly, mesoglycan, have been clinically studied in a number of trials and found to be effective in the treatment of venous and arterial leg diseases. Sulodexide, a highly puriﬁed glycosaminoglycan with proﬁbrinolytic properties, has also been used to treat patients with venous leg ulcers.19 A total of 235 patients were randomized to receive sulodexide or placebo for 3 months. The authors reported improved healing in the active treatment group compared with placebo. No further detailed work on this compound has been published. DRUGS THAT MODIFY LEUKOCYTE METABOLISM

The discovery of the involvement of leukocytes in the development of venous ulceration has opened new avenues of investigation.20 A number of drugs which modify white cell activation have been evaluated in patients with venous ulceration. Pentoxifylline Pentoxifylline is indicated in the management of peripheral arterial disease but has also been used in the management of venous ulceration. Research on this drug indicates that it has a potent effect on inhibition of cytokine-mediated neutrophil activation.21 The same workers also showed it to reduce white cell adhesion to endothelium and to reduce the release of superoxide free radicals produced in the so-called respiratory burst characteristic of neutrophil degranulation. A recent review identiﬁed nine clinical trials involving 572 patients in which pentoxifylline had been used with the aim of improving venous ulcer healing.22 Eight trials compared the drug with placebo, and in ﬁve compression was applied to the affected limb. The authors reported that the relative risk (RR) of healing with pentoxifylline compared with placebo was 1.41 [95% conﬁdence interval (CI) 1.19–1.66]. Pentoxifylline plus compression is more effective than placebo plus compression (RR of healing with pentoxifylline 1.30, 95% CI 1.10–1.54). There is evidence that pentoxifylline may be useful in the management of leg ulcers, especially when combined with compression. Antibiotics Venous ulcers contain a wide range of bacteria and this has led some practitioners to use topical and systemic antibiotics in an attempt to eradicate the bacteria. This is

probably a forlorn hope, since until the ulcer heals bacteria will colonize the ulcer but are not likely the cause of the problem. There are some disadvantages to antibiotics as well. The use of topical antibiotics in leg ulcers may lead to the emergence of resistant organisms and risk sensitizing the patient to the antibiotic.23,24 Some topical antiseptics and antibiotics exhibit cellular toxicity that exceeds their bactericidal activities and have been found to impair wound epithelialization.25 A detailed review of the use of antibiotics in chronic wounds has been published and includes a systematic analysis of 25 clinical trials of randomized design. Within this collection of trials were two addressing the use of systemic antibiotics and seven assessing the use of topical antimicrobial drugs. No conclusive evidence of improved wound healing was found with either systemic or topical treatment.26 Naturally, clinical infection of an ulcer must be treated, but this is best done by local ulcer toilet, unless cellulitis or septicemia are present. In these circumstances, intravenous antibiotics are usually indicated. Prostaglandin E1 Prostaglandin E1 (PGE-1) has a number of profound effects on the microcirculation, including reduction of white cell activation, platelet aggregation inhibition, small vessel vasodilatation and reduction of vessel wall cholesterol levels.27 It has been evaluated in the treatment of various aspects of arterial disease; less work has been done on its use in venous ulceration. An early trial of the use of intravenous PGE-1 in ulcers of both arterial and venous etiology reported improvement in four out of ﬁve venous ulcers on PGE-1 as opposed to four out of seven on placebo – hardly a dramatic result.28 A further trial yielded more impressive ﬁndings.29 Forty-four patients with proven venous ulceration took part in a double-blind placebo-controlled trial. Each received an infusion of PGE-1 (or placebo) over 3 hours daily for 6 weeks, in addition to standard dressings and compression bandaging. Those on PGE-1 demonstrated a signiﬁcant improvement in such parameters as edema reduction, symptoms, and “ulcer score,” based on depth, diameter, etc. Perhaps more importantly, 8 of 20 patients on active treatment had ulcers that healed completely within the trial period, whereas only 2 of 22 controls did. Recently, a randomized, placebo-controlled, single-blind study has been reported in which 87 patients with venous leg ulcers were treated for 20 days with an infusion of PGE-1 (Prostavasin, Schwarz Pharma, Monheim, Germany) or placebo, in association with topical therapy. The healing of ulcers was followed for 120 days after the commencement of treatment. The main outcome measure was the number of healed ulcers at the end of the study period. In the active treatment group, all ulcers healed in under 100 days, whereas in the placebo group only 84% did so by the end of the 120-day observation period (P < 0.05). This study demonstrates the effectiveness of PGE-1 in reducing the healing time of venous ulcers.30

Clinical practice guidelines

Prostacyclin analogs Iloprost (Schering, Berlin, Germany), a synthetic prostacyclin analog, has been used with success in the treatment of arterial and diabetic ulcers.31 The mechanism of action of prostacyclin includes increased ﬁbrinolytic activity,32 reducing leukocyte aggregation, and adhesion to endothelium33,34 in addition to its better known effects on platelet inhibition.35 A study in which this was applied topically to venous ulcers was disappointing with no difference between active treatment group and placebo.36 Iloprost is no longer used in the management of venous leg ulcers. Diosmin–hesperidin This combination of ﬂavonoid drugs has been used to manage the symptoms of chronic venous disease including edema of the lower limbs for many years. Their use for this application has been summarized above. More recently a number of clinical trials has been completed in which one ﬂavonoid drug was used to treat patients with venous leg ulcers. Micronized puriﬁed ﬂavonoid fraction (MPFF; Daﬂon 500 mg, Servier, France), which consists of 90% diosmin and 10% ﬂavonoids expressed as hesperidin, has been shown to protect the microcirculation from damage secondary to raised ambulatory venous pressure.37 It decreases the interaction between leukocytes and endothelial cells by inhibiting expression of endothelial intercellular adhesion molecule 1 and vascular cell adhesion molecule, as well as the surface expression of some leukocyte adhesion molecules (monocyte or neutrophil CD62L, CD11B).38 There are few known sideeffects, and interactions with other drugs have not been reported.37 In a meta-analysis, clinical trials were sought in which MPFF had been used as adjunctive therapy to compression and appropriate local care.39 Outcome measures included time to ulcer healing and proportion of healed ulcers. Five prospective, randomized, controlled studies in which 723 patients with venous ulcers were treated between 1996 and 2001 were identiﬁed. Conventional treatment (compression and local care) in addition to MPFF was compared with conventional treatment plus placebo in two studies (N = 309), or with conventional treatment alone in three studies (N = 414). The primary end-point was complete ulcer healing at 6 months. The results are expressed as reduction of the relative risk (RRR) of healing with 95% CIs. Since desired treatment effect is increased ulcer healing, RRR should be positive to indicate a beneﬁt of adjunctive MPFF over conventional therapy alone. At 6 months, the chance of healing ulcer was 32% better in patients treated with adjunctive MPFF than in those managed by conventional therapy alone (RRR 32%; 95% CI 3–70%). This difference was present from month 2 (RRR 44%; 95% CI 7–94%), and was associated with a shorter time to healing (16 weeks vs 21 weeks; P = 0.0034). The beneﬁt of MPFF was found in the subgroup of ulcers

363

between 5 and 10 cm2 in area (RRR 40%; 95% CI 6–87%), as it was in patients with ulcers of 6–12 months’ duration (RRR 44%; 95% CI 6–97%). These results conﬁrm that venous ulcer healing is accelerated by MPFF treatment. MPFF might be a useful adjunct to conventional therapy in large and longstanding ulcers which might otherwise be expected to heal slowly. PLATELET INHIBITORS

Aspirin The use of aspirin has been reported in a small number of patients undergoing treatment for leg ulceration.40 This effect has never been substantiated in a clinical trial of any type and there is no evidence of efﬁcacy for this purpose. Ifetroban Effects of the oral thromboxane A2 receptor antagonist ifetroban (250 mg daily) on healing of chronic lower extremity venous stasis ulcers has been studied in a welldesigned prospective, randomized, double-blind, placebocontrolled multicentre study.41 This drug has a profound inhibitory effect on platelet activation. The results show no efﬁcacy in inﬂuencing venous ulcer healing.

SUMMARY ●

●

●

●

Varicose veins and edema are best managed by the use of compression, surgery, or ablative techniques to remove incompetent saphenous trunks, varices, and perforating veins. Some phlebotonic drugs improve the symptoms and edema associated with venous disease. These could be used in association with compression for the management of troublesome symptoms. Venous ulcers are best managed by strong compression and wound management. In patients with incompetent superﬁcial veins and perforators, these should be managed by surgery or ablation techniques. Long-standing or large venous ulcers may beneﬁt from treatment with either pentoxifylline or micronized puriﬁed ﬂavonoid fraction used in combination with compression.

CLINICAL PRACTICE GUIDELINES ●

So when is it appropriate to prescribe phlebotonic drugs in patients with varicose veins or edema? In temperate climates the use of compression stockings is generally considered to be the most appropriate conservative measure. However, in hot climates the wearing of stockings is less acceptable for patients who may ﬁnd that they cause intolerable discomfort. There may be

364

●

Drug treatment of varicose veins, venous edema, and ulcers

some rationale in prescribing phlebotonics in these circumstances. Diosmin and hesperidin may be useful in trophic disorders as well as cramps and swelling. Rutosides may beneﬁt edema. (2B) Compression treatment and surgery to treat incompetent superﬁcial varices and perforating veins are the main lines of management in patients with venous leg ulcers. Only two drugs have been shown to have any inﬂuence on venous ulcer healing in metaanalysis – pentoxifylline and micronized puriﬁed ﬂavonoid fraction (MPFF). Both should be used in combination with compression and standard wound management. Efﬁcacy is probably most apparent in

●

large (5–10 cm2) long-standing ulcers (more than 6 months). These drugs have few side-effects and could be considered when compression alone has proved to be ineffective in countries where these compounds have been licensed. (1B) PGE-1 has also been shown to have efﬁcacy in promoting venous ulcer healing, but this is conﬁned to one randomized controlled trial. In addition, this drug must be given by intravenous infusion and has some signiﬁcant side-effects. More detailed work is required before a recommendation can be made for use in venous disease. (2A)

Guidelines 4.4.0 of the American Venous Forum on drug treatment of varicose veins, venous edema and ulcers No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.4.1 We suggest phlebotonic drugs to improve symptoms and edema associated with chronic venous disease. These could be used in association with compression for the management of troublesome symptoms

2

B

4.4.2 For long-standing or large venous ulcers we recommend treatment with either pentoxifylline or micronized puriﬁed ﬂavonoid fraction used in combination with compression

1

B

4.4.3 We suggest diosmin and hesperidin in trophic disorders as well as cramps and swelling. We suggest rutosides in patients with venous edema

2

B

REFERENCES 1. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and ﬁnal resolution. Clin Hemorheol Microcirc 2005; 33: 309–19. 2. Martinez MJ, Bonﬁll X, Moreno RM, et al. Phlebotonics for venous insufﬁciency. Cochrane Database of Syst Rev 2005; Issue 3, Art. No.: CD003229. 3. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufﬁciency. Cochrane Database of Systematic Reviews 2006; Issue 1, Art. No.: CD003230. 4. Bamigboye AA, Smyth R. Interventions for varicose veins and leg oedema in pregnancy. Cochrane Database of Systematic Reviews 2007; Issue 1, Art. No.: CD001066. 5. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004; 363: 1854–9. 6. Pascarella L, Bergan JJ, Mekenas LV. Severe chronic venous

7.

8.

9.

10.

11.

12.

insufﬁciency treated by foamed sclerosant. Ann Vasc Surg 2006; 20: 83–91. Dunford CE, Hanano R. Acceptability to patients of a honey dressing for non-healing venous leg ulcers. J Wound Care 2004; 13: 193–7. Palfreyman SJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2006; Issue 3, Art. No.: CD001103. O’Donnell TF Jr, Lau J. A systematic review of randomized controlled trials of wound dressings for chronic venous ulcer. J Vasc Surg 2006; 44: 1118–25. Greaves MW, Skillen AW. Effects of long-continued ingestion of zinc sulphate in patients with venous leg ulceration. Lancet 1970; ii: 889–91. Wilkinson EAJ, Hawke C. Oral zinc for arterial and venous leg ulcers. Cochrane Database of Systematic Reviews 1998; Issue 4, Art. No.: CD001273. Rojas AI, Phillips TJ. Patients with chronic leg ulcers show diminished levels of vitamins A and E, carotenes, and zinc. Dermatol Surg 1999; 25: 601–4.

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13. Wipke-Tevis DD, Stotts NA. Nutrition, tissue oxygenation, and healing of venous leg ulcers. J Vasc Nurs 1998; 16: 48–56. 14. Wissing UE, Ek AC, Wengstrom Y, et al. Can individualised nutritional support improve healing in therapy-resistant leg ulcers? J Wound Care 2002; 11: 15–20. 15. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982; ii: 243–5. 16. Browse NL, Jarrett PEM, Morland M, Burnand K. Treatment of liposclerosis of the leg by ﬁbrinolytic enhancement: a preliminary report. BMJ 1977; ii: 434–5. 17. Layer GT, Stacey MC, Burnand KG. Stanozolol and the treatment of venous ulceration: an interim report. Phlebology 1986; 1: 197–203. 18. Zeegelaar JE, Verheijen JH, Kerckhaert JA, et al. Local treatment of venous ulcers with tissue type plasminogen activator containing ointment. Vasa 1997; 26: 81–4. 19. Coccheri S, Scondotto G, Agnelli G, et al. Venous arm of the SUAVIS (Sulodexide Arterial Venous Italian Study) randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thromb Haemost 2002; 87: 947–52. 20. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration : a new hypothesis. BMJ 1988; 296: 1726–7. 21. Sullivan GW, Carper HT, Novick WJ, Mandell GL. Inhibition of the inﬂammatory action of interleukin-1 and tumour necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immunol 1988; 56: 1722–9. 22. Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2002; Issue 1, Art. No.: CD001733. 23. Lineaweaver W, Howard R, Soucy D, et al. Topical antimicrobial toxicity. Arch Surg 1985; 120: 267–70. 24. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufﬁciency and venous leg ulceration. J Am Acad Dermatol 2001; 44: 401–21. 25. Geronemus RG, Mertz PM, Eaglstein WH. Wound healing. The effects of topical antimicrobial agents. Arch Dermatol 1979; 115: 1311–14. 26. O’Meara SM, Cullum NA, Majid M, Sheldon TA. Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 2001; 88: 4–21. 27. Sinzinger H, Virgolini I, Fitscha P. Pathomechanisms of atherosclerosis beneﬁcially affected by prostaglandin E1 (PGE1): an update. Vasa 1989; Suppl 28: 6–13. 28. Beitner H, Hamar H, Olsson AG, Thyresson N. Prostaglandin E1 treatment of leg ulcers caused by venous or arterial incompetence. Acta Derm Venereol 1980; 60: 425–30.

29. Rudofsky G. Intravenous prostaglandin E1 in the treatment of venous ulcers: a double-blind, placebo-controlled trial. Vasa 1989; Suppl 28: 39–43. 30. Milio G, Mina C, Cospite V, et al. Efﬁcacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs. J Vasc Surg 2005; 42: 304–8. 31. Muller B, Krais T, Sturzebacher S, et al. Potential therapeutic mechanisms of stable prostacyclin (PGI2) mimetics in severe peripheral vascular disease. Biomed Biochim Acta 1988; 47: S40–4. 32. Musial J, Wilczynska M, Sladek K, et al. Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease. Prostaglandins 1986; 31: 61–70. 33. Belch JJF, Saniabadi A, Dickson R, et al. Effect of iloprost (ZK 36374) on white cell behaviour. In: Gryglewski RJ, Stock G, eds. Prostacyclin and its Stable Analogue Iloprost. Berlin: Springer-Verlag, 1987: 97–102. 34. Muller B, Schmidtke M, Witt W. Adherence of leucocytes to electrically damaged venules in vivo. Eicosanoids 1988; 1: 13–17. 35. Sturzebecher CS, Losert W. Effects of iloprost on platelet activation in vitro. In: Gryglewski RJ, Stock G, eds. Prostacyclin and its Stable Analogue Iloprost. Berlin: Springer-Verlag, 1987: 39–45. 36. Werner-Schlenzka H, Kuhlmann RK. Treatment of venous leg ulcers with topical iloprost: a placebo controlled study. Vasa 1994; 23: 145–50. 37. Lyseng-Williamson KA, Perry CM. Micronised puriﬁed ﬂavonoid fraction. A review of its use in chronic venous insufﬁciency, venous ulcers and haemorrhoids. Drugs 2003; 63: 71–100. 38. Shoab SS, Porter J, Scurr JH, Coleridge Smith PD. Endothelial activation response to oral micronised ﬂavonoid therapy in patients with chronic venous disease: a prospective study. Eur J Vasc Endovasc Surg 1999; 17: 313–18. 39. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized puriﬁed ﬂavonoid fraction. Eur J Vasc Endovasc Surg 2005; 30: 198–208. 40. Layton AM, Ibbotson SH, Davies JA, Goodﬁeld MJ. Randomised trial of oral aspirin for chronic venous leg ulcers. Lancet 1994; 34: 164–5. 41. Lyon RT, Veith FJ, Bolton L, Machado F. Clinical benchmark for healing of chronic venous ulcers. Venous Ulcer Study Collaborators. Am J Surg 1998; 176: 172–5.

32 Sclerotherapy in the management of varicose veins of the extremities* J. LEONEL VILLAVICENCIO Introduction Historical review Diagnosis and examination Treatment Materials

366 366 367 371 372

INTRODUCTION Important advances have occurred in the understanding of the pathophysiology and hemodynamics of varicose veins and their management. The wings of progress have brought new treatment techniques that are less invasive and more cosmetically acceptable than the traditional extensive long and small saphenous vein stripping in which multiple incisions often left unsightly scarring. In addition, the indications for sclerotherapy have been expanded by the introduction of improved techniques utilizing different physical forms of the detergent sclerosing agents that were used for decades in the USA, Europe, and other countries. Progress in the ﬁeld of endovascular catheterization has contributed to a safe and accurate delivery of sclerosant agents in either liquid or foam states. Sclerotherapy has been considered as the treatment of choice not only for varicose veins of the lower or upper extremities but also for hemorrhoids, vascular malformations such as small hemangiomas, and varicose veins of patients with Klippel–Trenaunay syndrome after surgery has eliminated the large varicose clusters. Spider veins or telangiectasias and other types of cosmetic nuisances where surgery has nothing to offer respond quite well to sclerotherapy. The dramatic technological advances of modern imaging techniques have stimulated

Techniques of sclerotherapy Adverse events Clinical practice guidelines References

373 375 377 379

the non-surgical practitioners as well as the surgeons to extend the realm of sclerotherapy to attempt correction of venous reﬂux in areas such as the saphenofemoral and saphenopopliteal junctions. The efforts to eliminate varicose veins by open surgery or sclerotherapy have been extended to evaluate new “less traumatic venous ablation techniques” using radiofrequency (RF) and endovenous laser (EVL) obliteration. Some representative mid-term results of prospective randomized trials comparing RF and EVL with traditional open surgery are now available.1–3

HISTORICAL REVIEW History is a great teacher but we tend to forget its lessons. It is always healthy to look to the past, recognize the errors made, correct the course, and redirect our efforts. The saphenous vein has always been the target of those interested in the management of varicose veins. It was quite natural that excision of the greater saphenous vein was attempted in 1860 by Trendelenburg.4 During the ﬁrst three decades of the 1900s, different surgical procedures were introduced to excise the greater saphenous vein, including the ﬁrst intraluminal stripping reported by Keller5 in the USA in 1905. In the pre-antibiotic era, when patients were recommended bed rest for 8–10 days, sepsis

*These guidelines represent the consensus of a group of physicians with expertise in sclerotherapy. They should not be considered as the only manner to practice sclerotherapy. It is recognized that there are alternative techniques that render acceptable results. The statements and recommendations contained in these guidelines are general in nature. Every patient needs to be considered and treated on an individual basis. The final decision on the procedure of choice rests on the physician after he has analyzed the needs of the patient.

Diagnosis and examination 367

and pulmonary embolism were frequent. After many years of experience in Europe, sclerotherapy was received with great expectations and practically replaced surgery in the management of varicose veins in the USA. McPheeters6 in 1927 and Dixon7 in 1930 introduced sclerotherapy in the Mayo Clinic using a solution of quinine and urethane. Sodium morrhuate was introduced in 1931 and it was extensively utilized in the USA during the next two decades. Failure of the sclerosing treatment of varicose veins as a single form of treatment was recognized by McPheeters6 and De Takats.8 One of the largest series emphasizing the poor long-term results obtained with the sclerosing treatment was published by Smith.9 The recognition of the importance of early ambulation in the prevention of deep venous thrombosis and pulmonary embolism and the extensive use of excellent antibiotics in the prevention and management of surgical sepsis gave a second chance to surgery. Myers10 in 1957 reported very satisfactory intermediate and late term results by an extensive operation for varicose veins utilizing new instrumentation of his own design. In a controlled, randomized study Einarsson et al.11 conﬁrmed the advantage of good surgery over sclerotherapy alone. The introduction of new techniques and the revival and improvement of the Orbach12 technique of “intravenous air block” stimulated the non-surgical practitioners as well as the surgical community to extend the realm of sclerotherapy to include the management of venous reﬂux in areas such as the saphenofemoral and saphenopopliteal junctions. The introduction of catheter delivery of sclerosing agents together with the safety of the duplexcontrolled injection are responsible for a true renaissance of sclerotherapy. These techniques opened new avenues of investigation and are currently being evaluated. Careful assessment and large randomized series of patients comparing liquid with foam sclerotherapy, with and without saphenous ablation, will provide new insight into the true value of sclerotherapy as a method of treatment for varicose veins. The guidelines at the end of this chapter for the use of sclerotherapy were initially developed by the Ad Hoc Committee on Sclerotherapy of the American Venous Forum. The recommendations in this chapter are the result of an updated review of the consensus. The physician considering sclerotherapy should be familiar with the following aspects of the procedure: indications, contraindications, and diagnostic methods to identify the etiology of the varices, their distribution and points of reﬂux. The physician should also have a thorough knowledge of the available sclerosing agents and their mode of action, materials, techniques, compression methods, complications, and long-term results. Every patient considered for sclerotherapy, either liquid or foam, must be informed of the nature of treatment that he or she will receive. Patients should also be told about the results that might be expected and the adverse events that may reasonably be anticipated from the treatment such as chemical superﬁcial thrombophlebitis,

pigmentation, skin necrosis, etc. All patients must sign an informed consent form. Preinjection photography is strongly recommended after the patient has consented to it. Often, patients forget how bad they were before treatment and there is no better document than a good photograph to clear any misunderstandings.

DIAGNOSIS AND EXAMINATION Clinical history A complete clinical history and physical examination should be performed during the initial visit. The magnitude and severity of the problem should be well deﬁned. In order to facilitate a universal understanding of the severity of venous disease, varicose veins should be classiﬁed at this time following the CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) classiﬁcation and venous severities scoring established by members of the American Venous Forum.13–15 The etiology of the varicose veins should be determined. Each one of the following four groups of varicosities has a different etiology, pathophysiology, and treatment. ●

● ●

●

Primary or familial. Telangiectasias are considered in this group. Secondary or post-thrombotic. Varicose veins associated with congenital malformations of venous predominance. Post-traumatic or secondary to acquired arteriovenous ﬁstula.

In most patients, the diagnosis can be made during the initial interview. Special emphasis should be placed on obtaining a history of diseases that may modify the therapeutic approach such as asthma, bleeding diathesis, history of deep venous thrombosis, and hypercoagulable states. The intake of medications that may interfere with the clotting mechanism, such as aspirin, anticoagulants and certain non-steroidal anti-inﬂammatory agents, should be investigated. The use of oral contraceptives, estrogens, and other hormonal agents whose role in the coagulation mechanisms is well known should also be investigated to prevent undesirable side-effects.

Physical examination The patient should be examined in the upright position under good illumination. Tangential lighting is excellent for demonstration of the bulging and size of varicose veins. The distribution of the varices should be carefully noticed. Primary varicose veins appear early in life and are usually present in one or more members of the family. They are

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particularly prone to appear after the burden of one or more full-term pregnancies. “Venous spiders” (telangiectasias), venous lakes, and other skin blemishes appear especially in women on the medial, posterior, and lateral aspects of the thigh and less often in the lower leg and calf. These blemishes have a striking familial tendency (Fig. 32.1). Varicose veins may appear in the extremities as sequelae of a post-thrombotic episode. In these cases, edema, pigmentation, eczema, induration, and venous ulcers may be present (Fig. 32.2). It is recognized that primary deep and superﬁcial venous insufﬁciency may produce similar manifestations. Patients with congenital malformations of venous predominance may have

varicose veins, “port-wine stains,” hypertrophy of soft tissues, and bone overgrowth of the extremity. In these patients, the presence of congenital arteriovenous ﬁstulae should be ruled out. Patients with predominantly venous malformations may beneﬁt from sclerotherapy (Fig. 32.3). This form of therapy is usually advised after surgical elimination of the large varicosities. The presence of active arteriovenous ﬁstulae is a contraindication for sclerotherapy. Varicose veins may also appear as a secondary manifestation of a traumatic arteriovenous ﬁstula. Often, this is the ﬁrst manifestation of an injury that might have occurred many years before. Hemodynamic effects on the venous system will depend on the location, size, and duration of the ﬁstula. Acquired arteriovenous ﬁstulae are treated surgically or by endovascular techniques. Sclerotherapy may be used only after the arteriovenous shunt has been corrected.

Figure 32.1 Extensive “spider veins” and venous lakes are cosmetic nuisances in which sclerotherapy has speciﬁc indications. This type of venous disease has a striking familial tendency.

Figure 32.2 Post-thrombotic or secondary varicose veins. They are sequelae of a deep venous thrombosis that occurred 12 years before. Its distribution in the medial aspect of the retromalleolar area of this patient is clearly visible. Sclerotherapy and compression are valuable adjuncts in the management of these challenging problems.

Figure 32.3 A port-wine stain, varicose veins of unusual distribution, limb size discrepancies and spongy venous malformations are distinctive features of the Klippel–Trenaunay syndrome. Sclerotherapy followed by compression are essential steps in these patients after surgery has eliminated the large venous clusters.

Diagnosis and examination 369

The venous tributaries of the internal iliac vein may be a pathway for venous hypertension originating in a large incompetent gonadal vein which dumps its large ﬂow directly into the pelvic veins and from there, via the internal pudendal, obturator and gluteal veins, varicose veins spread to the vulva and lower extremities. The distribution of the intrapelvic source of venous leakage is typically over the upper and medial aspects of the thigh and perineum. Often, there are large vulval varices which may need endovenous embolization of the intrapelvic source of venous reﬂux and, later on, sclerotherapy to complete the treatment.

Laboratory examination The clinical history and the physical examination need to be supplemented by laboratory data on an individual basis. In patients with a history of hypercoagulability or other manifestations of systemic disease, appropriate blood tests should be ordered. These include but are not limited to: protein S, protein C, antithrombin III, factor V Leiden, and lupus anticoagulant. Consultation with hematology is recommended before embarking on sclerotherapy treatment.

Non-invasive vascular examination In the new era of sclerotherapy, a large number of tests that were considered essential in the past have now been replaced by the judicial and competent use of a duplex ultrasound examination. At the bedside, Doppler ultrasound continues to be a valuable asset to evaluate reﬂux at the saphenofemoral and saphenopopliteal junctions in the upright patient (Fig. 32.4). These non-invasive vascular examinations should be utilized to evaluate the hemodynamics of the superﬁcial and deep venous systems, as well as detection of incompetent perforating veins and diagnosis of a hidden calf venous thrombosis. These tests are rarely indicated in cases of telangiectasia. In general, the routine use of these expensive vascular examinations in patients undergoing sclerotherapy should be discouraged. Echo-sclerotherapy (the use of ultrasound-guided injections) will be discussed later. Invasive studies such as ascending or descending phlebography are indicated in complex cases of venous disease such as congenital malformations, pelvic varices, and recurrent varicose veins to guide the physician in selecting a therapeutic option. In patients due to undergo deep valve reconstruction or transplantation, phlebography is essential.

Indications for sclerotherapy Surgery for varicose veins as practiced during the last 100 years has been largely replaced by modern techniques such

Figure 32.4 The value of Doppler examination on the upright patient is demonstrated in this case. An 8 MHz continuous-wave Doppler probe documents the connection between a large perforating vein on the posterior aspect, distal third of the thigh and grossly dilated clusters of varicose veins extending to the popliteal area and posterior aspect of the calf. The perforating vein was the only venous anomaly in this patient, who otherwise had competent saphenous systems.

as laser or radiofrequency saphenous ablation, which are discussed in Chapters 36, 37. Even though claims have been made that, by eliminating the incompetent greater saphenous vein, a large number of its varicose tributaries will decrease in size, we strongly believe that a good supplementary sclerotherapy treatment beginning on the second or third month after performing any of the abovementioned ablation techniques should be considered. Sclerotherapy is an excellent method of treatment, but has very deﬁnite indications. The judicious combination of surgery, any of the ablation procedures already mentioned, and sclerotherapy constitute the best management for most types of varicose veins. The following are the indications for sclerotherapy.

370

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Sclerotherapy in the management of varicose veins of the extremities

Superﬁcial venules, “venous spiders” (veins under 1 mm of internal diameter), venous lakes, and other venous blemishes. The treatment of these superﬁcial varicosities is mainly cosmetic even though some of them may be symptomatic. Varicosities 1–3 mm in diameter in the absence of detectable valvular reﬂux as evidenced by duplex examination. Postoperative residual veins are those under 3 mm in diameter that the surgeon chose not to excise in order to limit the number of incisions. They may be treated by sclerotherapy usually after the second postoperative month once the superﬁcial ecchymoses have disappeared. Varicosities 3–4 mm in diameter observed during the postoperative follow-up. These veins should be treated by sclerotherapy when they are not secondary to a missed competent perforator. Residual and/or recurrent incompetent perforators 4 mm or larger should be surgically divided under local anesthesia, although sometimes they can also be sclerosed with varying degrees of success or treated using RF heat delivered through small catheters under duplex control.16,17 Once the reﬂux is eliminated, the remaining varicosities may be treated by sclerotherapy. Small congenital vascular malformations of venous predominance such as localized hemangiomas. These may be successfully eliminated by sclerotherapy. In extensive venous malformations in which surgery is not indicated, sclerotherapy may offer palliative relief such as in the case of certain variants of the Klippel– Trenaunay syndrome, when there is hypoplasia or aplasia of the deep venous system. Bleeding varicosities (varicorrhage) can be controlled by the injection of a high-concentration sclerosing agent. The agent should be injected following the empty vein technique. Adequate compression is used for 1 week or less (30–40 mmHg). This treatment produces immediate thrombosis of the vein and temporarily controls the problem while deﬁnitive treatment is considered. Sclerotherapy of incompetent perforating veins requires expertise. According to most reports, it is accompanied by a high incidence of recurrence, and may lead to deep venous thrombosis. Injection of “duplex-guided” (echo-sclerotherapy) sclerosing agents at the saphenofemoral or saphenopopliteal junctions is not recommended. In most published series, the recurrence rate is high and the risks involved are real and should not be considered lightly.18 Incompetent large perforating veins (> 4 mm), properly identiﬁed, are best treated surgically. Efforts have been made to treat these large incompetent perforating veins using a small RF probe under duplex control. The results of this new technique are still under evaluation.16,17 For large varices surrounding a leg ulcer, sclerotherapy enhances ulcer healing by eliminating temporarily the

Figure 32.5 Elimination by sclerotherapy of the large veins surrounding a venous leg ulcer enhances healing by decreasing the venous hypertension in the area. This is a temporary measure while a focused, hemodynamic treatment is planned.

venous hypertension present around the ulcer area (Fig. 32.5).

Contraindications for sclerotherapy The list of contraindications for sclerotherapy varies in different countries and in different medical specialties. However, the following conditions are strong contraindications for sclerotherapy. ● Pregnancy. Pregnant women should preferably not be injected. However, in cases of threatening rupture of vulval varices or large varicose veins in the neighborhood of a leg ulcer, a localized injection can be performed in a pregnant woman to temporarily solve an important clinical problem. ● Elderly and sedentary patients. Sclerotherapy in the elderly (> 75 years) should be individualized. There are some elderly persons with normal skin and in good physical condition who may be submitted to sclerotherapy without problems. On the other hand, there are elderly and debilitated patients who are not good candidates for sclerotherapy because of their lack of mobility and increased risk for deep venous thrombosis. ● Generalized, severe systemic disease (diabetes, cardiac, renal, hepatic, pulmonary, collagen diseases and malignancies). ● Advanced rheumatic disease, osteoarthritis or any disease of the musculoskeletal system that interferes with the patient’s mobility. ● Arterial insufﬁciency of the lower extremities, as evidenced by intermittent claudication, coldness, skin atrophy and weak or absent pulses, is a contraindication. The ankle brachial index should preferably

Treatment 371

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be above 0.8. Patients with readings below this determination preferably should not be injected. Patients with history of severe allergic disease or bronchial asthma should be carefully evaluated. Even with the newer sclerotherapy agents, serious anaphylactic reactions have been reported on rare occasions. In cases of history of severe allergic disease, the safest sclerosing agents are 65% dextrose or hypertonic saline 11.7–23.4%. Febrile illnesses as manifested by fever (38°C or higher) with signs and symptoms of acute systemic disease. Acute superﬁcial thrombophlebitis or deep vein thrombosis. Obesity. Mobility is restricted in obese individuals with body mass index > 26. In addition, external compression is difﬁcult to apply. Treatment under these conditions should be individualized and the risk– beneﬁt of the procedure should be carefully considered and discussed with the patient. We prefer to motivate the patient to lose weight in order to have the treatment. Varicose veins in communication with a source of venous reﬂux, demonstrated by duplex ultrasound, have an unacceptably high incidence of recurrences. Patients on anticoagulants. Because of the risk of extensive ecchymosis secondary to the venipuncture, patients taking anticoagulants, aspirin, or antiinﬂammatory drugs should stop treatment one week before the injection if this treatment is necessary.

TREATMENT General considerations Patients with chronic venous insufﬁciency will beneﬁt following these general measures: ●

Elevation of the extremities. If there are no contraindications for elevation of the extremity (hiatal hernia, dyspnea), the patient should be advised to sleep with the foot of the bed elevated 10–15 cm, placing wooden blocks between the ﬂoor and the foot of the bed.

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External compression. This may be in the form of elastic bandages, elastic stockings, or non-elastic compression systems. It is recognized that compression is the mainstay form of treatment for venous disease. Hygiene of the extremity. Thorough cleansing and lubrication of the extremity should be recommended to every patient.

The sclerosing agents All currently employed sclerosing agents produce similar histological effects. The endothelial cells swell and become disrupted immediately after the injection. The acute inﬂammatory reaction forms a red thrombus. Depending on the agent concentration, the reaction may range from a complete lack of effect to a strong phlebitic and periphlebitic reaction. According to their mode of action, sclerosing agents may be classiﬁed into osmotic, detergent, chemical, and corrosive.19 Examples of osmotic agents are hypertonic sodium chloride 23.4%, glucose 65%, and sodium salicylate. The detergent agents are sodium tetradecylsulfate (Sotradecol; Bioniche Pharma, Belleville, ON, Canada), polidocanol (Aethoxysklerol; Globopharm, Kusnacht. Switzerland), sodium morrhuate, and ethanolamine. Corrosive agents are sodium and potassium iodide with the addition of benzyl alcohol and chromated glycerin (Scleremo; Laboratoires Therica, Louvier, France). Among the chemical agents, the representative is ethanol, a powerful, effective but dangerous agent that should be used only by experienced physicians. It is used mainly in the management of congenital vascular malformations.

Selection of the appropriate sclerosing agent (Table 32.1) Each sclerotherapy agent has a unique safety and efﬁcacy proﬁle. The agent, concentration, and quantity of the solution injected will be determined by the type and size as

Table 32.1 Guidelines for surgery and sclerotherapy Vein size

Telangiectasias (under 1 mm) Veins 1–3 mm Veins 3–6 mm Veins > 6 mm Saphenofemoral and saphenopopliteal Venous insufﬁciency

Hypertonic saline

11.7–23.4%* + lidocaine 15–23.4% + lidocaine – Foam sclerotherapy/vein hook excision Foam sclerotherapy/laser or radiofrequency Saphenous ablation

*Lower concentrations are used for smaller caliber veins.

Concentration of sclerosant Sodium Polidocanol tetradecylsulfate (Aethoxysklerol) (Sotradecol) 0.124–0.25% 0.5–0.75% 1–3%*

0.5% 0.75–1% 2–3%*

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well as the site of the varicose veins to be injected. The Food and Drug Administration (FDA) has approved sodium tetradecylsulfate, sodium morrhuate, and ethanolamine oleate. A phase 3 multicenter trial of polidocanol has been completed and the approval of this sclerosing agent is pending. It must be mentioned that polidocanol is widely used in other parts of the world and can be used as a pharmacy preparation in each state for a particular patient. Hypertonic saline, even though it is widely used either alone or with lidocaine in the treatment of telangiectasias and other smaller venous blemishes, is not an approved FDA sclerosing agent.20

Concentration of sclerosing agent for different vein sizes The success of sclerotherapy depends fundamentally on the application of the correct concentration of the agent for the vein size. Veins of small caliber need to be treated with lower concentrations of sclerosant than veins of large caliber (3 mm or larger). The appropriate concentrations are as follows. TELANGIECTASIAS (VENOUS SPIDERS)

Veins measuring 1 mm or less in diameter are best treated with a concentration of 0.125–0.250% sodium tetradecylsulfate or 0.50% polidocanol. Hypertonic saline at a strength of 11.7–23.4% mixed with a small amount of lidocaine to decrease the burning sensation has been extensively used in the management of small venous blemishes and telangiectasias (Fig. 32.1). It should be noted that some telangiectasias appear to be connected to larger feeding veins. The presence of these communications makes it necessary to treat the larger veins ﬁrst, as recommended by the French School of Sclerotherapy. Polidocanol 0.5% may, on occasion, be injected paravascularly without producing necrosis. VEINS MEASURING 1–3 MM IN DIAMETER

In these veins, concentrations of 23.4% hypertonic saline, 0.50–0.75% sodium tetradecylsulfate or 0.75–1% polidocanol are usually successful. The lower concentration (0.50%) should be used for the smaller vein size. As the vein approaches 3 mm in diameter, the higher concentration of 0.75% should be utilized. VARICOSE VEINS 3–6 MM IN DIAMETER

These veins are best treated with concentrations of 1–3% sodium tetradecylsulfate or 2–3% polidocanol. These concentrations are also useful in some small congenital vascular lesions of venous predominance with vessels ranging from 3 to 4 mm in diameter. Again, the lower concentration should be used for the veins of small size.

LARGE VEINS SURROUNDING VEIN ULCERS OF THE LEGS

Sclerosis of these veins with 3% sodium tetradecylsulfate or 3–4% polidocanol is successful in inducing thrombosis of the varices and is particularly useful to control an episode of varicorrhage. This method reduces perivenous hypertension and enhances healing of the ulcer while deﬁnitive measures for its treatment are being considered (Fig. 32.5). VARICOSITIES ASSOCIATED WITH CONGENITAL VASCULAR ANOMALIES

Small hemangiomas or varicosities accompanying malformations such as the Klippel–Trenaunay syndrome may be treated with high concentrations of sclerotherapy agents such as 3% sodium tetradecylsulfate or 4% polidocanol. Sclerotherapy in these cases is performed either to supplement surgery or as a sole form of treatment when surgery cannot be performed and the patient needs some form of palliation (Fig. 32.6).

Foam sclerotherapy Sclerotherapy agents, particularly the detergent sclerosants, have recently been increasingly utilized in the form of foam. Even though this physical form of the sclerosant agents has been known as the air block technique since 1944, it is not until now that foam sclerotherapy has been reintroduced.21,22 The administration of detergent sclerosing agents as microfoam into dilated varicose veins using a speciﬁc type of microbubbles modiﬁes the current conditions for sclerotherapy because the echogenicity of the microbubbles renders them visible using ultrasound color ﬂow. In addition, the amount of active agent is greatly reduced and, therefore, its toxicity is diminished. The microfoam is injected and its course followed by echo-duplex. The volume injected varies between 20 and 80 mL of sodium tetradecylsulfate or polidocanol. The real amount of the active agent delivered is smaller, since each milliliter of liquid sclerosant produces 4–8 mL of foam depending on the method used to create the foam. Cabrera and others reported impressive results in the management of congenital vascular malformations using microfoam sclerosants under duplex control.23,24

MATERIALS To perform sclerotherapy correctly, the following materials are necessary: ● ●

Disposable 1–3 mL syringes (non-Luer lock). If foam sclerotherapy is going to be used, add a threeway stopcock connected to two 5 mL plastic syringes.

Techniques of sclerotherapy 373

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An emergency kit should be available in every room where sclerotherapy is performed. It should contain epinephrine solution 1:1000, injectable corticoids (Solu-Cortef, Solu-Medrol; Pharmacia, Sandwich, UK), antihistamines, an Alupent (Boehringer Ingelheim, Ingelheim, Germany), inhaler, and a tank of oxygen. A photographic camera with synchronized ﬂash. A photo should be taken before and at least 16 weeks after the treatment. Patients often forget the pretreatment appearance. The photograph may clear any misunderstandings and may be a very valuable document in case of legal procedures.

TECHNIQUES OF SCLEROTHERAPY General principles Successful sclerotherapy is based on the elimination of the reﬂux points. Often, this is best accomplished surgically. Once the reﬂux points have been controlled, the treatment should proceed as follows. ●

●

Figure 32.6 Circumscribed venous dilatations (phlebangiomas) present in patients with congenital vascular malformations of venous predominance such as illustrated here can be successfully treated by serial treatments of sclerotherapy once the large veins have been surgically eliminated in patients with a patent deep venous system (Fig. 32.3). Post-sclerotherapy compression for 1–2 weeks decreases venous hypertension and brings relief to these patients.

●

● ●

●

● ● ● ●

●

Fine hypodermic needles 1.25 cm in length, short bevel, 27, 30, or 33 gauge. Skin antiseptic agent. Sterile gauze (10 × 10 cm) and other items for local compression, such as dental rolls, foam rubber cushions, felt pad. Sclerosing agent. The syringes should be properly labeled with the concentration and nature of the material utilized. A clear light source. Magnifying loops (magniﬁcation 2–3×). Caliper for vessel diameter measurement. External compression material, which may be in the form of gradient elastic stockings (20–30 mm pressure), elastic bandages, or short-stretch material. No. 65 Beaver surgical blades with handle (for microthrombectomy).

Large varices should be treated ﬁrst and the small ones last. Treatment should proceed from the most proximal varices to the most distal ones.

The small-caliber veins should always be injected with the lowest concentration of the sclerosing agent. Large veins are best treated with higher concentrations. The use of sclerosing solutions that are too strong for the size of the vein is still one of the most common errors and a potential source of skin necrosis.

Techniques for sclerotherapy of telangiectasias (spider veins) Good lighting and magniﬁcation (2–3×) are essential. Patients should be injected in the recumbent position beginning with injections in the regions that the patient considers the “worst area.” The technique of the “air block” is useful in small veins and telangiectasias (Fig. 32.7). The tiny air bubbles will produce immediate blanching of the vein when the needle is correctly placed. The technique of air block may be abandoned when enough experience has been acquired. Small volumes of the agent minimize discomfort for the patient and prevent complications. Each injection should deliver 0.25– 0.50 mL. Immediately after the injection, the veins appear reddish and swollen as a consequence of local inﬂammation. A total volume of sclerosing agent of 2–4 mL may be injected during the ﬁrst session distributed among different areas. The total volume of hypertonic saline may be up to 10 mL. The injected area is compressed with a thick piece of gauze, foam rubber cushions, or dental rolls.

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of gauze or a foam rubber cushion. Compression (20– 30 mmHg pressure) should be applied at least for 1 week and should not be removed during this period.

Post-sclerotherapy compression

Figure 32.7 The “air-block” technique for sclerotherapy of telangiectasias is illustrated here. A small amount of air mixed with the sclerosant agent produces tiny bubbles which can be readily seen during the slow injection of the agent and documents the intravenous position of the needle. The arrows point to slightly larger veins where treatment should be initiated. These larger veins connect with a rich network of telangiectasias and should be injected ﬁrst.

Firm external compression is applied over the entire leg, care being taken to protect the ﬂexion areas of the ankle and behind the knee using folded tissues or soft gauze. Thigh-high elastic stockings are more comfortable than elastic bandages, which tend to dislodge with patient activity. The compression is kept in place for a minimum of 3 days. One week later the leg is examined and any thrombus is evacuated with a no. 65 Beaver blade. In small veins, a no. 22 needle is effective in removal of the intravascular thrombus. Microthrombectomy will be described later. External compression is applied again for 3 days and the extremity is reexamined 1 week later. Patients are instructed to ambulate as much as possible and avoid prolonged standing or sitting positions.

Injection of veins 3–6 mm in diameter The veins should be examined with the patient in the upright position. Injection is performed in the recumbent position. A tilting table is ideal for sclerotherapy. For larger veins, a 0.6 cm long 26 or 27 gauge needle is best. In this technique, the vein is punctured, the tilted table elevated, and the injection performed into an “empty vein.” Aspiration of blood conﬁrms the intravascular position of the needle. The volume injected depends on the caliber of the vessel. An amount of 0.50 mL is usually sufﬁcient per vein site. Several sites along the course of the same vein may need to be injected. The total volume injected in different sites will depend on the sclerosing agent utilized and the manufacturer’s speciﬁcations but should not exceed 6–8 mL. After the injection has been completed, pressure is applied over the injected vein with a thick piece

External compression may be applied by several methods including the use of elastic bandages, local padding, and elastic stockings. Graduated compression is highly recommended, applying high pressures at the ankle and lower at the knee. Compression applied by bandages can be of the elastic or non-elastic type. For sclerotherapy, the most commonly used bandages are elastic. The patient must be instructed to apply the bandage correctly and to identify any source of problems secondary to the improper application of the bandage. The correct application of an elastic bandage is an art and must be taught to the health professional. Additional compression may be applied in special areas by using foam rubber cushions or folded gauze. The aim is to produce apposition of the inﬂamed vein walls and avoid thrombus formation.

Compression stockings Graduated compression stockings are available in belowthe-knee, above-the-knee, mid-thigh, thigh-high, and other styles. The type of stocking to be recommended will be determined by the anatomy of the extremity, as well as by the type of varicosity injected. Compression stockings are available as class I (10–20 mmHg), class II (20– 30 mmHg), class III (30–40 mmHg) and class IV (40– 50 mmHg). The stockings should be worn during the entire period of treatment. Other forms of compression such as non-elastic garments (CircAid, San Diego, CA, USA) are indicated in patients with leg ulcers or when an important lymphatic component is recognized. Pressures of 40–50 mmHg in the ambulatory patient are well tolerated in these cases.

Post-sclerotherapy microthrombectomy Following the injection of a sclerosing agent into veins of any size, it is common that, despite adequate compression, a thrombus forms within the injected vein. When left in situ, the thrombus organizes and the blood turns into hemosiderin, transforming the blue vein into a brownish cord. This is an adverse event called pigmentation. It occurs in approximately 20% of the cases and usually fades away spontaneously in about 80% of patients within 2 years. The thrombus, or intravascular hematoma as it is also known, may be easily evacuated during the ﬁrst 2–3 weeks after the injection, thus diminishing the amount of trapped blood and consequently the amount of

Adverse events 375

hemosiderin.25 It has been the experience of many investigators that the early evacuation of the thrombus leads to decreased incidence and severity of the pigmentation. The ideal time to evacuate the thrombus is during the ﬁrst 2–3 weeks when the material has not become organized. Although several authors have written about the value of thrombectomy to prevent pigmentation, there has been no documentation of their observations.26–28 There is one randomized prospective study documenting the beneﬁts of microthrombectomy when performed within the time described.29

thrombectomy procedures and aseptic technique must be followed. At the end of the procedure, compression is applied with a folded sterile 10 × 10 cm gauze pad. A Kerlix gauze bandage secures the compression pads in place. External compression is applied by an elastic stocking or elastic bandage. Compression is utilized for only 24 hours in small veins and a minimum of 3 days in larger veins.30 Photographs of the treated area should be obtained before and 12–16 weeks after the procedure.

ADVERSE EVENTS Microthrombectomy technique Thrombectomy of veins 1 mm of more can be performed either with a tip of a no. 65 Beaver blade or a microsurgical knife. A 22 gauge needle may also be used. The Beaver scalpel is an extremely sharp instrument superior to the no. 11 blade. After skin asepsis, a quick needle puncture or mini-stab incision (1.5 mm) is performed. Anesthesia is not necessary since the procedure is quick and the blade is sharp and relatively painless. A good rule of thumb is to make one puncture or mini-stab incision every 3 mm along the entire length of the thrombosed vein (Fig. 32.8). When the incision has been made, gentle extrusion of the thrombus can be performed between the tips of two cotton swabs (Q-tips). In veins larger than 1 mm, microthrombectomy should be performed through 2 mm mini-stab incisions placed 3–4 mm apart along the axis of the vein. The incision should be made with a no. 65 Beaver blade. Satisfactory thrombus extrusion cannot be obtained through needle punctures. In larger veins (3–6 mm in diameter), gentle extrusion of the thrombus is performed between the tips of the gloved ﬁngers. Gloves should be utilized in all

The adverse events may be immediate or delayed. Immediate adverse events in turn can be local or systemic. Immediate local adverse events are pain, swelling, redness, and allergy limited to the injected area. This is usually due to the chemical inﬂammation induced by the sclerosing agent. These symptoms gradually disappear and are greatly relieved by compression.

Immediate systemic adverse events Visual manifestations such as bright lights, migraine headaches, dizziness, and hypertension are rare manifestations that the physician should be aware of if the patient experiences them. They usually occur after injection of relatively large volumes of sclerosant. Taste perversion in the form of metallic taste has also been reported in some patients. Shock and anaphylactic reactions have been greatly reduced with the use of modern and more puriﬁed sclerotherapy agents. However, any physician performing sclerotherapy must be prepared to manage a major anaphylactic reaction. A kit containing

Figure 32.8 A thrombus forms quite frequently after the injection of a sclerosing agent in any size vein. The “trapped blood” turns into hemosiderin, which may transform a blue vein into an unsightly brownish cord. Thrombectomy using a microsurgical blade and “Q” tips extrudes the intravenous thrombus and greatly diminishes the possibility of pigmentation.

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Sclerotherapy in the management of varicose veins of the extremities

oxygen, epinephrine, and parenteral (intravenous) steroids should be available at all times. Another immediate adverse event is intra-arterial injection. INTRA-ARTERIAL INJECTION

This complication is serious and often leads to tissue necrosis. There are certain dangerous areas that must be avoided. The posterior tibial artery, because of its superﬁcial position at the ankle, is highly susceptible to this complication. The saphenofemoral and saphenopopliteal junctions are high-risk areas and should always be approached with care and through duplex-controlled retrograde catheterization. Direct puncture should always be avoided in these areas since the venous spasm subsequent to the puncture may dislodge the needle.

Delayed local adverse events These are pigmentation (Fig. 32.9), matting, ecchymosis, superﬁcial thrombophlebitis, and skin necrosis (Fig. 32.10). Hyperpigmentation has been described in the section on microthrombectomy. Matting is the development of a reddish area of very ﬁne vessels that appear in the surroundings of the injected vein. It occurs in 10–30% of all patients treated for telangiectasias and in about 15% of all patients treated for larger vessels (Fig. 32.11). Matting often resolves spontaneously within a year. Sometimes the problem may be permanent. Hormone therapy and obesity contribute to a higher incidence of matting. Laser treatment seems to be beneﬁcial in these cases.31,32 Ecchymosis occurs in about 20% of the patients, especially in older individuals with fragile skin. It usually

Figure 32.9 A common post-sclerotherapy adverse event is pigmentation of the injected veins. In 80% of the cases it fades spontaneously within 1–2 years. In other cases, it may be permanent.

Figure 32.10 An adverse event that occurs following extravascular injection of a sclerosing agent is skin necrosis. It may be the result of injecting into “red telangiectasias” that in reality are small arterioles. Most often it occurs after injecting a higher concentration of sclerosant than required by the vein size. Concentration of the sclerosing agent should always be in direct relation to the caliber of the injected vein.

Clinical practice guidelines

377

Compression after sclerotherapy Although there are physicians who do not use compression after a session of sclerotherapy, there are reasons to suggest that compression is beneﬁcial even in vessels of a small diameter.30 ●

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●

Figure 32.11 A rare adverse event of sclerotherapy is the presence of a ﬁne, reddish network of extremely small veins in an area of treated varicosities. It is called matting and may occur after treating telangiectasias or larger veins as in the illustrated case.

fades after the second or third week and is due to blood extravasation at the site of the venipuncture. Superﬁcial venous thrombophlebitis is a delayed local adverse event which occurs after the injection of a sclerosing agent. The injection produces acute chemical inﬂammation of the vein. Often, a thrombus is formed at the injected site and may involve veins located several centimeters away from the injection site. To prevent or decrease its occurrence, the amount of substance injected should be small (usually 0.5 mL or less) and compression should be applied on the injected vein immediately after the injection. When a thrombus is formed, microthrombectomy performed 2–3 weeks after injection is usually able to evacuate the thrombus and prevent hyperpigmentation.

●

In summary, excellent results can be obtained when the principles and guidelines of sclerotherapy are followed. Complete disappearance of varicosities may be observed as soon as a month after a single treatment. Most often, several sessions are necessary to eliminate the unsightly venules and telangiectasias (Fig. 32.12).

CLINICAL PRACTICE GUIDELINES ●

SKIN NECROSIS

Skin necrosis is usually the result of a too high concentration of a sclerosing agent for the size of the selected vein, extravasation of the chemical, or injection into a skin arteriole (red spider veins). It is usually limited to small areas and heals uneventfully following routine wound care.

●

●

THROMBOEMBOLISM

A serious delayed systemic adverse event is thromboembolism. Deep venous thrombosis is rare. However, it has been reported by several authors and is associated with injections into large segments of varicose veins using highconcentration agents in veins 8 mm or more. Difﬁculty in mobilization of the patient, prolonged bed rest, or sitting for prolonged periods of time contribute to increase the incidence of this complication. If unusual swelling or pain develops after the injection, the deep system should be thoroughly examined by duplex ultrasound scanning as soon as possible.

A more effective ﬁbrosis of the vessel can be obtained when there is direct apposition of the vessel walls. Compression will decrease the extent of thrombus formation in the injected vessel. When the thrombus is minimized there is a lesser degree of pigmentation. Good compression will improve the efﬁciency of the calf muscle and will prevent the extension of the thrombus into the deep system. Compression decreases the amount of discomfort secondary to the injection. The duration of compression for veins other than telangiectasias must be for a minimum of 1 week. In most European centers that follow the schools of Sigg and Fegan, compression is applied for 3 weeks.

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Sclerotherapy, either liquid or foam, is a well-accepted therapeutic method for all sizes of varicose veins. Telangiectasias are particularly suited for this form of treatment (27 [1B], 31 [1B]). As a single form of treatment for varicose veins, sclerotherapy has a high incidence of recurrences. The best results are obtained by combining it with either conventional surgery or endovenous saphenous ablation (11 [1A], 8 [1C]). The CEAP classiﬁcation and venous severity scoring have contributed to the international standardization of venous disease reports and treatment results (14 [1A], 15 [1A]). The physical form of the detergent sclerosants as microfoam has contributed to a renaissance of sclerotherapy as a form of treatment for varicose veins (21 [1B], 23 [1B). After sclerotherapy microthrombectomy in the ﬁrst 2–3 weeks signiﬁcantly reduces hyperpigmentation (29 [1A], 26 [2C]). Sclerotherapy has important applications in the management of vascular malformations (20 [1B], 23 [1B]).

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(a)

(b)

Figure 32.12 (a) Typical cluster of venous lakes, telangiectasias and small venules that are a nightmare to many female patients. Surgery is useless in these cases. (b) After ﬁve sessions and 11 months excellent results can be observed. (Courtesy of Dr. D. Duffy.)

Guidelines 4.5.0 of the American Venous Forum on sclerotherapy in the management of varicose veins of the extremities No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.5.1 Sclerotherapy, either liquid or foam, is a well-accepted therapeutic method for all sizes of varicose veins. We recommend sclerotherapy for treatment of telangiectasias

1

B

4.5.2 As a single form of treatment for varicose veins, sclerotherapy has a high incidence of recurrences. We recommend combining it with either conventional surgery or endovenous saphenous ablation

1

C

4.5.3 To reduce post-sclerotherapy hyperpigmentation, we suggest microthrombectomy in the ﬁrst 2–3 weeks after treatment

2

C

4.5.4 We recommend compression after sclerotherapy of telangiectasias and varicose veins

1

B

References 379

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

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2.

3.

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★6.

7. 8. ◆9.

★10.

◆11.

●12.

★13.

★14.

★15.

★16.

Lurie F, Creton D, Eklof B, et al. Prospective randomized study of endovenous radiofrequency obliteration versus ligation and stripping (EVOLVES): two year follow-up. Eur J Vasc Endovasc Surg 2005; 29: 67–73. Perala J, Rautio T, Biancari F et al. Radiofrequency endovenous obliteration versus stripping of the long saphenous vein in the management of primary varicose veins: 3 year outcome of randomized study. Ann Vasc Surg 2005; 19: 1–4 Rautio T, Ohinmaa. A, Perala J, et al. Endovenous obliteration versus conventional stripping operation in the treatment of varicose veins: a randomized controlled trial with comparison of the costs. J Vasc Surg 2002; 35: 958–65. Trendelenburg FV. Uber die Unterbindung der Vena Saphena Magna bei Unterschenkel Varizen. Beitr Klin Chir 1890; 7: 195. Keller WL. A new method of extirpating the internal saphenous and similar veins in varicose conditions: a preliminary report. NY Med J 1905; 82: 385. McPheeters HO. Injection treatment of varicose veins by the use of sclerosing solutions. Surg Gynecol Obstet 1927; 45: 541–7. Dixon FC. The results of injection treatment of varicose veins. Proc Staff Meet Mayo Clin 1930; 5: 42. De Takats G. Causes of failure in the treatment of varicose veins. JAMA 1931; 96: 1111–14. Smith FL. Varicose veins, complications and results of treatment of 5,000 patients. Milit Surg 1939; 85: 514. Myers TT. Results and techniques of a stripping operation for varicose veins. JAMA 1957; 163: 87. Einarsson E, Eklof B, Neglen P. Sclerotherapy or surgery for varicose veins: a prospective, randomized study. Phlebology 1993; 8: 22–6. Orbach EJ. Sclerotherapy of varicose veins: utilization of intravenous air-block. Am J Surg 1944; 66: 362–6. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: 635–45. Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic disease of the lower extremities: the CEAP classiﬁcation. Mayo Clin Proc 1996; 71: 338–45. Rutherford RB, Padberg FD Jr., Comerota AJ, et al. Venous severities scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. Whiteley MS, Holstock JM, Price BA, et al. Radiofrequency ablation of reﬂuxing great saphenous systems, Giacomini veins and incompetent perforating veins using VNUS closure and TRLOP technique. Phlebology 2003; 18: 52.

17. Peden EK, Lumsden AB. RF ablation of incompetent perforators using the VNUS closure RFS stylet. Endovasc Today 2007; 1 (Suppl.): 15–17. 18. Bishop CCR, Fronek HS, Fronek A, et al. Real time color duplex scanning sclerotherapy of the greater saphenous vein. J Vasc Surg 1991; 14: 505–8. ◆19. Imhoff E, Stemmer R. Classiﬁcation and mechanism of action of sclerosing agents. Phlebologie 1969; 22: 145–8. ◆20. Villavicencio JL, Gomez ER, Coffey JA, et al. What the vascular surgeon should know about sclerotherapy in the management of varicose veins. In: Veith FJ, ed. Current Critical Problems in Vascular Surgery, vol. 3. St Louis, MO: Quality Medical Publishing, 1991: 128–34. ★21. Cabrera GJ, Garnica-Olmedo MA. Elargissement des limites de la sclerotherapie: nouveaux produits sclerosants. Phlebologie 1997; 50: 181–8. 22. Sadoun S, Benigni JD. La mousse de sclerosants: etat de l’art. In: Rabe E, Gerlach H, Lechner W, eds. Phlebology 1999. Cologne: Viavital Verlag, 1999: 146. ◆23. Cabrera J. Application techniques for sclerotherapy in microfoam form. In: Henriett JP, ed. Foam Sclerotherapy. State of the Art. Paris: Editions Phlebologiques Françaises, 2002: 39–44. ◆24. Yamaki T, Nozaki M, Sasaki K. Color duplex guided sclerotherapy for the treatment of venous malformations. Dermatol Surg 2000; 26: 323–8. 25. Scott C, Seiger E. Postsclerotherapy pigmentation: is serum ferritin level an accurate indicator? Dermatol Surg 1997; 23: 281–2. 26. Goldman MP. Complications and adverse sequelae of sclerotherapy. In: Goldman MP, Weiss RA, Bergan JJ, eds. Varicose Veins and Telangiectasias: Diagnosis and Treatment. St Louis, MO: Quality Medical Publishing, 1999: 300–79. ◆27. Duffy DM. Techniques of small vessel sclerotherapy. In: Goldman MP, Weiss RA, Bergan JJ, eds. Varicose Veins and Telangiectasias: Diagnosis and Treatment. St Louis, MO: Quality Medical Publishing, 1999: 518–47. 28. Georgiev M. Postsclerotherapy hyperpigmentation: a one year follow-up. J Dermatol Surg Oncol 1990; 16: 608–10. ★29. Scultetus A, Villavicencio JL, Kao TC, et al. Microthrombectomy reduces postsclerotherapy pigmentation: multicenter randomized trial. J Vasc Surg 2003; 38: 896–903. 30. Weiss RA, Weiss MA. Resolution of pain associated with varicose and telangiectatic leg veins after compression therapy. J Dermatol Surg Oncol 1990; 16: 333–6 . ◆31. Davis LT, Duffy DM. Determination of incidence and risk factors for post-sclerotherapy telangiectatic matting of the lower extremity: a retrospective analysis. J Dermatol Surg Oncol 1990; 16: 327–30. 32. Goldman MP. Laser and non-coherent pulsed light treatment of leg telangiectasias and venules. In: Goldman MP, Bergan JJ, eds. Ambulatory Treatment of Venous Disease. St Louis, MO: Mosby, 1996: 89–98.

33 Foam sclerotherapy JOSHUA I. GREENBERG, NIREN ANGLE AND JOHN J. BERGAN Introduction History Foam preparation Technique Results

380 380 382 383 383

Contraindications and adverse effects Conclusion Clinical practice guidelines References

385 387 387 388

INTRODUCTION

HISTORY

In these ﬁrst years of the twenty-ﬁrst century, the era of minimal access surgery is an established fact. Patients are now well informed, and prefer fewer and smaller incisions in searching for physicians and procedures that promise a quicker recovery. At the same time, evidence-based medicine is slowly making its way into the realm of surgery. The treatment of varicose veins has exempliﬁed this trend toward less invasive yet durable techniques. Varicose vein procedures are subject to these forces. The one best intervention to satisfy these demands is foam sclerotherapy, the subject of this chapter. The history of foam sclerotherapy is a fascinating story of ﬁts and starts; yet, it is clear that it represents a treatment strategy with great potential. Sclerosants cause irreversible damage to the vascular endothelium by disrupting cell membranes, resulting in sustained vasospasm and denudation of the venous monolayer. The end result is ﬁbrous obliteration of the vessel lumen. Available evidence suggests that the mechanism is the same whether the physical phase of the inciting agent is liquid or foam. Prospective randomized outcome data support the hypothesis that foam sclerotherapy is superior to liquid sclerotherapy. The reason for this appears to be twofold. First, the physical properties of foam afford more efﬁcient contact with its target, the venous endothelium. Second, because the local efﬁciency of sclerosant is increased, less volume of the agent may be given. The result appears to be few local and systemic complications. In this chapter, we describe the history of therapeutic foam, methods of foam preparation and delivery, extent of evidence-based knowledge in foam sclerotherapy, and conclude with some clinical guidelines.

The history of sclerosing foams used to treat lower extremity varicose veins spans six decades, and is marked by a recent renewal of interest (Fig. 33.1). The origins of foam sclerotherapy can be traced to Stuart McAusland. In 1939, he used sodium morrhuate froth from a shaken bottle aspirated into a syringe.1 The resultant was used for injection of telangiectasias with remarkable success. The 1944 paper from Egmont James Orbach is erroneously referenced as the seminal work on foam sclerotherapy. Foam sclerotherapy was neither employed nor suggested in this work. The publication did, however, make observations that were prescient and had the potential to revolutionize phlebology. Orbach injected liquid sclerosant into a vein collapsed between two tourniquets and released the proximal tourniquet to allow proximal passage of the material.2 In order to generate prolonged and more intimate contact between the sclerosant and the endothelium, he devised the “air-block” technique by injecting air prior to the sclerosant to prevent dilution of the agent and prolong contact with the endothelium. This discovery is relevant because foam acts through a similar mechanism in a process that has been called “foam-block” (Fig. 33.2). Karl Sigg applied the air-block technique to the creation of foam, recognizing that it could serve the same purpose as air in effecting a longer dwell time on the endothelial interface.3 Orbach’s next contribution to foam sclerotherapy occurred in 1950. This was a comparison of the efﬁcacy of liquid with foam sclerosant.4 The paper was an early attempt to compare two techniques in the absence of an evidence-based environment. Orbach noted increased vasospasm in the foam group compared with the liquid

History 381

1939

McAusland

1944

1949

1950

1956

Orbach

Sigg

Orbach

Flückiger

“Froth” in telangiectasia

Foam block technique Air block technique

1963

Lunkenheimer

Retro-injection/leg elevation Vasospasm and foam

1995

Cabrera

1997

2000

Monfreux

Tessari

Rotating brush technique

Use of polidocanol foam

Tourbillon technique

Low-pressure technique

Figure 33.1 The history of foam sclerotherapy spans the last years of the twentieth century in preparation for its increasing use in the twenty-ﬁrst century.

a Air

b Foam

Figure 33.2 Orbach’s theory was simple but elegant. (a) Air injected into a small vein will “block” the dilution of a liquid introduced thereafter. (b) It was subsequently discovered that foam has the ability to generate an analogous effect termed “foam-block.”

group. He also noted an increased efﬁcacy in a setting of vasospasm and a profound response in smaller veins. Vasospasm now detected on duplex ultrasound has become an important measure of treatment success. In 1956, Peter Flückiger described the role of “retrograde injection” and leg elevation wherein a proximal vein could be injected and the passage of foam sclerosant could be assessed in the absence of ultrasound imaging by palpation of crepitus and guided by massage.5 In this way, passage of the sclerosant could be directed in a distal direction rather than in the direction of blood ﬂow. Flückiger’s other contribution to foam sclerotherapy was to note the relationship between an increased surface area with a decreased bubble size, thus allowing stronger sclerosing effect with smaller amounts of sclerosants. Flückiger was critical of the air-block technique of Orbach and Sigg, ﬁnding it unsatisfactory in terms of manufacture of high-quality foam for his retrograde injections. He wanted foam bubbles of equal size and thus

equal surface tension to avoid unwanted heterogeneous foam. He invented the aspiration technique, in which a needle bevel was partially submerged in a vial of Varsyl thereby generating an air–liquid interface and resultant foam.6 Two surgeons, Heinz Mayer and Hans Brücke, with their invention of the double-piston syringe, ushered in the modern age of foam sclerotherapy.7 This device as described in 1957 contained two plungers, one served as the main plunger and the other contained numerous small holes (Fig. 33.3). Mayer and Brücke used Phlebocid for generation of foam by excursion of the smaller plunger against the air–liquid interface in the syringe. This creates extremely uniform small bubbles that have come to be known as “microfoam.” Polidocanol, the sclerosant currently in widespread use in Europe, the Far East and North America, was not reported in use until 1963 by Peter Lunkenheimer. He used the agent with excellent results before it was approved for general use in Germany.8 Juan Cabrera Garrido ﬁrst described the use of sclerosant “microfoam” made by using a novel rotating brush and a carbon dioxide carrier.9 The half-life of the foam was found to be dependent upon the content of carbon dioxide. More carbon dioxide to sclerosant ratio

Figure 33.3 The Mayer–Brücke device. The inner plunger with numerous tiny holes can rapidly be moved forward and backward to mix sclerosant and air contained within the syringe. The outer plunger was used for injection of the viscous and ﬁne-bubbled foam. (Reprinted with permission from the American Society of Dermatologic Surgery, Inc. Dermatol Surg 2004; 30: 698.)

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Foam sclerotherapy

resulted in faster degradation of the foam. Cabrera used the foam to treat the great saphenous vein, varicosities and venous malformations with dramatic success (see Results). The large initial volumes of foam used by Cabrera are not recommended for use in current practice.

FOAM PREPARATION At the 2003 European Consensus Meeting on Foam Sclerotherapy, sclerosing foam was deﬁned as a dispersion of gas in a liquid sclerosing solution in which the gas is physiologically tolerated at therapeutic doses.10 Foam can be characterized in terms of the following properties: type and concentration of the sclerosing agent; type of gas; ratio of liquid to gas; size of bubbles; method of preparation; and the time between processing and use. The gas fraction of therapeutic foam is typically 0.52. Alessandro Frullini suggested that foam size can be categorized into macrofoam (bubbles larger than 500 μm), minifoam (bubbles between 250 and 500 μm), and microfoam (bubbles smaller than 250 μm).11 Heterogeneity in foam preparation technique has plagued efforts to achieve consistent in vivo results in clinical trials. The three current methods in use for foam preparation were reﬁned and published by Alain Monfreux in 1997, Lorenzo Tessari in 2000 (ﬁrst described in 1999), and Hamel-Desnos in 2001. Elaborating on the techniques of Gillsberger, Monfreux devised the “methode MUS” using a negative pressure system published in 1997.12 A negative pressure system is created when a piston draws subatmospheric air into a syringe through small gaps between the piston and syringe. There is signiﬁcant variability in the resultant foam depending on the type of syringe and the mode of pulling back the piston. The Tessari technique (or Tourbillon technique) is a modiﬁcation of a technique initially pioneered in the laboratory of Belcaro et al.13 It uses two syringes varying from 2 to 10 mL in capacity connected by a three-way stop-cock (Fig. 33.4). Only sodium tetradecyl sulfate was used by Tessari and colleagues. Air and liquid sclerosant were mixed in 20 passages while the aperture in the threeway stop-cock was decreased to generate a microfoam. It was noted that over 20 passages did not alter foam architecture, that using saline instead of sterile water created larger bubbles, and that higher concentration of sclerosant produced a less stable foam. Foam lasting less than 2 minutes is considered less stable as 2 minutes marks the usual time required to perform an injection. In the 2001 report by Tessari et al.,14 no mention was made of the ratio of air to liquid; but subsequent reports proposed 5:2 or 4: 1 air–liquid ratios. The known variability in foam produced by different syringe types and needle sizes prompted Hamel-Desnos et al. to propose the double-syringe system technique in 2001. They published this technique in a case series in

Figure 33.4 Tessari’s technique is so simple that it has become dominant in foam generation. Syringe contents are passed from one syringe into the other. Note the angulation of the connector lock to reduce the size of the foam bubbles.

2003.15 This was the ﬁrst attempt to standardize materials in hopes of producing uniformity in a small-bubble viscous foam for use in prospective clinical trials. The required method included a 10 mL Omniﬁx syringe, a 10 mL injection syringe (each with a Luer lock connection), a Combidyn adaptor, and a 0.2 μm ﬁlter. A total of 8 mL of air was drawn into the injection syringe before 2 mL of 3% polidocanol was used to ﬁll the Omniﬁx (B Braun, Melsungen, Germany) syringe. The connector was used to join both syringes. A total of ﬁve pumps with additional pressure to mix both solutions followed by seven pumps without additional pressure was employed. Foam generated in this manner has a liquid–air ratio of 1:5, a half-life of approximately 150 seconds and a mean bubble size of 70 μm.16 A practical note must be added. At this time, only sodium tetradecyl sulfate, a commercially available sclerosant (manufactured by Bioniche Pharmaceuticals, Belleville, ON, Canada), is approved by the US Food and Drug Administration (FDA) for the treatment of varicose veins. However, incorporating this into foam changes this approved substance into an “off-label” use. So there is no FDA approved foam sclerosant in the USA. In Europe, however, Varisolve (Provensis Ltd, London, UK) is a commercially available sclerosant. Polidocanol can be purchased from licensed compounding pharmacies and compounded into 1–3% solutions according to guidelines published by the FDA and utilized in accordance with recommendations from the American College of Phlebology that can be found on its website (www.phlebology.org). In summary, microfoam used in current sclerotherapy applications can be made efﬁciently from detergent agents such as Sotradecol (sodium tetradecyl sulfate; Bioniche Pharma, Belleville, ON, Canada) and polidocanol at any

Results 383

concentration between 0.25% and 3%. In our practice, we exclusively use the Tessari technique with polidocanol 1–3% in two 5 mL latex-free syringes creating an air–liquid sclerosant ratio of 5:2.

TECHNIQUE The effective delivery of foam sclerotherapy is easy. As with liquid sclerotherapy, it must be injected properly, and must be injected into a proper patient. Nursing staff and ancillary personnel should be familiar with the drugs, indications, and possible side-effects. Depending on local availability, a procedure room in a quiet ofﬁce is best for injecting foam sclerosant. Other than the drug and the consumable supplies described in Foam preparation, other necessary equipment includes a high-quality color duplex ultrasound (5–15 MHz) transducer unit and emergency equipment. The latter is indicated in rare cases of drug reaction to sodium tetradecyl sulfate foam. When a patient is seen in the ofﬁce on referral for varicose veins, a focused history and physical examination is performed. A standing venous reﬂux Doppler examination is performed according to a previously published protocol.17 Measurement diameters of reﬂuxing venous segments and exit and reentry perforating veins are recorded. In cases of venous ulceration, the relationship between pathological perforating veins and ulceration is documented and the size of the ulcer in three dimensions is recorded. In decision-making regarding the treatment of the patient with varicose veins, one must consider not just one ﬁnding, but the entirety of the patient’s history, physical examination, and standing venous reﬂux Doppler examination in the context of evidence-based guidelines (Table 33.1). Once a decision is made to proceed with foam sclerotherapy, we use polidocanol in a 1–3% dilution. The ability to use the proper concentration of foam in the correct vein requires training and experience but there is a broad latitude of safety. Foams with greater viscosity (i.e., more concentrated) are best used in larger veins. Highviscosity foams are more powerful than low-viscosity foams, which, in turn, are more powerful than liquid sclerosants. There is grade 1 evidence that relates highviscosity foam to more complications in smaller diameter veins.15

A deliberate choice must be made between ultrasound cannulation of the great saphenous vein and simple cannulation of an available varix. In the latter case, a varicose vein tributary to the greater saphenous vein is identiﬁed. Under direct ultrasonographic observation, the foam is injected toward the saphenofemoral junction (usually about 5 mL). Firm pressure against the groin may be maintained with the ultrasound transducer to prevent central migration of the foam. This may be unnecessary. Next, the extremity is elevated 45° and a bolus is injected to ﬁll distal incompetent veins (usually about 3 mL). Foam ﬂows through incompetent valves and is blocked from passing distally by competent valves. The deep venous system is carefully interrogated with the ultrasound probe. In case of foam migration to the deep system, vigorous ankle ﬂexion–extension will dissipate the foam fragments. The question naturally arises of how much volume should be used in a foam injection? A number of animal and human studies conﬁrm that a remarkable amount of air is tolerated within the circulatory tree. Indeed, Cabrera used volumes upwards of 20 mL and more for his injections, although he reported a deep vein thrombosis (DVT) rate of 6%.18 The question of optimal injection volume was addressed at the 2003 European Consensus Meeting.10 We generally use 8–15 mL of foam. The aftercare of a patient treated with foam sclerotherapy is quite simple. Focal compression over varicose clusters is supplemented by a class III 30–40 mmHg stocking and further aided by appropriate elastic bandages. The objective of this treatment is to avoid trapping blood and to maintain vein wall apposition so that the vessels, now stripped of their endothelium, will undergo ﬁbrosclerotic healing. We recommend 48–72 hours of initial ﬁrm compression, although 7–10 days might be better.

RESULTS Cabrera and his colleagues in Granada, Spain, reported their experience with the rotating brush foam technique to treat great saphenous veins and venous malformations. Sodium tetradecyl sulfate foam was used in concentrations up to 3% and volumes up to 20 mL. After 5 years of followup, 81% of treated veins showed complete ﬁbrosis. It was

Table 33.1 Evidence-based indications: foam sclerotherapy Evidence level 1A Long saphenous reﬂux C2–C6 varicose veins Recurrent varicose veins

Evidence level 1C

Evidence level 2C

Venous ulcers Lipodermatosclerosis Short saphenous reﬂux Venous malformations32

Varicocele33 Angiodysplasia Vascular tumors34

384

Foam sclerotherapy

notable that their early experience with foam volumes of 20 mL or greater resulted in deep venous thrombosis in 6% of patients.18 Tessari’s report13 published in 2000 was a feasibility study for his newly devised technique. By the author’s own admission, it was not intended to provide evidence for immediate universal application. But rather, he stated that “this new method for producing foams holds great promise.” Indeed, standardization issues and ongoing reﬁnements were evident in this study. Tessari and colleagues used the technique described above exclusively with sodium tetradecyl sulfate to treat three groups of patients under ultrasonographic direction.19 Group A had great saphenous, small saphenous, or recurrent inguinal reﬂux (mean vessel diameter 7 mm). This group received 1–3% sodium tetradecyl sulfate (average 3 mL). Group B had postsurgical varicosities, varicosities due to incompetent perforating veins, or single-tributary disease (mean vessel diameter 3.8 mm). This group had collaterals that varied in size and thus so did the treatment (0.3–1% sodium tetradecyl sulfate) and quantity (3–5 mL). Group C consisted of minor varicosities treated with only 0.1–0.2% sodium tetradecyl sulfate (2–3 mL). All patients wore graded compression stockings for 30 days. The results from Tessari’s experience are very impressive. Nearly all the patients treated in his series demonstrated obliteration of the treated saphenous veins and other varicosities with between one and four treatment sessions. Group C patients with smaller varicosities showed excellent cosmetic outcomes. Complications included a few cases of skin necrosis up to 1 mm, two cases of scotomas, and one case of phlebitis. The authors were impressed with the potency of this technique when used to treat great and small saphenous vein reﬂux. As a corollary, they expressed cautious optimism about its use in smaller varicosities. While grade 1 evidence for the utility of foam sclerotherapy was developing, we used ultrasound-guided sclerosant foam injection to treat severe chronic venous insufﬁciency, varicose veins, venous angiomata, and recurrent varicose veins after standard surgery.20 Foam generation was performed using the Tessari technique and access was nearly always through a varicose tributary to the great saphenous vein. As explained in Foam preparation, we routinely compound polidocanol to 1%, 2%, or 3% strength in an air–liquid sclerosant ratio of 5:2. In the group of patients with chronic venous insufﬁciency, lipodermatosclerosis, atrophie blanche, healed venous ulcers, or open venous ulcers were treated. There were 44 patients with 60 limbs that ﬁt into one of three therapeutic arms: group 1, compression treatment only; group 2, crossover patients who failed conservative management; and group 3, ﬁrst-line treatment with foam sclerotherapy. In group 1, 12 individuals (44%) became patients in crossover group 2. In other words, these 12 patients failed compression therapy and were treated with foam

sclerotherapy. In this group, all eight ulcers healed within 6 weeks. In group 3 all 11 ulcers healed within 1 month. Statistical analysis revealed that sclerosant foam healed ulcers faster and was more effective than compression at 2 weeks. At 4 weeks, patients treated with foam were more likely to have less pain and to have healed ulcers. Immediate complications included one acute DVT (in a muscular vein) and two iatrogenic ulcers. There was only one treatment failure in a patient with well-established chronic venous insufﬁciency and occult femoropopliteal arterial occlusive disease. Using ultrasound examination, it is possible to see a tangle of small venules underlying venous leg ulcers (Fig. 33.5). This cluster of interwoven venules is also seen under lipodermatosclerosis and is in direct connection with incompetent and reﬂuxing superﬁcial veins as well as outﬂowing perforating veins. We believe that venous ulcers are perpetuated and lipodermatosclerotic skin is inﬂamed because of local venous hypertension transmitted from incompetent perforating veins and reﬂuxing superﬁcial veins (Fig. 33.6). Foam sclerotherapy affords access to this microcirculation, which is otherwise inaccessible by surgical techniques. Superﬁcial vein stripping or removal of reﬂuxing superﬁcial veins as well as interruption of perforating veins has an indirect inﬂuence on the local venous hypertension, whereas foam sclerotherapy has a direct effect in closing or obliterating the venular caput medusa that underlies lipodermatosclerosis and venous leg ulcer. Grade 1 evidence in support of foam sclerotherapy exists for a number of disparate conditions represented in the guidelines proposed at the end of this chapter. Our recommendations are based on several robust case series and a small number of small randomized controlled trials

Telangiectasia Dermis Reticular vein Varicose tributary Perforating vein LSV

Superficial fascia Perforating vein Deep fascia Deep vein

Figure 33.5 The relationships between major axial veins, varicosities, and associated perforating veins. Note the accompanying telangiectasias. (Diagram originally developed by George Sömjen.)

Contraindications and adverse effects 385

Distal vein

Proximal vein

Subcutaneous layer Subfascial layer Perforating vein

Perforating vein

Figure 33.6 The tangle of veins under a venous ulcer or lipodermatosclerotic skin. Note that the proximal vein and perforating veins are sources of venous hypertension and that direct ablation of the venous network blocks the venous pressure effects on the skin. (Diagram originally developed by Ralph DePalma.)

(RCTs). Most of the few RCTs designed to test the hypothesis that foam is superior to either liquid or surgery have methodological ﬂaws, technical inconsistencies, and lack transparency in reporting of data. An explanation for at least some of this is seen in the 10 year RCT referred to as the VEDICO trial.21 This report states that “In a world of evidence-based medicine – where evidence is exclusively collected in very expensive trials, concerning very expensive treatments, leading to high proﬁts – nobody is really interested in evaluating treatments for venous diseases.”21 And so, the lack of good prospective randomized data from multicenter, multinational trials is strikingly absent. But we agree with the VEDICO trialists that good registry data instead of good RCT data is the best that is available today. Results from the RCTs available at this time are presented in Table 33.2. What is evident is that a small number of patients enrolled with highly variable indications, a variety of techniques, and a mixture of follow-up protocols. One of the trials offers minimal weight if viewed objectively: Kern et al.22 reported very short follow-up only in women using non-standard criteria (photographs, pain on injection, patient satisfaction scores). In contrast, Hamel-Desnos et al.15 and Yamaki et al.23 provide important data comparing foam with liquid in sclerotherapy. We did not include the latter in Table 33.2 because patient accrual was not performed in a randomized fashion. It is, however, worth noting that Yamaki et al.23 provide compelling cohort data that suggest the superiority of foam over liquid in terms of early saphenous vein occlusion and freedom from recurrence at 1 year. Alòs et al.24 also provide qualitative data on the efﬁcacy of foam versus liquid sclerotherapy. Their study demonstrates a statistically signiﬁcant advantage of foam over liquid at 1 year of follow-up in treating a diverse conglomeration of veins. They demonstrate that patient satisfaction is the same with both techniques and that both

techniques are safe. An added observation is that foam sclerotherapy tends to be more painful than liquid. The most robust RCTs include the VEDICO trial21 and the more contemporary trial from Bountouroglou et al.25 Both trials enrolled a matched set of patients and treated primary varicose veins with similar techniques. They both sought to make important comparisons and generate new observations. At 3 months, both trials demonstrated similar efﬁcacy and safety when comparing liquid with foam and saphenofemoral junction ligation and foam with saphenofemoral junction ligation/stripping. A trend toward hyperpigmentation was seen with foam treatment and saphenous nerve injury with vein stripping. Bountouroglou et al.25 also showed that the hybrid procedure (saphenofemoral junction ligation and foam) improves efﬁciency, cost, and time to normal activities. The VEDICO trial provides the longest available prospective randomized data involving foam sclerotherapy. It also provides the ﬁrst evidence from lung scintigraphy and transesophageal echocardiography that foam is well dissolved and safe in the pulmonary circulation. The long-term data from this trial on foam as a single modality is less exciting. The data suggest that substantially more veins are present at 10 years when foam is used as a single modality than when surgery or surgery and foam are used. If true, this still provides an important place for foam in the treatment of primary varicose veins in older patients and in all patients undergoing concomitant or sequential saphenofemoral junction ligation.

CONTRAINDICATIONS AND ADVERSE EFFECTS Contraindications to foam sclerotherapy are essentially the same as those for liquid sclerotherapy, with careful consideration given to the increased potency of the foam. Considering the exclusion criteria used in published randomized trials, Table 33.3 summarizes the current contraindications to foam sclerotherapy. There are three groups of patients in whom one must use judicious volumes of foam sclerosant. First, patients with a history of severe migraine might be more susceptible to transient migraine aura symptoms. Second, patients with a patent foramen ovale are more susceptible to systemic dissemination of foam. Finally, patients with May– Thurner or Klippel–Trenaunay syndrome often have coagulation abnormalities after treatment of venous malformations.26 This predisposes them to both bleeding and thrombosis owing to an underlying consumption coagulopathy. Very severe complications of foam sclerotherapy have not been reported. The largest published experience with complications of foam injection comes from Henriet27 in France. He describes more than 10 000 treatment sessions using 5% polidocanol over a 3 year period (patient average age 51). Eighty percent of these were injections

386

Foam sclerotherapy

Table 33.2 Randomized controlled trials: foam sclerotherapy Authors

Randomized/ label

Trial arms

Participants

Targets

Follow-up

Bountouroglou et al.25

Yes/open

1. SFJ ligation + Foam* = 30 2. Surgery (SFJ ligation, GSV saphenectomy) = 28

53% female (mean age 43)

Primary symptomatic varices

3 months with DUS

Alòs et al.24

Yes/open

1. Liquid = 75 2. Foam*= 75 Patient as own control

92% female (mean age 59)

Kern et al.22

Yes/“single blind”

1. Liquid = 48 2. Foam† = 51

100% female (mean age 47)

Hamel-Desnos et al.15

Yes/open

1. Liquid = 43 2. Foam‡ = 45

Not stated

GSV 1 year. incompetence Percentage with varices follow-up not stated

Belcaro et al.,21 “VEDICO trial”

Yes/open

1. Liquid = 123 2. High-dose liquid = 112 3. Multiple ligations = 132 4. Stab avulsions = 122 5. Foam§= 129 6. SFJ ligation + liquid = 131

70% female (mean age 43)

Uncomplicated 10 year, primary 84% varicose veins

Outcomes

87% group 1 and 93% group occlusion of targets on DUS (no statistical difference). Shorter procedure, less expensive, faster return to work, better quality of life scores for group 1 Reticular 1 year: 85% 94% foam and varices, follow-up 54% liquid. postoperative with DUS Occlusion of varices by blinded target at 3 outside SFJ observer months (P < 0.001) Primary 5 weeks, Comparable telangiectasias 97%. efﬁcacy in and thigh Photographs terms of a reticular veins by two “vessel blinded clearance observers score”

*Tessari technique (sodium tetradecyl sulfate or polidocanol) with duplex ultrasound guidance. †Monfreux technique (polidocanol) without duplex ultrasound guidance. ‡Double-syringe system (polidocanol) with duplex ultrasound guidance. §Irvine technique (Tessari-like technique predecessor; polidocanol) with duplex ultrasound guidance. DUS, duplex ultrasound scanning; GSV, great saphenous vein; SFJ, saphenofemoral junction.

84% foam and 40% liquid elimination of reﬂux at 3 weeks. At 1 year, two foam and six liquid recurrences 10 year reintervention/ failure rates: 1. 10%/46% 2. 8%/44% 3. 11%/32% 4. 30%/34% 5. 8%/40% 6. 6%/29%

Complications

Group 1, 17% resolving skin pigmentation; 10% thrombophlebitis. Group 2, 9% saphenous nerve injury

None except 4%. Severe pain foam and 0% liquid

33% and 17% showed matting, microthrombi, and pigmentation in liquid and foam groups, respectively One case of “slight vagal discomfort”

None stated; 12 negative lung scintigraphy examinations reported

Clinical practice guidelines

Table 33.3 Contraindications to foam sclerotherapy Contraindications Known allergy to local anesthetic Known allergy to sclerosant agent Acute deep vein thrombosis Coagulopathy Peripheral vascular disease (ankle brachial index < 0.8) Pregnancy

Relative contraindications Patent foramen ovale History of severe migraines May–Thurner syndrome Klippel–Trenaunay syndrome

387

CONCLUSION Foam sclerotherapy is an important tool in the armamentarium of modern phlebology. Foam must be looked upon not as an entirely new class of treatment. Its utility and potency must be respected. With proper patient selection and evidence-based protocols, foam sclerotherapy is a proven safe, simple, and effective method for improving treatment of a wide variety of venous diseases and disorders.

CLINICAL PRACTICE GUIDELINES ●

into reticular varicosities and frank varicose veins. Nine patients had immediate visual disturbances, eight had blurred vision lasting several minutes, one had monocular blindness that lasted 2 hours. Other immediate complications included vomiting in one patient and migraine in seven patients. All complications resolved. To establish the safety of foam sclerotherapy, a multicenter prospective registry was established in 22 phlebology clinics in Europe. During the study period, which included the injection session and 1 month followup, 6395 foam cases were included. Thirty-seven adverse events (0.5%) occurred with foam.28 Nineteen cases of transient visual disturbances were reported. One case of femoral vein thrombosis was the only severe adverse event in this study. The authors concluded that foam sclerotherapy was safe. Results from the randomized trials reviewed above show that foam is as safe as liquid when used in small volumes in large veins. In fact the VEDICO trial used lung scintigraphy to establish the safety of foam in a randomized clinical trial. There were no pulmonary perfusion defects identiﬁed with injections of up 10 mL of foam.21 Foam sclerotherapy does produce a deﬁnite trend toward more transient visual disturbances and migraine in predisposed individuals than liquid sclerotherapy. This is most probably due to passage of foam particles through a patent foramen ovale. Other complications observed in larger series and clinical trials include superﬁcial thrombophlebitis, cough, and skin discoloration. Skin necrosis from foam injection into small-caliber reticular veins and telangiectasias are also a rare but clearly documented complication.29 In our local experience during the past 12 months in the Vein Institute of La Jolla, adverse events described above have been totally absent in patients whose treatment is terminated by 45° leg elevation for 10 minutes. Presumably, foam reverts to its former liquid state and foam particles are not transmitted through a patent foramen ovale to the left heart circulation. This follows a 1.9% incidence of adverse events prior to late fall of 2005.

●

●

●

●

A properly performed systematic review or even metaanalysis of foam sclerotherapy has not been published yet. Indeed in its examination of patients treated with liquid sclerotherapy the Cochrane Database of Systematic Reviews ﬁnds insufﬁcient evidence to preferentially recommend the use of sclerotherapy over surgery.30 The American College of Chest Physicians has published recommendations for evidence grading as described elsewhere in this volume.31 After a review of available reports, we have formulated recommendations according to this scheme. Grade 1A evidence exists to support the use of foam sclerosant generated by the Monfreux, Tessari, and the double-syringe system techniques for the treatment of symptomatic reﬂux of the great saphenous vein, C2–C6 patients with varicose veins, and recurrent varicose veins. Grade 1B evidence exists to support the use of duplex ultrasound-guided foam injection. Downgrading occurred for want of prospective data comparing image-guided with “blind” injection of varices. Overwhelming evidence from observational studies elevate this evidence to grade 1B. Evidence exists to support foam over liquid sclerotherapy, but because of the ﬂawed methodology, inconsistent techniques, and divergent results found in RCTs this evidence is reduced to grade 1B. A preponderance of exceptional case series salvage the grade as the superior efﬁcacy and minor risk associated with foam compared with liquid has been well documented. Grade 1C evidence exists to support the use of foam sclerotherapy to treat saphenous vein incompetence, venous ulcers, lipodermatosclerosis, and venous malformations when compared with conservative therapy (e.g., compression). Downgrading is for lack of RCTs involving these conditions or inadequately powered RCTs to render meaningful evidence (in the case of small saphenous vein incompetence). Grade 1C evidence exists to support the use of the following foam volumes: for C2–C6 patients with varicose veins, 6–8 mL of foam per session using the Tessari or doublesyringe system techniques. For C1 telangiectasia and

388

Foam sclerotherapy

Guidelines 4.6.0 of the American Venous Forum on foam sclerotherapy* No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.6.1 We suggest the use of foam sclerosant generated by the Monfreux, Tessari, and the double-syringe system techniques for the treatment of symptomatic reﬂux of the great saphenous vein, C2–C6 varicose veins, and recurrent varicose veins

2

B

4.6.2 We suggest the use of foam sclerotherapy to treat saphenous vein, tributary varicose vein, and perforator vein incompetence in patients with venous ulcers, lipodermatosclerosis, and venous malformations when compared with conservative therapy (e.g., compression)

2

B

*Dr. Bergan’s outstanding pioneer work has to be adopted in the USA by other investigators. Until further evaluations, including prospective randomized studies, are completed these recommendations can be supported by the American Venous Forum.

●

reticular veins, no more than 0.5 mL of foam per injection. Grade 2A evidence exists to support the superiority of foam over liquid for C1 telangiectasias and reticular veins and recurrent varicose veins. Downgrading was instituted for lack of clear equality in terms of safety in randomized trials.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline

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32.

33. 34.

sclerotherapy or embolization of vascular anomalies. Am J Roentgenol 2001; 177: 1359–63. Henriet JP. Un an de pratique quotidienne de la scléothérapie (veines reticularies et téleangiectasies) par mousse de polidocanol: faisabilité, résultats, complications. Phlébologie 1997; 50: 355–60. Guex JJ, Allaert FA, Gillet JL, Chleir F. Immediate and midterm complications of sclerotherapy: report of a prospective multicenter registry of 12,173 sclerotherapy sessions. Dermatol Surg 2005; 31: 123–8. Bergan JJ, Weiss RA, Goldman RP. Extensive tissue necrosis following high-concentration sclerotherapy for varicose veins. Dermatol Surg 2000; 26: 535–42. Rigby KA, Palfreyman SJ, Beverly C, Michaels JA. Surgery versus sclerotherapy for the treatment of varicose veins. Cochrane Database Syst Rev 2004; Issue 4. Art. No.: CD004980. Guyatt G, Gutterman D, Bauman MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest 2006; 129: 174–81. Cabrera J, Cabrera J Jr, Garcia-Olmedio MA, Redondo P. Treatment of venous malformations with sclerosant in microfoam form. Arch Dermatol 2003; 139: 1409–16. Lord DJ, Burrows PE. Pediatric varicocele embolization. Tech Vasc Interv Radiol 2003 6 (4): 169–75. Vogel H, Niemeier J. Indications, procedures and choice of embolization material in transcatheter vascular occlusion. Rontgenblatter 1985; 38 (8): 265–9.

34 Percutaneous laser therapy of telangiectasias and varicose veins THOMAS M. PROEBSTLE Introduction Etiology and pathogenesis Clinical manifestation and classiﬁcation Pretreatment diagnostics and requirement Selection of patients Fundamentals of light–tissue interaction Lasers and intense pulsed light for transcutaneous therapy of telangiectasias

390 390 391 392 392 392 394

INTRODUCTION According to a recent epidemiologic study on more than 3000 randomly assigned persons in Germany,1 only 9.6% of the population are free from any kind of varicosity, 59% show isolated leg telangiectasias, and 31.3% have clinically relevant varicose veins or even more pronounced clinical signs such as edema, skin changes, or venous ulcer disease. Not surprisingly, varicose vein surgery is, overall, the most frequent type of surgery in Germany with as many as 300 000 operations a year. Today, many people are aware of varicose veins and their associated risks, such as deep vein thrombosis and lung embolism, and the clinical symptoms of advanced chronic venous disorders are also known to the general population. Additionally, the development of a speciﬁc life style over recent decades with an increased awareness of body appearance, including the cosmetic aspect of the legs, has led to patients requesting modern treatment modalities. Patients frequently seek resolution of clinical symptoms and expect a lack of impairment of their social or physical quality of life during the time of treatment; furthermore, they expect cosmetically excellent if not outstanding results thereafter. Over the last 5 years, lasers and light sources for the transcutaneous treatment of small varicosities and catheter-based systems for the percutaneous treatment of clinically relevant varicose veins have reached a level of technology which now – in contrast to many of the

Cooling systems Side-effects and complications Alternative treatment options Future directions Clinical practice guidelines References

396 396 397 397 398 398

traditional treatment approaches – can comply with most of these demands.

ETIOLOGY AND PATHOGENESIS The etiology of venous disorders including varicose veins and leg telangiectasias is complex and still incompletely understood. Besides idiopathic causes, some confounders of varicose veins are known, and in addition a variety of different diseases can be involved in the development of varicose vein disease; for example, prothrombotic disorders, which may cause deep vein thrombosis and subsequently frequently cause new varicose veins associated with post-thrombotic deep vein reﬂux. The etiological and pathophysiological aspects of venous disorders are dealt with in more detail in preceding chapters and will not be repeated here. Leg telangiectasias are frequently idiopathic and are mainly of cosmetic interest to the patient. However, as shown in Box 34.1, there are many localized or systemic diseases known to dermatologists that may cause the appearance of leg telangiectasias.2,3 It is important that dermatologists know these causes because some of the underlying conditions may be associated with skin hypersensitivity to light exposure and therefore any laser or intense pulsed light (IPL) treatment would not only be ineffective but potentially harmful to the patient and therefore be contraindicated.

Clinical manifestation and classiﬁcation 391

BOX 34.1 Causes for leg telangiectasia Primary telangiectasia Nevus ﬂammeus Klippel–Trenaunay syndrome Nevus anemicus with telangiactasias Angiomas and angiokeratomas Angioma serpiginosum Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome) Ataxia telangiectasia (Louis–Bar syndrome) Generalized essential telangiectasia Hereditary benign telangiectasia Spider telangiectasia Bloom’s syndrome

Secondary telangiectasia Causes associated with chronic venous disease Idiopathic telangiectasia (C1 according to CEAP classiﬁcation) Dermatitis/capillaritis alba (C4 CEAP) Exogenous causes Toxic exposure to infrared radiation, ultraviolet light or X-ray Exposure to toxic or allergenic chemicals Microbiological agents, e.g., acute (red) and chronic (bluish) Borrelia infection Blunt tissue trauma Cutaneous drug reactions, e.g., corticosteroids Autoimmune disease Lupus erythematosus Dermatomyositits Progressive systemic sclerosis Morphea Cryoglobulinemia Causes with a genetic background Xeroderma pigmentosum Goltz’s syndrome Congenital poikiloderma (Rothmund–Thomson syndrome) Congenital neuroangiopathiy (Maffucci’s syndrome) Cutis marmorata telangiectatica congenita Dyskeratosis congenita Unilateral nevoid telangiectasia Angiokeratoma corporis diffusum CEAP, C, clinical; E, etiology; A, anatomy; P, pathophysiology. (M. Fabry)

clinically insigniﬁcant but cosmetically most disturbing small veins. The clinical stage C1, which in general represents telangiectasias and reticular varicose veins with diameters below 3 mm, represents a variety of small vessels, sometimes requiring different treatment approaches. Several classiﬁcations, therefore, have been proposed to provide a more detailed view of leg telangiectasias and small varicose veins. Initially, leg telangiectasias were described morphologically, naming their patterns as linear, arborized or Besenreiser type; spider or star like; and punctiform or papular.5 This morphologic view frequently helps to identify the origin of the telangiectasia, which may be connected through a feeder vein to the more deeply located parts of the venous system and where any treatment would probably be most efﬁcient.6,7 When laser treatment of telangiectasias was introduced, with the concepts of thermal relaxation time and selective photothermolysis,8 the diameter of the vessel became probably the most important parameter. Teleangiectasias were separated into diameters below 0.2 mm, between 0.2 and 1 mm, and between 1 and 2 mm. Veins greater than 2 mm in diameter are called reticular veins. Additionally, the color of the vessel provides important information. Owing to the general properties of light reﬂection and scattering, vessels that are otherwise identical appear more bluish if located deeper in the skin than those that are more superﬁcial.9 Furthermore, it has been demonstrated that red and blue telangiectasias differ signiﬁcantly in their oxygen saturation,10 implying that red vessels contain more arterial blood than blue ones. More recent classiﬁcations of telangiectasias and visible varicose veins11,12 combine different aspects of the abovementioned criteria and are most helpful in daily clinical use (Table 34.1).

Table 34.1 Classiﬁcation of leg telangiectasias according to Duffy11 and Goldman12 Type 1 1A 1B

2

CLINICAL MANIFESTATION AND CLASSIFICATION The CEAP classiﬁcation4 offers a suitable and wellaccepted system for the description of venous disease. However, it is less suited for the categorization of these

3 4

Description Telangiectasia, spider vein 0.1–1.0 mm diameter, color red to cyanotic Telangiectatic matting 0.2 mm diameter, color red Communicating telangiectasia Type 1 veins in direct communication with varicose veins of the saphenous system Mixed telangiectatic/varicose veins without direct communication with the saphenous system 1–6 mm diameter, color cyanotic to blue Non-saphenous varicose veins (reticular veins) 2–8 mm diameter, color blue to blue–green Saphenous varicose veins Usually diameter above 8 mm, color blue to blue–green

392

Percutaneous laser therapy of telangiectasias and varicose veins

PRETREATMENT DIAGNOSTICS AND REQUIREMENT Before starting treatment of any venous disorder, a diagnostic work-up including a physical examination, a patient interview, and a duplex–Doppler ultrasound should be performed. During such a work-up, the sources of pathological venous reﬂux in the deep veins, in perforating veins, and in the saphenous systems need to be identiﬁed as well as regions of hemodynamically relevant obstruction, if there are any at all. Additionally, other reasons for the development of telangiectasias or visible varicose veins as listed in Box 34.1 need to be identiﬁed to prevent harm to the laser treatment candidate. After understanding the pathology of the leg’s venous hemodynamics, if present, saphenous and perforator reﬂux need to be corrected ﬁrst before small superﬁcial vessels are addressed by any treatment modality. This strategy is based on the frequent connections of visible varicosities and deeper located incompetent veins6,7 and removes venous hypertension from the laser target.

BOX 34.2 Confounders of successful laser or intense pulsed light treatment of telangiectasias ●

●

●

●

●

●

●

Selection of wavelength according to the absorption characteristics of the target and overlying tissue. Sufﬁcient dosing of the laser energy in terms of laser ﬂuence (J/cm2) to achieve reliable vessel closure. Selection of laser pulse duration not to exceed the thermal relaxation time of the target. Oversizing of the beam diameter to correct the penetration depth for scattering losses. Achievement of homogeneous volumetric target heating with an optimum combination of wavelength selection, adjustment of laser ﬂuence, and pulse duration. Adjustment of pulse duration with respect to the patient’s pain perception. Surface cooling for pain reduction and epidermal rescue.

SELECTION OF PATIENTS Any patient presenting with telangiectasias can receive laser or IPL treatment as an alternative for sclerotherapy if none of the contraindications as listed in Box 34.1 applies. Laser therapy is a modern, fast, and easy treatment that offers patients treatment without needle injury, without wound dressing, and – in the hands of many physicians – without post-treatment compression stockings. Unlike sclerosants, there is no maximum total dose of laser light. Therefore, treatment of both legs as a whole in one session is possible. Laser or IPL treatment of telangiectasias are treatment options that combine perfectly with endovenous treatments of saphenous veins and are ideal for patients who seek minimum impairment of their quality of life during and after treatment. There are also indications for laser treatment in patients who are unable to receive sclerotherapy: ● ● ● ●

●

needle-phobic patients sclerotherapy-resistant telangiectasias telangiectatic matting patients with pronounced hyperpigmentation after sclerotherapy intolerance to sclerosant.

FUNDAMENTALS OF LIGHT–TISSUE INTERACTION The successful treatment of telangiectasias by the use of lasers or IPL sources has to meet a number of conditions which are determined by the physics of light–tissue interaction. The most important parameters and conditions are listed in Box 34.2.

The selection of a wavelength determines principally whether the light energy can pass through overlying skin tissue and hence reach the target tissue; here, a venous vessel of any given diameter at all. Between approximately 600 and 1200 nm the human skin as a whole has a so-called optical window, i.e., an absorption minimum of the skin with an average absorption coefﬁcient in the order of 5/cm. The relevant chromophores of human skin which are responsible for absorption of electromagnetic energy in this part of the spectrum are hemoglobin in the dermis and melanin in the overlying epidermis. Water only starts to contribute at the infrared end of this part of the spectrum with wavelengths above 1000 nm. Figure 34.1 shows the most important absorption curves. Two examples of epidermal light absorption are given for fair skin and medium tanned skin with an epidermal volume fraction of melanocytes fmel of 3% and 15%, respectively, calculated as described elsewhere.13 In the dermis, the baseline absorption is characterized by the absorption proﬁle of hemoglobin. Figure 34.1 shows the curve with an estimated dermal blood content of 0.2% and a hemoglobin concentration in the blood of 10 mmol/L. However, along the whole range of wavelengths this absorption is about 100-fold weaker than the absorption of blood alone, which is the laser target in any transcutaneously treated vessel. It is easily seen that the 532 nm wavelength is absorbed about 100-fold more by hemoglobin (231/cm) than the 1064 nm wavelength (2.2/cm).14 The same is true for melanin, which absorbs the 532 nm wavelength about eightfold more (approximately 400/cm) than the 1064 nm wavelength (approximately 50/cm). Water absorption does not play a role in either of the wavelengths. In summary, the 532 nm wavelength penetrates signiﬁcantly less deeply

Fundamentals of light–tissue interaction

Absorption coefficient/cm

10 000.0 Oxygenated blood Hb⫽10 mmol/L

1000.0

Deoxygenated blood Hb⫽10 mmol/L Medium tanned skin fmel⫽15%

100.0 10.0

Fair skin fmel⫽3%

1.0

Dermis, 0.2% blood Hb⫽10 mmol/L

0.1 0

200

400 600

800 1000 1200

Wavelength (nm)

Figure 34.1 Absorption spectrum of blood with oxygenated and deoxygenated hemoglobin at a concentration of 10 mmol/L. Epidermal absorption of medium tanned and fair skin calculated with a melanosome volume fraction of 15% and 3% respectively. Dermal absorption calculated with a blood volume fraction of 0.2% and oxygenated hemoglobin at a concentration of 10 mmol/L. All curves given in the wavelength range between 250 and 1000 nm.

than the 1064 nm wavelength both in blood and in bloodless skin14 (Fig. 34.2). The amount of laser energy which ﬁnally reaches the target vessel determines whether the vessel will be permanently closed. When treating superﬁcial veins a sufﬁcient ﬂuence will elicit an immediate visible reaction such as shrinkage or thrombosis of the vessel.14 Proper ranges of ﬂuence are wavelength dependent and start from 4 J/cm2 for ﬂashlamp pumped dye lasers (FPDL) when treating superﬁcial vessels of 0.1 mm diameter15 and can reach 580 J/cm2 in long-pulse neodymium-doped yttrium aluminum garnet (Nd:YAG) systems.16

532 nm

393

When administering the desired amount of laser energy to the target vessel the time in which it is delivered is also crucial. According to the principle of selective photothermolysis,8 the laser pulse duration should not reach the thermal relaxation time of the target tissue. Thermal relaxation describes the time-course of heat transfer, usually by conduction, from the heated up target structure to the cooler surrounding tissue. The equation describing this phenomenon is an e-function with the thermal relaxation time as its time constant. Practically, this means that, if administering laser pulses that are longer than the thermal relaxation time of the target tissue, the advantage of higher absorption in the target tissue is removed. To estimate the magnitude of the thermal relaxation time, its value in seconds is approximately the square of the target diameter, e.g., the thermal relaxation time is about 250 ms in a 0.5 mm diameter vessel or about 40 ms in a 0.2 mm diameter vessel. Actually, the thermal relaxation times are a little bit shorter than these estimates, which actual pulse durations should stay below. Additionally, for successful ablation of superﬁcial varicose veins, the actual penetration depth of the laser light should be considered. Interestingly, this depth is not only dependent on the wavelength of the laser light and its absorption characteristics, but also on its scattering behavior. The actual penetration depth, therefore, can be increased by increasing the beam diameter (Fig. 34.3). Owing to the above-mentioned scatter effects, the originally cylindrical laser beam forms a pencil-like tip before being completely absorbed by surrounding tissue. This is because of the phenomenon of forward scattering, in which the vanishing of the laser beam takes longer and happens at greater tissue depth with administering greater beam diameters. After considering the absorption characteristics of skin tissue and hemoglobin in general, those of the target

1064 nm

a a b b

c c

Figure 34.2 Semiquantitative display of penetration depths of 532 nm and 1064 nm into human skin according to absorption characteristics shown in Fig. 34.1. (a) epidermis; (b) dermal layer; (c) subcutaneous fat.

Figure 34.3 Semiquantitative display of penetration depths of 1064 nm into human skin according to different beam diameters. Penetration is deeper for larger beam diameters because of the physical effect of forward scattering (Mie scattering). (a) epidermis; (b) dermal layer; (c) subcutaneous fat.

394

Percutaneous laser therapy of telangiectasias and varicose veins

structure, i.e., the geometry of the vein vessel itself, require a closer look with respect to volumetric heating. If a wavelength is used that is absorbed too much by hemoglobin, at least in vessels of larger diameter, the remote parts of the vessel do not get heated enough because the energy is predominantly absorbed in the part of the vessel ﬁrst hit by the laser beam. In contrast, a wavelength which is absorbed more moderately by hemoglobin is able to heat up the vessel as a whole. Figure 34.4 shows this for a 532 nm laser beam in comparison with a 1064 nm beam. For this reason, larger vessels with diameters in the order of 1 mm cannot be successfully treated with short laser wavelengths such as 532 nm, 585 nm, or even 595 nm. Next to the thermal relaxation time, the administered wavelength, and the ﬂuence, different effects are achieved if a certain energy dose – or ﬂuence – is administered with a short or a long pulse duration. For example, for the 1064 nm ND:YAG laser it has been shown that longer pulse durations between 20 and 60 ms consistently produce better clinical results than 3 ms pulse durations in vessels with a mean diameter of 0.8 mm.16 Histopathology has supported these ﬁndings, showing marked shrinkage of perivascular collagen with longer pulses whereas short pulses of 3 ms were able to produce only a thrombotic occlusion of the vessel. In conclusion, it seems that substantial heat damage around the target vein, at least a solid heat damage of the entire vessel wall, is an absolute requirement to achieve instant and durable vein occlusions. However, longer durations of laser pulses are more painful than shorter pulses,14 and therefore a patient’s pain sometimes does not allow the administration of longer pulse durations; in particular, pulses above 100 ms duration are not tolerated by many patients.

532 nm

1064 nm

a

b

c

Figure 34.4 Semiquantitative display of different volume heating effects of blood vessels caused by either 532 nm or 1064 nm irradiation. Owing to higher absorption by blood at 532 nm, larger vessels get heated only at the most superﬁcial parts, producing a kind of a shield for more remote vessel parts, which stay cool. A wavelength of 1064 nm heats the vessel more uniformly because of a lower absorption coefﬁcient. (a) epidermis; (b) dermal layer; (c) subcutaneous fat.

To reduce pain and to minimize the risk of numerous side-effects elicited by heat damage of the skin, the use of skin cooling is mandatory today. Local use of ice cubes or administration of cooled gel before laser treatment or laser ﬁring through ice cubes are historical methods which cannot guarantee reproducible results. Nowadays, sophisticated dynamic spray cooling devices, chilled contact tips, or cool air generators are available as discussed below.

LASERS AND INTENSE PULSED LIGHT FOR TRANSCUTANEOUS THERAPY OF TELANGIECTASIAS During the last 5 years, treatment of telangiectatic vessels of the legs has reached a level which now allows transcutaneous therapy in most cases. Clearly, there has been an increase in pulse durations, in ﬂuences, and, generally, also in wavelength. Today, a variety of laser and IPL systems is available for treatment of leg telangiectasias of any diameter between 0.1 and 2.0 mm.

532 nm potassium titanylphosphate (KTP) laser The frequency-doubled 532 nm Nd:YAG laser system is particularly useful for the treatment of red leg telangiectasias with small diameters below 0.7 mm. It is most effective if used on skin types I–III and is problematic in tanned or dark-skinned patients because of the high absorption of melanin at this wavelength. The 532 nm laser was initially used with ﬂuences between 14 and 20 J/cm2, with pulse durations of 10– 15 ms, and with spot sizes of 3–5 mm in 50 patients with leg telangiectasias of varying diameters; 83% of patients showed a clearance of 50% or more after two treatments. With the above-mentioned parameters and a chilled tip for contact cooling, the 532 nm KTP laser proved less painful than laser systems with longer wavelengths.17 In another study of 15 patients, clinical results were corroborated on telangiectasias below 0.75 mm diameter. A clearance of more than 75% was achieved after two treatment sessions using a ﬂuence of 16 J/cm2 with 10 ms pulse durations and three passes over the same treatment area each session.18 Another study conﬁrmed the favorable pain and side-effect proﬁle but found vessel clearance inferior to a long-pulse dye laser. The authors recommended the use of the KTP laser system in conjunction with sclerotherapy of larger feeding reticular veins.19 However, when using a multipulse mode with three stacked pulses of 100 ms, 30 ms, and 30 ms duration, each separated by a gap of 250 ms, with a ﬂuence of 60 J/cm2 and a beam diameter of 0.75 mm, clearance in leg telangiectasias of 0.5–1.0 mm diameter was 85% after three

Lasers and intense pulsed light for transcutaneous therapy of telangiectasias 395

and 93% after four treatment sessions, most likely taking advantage of methemoglobin formation during the ﬁrst of the three pulses.20 In another study, no efﬁcacy of the KTP laser was found on vessels with diameters of 0.7 mm or above.21

578 nm copper bromide laser The copper bromide laser is suitable for red leg telangiectasias. In a study of 46 patients, 75–100% clearance was achieved after an average of 1.7 treatments of vessels with diameters below 1.5 mm. Fluences were in the range of 50–55 J/cm2 , a contact cooling system with a temperature between 1°C and 4°C.22

Flashlamp pumped pulsed dye laser More than 20 years ago, this laser was the ﬁrst one taking advantage of the concept of selective photothermolysis and the ﬁrst one to achieve remarkable results in very small red vessels with diameters below 0.1 mm such as in telangiectatic matting. At that time with a wavelength of 577 nm and pulse durations of 360 μs, it was shown to be suitable for the treatment of infantile hemangiomas or port-wine stains. It did not show remarkable effects on patients with leg telangiectasias.23 When targeting blue leg telangiectasias with a wavelength of 585 nm and a pulse duration of 450 μs it also showed only very limited success with a clearance rate of 30% and frequent hyperpigmentation thereafter.24 In the mid-1990s, dye lasers with a wavelength of 595 nm and a pulse duration of 1.5 ms were introduced. One study with ﬂuences of 15 or 18 J/cm2 after one single treatment showed clearance in up to 65% of patients when treating vessels between 0.6 and 1.1 mm in diameter.25 Another study reported 100% clearance in leg telangiectasias below 0.5 mm diameter, and 80% in vessels with diameters between 0.5 and 1.0 mm.26 In 10 patients, more than 75% clearance after three treatments every 6 weeks was achieved with minimal side-effects using a 595 nm dye laser with 1.5 ms pulse duration. Fluences between 15 and 20 J/cm2 were used on leg telangiectasias with diameters below 1.5 mm.27 In another comparative study on 87 patients and 257 treatment sites, a wavelength of 595 nm was compared with a wavelength of 600 nm using 1.5 ms pulse duration and ﬂuences of 16, 18 and 20 J/cm2. A clearance rate above 50% in up to 80% of patients was noted after a single treatment. The authors found best results with higher ﬂuences on vessels below 0.5 mm in diameter. Pigment changes were noticed in 32% of cases.28 The use of a dynamic cooling device in conjunction with 595 nm and 1.5 ms pulse duration treatment reduced patient discomfort without diminishing an average clearance rate of 68%.29 Introduction of dye lasers with pulse durations of 40 ms allowed treatment

without, or at least with diminished production of, purpuric lesions after laser treatment. With the use of an extended pulse width of 40 ms and a ﬂuence of 16 J/cm2, administering up to three passes over the same location during one session, after a total of two treatment sessions 70% of leg vessels showed a clearance of 75–100%. A –4°C air cooling system was used during treatment.30 After only one treatment of submillimeter telangiectasias with the 595 nm dye laser at 40 ms pulse duration with a ﬂuence of 25 J/cm2 and spray cooling, about half of the patients had clearance of 50% or more. In the same study 532 nm KTP laser treatment with 50 ms pulse duration and a ﬂuence of 20 J/cm2 and contact cooling gave similar results.31

755 nm long-pulse alexandrite laser The long-pulse alexandrite laser in the near infrared at a wavelength of 755 nm proved to be most effective in a double pulse mode (frequency 1 Hz) at a ﬂuence of 20 J/cm2 with pulse durations of 5–10 ms.32 Small vessels with diameters below 0.4 mm did not show signiﬁcant responses whereas larger telangiectasias showed a 63% reduction after three treatments in 4 week intervals. Subsequent sclerotherapy improved laser results signiﬁcantly. Another study showed that long-pulse alexandrite laser treatment at 3 ms pulse duration and ﬂuences of 60–70 J/cm2 for treatment of veins of 0.3– 3.0 mm diameter frequently caused signiﬁcant inﬂammatory skin reaction, purpura, and telangiectatic matting. Despite that side-effect proﬁle, only 33% of patients had more than 75% clearance after up to three treatment sessions.33 When using the 755 nm alexandrite laser with a ﬂuence of 90 J/cm2 15 out of 20 patients had a clearance of 25–75% of treated telangiectasias with diameters from 0.3 to 1.3 mm. However, in 75% of cases hyperpigmentation was noted.34

Diode lasers between 810 nm and 980 nm In one study using an 810 nm diode laser with a 5 mm spot size and a pulse protocol of four consecutive stacked pulses (frequency 2 Hz) each of a ﬂuence of 3–4.5 J/cm2, no sideeffects, but also no clearance of leg telangiectasias, were observed.35 Inconsistent results with only 29% of sites clearing by more than 75% were also reported from another group using an 810 nm long-pulse diode laser on vessels with diameters between 0.3 and 3.0 mm.33 Using a 940 nm diode laser with a 1 mm spot size, a pulse duration of 40–70 ms and ﬂuences between 300 and 350 J/cm2 a single treatment resulted in a clearance of more than 75% of treated telangiectasias, in 12 of 26 patients (46%).36 The same group reported an additional 1 year follow-up with further improvement of clearing rates in 35% of patients.37 Another group from France using spot diameters between 0.5 and 1.5 mm, a pulse duration of 10–70 ms and ﬂuences

396

Percutaneous laser therapy of telangiectasias and varicose veins

slightly above 300 J/cm2 found clearance rates superior to 75% after up to three treatment sessions in only 13% of cases if vessel diameters were below 0.4 mm and in 88% of cases if vessel diameters were between 0.8 and 1.4 mm.38 An 810 nm laser used with a 12 mm spot size, a pulse duration of 60 ms and ﬂuences in the range 80–100 J/cm2 managed to clear 43% of spider veins completely after one session with two treatment passes.39 A combination of a 915 nm diode laser with 1 MHz radiofrequency (RF) energy with up to three treatment sessions showed more than 75% clearance in 77% of treatment sites when using 80–140 J/cm2 laser ﬂuence and 80–100 J/cm3 of RF energy with pulses of 100–300 ms duration.40 A 980 nm diode laser which was used with a contact cooling device, with ﬂuences between 300 and 500 J/cm2 and pulse durations of 150 ms achieved up to 50% clearance in 60% of patients; however, with such long pulse durations pain was pronounced in the majority of patients.41

1064 nm long-pulse Nd:YAG laser The wavelength of 1064 nm shows less absorption in melanin than shorter laser wavelengths and is less absorbed in hemoglobin. Because of the relatively low hemoglobin absorption, laser energy can also heat up the larger vessels as a whole. In 1999, Weiss and Weiss42 reported a study on 30 patients using a Nd:YAG laser at 1064 nm wavelength with a pulse duration of 16 ms. They observed a 75% improvement after a single treatment in 0.5–3.0 mm diameter vessels.42 Another study reported 64% clearance after a maximum of three treatment sessions using a 1064 nm Nd:YAG laser with a contact cooling device. This study used a 6 mm spot size, pulse durations up to 14 ms and a ﬂuence of 130 J/cm2 to treat vessel diameters between 0.2 and 4.0 mm.43 Clearances of 75–100% were achieved when using the Nd:YAG system for telangiectasias of only 1.0–4.0 mm diameter, but treating 0.1–1.0 mm vessels with a 550 nm IPL device.44 Interestingly, in comparison with Sotradecol (Bioniche Pharma, Belleville, ON, Canada) sclerotherapy, in leg telangiectasias of 0.25–3.0 mm diameter, the long-pulse Nd:YAG laser achieved equal results.45 Utilizing a spray cooling device, long-pulse Nd:YAG treatment of leg veins of 0.3–3.0 mm diameter showed clearance of more than 75% in 85% of treated sites after a maximum of three sessions.46 This ﬁnding was corroborated in vein diameters between 1.0 and 3.0 mm. With a single treatment using a ﬂuence of 100 J/cm2 and pulse duration of 50 ms a clearance of more than 75% was achieved in 66% of cases.47 In a highly interesting approach to take advantage of methemoglobin formation using a non-uniform pulse sequence, a French group achieved a clearance rate of 98% after three sessions. They used a 2 mm spot, ﬂuences between 300 and 360 J/cm2 and a contact cooling device to treat blue leg telangiectasias of diameters between 1 and 2 mm.48

Intense pulsed light Intense pulsed light sources make use of neither monochromatic nor coherent light emission. There is a polychromatic spectrum emitted which is deﬁned by ﬁlters placed between the IPL source and the patient. In its initial phase without concomitant use of special cooling devices, side-effects such as skin burns or hyperpigmentation could happen more easily than with today’s devices. However, even in its early days, IPL was able to achieve clearance of leg telangiectasias. In a multicenter trial treating 369 lesions in 159 patients, a clearance of more than 75% was achieved in 79% of vessels between 0.1 and 3 mm diameter. The rate of adverse effects was low.49 Also in the early days of IPL, another study showed that it is most effective in small red vessels with diameters below 0.2 mm with an immediate clearance of 82%, whereas only 60% clearance was achieved with IPL treatment of diameters between 0.5 and 1.0 mm.50 In a more recent comparative study between Nd:YAG and IPL, the IPL treatment was judged to be more effective in vessels with diameters below 1.0 mm whereas leg veins of more than 1.0 mm diameter were more effectively treated by the Nd:YAG laser.51 Logically, treatment approaches combining IPL treatment for smaller vessels with diameters below 1.0 mm and Nd:YAG laser treatment for vessels with diameters above 1.0 mm were reported to be very successful.44,52

COOLING SYSTEMS Skin cooling is crucial to minimize thermal side-effects on skin structures apart from telangiectasias. Today, cooling the skin with ice cannot be judged reproducible enough, but it is more reliable than the use of cooled gels. Gels provide a temperature decrease of only about 5°C and can even disturb the spot geometry of the laser beam and account for energy loss of about 35%.28 Reliable and more effective techniques are contact cooling devices,22,31,43 e.g., sapphire handpieces, dynamic spray cooling29,31,46 using tetraﬂuoroethane, or low temperature air-cooling devices.22,30,53 Also for IPL a collar contact cooling device improved clinical results allowing the delivery of higher ﬂuences with less pain.54

SIDE-EFFECTS AND COMPLICATIONS To identify patients prone to idiopathic hypersensitivity reactions after laser treatment, a test treatment of a small area is absolutely necessary before a full treatment session is administered. Furthermore, informed consent about the following treatment-related risks should be signed by the patient. The most frequent side-effects of laser treatment are:

Future directions 397

● ● ● ●

transient or, rarely, permanent hyperpigmentation telangiectatic matting incomplete elimination of telangiectasias treatment-related pain.

●

●

●

Restricted to special laser types, particularly to the older ﬂashlamp pumped dye lasers, is the side-effect of purpura. As described above, long-pulse alexandrite laser therapy of leg telangiectasias under certain conditions is associated with a pronounced inﬂammatory skin reaction. Hyperpigmentation can happen with the use of any laser or IPL light source but is more likely to happen after treatment of telangiectasias with shorter wavelength lasers such as 532 nm KTP devices. Patients with activation of their pigmentary system after sunny vacations or use of sunbeds should strictly avoid laser or IPL treatments. Likewise, sun exposure and use of sunbeds should be strictly avoided after laser therapy as long as any skin response is visible, usually for 3–4 weeks. Dark-skinned patients should be treated with special caution – if treated at all. A less frequent side-effect of laser treatment is thrombosis of telangiectasias, which is mostly associated with diameters above 1 mm. To accelerate the clearing of this phenomenon, any thrombosis should be removed by needle puncture within the ﬁrst week after treatment. Rare complications of laser treatment include blistering of the skin with or without subsequent scarring. These side-effects most frequently happen with overdosing of laser energy. Overdosing of laser or IPL can happen in conjunction with: ●

administration of too high ﬂuences

inadvertent pulse stacking or inadvertent overlapping of pulses intended pulse stacking with too short cooling intervals in between inappropriate cooling of the skin surface during treatment.

Also, laser treatment of skin which is covered with lotions or ointments can result in skin burns and hyperpigmentation. Removal of all of these external factors before laser treatment is therefore mandatory.

ALTERNATIVE TREATMENT OPTIONS The only serious alternative option to laser or IPL treatment of leg telangiectasias is sclerotherapy with liquid or foam sclerosants. The technique of sclerotherapy is presented in detail elsewhere in this book.

FUTURE DIRECTIONS The laser and IPL treatment of leg telangiectasias still offers great potential. Bimodal wavelength approaches, longer pulse durations, and improved skin cooling have contributed much to more effective laser and IPL treatment of leg telangiectasias.55 Despite a solid theoretical basis, concepts such as the exploitation of laser-induced methemoglobin formation are still not fully developed.48,56 Similarly, feedback loops for measurement of vessel and skin temperature during

Guidelines 4.7.0 of the American Venous Forum on percutaneous laser therapy of telangiectasias and varicose veins No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.7.1 For telangiectasias with vein diameters below 0.5 mm and for telangiectatic matting we recommend the ﬂashlamp pumped dye lasers at 595 nm wavelength

1

C

4.7.2 For telangiectasias with diameters below 0.7 mm we recommend the KTP (potassium titanylphosphate) laser at 532 nm wavelength

1

C

4.7.3 For large telangiectasias up to 3 mm vein diameter we suggest treatment with long-pulse Nd:YAG (neodymium-doped yttrium aluminum garnet) lasers at 1064 nm wavelength

2

C

4.7.4 During laser treatment we recommend cooling to avoid thermal skin damage using dynamic spray cooling, contact cooling, or cooled air

1

C

4.7.5 We do not recommend cosmetic laser treatment of leg telangiectasias in a tanned skin with increased melanin content after sun exposure

1

A

398

Percutaneous laser therapy of telangiectasias and varicose veins

laser treatment and subsequent online adjustment of laser ﬂuence and skin cooling are technically possible but have not yet been introduced into daily clinical practice. The same is true for automatic scanner systems that can direct the laser beam to the previously traced course of the target vessel.

CLINICAL PRACTICE GUIDELINES ●

●

●

●

For small leg telangiectasias with diameters below 0.5 mm and telangiectatic matting, ﬂashlamp pumped dye lasers at 595 nm are effective (26 [1C], 28 [1B], 30 [1C]). The KTP laser at 532 nm is suitable for diameters below 0.7 mm (18 [1C], 21 [1C]). Multipass treatment (18 [2C], 30 [2C]) or pulse stacking (20 [2C]) may improve clinical results. Larger telangiectasias up to 3 mm diameter can be effectively treated by long-pulse Nd:YAG lasers with 1064 nm wavelength (42 [1C], 45 [1C], 46 [1C], 47 [1C]). Effective skin cooling is mandatory to avoid thermal skin damage. Appropriate cooling devices are dynamic spray cooling (29 [1C], 31 [1C], 46 [1C]), contact cooling (22 [1C], 31 [1C], 43 [1C]), or cooled air (30 [1C]). Cooled gels provide neither sufﬁcient nor homogeneous skin cooling (28 [1C]). In human skin, melanin is the main competing light absorber to hemoglobin (13 [1A]); therefore, laser treatment of telangiectasias can cause the side-effect of long-lasting hyperpigmentation. An increased epidermal melanin content after sun exposure – a socalled tanned skin – therefore should be regarded as a contraindication to cosmetic laser treatment of leg telangiectasias.

REFERENCES ● ◆

= Key primary paper = Major review article ●1.

◆2.

◆3.

●4.

5.

6.

Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen Gesellschaft fuer Phlebologie. Phlebologie 2003; 32: 14. Goldman MP, Bennet RG. Treatment of telangiectasia: a review. J Am Acad Dermatol 1987; 17: 167–82. Neumann HAM, Kockaert MA. The treatment of leg telangiectasia. J Cosmet Dermatol 2003; 2: 73–81. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. Redisch W, Pelzer RH. Localized vascular dilatations of the human skin: capillary microscopy and related studies. Am Heart J 1949; 37: 106–8. De Faria JL, Moreas IN. Histopathology of the telangiectasias associated with varicose veins. Dermatologica 1963; 127: 321–9.

7. Weiss RA, Weiss MA. Doppler ultrasound ﬁndings in reticular veins of the thigh subdermic lateral venous system and implications for sclerotherapy. J Dermatol Surg Oncol 1993; 28: 7–12. ●8. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983; 220: 524–7. 9. Kienle A, Lilge L. Why do veins appear blue? A new look at an old question. Appl Opt 1996; 35: 1151–60. 10. Sommer A, van Mierlo PLH, Neumann HAM, Kessel AGH. Red and blue telangiectasias: difference in oxygenation? Dermatol Surg 1997; 23: 55–9. 11. Duffy DM. Small vessel sclerotherapy: an overview. Adv Dermatol 1988; 3: 221–42. 12. Goldman MP, Bergan J, Geux JJ. Sclerotherapy: Treatment of Varicose and Telangiectatic Veins (4 ed). Elsevier 2006 p 41. 13. Jaques SL. Skin optics summary. 1998. Available from: http://omlc.ogi.edu/news/jan98/skinoptics.html. ●14. Ross EV, Domankevitz Y. Laser treatment of leg veins: physical mechanisms and theoretical considerations. Lasers Surg Med 2005; 36: 105–16. 15. Kono T, Takashi Y, Ercocen AR, Fujiwara O. Treatment of leg veins with the long pulse dye laser using variable pulse durations and energy ﬂuences. Lasers Surg Med 2004; 35: 62–7. 16. Parlette EC, Groff WF, Kinshella MJ, et al. Optimal pulse durations for the treatment of leg telangiectasias with a neodym YAG laser. Lasers Surg Med 2006; 38: 98–105. 17. Adrian RM. Treatment of leg telangiectasias using a longpulse frequency-doubled neodymium YAG laser at 532 nm. Dermatol Surg 1998; 24: 19–23. 18. Bernstein EF, Kornbluth S, Brown DB, Black J. Treatment of spider veins using a 10 millisecond pulse-duration frequency-doubled neodym YAG laser. Dermatol Surg 1999; 25: 316–20. 19. West TB, Alster TS. Comparison of the long-pulse dye (590-595 nm) and KTP (532 nm) lasers in the treatment of facial and leg telangiectasias. Dermatol Surg 1998; 24: 221–6. 20. Fournier N, Brisot D, Mordon S. Treatment of leg telangiectases with a 532 nm KTP laser in multipulse mode. Dermatol Surg 2002; 28: 564–71. 21. Spendel S, Prandl EC, Schintler MV, et al. Treatment of spider leg veins with the KTP (532 nm) laser: a prospective study. Lasers Surg Med 2002; 31: 194–201. 22. Sadick NS, Weiss R. The utilization of a new yellow light laser (578 nm) for the treatment of class I red telangiectasia of the lower extremities. Dermatol Surg 2002; 28: 21–5. 23. Polla LL, Tan OT, Garden JM, Parrish JA. Tunable pulsed dye laser for the treatment of benign cutaneous vascular lesions. Dermatologica 1987; 174: 11–17. 24. Wiek K, Vanscheidt W, Ishkhanian S, et al. Selective photothermolysis of superﬁcial varicose veins telangiectasias of the lower extremity. Hautarzt 1996; 47: 258–63.

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25. Hsia J, Lowery JA, Zelickson B. Treatment of leg telangiectasia using a long-pulse dye laser at 595 nm. Lasers Surg Med 1997; 20: 1–5. 26. Reichert D. Evaluation of the long-pulse dye laser for the treatment of leg telangiectasias. Dermatol Surg 1998; 24: 221–6. 27. Bernstein EF, Lee J, Lowery J, et al. Treatment of spider veins with the 595 nm pulsed-dye laser. J Am Acad Dermatol 1998; 39: 746–50. 28. Hohenleutner U, Walther T, Wenig M, et al. Leg telangiectasia treatment with a 1.5 ms pulsed dye laser, ice cube cooling of the skin and 595 vs 600 nm: preliminary results. Lasers Surg Med 1998; 23: 72–8. 29. Buscher BA, McMeekin TO, Goodwin D. Treatment of leg telangiectasia by using a long-pulse dye laser at 595 nm with and without dynamic cooling. Lasers Surg Med 2000; 27: 171–5. 30. Tanghetti E, Sherr E. Treatment of telangiectasia using the multi-pass technique with the extended pulse width, pulsed dye laser. J Cosmet Laser Ther 2003; 5: 71–5. 31. Woo WK, Jasmin ZF, Handley JM. 532 nm Nd:YAG and 595 nm pulsed dye laser treatment of leg telangiectasia using ultralong pulse duration. Dermatol Surg 2002; 29: 1176–80. 32. McDaniel DH, Ash K, Lord J, et al. Laser therapy of spider leg veins: clinical evaluation of a new long pulsed alexandrite laser. Dermatol Surg 1999; 25: 52–8. 33. Eremia S, Li C, Umar SH. A side-by-side comparative study of 1064 nm Nd:YAG, 810 nm diode and 755 nm alexandrite lasers for treatment of 0.3–3.0 mm leg veins. Dermatol Surg 2002; 28: 224–30. 34. Brunnberg S, Lorenz S, Landthaler M, Hohenleutner U. Evaluation of the long pulsed high ﬂuence alexandrite laser therapy of leg telangiectasia. Lasers Surg Med 2002; 31: 359–62. 35. Varma S, Lanigan SW. Laser therapy of telangiectatic leg veins: clinical evaluation of the 810 nm diode laser. Clin Exp Dermatol 2000; 25: 419–22. 36. Kaudewitz P, Klovekorn W, Rother W. Effective treatment of leg vein telangiectasia with a new 940 nm diode laser. Dermatol Surg 2001; 27: 101–6. 37. Kaudewitz P, Klovekorn W, Rother W. Treatment of leg vein telangiectases: 1-year results with a new 940 nm diode laser. Dermatol Surg 2002; 28: 1031–4. 38. Passeron T, Olivier V, Duteil L, et al. The new 940 nm diode laser: an effective treatment for leg venulectasia. J Am Acad Dermatol 2003; 48: 768–74. 39. Wollina U, Konrrad H, Schmidt WD, et al. Response of spider leg veins to pulsed diode laser (810 nm): a clinical, histological and emission spectroscopy study. J Cosmet Laser Ther 2003; 5: 154–62. 40. Chess C. Prospective study on combination diode laser and radiofrequency energies (ELOS) for the treatment of leg veins. J Cosmet Laser Ther 2004; 6: 86–90.

41. Levy JL, Berwald C. Treatment of vascular abnormalities with a long-pulse diode at 980 nm. J Cosmet Laser Ther 2004; 6: 217–21. 42. Weiss RA, Weiss MA. Early clinical results with a multiple synchronized pulse 1064 nm laser for leg telangiectasias and reticular veins. Dermatol Surg 1999; 25: 399–402. 43. Sadick NS. Long-term results with a multiple synchronized-pulse 1064 nm Nd:YAG laser for the treatment of leg venulectasias and reticular veins. Dermatol Surg 2001; 27: 365–9. 44. Sadick NS. A dual wavelength approach for laser/intense pulsed light source treatment of lower extremity veins. J Am Acad Dermatol 2002; 46: 66–72. 45. Coles CM, Werner RS, Zelickson BD. Comparative pilot study evaluating the treatment of leg veins with a long pulse Nd:YAG laser and sclerotherapy. Lasers Surg Med 2002; 30: 154–9. 46. Eremia S, Li Cy. Treatment of leg and face veins with a cryogen spray variable pulse width 1064- nm Nd:YAG laser: a prospective study of 47 patients. J Cosmet Laser Ther 2001; 3: 147–53. 47. Omura NE, Dover JS, Arndt KA, Kauvar AN. Treatment of reticular leg veins with a 1064 nm long-pulsed Nd:YAG laser. J Am Acad Dermatol 2003; 48: 76–81. ●48. Mordon S, Brisot D, Fournier N. Using a “non uniform pulse sequence” can improve selective coagulation with a Nd:YAG laser (1.06 microm) thanks to met-hemoglobin absorption: a clinical study on blue leg veins. Lasers Surg Med 2003; 32: 160–70. 49. Green D. Photothermal sclerosis of leg veins. Dermatol Surg 1997; 23: 303–5. 50. Schroeter C, Wilder D, Reineke T, et al. Clinical signiﬁcance of an intense pulsed light source on leg telangiectasias of up to 1 mm diameter. Eur J Dermatol 1997; 7: 38–42. 51. Fodor L, Ramon Y, Fodor A, et al. A side-by-side prospective study of intense pulsed light and Nd:YAG laser treatment for vascular lesions. Ann Plast Surg 2006; 56: 164–70. 52. Colaiuda S, Colaida F, Gasparotti M. Treatment of deep underlying reticular veins by Nd:YAG laser and IPL source. Minerva Cardioangiol 2000; 48: 329–34. ◆53. Alora MBT, Anderson RR. Recent developments in cutaneous lasers. Lasers Surg Med 2000; 26: 108–18. 54. Weiss RA, Sadick NS. Epidermal cooling crystal collar device for improved results and reduced side effects on leg telangiectasias using intense pulsed light. Dermatol Surg 2000; 26: 1015–18. 55. Sadick N, Weiss R, Goldman M. Advances in laser surgery for leg veins: bimodal wavelength approach to lower extremity vessels, new cooling techniques and longer pulse durations. Dermatol Surg 2002; 28: 16–20. ●56. Mordon S, Rochon P, Dhelin G, Lesage JC. Dynamics of temperature dependent modiﬁcations of blood in the near infrared. Lasers Surg Med 2005; 37: 301–7.

35 Surgical treatment of the incompetent saphenous vein ADAM HOWARD, DOMINIC P.J. HOWARD AND ALUN H. DAVIES Introduction History and development of saphenous varicosity surgery Clinical presentation and assessment of saphenous incompetence Investigation of saphenous incompetence Treatment options for saphenous incompetence Surgical treatment of primary saphenous incompetence Complications of varicose vein surgery and their prevention

400 400 401 402 403 403 404

INTRODUCTION Incompetence of the great saphenous vein (GSV) and the small saphenous vein (SSV) commonly results in the clinical presentation of varicose veins with the associated symptoms of leg aching, itching, throbbing, and cosmetic unsightliness. However, saphenous incompetence can present with or lead to “skin changes of venous hypertension,” frank ulceration, superﬁcial thrombophlebitis, and/or spontaneous hemorrhage. Lower limb venous insufﬁciency causes signiﬁcant socioeconomic, health, and medical problems. Major trunk varicosities have been found in a cross-sectional population survey to affect approximately 40% of men and 30% of women, with a higher proportion of both sexes with reticular varices.1 The presence of venous disease has a negative impact on the quality of life of patients;2 a Scandinavian study reported that approximately one in 10 patients with venous insufﬁciency was unable to attend their employment.3 In the UK, approximately 80 000 varicose vein operations are performed each year,4 and the treatment of lower limb venous disease accounts for up to 2% of total healthcare expenditure.5 In the USA, reports of the prevalence of chronic venous insufﬁciency vary from < 1% to 40% in females and from < 1% to 17% in males, whereas prevalence estimates for varicose veins are higher at < 1% to 73% in females and between 2% and 56% in males.6

Surgery for recurrent saphenous incompetence The role of surgery in chronic venous insufﬁciency Outcome assessment and quality of life in patients with saphenous incompetence Integrated care pathway Conclusions Clinical practice guidelines References

404 405 405 405 405 406 406

HISTORY AND DEVELOPMENT OF SAPHENOUS VARICOSITY SURGERY Reports of varicose veins span back before 2000 BC, and one of the earliest reliable reports of varicose vein surgery is from AD 1465 in a Turkish surgical text Imperial Surgery. In 1891, Frederick Trendelenburg, the surgeon-in-chief at Leipzig, developed the surgical treatment of varicose veins by advocating the ligation of the GSV at the mid-thigh level. However, it was not until the beginning of the twentieth century when Tavel recommended ligation of the saphenofemoral venous junction (SFJ) and Keller and Mayo suggested stripping of the GSV that the operative techniques started to become more reﬁned.7,8 From the 1930s to the 1950s Linton and Cockett described the surgical treatment of perforator veins by subfascial ligation,9 but these techniques have been superseded by the subfascial endoscopic perforator surgery (SEPS) technique, which has the beneﬁt of avoiding large incisions in areas of compromised skin integrity. However, the indication for SEPS has met some resistance from parts of the vascular surgical community. The problem of recurrent saphenous incompetence soon became signiﬁcant and clinical trials to investigate the sources of recurrence have since been performed. Recurrent varicosities were found to be due to either “new” varicosities at sites separate from the previous surgery, “persistent” varicosities – missed at the original surgery –

Clinical presentation and assessment of saphenous incompetence 401

and “true” recurrent varicosities caused by duplex saphenous systems, perforating veins, and neovascularization. Studies have shown that stripping of the long saphenous vein signiﬁcantly reduces recurrence.10–13 In order to combat the regrowth of neovasculature between remnant thigh varicosities and the saphenofemoral stump, a number of surgeons have investigated techniques that incorporated the use of a “barrier” between the two by interpositioning a prosthetic mesh, a polytetraﬂuoroethylene patch, pectineus ﬂap, or preventing exposure of the endothelium with non-absorbable suture closure. These techniques have had variable results.14–17 Other ingenious techniques with reported low-recurrence rates have been described that avoid transection and stripping of the GSV by performing external or open valvular repair at the SFJ.18,19 More recently preoperative duplex ultrasound imaging has become the vogue for primary varicose veins because of the theoretical reduction in great and small saphenous recurrence when the surgery is tailored to the duplex ﬁndings; however, there are no randomized data to conﬁrm these suppositions.2,20,21 In addition, duplex ultrasound provides improved accuracy with the positioning of the incision for saphenopopliteal ligation and information on the status of any concurrent deep venous disease. During the last decade new minimally invasive techniques have become more prominent in the surgical management of saphenous incompetence, these include endovenous laser therapy (EVLT), radiofrequency, and duplex-guided foam sclerotherapy. These potentially offer reduced complications and operative time, increased use of local anesthetic rather than general anesthetic techniques, and outpatient varicose vein treatment. The short-term recurrence rates are similar to open surgery; however, the longer term recurrence of these new treatment modalities is under investigation.22

CLINICAL PRESENTATION AND ASSESSMENT OF SAPHENOUS INCOMPETENCE Symptoms of saphenous varicosities The patients’ complaints about varicosities can be divided into physical and psychological symptoms. The physical symptoms frequently include pain, swelling, heaviness, itching, and cramps. The symptoms tend to be more pronounced toward the end of the day, especially after long periods of standing. More severe symptoms are related to complicated varicosities such as those causing venous ulceration. Psychological symptoms are related to the cosmetic appearance of varicose veins and reduced quality of life.

Clinical signs of saphenous varicosities Saphenous varicose veins are visible, palpable, dilated (> 4 mm), tortuous, elongated, subcutaneous veins that

are usually clearly visible apart from in the obese patient. Varicose veins are classiﬁed into trunk varices and tributaries, reticular varices, and thread veins. The last two are very superﬁcial subcutaneous and dilated intradermal venules, respectively, that have no direct connection with saphenous varices. Superﬁcial thrombophlebitis, bleeding, varicose eczema, pigmentation, lipodermatosclerosis, and venous ulceration can complicate simple varicose veins.

Taking a relevant history It is important to ensure when questioning a patient that the symptoms are due to venous disease by excluding musculoskeletal, neurological, dermatological, and arterial causes of lower extremity conditions. However, any of these conditions can coexist with varicose veins and the relative contributions of their symptoms and their effect on potential complications need to be taken into account before considering venous intervention. A clear history of venous thromboembolism, previous venous ulceration, and surgery must be obtained. In women, a history of vulval varices, secondary to internal iliac and ovarian vein incompetence, should be sought as these can be present in conjunction with saphenous varices and the history is often not forthcoming. Extensive unilateral varicose veins in a young person should raise the clinician’s suspicion for Klippel–Trenaunay–Weber syndrome. Patients have a classic triad of venous varicosities, limb hypertrophy, and port-wine staining. These patients have an abnormal or absent deep venous system. An appraisal for the patient’s safety with regard to the planned intervention from a medical and anesthetic point of view is also vital together with consideration for the need for venous thromboprophylaxis.

Physical examination The patient should be examined after standing for more than 2 minutes in a warm room with good lighting. The leg in question needs to be slightly ﬂexed at the hip and knee with the body weight supported by the contralateral leg. Inspection of great (Fig. 35.1) and small (Fig. 35.2) saphenous varicosities should be made, taking into account any skin changes (Fig. 35.3) associated with chronic venous insufﬁciency. Varicosities can then be palpated, a cough impulse is often present with saphenofemoral incompetence, the “tap” test will indicate possible trunk valvular reﬂux, and the Tredelenburg–Brodie test may also provide information on the possible sites of incompetence; however, these tests can be unreliable. Perthes’ test is rarely used. The use of hand-held Doppler (continuous-wave Doppler) has largely replaced these clinical bedside tests. The use of hand-held Doppler (HHD) can be learnt so as to provide up to 95% accuracy for detecting GSV insufﬁciency.23 In general, HHD is

402

Surgical treatment of the incompetent saphenous vein

commonly used to reliably detect venous trunk insufﬁciency, but the suspected presence of incompetent SSV, perforating veins, and/or deep veins or the presence of recurrent varicose veins normally requires the use of duplex ultrasound, which is a combination of color Doppler and B-mode imaging.

INVESTIGATION OF SAPHENOUS INCOMPETENCE

Figure 35.1 Great saphenous varicosities.

Over the last two decades the investigations for venous disease have become more accurate and increasingly less invasive. Generally, investigations provide either anatomical information for diagnosis and planning surgical management or functional information that provides a measure of the severity of the venous disease and thereby further delineates the need for intervention.

Duplex ultrasound

Figure 35.2 Small saphenous varicosities.

Duplex ultrasound assessment should ideally be performed on the majority of patients with saphenous incompetence who are likely to undergo surgery.2,20,21 Some may argue that clinical examination with HHD is adequate, but a proportion of patients may receive inappropriate or insufﬁcient venous surgery as a result of not undergoing duplex assessment.24,25 Duplex imaging has also been used to identify a proportion of patients who have segmental saphenous incompetence, whereby parts of the GSV trunk or the SFJ may not be incompetent in the presence of GSV varicosities. This has led to selective surgery for only the incompetent segments, which has the beneﬁt of reduced morbidity and preservation of vein for future arterial bypass surgery. This approach is popular in some parts of the USA; nevertheless, it is not commonplace in the UK. Long-term studies have shown that a preserved varicose GSV is rarely used later in life for arterial surgery.26

Venography

Figure 35.3 Lipodermatosclerosis and pigmentation.

Traditional venography has largely been superseded by duplex ultrasound mainly because of its invasive nature. However, ascending venography provides practical anatomical information on the deep veins of the leg and can be useful at investigating the iliac and the inferior vena cava when the body habitus of the patient negates the use of duplex. Still, the advent of magnetic resonance and computed tomographic venography have reduced further the use of traditional contrast venography as these modalities are particularly good at investigating these areas for venous disease and for venous malformations.

Surgical treatment of primary saphenous incompetence 403

Peroperative varicography for identiﬁcation of the saphenopopliteal junction (SPJ) and origins of recurrent incompetence again is rarely used unless duplex is not available.

Other investigations These investigations are used in venous research or if the assessment of venous symptoms and function proves difﬁcult. Plethysmography provides functional detail on venous incompetence, such as venous reﬁlling times, venous outﬂow rates from the leg, residual volume fractions, and calf muscle pump function. Ambulatory venous pressure measurement provides a direct assessment of superﬁcial venous pressure at the foot level. Foot volumetry is a non-invasive test that monitors changes in foot volume after ankle exercises.

TREATMENT OPTIONS FOR SAPHENOUS INCOMPETENCE A conservative approach to saphenous varicosities should always be considered especially in the elderly or in those with signiﬁcant comorbidity. Compression hosiery is the mainstay of conservative treatments along with skin emollients and leg elevation. Graduated compression with at least 20 mmHg at the ankle helps to relieve symptoms, conceal varicosities, and reduce the progression of skin changes. The main problem is the compliance of wearing stockings, particularly in the young, who often refuse. For young patients and older patients who are deemed safe for surgery, there are a number of interventional alternatives. Open surgery still remains the “gold standard”; however, this may not be for much longer. The long-term data on less invasive laser ablation and duplex-guided foam sclerotherapy techniques will provide a better guide on the future indications of speciﬁc treatment modalities. Nevertheless, as these techniques seem to be less invasive and hence can easily be repeated with minimal morbidity, they will probably remain as a major part of the practice even if their long-term recurrence rates are found to be only similar to superﬁcial venous surgery. Informed consent is a vital aspect of the surgical management of saphenous insufﬁciency. Correctly obtained written informed consent and good communication are necessary to ensure that the patient understands the potential beneﬁts and complications of varicose vein surgery. This process avoids inappropriate surgery, patient dissatisfaction, and complaints. The patient should be warned about the risks of wound infection, bruising, paresthesiae, deep vein thrombosis, residual veins after surgery (and that these can undergo subsequent injection sclerotherapy), recurrence, and any associated risks of the anesthetic.

SURGICAL TREATMENT OF PRIMARY SAPHENOUS INCOMPETENCE Surgery for the great saphenous vein Saphenous surgery is usually a day surgical procedure frequently under general anesthetic or occasionally under regional anesthesia. A suitably prepared patient undergoes sharp dissection of the saphenofemoral junction via a groin skin crease incision, in the “head-down” supine position with the hip (and knee) partially ﬂexed and externally rotated. In the obese patient, the incision is positioned more cranially as the SFJ lies above the skin crease. In order to aid the positioning and limit the size of the groin incision we mark preoperatively the site of the cough impulse produced at the SFJ on standing. All tributaries should be ligated and transected beyond the secondary branch to prevent redirection of superﬁcial venous ﬂow and subsequent recurrence. The SFJ should be ligated or transﬁxed ﬂush with the common femoral vein (CFV) without causing narrowing and then transected. Some authors recommend non-absorbable suture closure for the SFJ and absorbable suture for the tributaries.17 Care should be taken with the superﬁcial external pudendal artery that passes between the GSV and CFV at the level of the SFJ; this vessel also acts as a useful anatomical landmark but can pass anterior to the GSV in 5–10% of cases. The deep external pudendal vein and posteromedial and anterolateral thigh branches of the GSV should be ligated and transected. The GSV should be removed to a level just below the knee so as to deal with the below-knee perforating vein of Boyd. Stripping of the GSV to the ankle increases the risk of saphenous nerve damage.27–29 There are a number of different options for removing the GSV; most commonly this is by stripping or by segmental avulsion, which is recommended by some surgeons because of the potential for less saphenous nerve damage and tissue trauma. Stripping requires plastic or metal wires or rods. The Babcock device is an intraluminal stripper with an acorn-shaped head that pleats up the vein as it pulls the vessel loose from its attachments. The “acorn” stripper head is still used by many surgeons, but this creates a subcutaneous tunnel around the GSV and, in order to prevent a large exit wound around the knee, it should be retrieved out of the groin wound (once the GSV has been stripped) by using a pre-tied long ligature. The PIN (perforation–invagination) stripper consists of a rod that punctures the vein at the knee level, and a small skin exit incision (approximately 3 mm) is used to retrieve the stripper along with the disconnected GSV. We use a plastic stripping wire without the use of an “acorn” and secure the proximal transected end of the GSV to the stripper with a long “heavy” ligature to enable the removal of the “stripped vein” and stripper from the groin wound. Subsequent multiple avulsions or phlebectomies are performed on the remaining GSV varicosities. These are performed with phlebectomy “hooks” or “mosquito”

404

Surgical treatment of the incompetent saphenous vein

artery forceps via small 2–3 mm incisions. Phlebectomy incisions can be made in the direction of Langer’s lines or in the transverse direction, which we prefer; we recommend 6/0 non-absorbable suture closure of these incisions. For cosmetic reasons, the size of the phlebectomy incisions can be minimized by using an ophthalmic Beaver scalpel or a 19G needle. Phlebectomies should be avoided over the head of the ﬁbula and around and below the ankle joint for fear of causing nerve or arterial injury respectively. Inﬁltration of the groin wound with long-acting local anesthetic has been shown to reduce postoperative opiate requirements.30 The leg is dressed and bandaged with crepe or a graduated compression stocking.

Surgery for the small saphenous vein This procedure is commonly carried out with the patient anesthetized in the prone position; however, some surgeons recommend the lateral position. A small transverse popliteal skin crease incision is made just below the level (approximately 1.5 cm) of the SPJ that has been accurately determined and marked on a preoperative duplex scan. The proximal SSV and SPJ is exposed. Care must be taken with retraction and the use of diathermy below the deep fascia because of the nearby common peroneal nerve and sural nerve (which can be adherent to the SSV); we use a small self-retractor positioned above the deep fascia. Flexion of the knee joint improves the visualization of the SPJ in the popliteal fossa and subsequent dissection. The SPJ is then ligated and the SSV transected at this level. There is debate over whether it is safe to strip the SSV to the mid-calf level, segmentally avulse or just to remove a short segment (~10 cm). A survey from the Vascular Society of Great Britain and Ireland revealed that most vascular surgeons performed dissection to identify the SPJ without formal exposure of the popliteal vein and most excise a proximal 10 cm of SSV rather than strip.31 Care should be taken with phlebectomies in the SSV region as inaccurate use of the “hook” may avulse the sural nerve in the lower calf where it lies more superﬁcially.

weeks. Wound infections most commonly occur after groin exploration and have a prevalence of about 1%. Nerve injury ranges from temporary numb patches over phlebectomy sites, which are very common, to true permanent neuropraxia of either the saphenous nerve during stripping of the GSV below the knee or the sural nerve during surgery for the SSV in the popliteal fossa. True permanent neuropraxia may occur in up to 5% of patients. Other signiﬁcant complications include healing ﬁbrosis and recurrence of disease. Healing ﬁbrosis can produce ﬁrmness under the operation scars or in the line of the removed veins. The traditional surgical technique is associated with long-term recurrence rates of approximately 20–30%.32,33 The cause of recurrence is not clear and may include inaccurate initial diagnosis, surgical technique, development of new veins (neovascularization), or progression of the underlying disease. Operative complications can be kept to a minimum by complying with the following evidence-based recommendations. ●

●

●

●

●

●

●

●

●

Dividing the GSV tributaries beyond the secondary branch may reduce recurrence [2C]. Excluding the exposed SFJ endothelium with a nonabsorbable suture closure reduces neovascularization [2B]. Stripping of the GSV to the knee, as discussed earlier, has been shown to reduce recurrence10–13 [1A]. Stripping of the GSV to the knee level and not to the ankle reduces the rate of neuropraxia by two- to ﬁvefold to approximately 10%34,35 [1B]. PIN or inversion stripping and segmental avulsion of the GSV reduces hematoma formation36–38 [1B]. Tourniquet use around the thigh has been shown to reduce intraoperative blood loss and subsequent hematoma formation39,40 [1B]. Postoperative compression bandaging has also been shown to reduce hematoma formation41 [1C]. Postoperative pain is treated effectively with intraoperative local anesthetic, systemic analgesia and postoperative non-steroidal anti-inﬂammatory drugs42,43 [1C]. Performing bilateral varicose vein surgery has not been shown to increase complications44 [2B].

COMPLICATIONS OF VARICOSE VEIN SURGERY AND THEIR PREVENTION Varicose vein surgery can be complicated by any of the recognized complications associated with open limb surgery. These relate to the mode of anesthetic and/or to the incisions and subsequent dissection. The early complications of surgery include discomfort, bruising, bleeding, wound infections, deep venous thrombosis, and nerve injury. It is common for a small amount of blood to ooze from phlebectomy sites during the ﬁrst 12 hours; this usually stops spontaneously, especially if light pressure is applied. Bruising is variable and normally clears within 3

SURGERY FOR RECURRENT SAPHENOUS INCOMPETENCE The indications for surgery on recurrent disease are the same as those for primary disease. However, the outcome of recurrent varicose veins surgery is often less successful and associated with more complications. A classiﬁcation of recurrent varicose veins was devised by Stonebridge et al.45 The majority of recurrences are due to inadequate groin surgery, i.e., failure to divide the saphenous vein ﬂush with the common femoral vein or to perform stripping.

Integrated care pathway

Clinically relevant recurrence at the SFJ or SPJ is considered to be greater than 3 mm in diameter on duplex.32 The main principle with repeating groin surgery is that the SFJ should not be approached directly through the previous scar tissue, as this may lead to signiﬁcant bleeding and inadvertent damage to the common femoral vein and an increased likelihood of inadequate surgery. The junction should be approached usually by a lateral approach. The artery is exposed and the dissection continued medially to the “SFJ recurrence,” which is ligated and divided before more superﬁcial dissection is commenced. It is important to strip the long saphenous vein if this has not been performed at the primary operation. Recurrent tributaries undergo phlebectomy as for primary varicosities. Recurrent surgery for the SSV and dissection of the SPJ is similar to the technique for primary SSV surgery; the associated artery is not usually exposed as with recurrent SSV surgery. However, it must be stated that the recent increase in popularity for EVLT has given vascular surgeons a foretaste of the potential impact that this modality will probably have on recurrent venous surgery as EVLT has the advantage of avoiding the need for a recurrent groin incision and dissection.

THE ROLE OF SURGERY IN CHRONIC VENOUS INSUFFICIENCY Treatment goals for patients with chronic venous insufﬁciency include reduction of edema, lipodermatosclerosis (a ﬁbrosing panniculitis of the subcutaneous tissue), and healing of ulcers. Superﬁcial vein surgery has been evaluated both for the treatment of venous ulcers and for prevention of recurrence. Surgery is thought to produce beneﬁcial effects via reduction of venous reﬂux from the deep to the superﬁcial veins by removing incompetent superﬁcial veins, thereby modifying the effect of venous hypertension upon the cutaneous tissues.46 Regarding venous ulceration speciﬁcally, randomized trials have found that superﬁcial venous surgery did not improve ulcer healing but signiﬁcantly reduced ulcer recurrence compared with compression therapy alone.47,48 Surgery is not recommended in patients who are at signiﬁcant risk of venous thromboembolism and/or anesthetic complications.

OUTCOME ASSESSMENT AND QUALITY OF LIFE IN PATIENTS WITH SAPHENOUS INCOMPETENCE The outcome of varicose vein surgery can be assessed subjectively by measuring improvements in symptoms, appearance, and functioning, or objectively by recording the success of the procedure with regard to cosmetic

405

improvements, recurrence, ulcer healing, and complications. Health-related quality of life (HRQL) assessments and symptom and clinical severity scores have been formally developed over recent decades to provide subjective outcome evaluation in vascular surgery. Generic measures of HRQL and disease-speciﬁc HRQL measures have shown that varicose vein surgery improved the quality of life of patients. These studies used the SF-36 alone,49,50 in combination with the Aberdeen Varicose Veins Questionnaire (AVVQ),51 a speciﬁc HRQL, and the AVVQ alone.52 Objective measurements of the severity of varicose veins and venous disease in general have been developed for clinical, audit, and research purposes. These include the clinical–etiology–anatomy–physiology (CEAP) classiﬁcation for chronic venous disorders, which was recently revised by the American Venous Forum53 and the Venous Clinical Severity Score (VCSS).54

INTEGRATED CARE PATHWAY The nature of varicose vein surgery permits the system of the “integrated care pathway” to be adopted as the treatment typically follows a similar pathway of management steps for each patient, especially if performed as a day-case procedure.55 The integrated care pathway (ICP) involves ﬁve main steps for each patient: 1. 2. 3. 4. 5.

preassessment pre-procedure preparation surgical treatment postoperative recovery discharge preparation.

These steps are performed by all members of the health professional team and the clinicians’ documentations are recorded in a proforma-based ICP booklet kept within the patient’s hospital notes. The ICP and booklet ensures that all of the relevant steps for each patient undergoing varicose vein surgery are efﬁciently carried out and correctly recorded.

CONCLUSIONS Saphenous varicosities and the complications of saphenous incompetence are common conditions that interfere with patients’ quality of life and activities of daily living. The surgical treatment has been developed over many years with the major advances achieved over the last 50 years. The key management and technical points for successful saphenous varicosity surgery are summarized below. Open saphenous surgery remains the “gold standard”; however, this may change in the foreseeable future with

406

Surgical treatment of the incompetent saphenous vein

Guidelines 4.8.0 of the American Venous Forum on surgical treatment of the incompetent saphenous vein No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.8.1 For treatment of the incompetent great saphenous vein we recommend high ligation and inversion stripping of the saphenous vein to the level of the knee

1

B

4.8.2 To decrease recurrence we suggest ligation and division of the saphenous vein tributaries beyond their secondary branches

2

C

4.8.3 To reduce hematoma formation we recommend postoperative compression bandage

1

C

the recent introduction of catheter-directed endovenous ablation techniques, particularly for recurrent varicosity surgery. At present, the short-term efﬁcacy of endovenous laser treatment seems to be similar to that of surgical saphenectomy.22 Therefore, saphenectomy may be a much less attractive alternative for patients if the long-term efﬁcacy of these minimally invasive procedures proves to be similar to that of surgery. The future of traditional varicose vein surgery therefore depends on the long-term efﬁcacy of the catheter-directed endovenous ablation techniques.

2.

3.

4.

CLINICAL PRACTICE GUIDELINES

5.

●

6.

●

●

●

●

●

Adequate informed consent is necessary to ensure patient satisfaction and appropriate surgery (56 [1C]). Preoperative duplex ultrasound is indicated for SSV and recurrent saphenous surgery (23 [1B]) and ideally for before primary varicosity surgery (2, 20, 21 [1B]). Dividing the GSV tributaries beyond the secondary branch may reduce recurrence [2C]. Stripping of the GSV to the knee, as discussed above, has been shown to reduce recurrence (10–13 [1A]) and neuropraxia (34,35 [1B]). Inversion stripping and segmental avulsion of the GSV reduces hematoma formation (36,37 [1B]). The surgical treatment of saphenous incompetence is amenable to management by an integrated care pathway (55 [1C]).

7.

8. 9.

●10.

11.

REFERENCES 12. = Key primary paper ◆ = Major review article ★ = First formal publication of a management guideline ●

13. ●1.

Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins and chronic venous insufﬁciency in men and

women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 1999; 53: 149–53. Blomgren L, Johansson G, Bergqvist D. Quality of life after surgery for varicose veins and the impact of preoperative duplex: results based on a randomised trial. Ann Vasc Surg 2006; 20: 30–4. Biland L, Widmer LK. Varicose veins and chronic venous insufﬁciency: medical and socioeconomic aspects, Basle study. Acta Chir Scand 1988; 544: 9–11. Williams B, McGill J, Rushton L. Private funding of elective hospital treatment in England and Wales, 1997–8: national survey. Br Med J 2000; 320: 904–5. Laing W. Chronic Venous Diseases of the Leg. London: Ofﬁce of Health Economics, 1992. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufﬁciency and varicose veins. Ann Epidemiol 2005; 15: 175–84. Bernstein M, Koo HP, Bloom DA. Beyond the Trendelenburg position: Friedrich Trendelenburg’s life and surgical contributions. Surgery, St Louis 1999; 126: 78–82. Browse NL, Burnand KG, Lea Thomas M. Diseases of the Veins. London: Edward Arnold, 1988. Linton RR. The communicating veins of the lower leg and the operative technique for their ligation. Ann Surg 1938; 107: 582–93. Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ. Stripping the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: ﬁve year results. J Vasc Surg 1999; 29: 589–92. Munn SR, Morton JB, Macberth WAAG, McLeish AR. To strip or not to strip the long saphenous vein. A varicose vein trial. Br J Surg 1981; 68: 426–8. Rutgers PH, Kitslar PJEHM. Randomised trial of stripping versus high ligation combined with sclerotherapy in the treatment of the incompetent greater saphenous vein. Am J Surg 1994; 168: 311–15. Sarin S, Scurr JH, Coleridge-Smith PR. Stripping of the long saphenous vein in the treatment of primary varicose veins. Br J Surg 1994; 81: 1455–8.

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31.

Glass GM. Prevention of recurrent saphenofemoral incompetence after surgery for varicose veins. Br J Surg 1989; 76: 210. Earnshaw JJ, Davies B, Harradine K, Heather BP. Preliminary results of PTFE patch. Saphenoplasty to prevent neovascularisation leading to recurrent varicose veins. Phlebology 1998; 13: 10–13. Gibbs P, Foy DMA, Darke SG. Recurrent varicose veins: to patch or not to patch. Br J Surg 1999; 86: A112–13. Frings N, Nelle A, Tran P, et al. Reduction of neoreﬂux after correctly performed ligation of the saphenofemoral junction. A randomised trial. Eur J Vasc Endovasc Surg 2004; 28: 246–52. Lane RJ, Graiche JA, Coroneos JC, Cuzzilla ML. Long-term comparison of external valvular stenting and stripping of varicose veins. ANZ J Surg 2003; 73: 605–9. Yamaki T, Nozaki M, Sasaki K. Alternative greater saphenous vein-sparing surgery: valvuloplasty combined with axial transposition of competent tributary vein for the treatment of primary valvular incompetence: 18 month follow-up. Dermatol Surg 2002; 28: 162–7. Jutley RS, Cadle I, Cross KS. Preoperative assessment of primary varicose veins: a duplex study of venous incompetence. Eur J Vasc Endovasc Surg 2001; 21: 370–3. Blomgren L, Johansson G, Bergqvist D. Randomised clinical trial of routine preoperative duplex imaging before varicose vein surgery. Br J Surg 2005; 92: 688–94. Min RJ, Zimmet SE, Isaacs MN, Forrestal MD. Endovenous laser treatment of the incompetent greater saphenous vein. J Vasc Interv Radiol 2001; 12: 1167–71. Darke SG, Vetrivel S, Foy DMA, et al. A comparison of duplex scanning and continuous wave Doppler in the assessment of primary and uncomplicated varicose veins. Eur J Vasc Endovasc Surg 1997; 14: 457–61. Mercer KG, Scott DJA, Berridge DC. Preoperative duplex imaging is required before all operations for primary varicose veins. Br J Surg 1998; 85: 1495–7. Wills V, Moylan D, Chambers J. The use of routine scanning in the assessment of varicose veins. ANZ J Surg 1998; 68: 41–4. Hammersten J, Pedersen P, Cederlund CC, Campanello M. Long saphenous vein-saving surgery for varicose veins. A long-term follow-up. Eur J Vasc Surg 1990; 4: 361–4. Negus D. Should the incompetent saphenous vein be stripped to the ankle? Phlebology 1986; 1: 33–6. Cox SJ, Wellwood JM, Martin A. Saphenous nerve injury caused by stripping of the long saphenous vein. Br Med J 1974; 1: 415–17. Docherty JGL, Morrice JJ, Ben G. Saphenous neuritis following varicose vein surgery. Br J Surg 1994; 81: 695–8. Onuma OC, Beam PE, Khan U, et al. The inﬂuence of the effective analgesia and general anaesthesia on patients’ acceptance of day case varicose vein surgery. Phlebology 1993; 8: 29–31. Winterborn RJ, Campbell WB, Heather BP, Earnshaw JJ. The management of short saphenous varicose veins: a survey of

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the members of the vascular society of Great Britain and Ireland. Eur J Vasc Endovasc Surg 2004; 28: 400–3. Hartmann K, Klode J, Pﬁster R, et al. Recurrent varicose veins: sonography-based re-examination of 210 patients 14 years after ligation and saphenous vein stripping. Vasa 2006; 35: 21–6. Porter JM; Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: 635–45. Critchley G, Handa A, Maw A, et l. Complications of varicose vein surgery. Ann R Coll Surg Engl 1997; 79: 105–10. Holme J, Sjkajaa K, Holme K. Incidence of lesions of the saphenous nerve after partial or complete stripping of the long saphenous vein. Acta Chir Scand 1990; 156: 145–8. Khan RBN, Khan SN, Greaney MG, Blair SD. Prospective randomised trial comparing sequential avulsions with stripping of the long saphenous vein. Br J Surg 1996; 83: 1559–62. Lacroix H, Nevelsteen A, Suy R. Invaginating versus classic stripping of the long saphenous vein. A randomised prospective study. Acta Chir Belg 1999; 99: 22–5. Durkin MT, Turton EPL, Scott DJA, Kent P. A prospective randomised trial of PIN versus conventional stripping in varicose vein surgery. Ann R Coll Surg Engl 1999; 81: 171–4. Rigby KA, Palfreyman SJ, Beverley C, Michaels JA. Surgery for varicose veins: use of tourniquet. Cochrane Database Syst Rev 2002; Issue 2. CD001486. Corbett R, Jayakumar KN. Clean up varicose vein surgery: use a tourniquet. Ann R Coll Surg Engl 1989; 71: 57–8. Travers JP, Rhodes JE, Hardy JG, Makin GS. Postoperative limb compression in reduction of haemorrhage after varicose vein surgery. Ann R Coll Surg Engl 1993; 75: 119–22. Rautoma P, Santanen U, Luurila H, et al. Preoperative diclofenac is a useful adjunct to spinal anaesthesia for day case varicose vein repair. Can J Anaesth 2001; 48: 661–4. Aromaa U, Asp K. A comparison of naproxen, indomethacin, and acetylsalicyclic acid in pain after varicose vein surgery. J Int Med Res 1978; 6: 152–6. Shamiyeh A, Schrenk P, Wayand WU. Prospective trial comparing bilateral and unilateral varicose vein surgery. Langenbecks Arch Surg. 2003; 387: 402–5. Stonebridge PA, Chalmers N, Beggs I, et al. Recurrent varicose veins: a varicographic analysis leading to a new practical classiﬁcation. Br J Surg 1995; 82: 60–2. Stacey MC, Burnand KG, Layer GT, Pattison M. Calf pump function in patients with healed venous ulcers is not improved by surgery to the communicating veins or by elastic stockings. Br J Surg 1988; 75: 436–9. Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomised clinical trial. Eur J Vasc Endovasc Surg 2003; 25: 313–17.

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Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004; 363: 1854–9. Sam RC, MacKenzie RK, Paisley AM, et al. The effect of superﬁcial venous surgery on generic health-related quality of life. Eur J Vasc Endovasc Surg 2004; 28: 253–6. Baker DM, Turnbull NB, Pearson JC, Makin GS. How successful is varicose vein surgery? A patient outcome study following varicose vein surgery using the SF-36 Health Assessment Questionnaire. Eur J Vasc Endovasc Surg 1995; 9: 299–304. Smith JJ, Garratt AM, Guest M, et al. Evaluating and improving health-related quality of life in patients with varicose veins. J Vasc Surg 1999; 30: 710–19. MacKenzie RK, Lee AJ, Paisley AM, et al. Patient operative,

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and surgeon factors that inﬂuence the effect of superﬁcial venous surgery on disease-speciﬁc quality of life. J Vasc Surg 2002; 36: 896–902. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. Rutherford RB, Padberg FT Jr, Comerota AJ, et al. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. Baker D, Higgs B, Beard J. Surgical Management of Varicose Veins: Pathways of Care in Vascular Surgery. Newcastle: Joint Vascular Research Group, 2002: 255–62. Dillon MF, Carr CJ, Feeley TM, Tierney S. Impact of the informed consent process on patients’ understanding of varicose veins and their treatment. Ir J Med Sci 2005; 174: 23–7.

36 Radiofrequency treatment of the incompetent saphenous vein ROBERT F. MERCHANT AND ROBERT L. KISTNER Introduction Technique Management of complications Experiences at the Reno Vein Clinic Experience at the Straub Clinic

409 410 411 412 412

INTRODUCTION Investigations into the therapeutic use of radiofrequency (RF) energy in man occurred as early as the late nineteenth and early twentieth centuries. Technological advances increased interest in RF applications. Because of its precise control of energy delivery and reliability, it has been used for decades in neurosurgical techniques.1 By the 1980s cardiac arrhythmias were being treated with RF devices.2 Usage expanded to include treatment of various malignancies (including hepatic, renal, musculoskeletal, breast, lymph, spleen, pulmonary)3,4 as well as ophthalmologic maladies, gastric reﬂux, sleep apnea, and aesthetic dermatological conditions.5,6 Berjano5 reported that the number of scientiﬁc papers published on the topic of therapeutic RF energy use increased from 19 in 1990 to 825 in 2005. As a less invasive alternative to vein stripping for elimination of saphenous vein reﬂux, the percutaneous catheter-based radiofrequency Closure procedure (VNUS Medical Technologies, San Jose, CA, USA) was introduced in Europe in 1998 and in the USA in 1999. Following initial experience with the Closure procedure and early technique modiﬁcations, it became clear that reﬂux at the saphenofemoral junction (SFJ) could be eliminated by obliteration of the great saphenous vein (GSV) in the thigh without resorting to dissection and ligation of all contributing branches near the SFJ,7,8 thus eliminating the need for a groin incision and potential for minor and even major complications that can occur

Long-term closure results The future Conclusions Clinical practice guidelines References

412 414 414 416 416

following traditional ligation and stripping procedures, and leaving intact venous return and lymphatic drainage from the abdominal wall and lower extremity. The validity of this strategy has been borne out by several published mid-term reports.9–12 Pichot et al.11 coordinated an extensive 2 year follow-up ultrasound evaluation study from ﬁve VNUS Registry centers. The results showed that 58/63 (92.1%) treated GSV segments remained free of reﬂux. Junctional tributary reﬂux was seen in 7/63 (11.1%) limbs, four of which were associated with the SFJ as the sole source of reﬂux. Neovascularization was not observed in any treated limbs. Data on over 1000 limbs treated without high ligation have been collected in an ongoing Registry of the VNUS Closure Treatment Study Group, which consists of 35 centers from the USA, Europe, and Australia. Early results from this registry at various follow-up periods throughout January 2002, as reported by Merchant et al.,13 show successful ablation ranging from 93% at 1 week to 85% at 2 years, with absence of vein reﬂux (deﬁned as absence of reversed ﬂow at or near the SFJ or in any segment of the treated vein) of 90% at 2 years, and patient satisfaction of 95% at 2 year follow-up. In addition, 111 of 142 limbs with 2 year duplex ultrasound (DUS) examinations were also scanned at 1 year; of these, only two (1.8%) changed from reﬂux-free at 1 year to evidence of reﬂux with DUS at 2 years.13 Five year VNUS Closure Registry results on vein segments treated with 85°C have been reported and patterns of failure were described; this will be discussed later in this chapter.

410

Radiofrequency treatment of the incompetent saphenous vein

TECHNIQUE Unlike earlier attempts to obliterate the saphenous vein by diathermy, the endovenous Closure procedure uses RF energy to heat the vein wall. Bipolar electrodes at the tip of an intralumenally placed catheter are positioned in contact with the vein wall. Electric current ﬂowing between the electrodes through the vein wall tissue generates heat by a phenomenon called “resistive heating.” The heating causes a physical shortening of the collagen ﬁbril of the vein wall primarily in the subendothelial layers. The vein diameter is narrowed while at the same time denatured blood proteins congeal to obliterate the vein lumen. The entire vein is affected by this process, much like soft boiling an egg. The dark brown–greenish black material noted on the catheter represents denatured hemoglobin and blood proteins and is not “carbonized tissue.” Over the next several months, usually 10–12, and certainly by 2 years, the vein ﬁbroses and is seen to vanish on duplex ultrasound in over 86% of cases.11 The process is controlled by a computerized generator which monitors electrode temperature and adjusts energy levels to achieve a constant heating of the vein wall at a user-selectable temperature, typically 85°C or 90 ± 3°C. As the heating occurs, the catheter is withdrawn from the vein typically at a rate of 2–4 cm per minute. The major steps of the technique as currently practiced at the Reno Vein Clinic are as follows: 1. Patient anesthesia. Choice of anesthesia is a matter between the physician and the patient. However, the procedure itself is well suited for local anesthesia or regional ﬁeld block such as a femoral nerve block. General anesthesia offers at least one drawback – that being the inability of the anesthetized patient to communicate nerve pain which might be the result of the heat produced by the catheter as it is withdrawn through the vein and comes into proximity with an overlying sensory cutaneous nerve. Minimal sedation with oral (diazepam) or intravenous (midazolam and fentanyl) agents is recommended to provide adequate anxiolysis and analgesia. We have found in our practice that short-acting agents delivered intravenously offer better control with quick recovery and better patient comfort, thus allowing fast-track post-procedure discharge from the facility or ofﬁce. Intravenous midazolam (diazepam family) may offer some protection against lidocaine toxicity. 2. Catheter insertion. The catheter is inserted into the vein at its nearest point to the skin surface, usually just below or above the knee using a standard percutaneous (Seldinger) or cut-down technique. The catheter tip is positioned using ultrasound guidance approximately 2 cm distal to the SFJ. All current Closure devices feature a central lumen that will accommodate either a 0.046 cm (ClosureRFS, ClosureRFSﬂex) or 0.064 cm (ClosurePLUS and ClosureFAST) diameter guide wire,

to allow maneuverability through tortuous or difﬁcult vein segments. 3. Limb anesthesia and vein compression. Once the catheter has been positioned safely below the SFJ, tumescent anesthesia can be introduced using a variety of methods. It is important to use ultrasound visualization in order to insure that the ﬂuid is placed beneath the saphenous fascia and above the deep muscular fascia and that it surrounds the vein completely, which serves to contain the radiant heat within the treated vein without signiﬁcantly affecting adjacent cutaneous and sensory nerve tissues.14 The infusate also compresses the saphenous vein and its inﬂow branches in order to produce a “dry” vein. Contraction of the vein diameter is another beneﬁt if diluted epinephrine is included in the tumescent anesthetic ﬂuid. Tumescent anesthesia, using generous volumes of buffered lidocaine 1% with epinephrine 1:100 000 diluted to 0.1% placed properly, results in relatively pain-free status (Table 36.1). Care must be taken to avoid lidocaine toxicity – dosage guidelines are 7 mg/kg body weight, and no more than 500 mg should be used at one setting. Bilateral limb procedures may require alternate anesthesia choice such as general or regional (femoral nerve block, spinal, or epidural). 4. Energy delivery. During vein heating, the patient is positioned in a gentle Trendelenburg position, approximately 15–20°. Gentle manual pressure with the DUS probe is applied to the SFJ area and then along the course of the vein as necessary, while the catheter is withdrawn distally. 5. Perioperative ultrasound. DUS should be used in all cases to document satisfactory closure of the treated vein just before removing the catheter from the vein. A curious ﬁnding on ultrasound that may be observed is echogenic movement depicted in the occluded vein despite having obliterated the lumen. It probably represents movement of saline solution infused through the Closure catheter in the vein and around the blood plug despite adequate obliteration of the lumen. If signiﬁcant ﬂow remains, the vein should be retreated. If some ﬂow persists after two catheter passes, we

Table 36.1 Tumescent anesthesia solution preparation Ringer’s lactate Withdraw 50 mL

500 mL –50 mL 450 mL

Add lidocaine 1% with epinephrine 1:100 000

+50 mL 500 mL

Add sodium bicarbonate (NaHCO3) 8.4%

+16 mL

Resultant solution is lidocaine 0.1% with epinephrine 1:1 000 000

516 mL

Management of complications 411

recommend ceasing the procedure at that point as the vein may close overnight or in a few days as vein swelling occurs as a result of thermal injury. 6. Postoperative instructions. The patient is encouraged to ambulate immediately, and in some cases may return to normal activities on the same day. Postoperative ultrasound imaging of the SFJ within 3 days is an essential part of the protocol to check for successful obliteration and absence of clot extension into the common femoral vein. What is usually seen at this initial check is remarkably similar to an acute thrombosis of the vein with dilation and ﬁlling of the vein lumen with echo-dense signals and failure to compress with externally applied pressure. This represents an element of thrombosis which aids the obliteration process.

MANAGEMENT OF COMPLICATIONS Data collected for the VNUS Closure Study Group Registry were prospective, looking for nerve injury, clot extension, hematoma, phlebitis, skin burns, and infection.13 Only limbs treated at 85°C and seen within the ﬁrst postoperative week were included in the report. Results are shown in Table 36.2. The most serious complication, although rare, is clot extension into the common femoral vein as it can lead to deep vein thrombosis (DVT) if not recognized and treated early with either low-molecular-weight heparin (LMWH) or operative thrombectomy. Duplex ultrasound is a crucial component of the Closure protocol and should be performed within 72 hours of the procedure. It is the practice at both the Reno Vein Clinic and the Kistner Vein Clinic to see all cases on the ﬁrst postoperative day and to include a postoperative duplex scan during that visit. If there is evidence of obliteration of the GSV “ﬂush” with the common femoral vein (no spontaneous superﬁcial

epigastric vein ﬂow) or slightly extending into the deep vein, then LMWH is prescribed at therapeutic doses for 6 days and aspirin 325 mg is started on day 7 and continued for 1 month. This protocol was used in ﬁve cases at the Reno Vein Clinic and DVT did not occur subsequently. One case of clot extension obscuring approximately 40–50% of the transverse diameter of the common femoral vein was seen at postoperative day 1 and was treated successfully with operative thrombectomy, LMWH for 1 week, and then aspirin for 1 month. Nerve injury associated with RF ablation is seen as areas of hypoesthesia noted on follow-up examination in the ﬁrst postoperative week. The majority of these occurred in the early Closure cases before the routine instillation of tumescent anesthesia. To avoid nerve injury, following the early clinical experience, the Closure procedure was recommended to be limited to above knee GSV treatments.15 The greater saphenous nerve is actually adherent to the GSV in the distal leg and injury to this nerve is usually unavoidable when RF ablation is attempted much below the knee.8 Skin burns, initially seen in early Closure cases, essentially have vanished since the institution of tumescent anesthesia13,16 and the abandonment of the Eschmark leg wrap. The Eschmark rubber bandage has a tendency to roll back when applied to the funnel-shaped thigh, in which case it can act as a tight rubber band to push the skin closer to the saphenous vein. Ablation in the thin or skinny leg should prompt careful attention to detail to minimize thermal injuries to the overlying skin due to excessive external compression, which can arise from the Eschmark bandage or the DUS probe during intraoperative monitoring. Phlebitis can occur with the Closure procedure as in any treatment of varicose veins and it is usually the result of residual blood trapped within vein segments. Some degree of phlebitis is inherent in the whole process since the obliteration occurs as a result of injury to the vein by

Table 36.2 Complications reported from the Closure Study Group Complication

DVT (accompanied by pulmonary embolism in one instance) Skin burn – ﬁrst half of study Skin burn – second half of study Infection Clinical phlebitis Clinical phlebitis Paresthesia Paresthesia Paresthesia Paresthesia DVT, deep vein thrombosis.

Follow-up interval

Rate of occurrence, % (n/N)

1 week

1.0 (3/286)

1 week 1 week 1 week 1 week 6 months 1 week 6 months 12 months 24 months

4.2 (6/143) 0 (0/143) 0 (0/286) 2.1 (6/286) 0.4 (1/223) 15.0 (43/286) 9.4 (21/223) 3.9 (9/232) 5.6 (8/142)

412

Radiofrequency treatment of the incompetent saphenous vein

the heating process. It is occasionally seen as a tender, erythematous, or ecchymotic band over the treated vein in the distal thigh. It resolves over several weeks without any speciﬁc treatment other than for symptomatic relief, e.g., the use of non-steroidal anti-inﬂammatory drugs, heat, and compression hosiery. Patients may describe a curious sensation which occurs during the second or third postoperative week along the treated vein segment, usually in the distal thigh. They may experience a spontaneous or persistent dull feeling, or “bogginess,” or sharpness when stretching or extending the treated leg. This could represent an inﬂammatory process which occurs as the body is healing the scald injury of the treated vein segment. The sensations usually abate over several weeks, consistent with the normal healing time of injured tissues.

EXPERIENCES AT THE RENO VEIN CLINIC At the Reno Vein Clinic our routine practice is to conduct the ﬁrst postoperative clinical and DUS examination at 1 day after RF obliteration, with periodic subsequent wellness visits as patient schedules permit. Following procedures performed from 1999 to March 2006 (using 90°C since April 2002), we documented a total of 29 failures from 598 RF obliteration procedures having 1 day postoperative DUS. All failures were detected at or before a 3 year follow-up examination. There were 124 duplex examinations conducted beyond 3 years, 34 of which were 5 years or more following intervention, with no further failures observed. Only one case of DVT occurred related to aggressive heating near the SFJ. Since instituting routine use of tumescence only two cases of second-degree burns have occurred, both on skinny male limbs; and only a 2% temporary paresthesia rate has been seen. Further details on our complications, which parallel the broader experience with the Closure procedure, were previously reported.17 In three cases of SFJ reﬂux abolition, documented as successful 1 day postoperatively, reﬂux developed within 3 months (n = 2) and 9 months (n = 1) through the SFJ and into preexisting varicose veins via the anterolateral saphenous vein. Because of technical difﬁculties, signiﬁcant thigh varicose veins had been left untreated at the time of the Closure procedure. These three speciﬁc personal observations suggest that SFJ incompetence may be secondary to downstream venous insufﬁciency rather than a primary contributor to superﬁcial venous insufﬁciency.

Other saphenous veins Since January 2002, RF ablation at the Reno Vein Clinic has been extended to include several cases of anterior and posterior branches of the GSV in the proximal thigh. These results generally parallel those of the GSV. Also since then,

55 small (lesser) saphenous veins were successfully treated, with one case of temporary sural nerve injury. All veins were conﬁrmed closed at the 1 day postoperative visit. When 90°C is used, successful short-term and mid-term outcomes appear to mimic those seen in the GSV group. In the case of small saphenous vein treatment, careful ultrasound guidance is critical for precise placement of the catheter electrodes to avoid inadvertent heating of the posterior tibial nerve; in our experience, pain located in the heel or foot at onset of heating indicates placement too close to the nerve. Tumescent anesthesia inﬁltrated circumferentially around the SSV is a must to avoid injury to the sural nerve, which usually lies near the vein. We have also begun extending the application of temperature-controlled RF vein obliteration to the treatment of incompetent perforators (up to 5 mm diameter) and 3–4 mm diameter short segment reﬂuxing primary or tributary veins such as small saphenous, posterior, and anterior saphenous veins. The rigid 2 mm by 15 cm long ClosureRFS stylet and the ﬂexible 2 mm by 30 cm long ClosureRFSﬂex catheter can each be introduced over a 0.046 cm guide wire and positioned under DUS guidance.

EXPERIENCE AT THE STRAUB CLINIC The experience of Kistner and colleagues with the Closure procedure at Honolulu’s Straub Clinic in the ﬁrst 24 months of its use there, commencing in April 2000, comprised 300 total operated limbs treated, with serial duplex ultrasound scan follow-up for 1 year or longer in 160 cases.18 Tortuous veins and aneurysmal veins were not excluded, nor were veins with focal areas of internal diameter greater than 12 mm. Adjunctive procedures of phlebectomy or perforator interruption were performed in 95% of these cases. Conversion of the procedure to open ligation and stripping was 3% during this period, with fewer conversions needed as the learning curve progressed, particularly of vein access and advancing the catheter tip to the SFJ. The other 97% of cases achieved successful initial closure as determined on the operating table by duplex scan criteria. The complications in this experience were limited to one skin burn in the second case, recurrent reﬂux in three cases on postoperative duplex study, DVT in 2/300 (0.7%), miscellaneous minor problems in 1%, and no mortality. The DVTs both occurred in the common femoral vein, were found at the ﬁrst 24 hour postoperative scan, and were managed by thrombectomy with no subsequent sequelae and no clinical pulmonary emboli.

LONG-TERM CLOSURE RESULTS In 2005, Merchant et al.19 reported the 5 year Closure Study Group outcomes on 1222 vein segments treated at

Long-term closure results

85°C. These data, which included procedures performed during initial learning curve periods, were collected from 34 international centers, 12 of which provided long-term follow-up. Reﬂux-free and vein occlusion rates in 117 limbs examined at 5 years were 83.8% and 87.2%, respectively. A duplex image taken at 5 years of an occluded GSV and patent epigastric tributary is shown in Fig. 36.1. Clinical symptom improvement, measured by absence of limb pain, fatigue or edema, was observed in 85–94% of limbs classiﬁed as having anatomic success at annual intervals over the 5 year period. Over the same interval, the 185 (15.1%) limbs presenting by duplex ultrasound examination as anatomical failures exhibited 70–80% clinical improvement. The failures had either ﬂow in a segment of or the entire treated vein, or groin reﬂux despite a completely occluded GSV trunk. Anatomical failures were categorized into three types, illustrated in Fig. 36.2. ●

Type I (non-occlusion) failure referred to veins that failed to occlude initially and never occluded during the follow-up. There were 23 limbs in this category,

(a)

●

●

413

consisting of 12.4% (23/185) of all anatomical failures. Among these 23 limbs, 34.8% (8/23) were signiﬁcantly narrowed with no reﬂux. Type II (recanalization) failure referred to veins that were initially occluded but recanalized, partly or completely, at a later time point. This category comprised 129 limbs, accounting for 69.7% (129/185) of the total anatomical failures. Among the type II limbs, 34.1% (44/129) exhibited no reﬂux. There was documentation in 23.3% (30/129) of type II limbs that the recanalization was directly related to either a reﬂuxing tributary or an incompetent thigh perforating vein. Type III (groin reﬂux) failure referred to the situation in which the vein trunk was occluded but reﬂux was detected in the groin, often involving an accessory vein. There were 33 type III limbs, making up 17.8% (33/185) of all anatomical failures.

It was found that faster catheter pullback speed and greater body mass index were each signiﬁcantly associated with failure. Varicose vein recurrence was more apt to occur in limbs with type II or type III failure mode.19

(b)

Figure 36.1 On the left, a duplex ultrasound image of the area near the saphenofemoral junction 1 week following radiofrequency obliteration of the great saphenous vein (GSV). The image on the right was recorded at 5 year follow-up. Transverse views of patent tributaries (Trib) are seen. There are no longer any discernible landmarks for the GSV. (From Merchant et al.19 Images courtesy of Olivier Pichot, MD). Epi, superﬁcial epigastric vein; FE, femoral vein.

(a)

(b)

SFJ

(c)

SFJ

(d) SFJ

SFJ

CFV

CFV

GSV

CFV

GSV

GSV

CFV

GSV

Figure 36.2 The three types of anatomical failure. (a) Type I, failure of the great saphenous vein (GSV) to completely occlude, with or without reﬂux present. (b and c) Type II, partially recanalized GSV. (d) Type III, the treated GSV is occluded, but reﬂux is present involving branches near the saphenofemoral junction (SFJ). CFV, common femoral vein. (From Merchant et al.19)

414

Radiofrequency treatment of the incompetent saphenous vein

Several prospective randomized studies on the early results of Closure treatment without high ligation compared with vein stripping and ligation have been published20–23 and show signiﬁcant clinical superiority of the Closure procedure. In a study from one center in Oulu, Finland,20 signiﬁcant advantages of the Closure treatment were shown regarding less pain, early return to activities, fewer sick leaves from work, and better quality of life scores. When these ﬁndings included time lost from work, the authors found Closure treatment to be cost-effective despite initial high hospital costs. A 3 year follow-up report demonstrated a durable ablation in all 15 RFtreated limbs.24 Another study was from ﬁve centers in the USA and Europe,21 and it was designed to determine the early beneﬁts of the procedure with follow-up limited only to 4 months. Early 3 week results showed signiﬁcant advantage of the Closure procedure in that there was less pain, earlier return to activities and work, better quality of life scores, and better cosmetic results. When these patients were seen at the 4 month follow-up, these advantages had disappeared. Although the study was not designed to evaluate cost-effectiveness, when the severity of infectious complications (which occurred only in the stripping and ligation group) was factored in, the authors opined a probable cost beneﬁt to Closure. A 1 and 2 year follow-up of this multicenter study by Lurie et al.12 showed that 41% of obliterated GSVs became ultrasonically undetectable, and another 51% remained visible, but exhibited progressive diameter shrinkage. Vein remnants that remained visible by DUS were larger at the time of RF ablation than those that became invisible. Clinical status of limbs that underwent RF ablation was at least equal to the status of limbs that received vein stripping. The cumulative rate of recurrence of varicose veins was 14.3% in the RF group compared with 20.9% in the stripping group. Using the CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) clinical classiﬁcation system, 33% of RF patients and 28% of stripping patients had no signs of venous disease at 2 years. Quality of life questionnaires were administered at all follow-up visits. While the observed superiority of the RF group over the stripping group diminished by 4 months, it reemerged at both the 1 and 2 year time intervals.

THE FUTURE The endovenous Closure procedure has evolved from the originally introduced catheter and techniques to introduction of improved devices (Closure PLUS) and techniques (tumescence) designed to improve outcomes and reduce the incidence of complications, and newly designed devices (ClosureRFS and ClosureRFSﬂex) to broaden applications. On the horizon is the ClosureFAST catheter, which is intended to substantially shorten procedure time. The device has a 7 cm heating element that remains

stationary during a 20 second long energy delivery period. The catheter is then repeatedly retracted 6.5 cm and energized for 20 seconds at each segment until the desired length of vein has been treated. The ClosureFAST catheter has undergone successful early clinical studies. In a series, initially presented by Proebstle, of more than 200 treated limbs, the average energy delivery time was 2.2 minutes over an average 37 cm vein length; 16.6 minutes average elapsed time from catheter insertion to ﬁnal removal. Initial vein occlusion was 100%, and all veins examined at up to 6 months follow-up remained closed.25

CONCLUSIONS The evidence published in peer-reviewed journals, four studies of which are level 1, suggests that, at least up to 5 years, outcomes of RF obliteration of saphenous vein reﬂux are similar to traditional stripping and ligation. The risks of serious complications such as DVT are low and similar to those that attend stripping and ligation. Lesser complications, when they do occur, are time limited and usually of minor consequence. Using the RF Closure equipment and employing current techniques at 90°C, an experienced clinician, modifying details to suit individual clinical settings, can expect the following: (1) 98–99% successful initial ablation; (2) complications such as common femoral vein clot extension and DVT, temporary sensory thermal nerve injury, and second-degree thermal skin injury at rates of < 1%; and (3) 5 year ablation and reﬂux-free outcomes of > 90%. In high-risk patients, e.g., the obese or those taking anticoagulants or having comorbidities, the Closure procedure may be the better treatment because of the advantages it offers over traditional surgical methods, especially regarding less trauma. In cases in which reﬂux originates distal to the saphenofemoral junction (which can be appreciated only by DUS), the Closure method is ideally suited. Neovascularization following this procedure at the saphenofemoral junction appears to occur only rarely and may not be a factor in later recurrent varicose veins, a possible distinct advantage in comparison with surgical stripping and high ligation.11,26 The fate of the persistent patency found in the superﬁcial epigastric vein and other less frequently seen groin branches and the pattern of failures of the Closure procedure has been described recently in the 5 year report by the Closure Study Group and the results are encouraging for long-term successful relief from superﬁcial venous hypertension and reﬂux. In our practices, we have found that the features offered in the RF Closure system (Table 36.3) provide for a safe, convenient, and well-tolerated procedure. Our combined experiences conﬁrm minimal to absent pain, early return to activity within 12–48 hours in most cases, and early return to work depending more upon the individual’s desire to return to work rather than upon any medical

Conclusions 415

Table 36.3 Advantageous features of the radiofrequency Closure system Feature Single-use device Tightly controlled operating temperature Multiple conﬁgurations for multiple uses

Catheter central lumen

Advantage Reassurance to patient of biohazard safety Delivered over a discrete (0.5 cm) area Stays below water boiling temperature Closure catheters 6 Fr and 8 Fr; ClosureRFS; ClosureRFS-Flex Saphenous trunks: GSV and SSV Major tributaries: Accessory saphenous Posterior saphenous Saphenofemoral (intersaphenous vein) Perforating veins: thigh and calf Irrigation for cooling vein immediately following thermal delivery Over-the-wire capability as aid for successful manipulation through tortuous anatomy

GSV, great saphenous vein; SSV, small saphenous vein.

necessity to defer the return. The choice of Closure treatment is extremely popular with patients both pre- and postoperatively. Many individuals harbor a fear of the stripping procedure, which may not be truly warranted but is nevertheless real, while most approach the Closure technique as acceptable for the magnitude of the problem they experience. Even when informed that long-term knowledge of the ultimate comparative effects of Closure versus stripping is still not known, most patients state that this is not a deciding factor for them.18 As of October 2006, an estimated 150 000 procedures have been performed worldwide.

Radiofrequency obliteration of saphenous vein reﬂux, in our opinion, given the caveat that it be done by a qualiﬁed physician, has become a safe, effective, and preferred alternative to traditional surgical techniques, further evidenced by many publications, including the Closure Study Group 5 year outcomes. Whether it deserves to be the treatment of choice among endovenous obliteration procedures will require further well-designed randomized studies, possibly employing the failure classiﬁcation system described herein for objective comparison of outcomes. In the meantime, it makes sense to offer this innovative technology as a primary choice for patients with saphenous vein reﬂux of primary origin.

Guidelines 4.9.0 of the American Venous Forum on radiofrequency treatment of the incompetent saphenous vein No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.9.1 Radiofrequency ablation of the great saphenous vein is safe and effective and we recommend it for treatment for saphenous incompetence

1

A

4.9.2 Clinical outcome after radiofrequency ablation of the great saphenous vein up to 5 years is comparable to traditional stripping and ligation

–

C

4.9.3 Because of reduced convalescence, complications, and morbidity, we suggest radiofrequency ablation of the great saphenous vein in high-risk patients such as the obese, those takings anticoagulants, and those with signiﬁcant medical problems

2

C

416

Radiofrequency treatment of the incompetent saphenous vein

CLINICAL PRACTICE GUIDELINES ●

●

●

Radiofrequency ablation of great saphenous vein insufﬁciency is a safe and effective treatment (12 [1A], 19 [1B], 22 [1A], 23 [1A]). Outcomes of RF ablation of great saphenous insufﬁciency are comparable to traditional stripping and ligation for at least 5 years (10 [1B], 11 [1C], 12 [1A], 19 [1B]). Because of reduced convalescence, complications, and morbidity associated with the procedure, RF ablation for saphenous vein insufﬁciency should be considered a primary treatment for high-risk patients such as the obese, those taking anticoagulants, and those with signiﬁcant medical problems (9 [2C], 12 [2C], 19 [2C]).

10.

11.

12.

13.

14.

ACKNOWLEDGMENT The authors wish to express their gratitude to Jeffrey S. Frisbie for his technical assistance in the preparation of this chapter.

●15.

16.

REFERENCES ● ◆

= Key primary paper = Major review article ◆1.

◆2.

◆3.

◆4.

◆5.

◆6.

7.

8.

9.

Liu JK, Apfelbaum RI. Treatment of trigeminal neuralgia. Neurosurg Clin N Amer 2004; 15: 319–34. Filingeri V, Gravante G, Cassisa D. Physics of radiofrequency in proctology. Eur Rev Med Pharmacol Sci 2005; 9: 349–54. Brown DB. Concepts, considerations, and concerns on the cutting edge of radiofrequency ablation. J Vasc Interv Radiol 2005; 16: 597–613. Gillams AR. The use of radiofrequency in cancer. Br J Cancer 2005; 92: 1825–9. Berjano EJ. Theoretical modeling for radiofrequency ablation: state-of-the-art and challenges for the future. Biomed Eng Online 2006; 5: 24. Sadick N, Sorhaindo L. The radiofrequency frontier: a review of radiofrequency and combined radiofrequency pulsed-light technology in aesthetic medicine. Facial Plast Surg 2005; 21: 131–8. Chandler JG, Pichot O, Sessa C, et al. Deﬁning the role of extended saphenofemoral junction ligation: a prospective comparative study. J Vasc Surg 2000; 32: 941–53. Chandler JG, Pichot O, Sessa C, et al. Treatment of primary venous insufﬁciency by endovenous saphenous vein obliteration. Vasc Surg 2000; 34: 201–14. Nicolini P; Closure Group. Treatment of primary varicose veins by endovenous obliteration with the VNUS closure

17.

18.

19.

20.

21.

22.

system: results of a prospective multicentre study. Eur J Vasc Endovasc Surg 2005; 29: 433–9. Merchant RF, Pichot O, Myers KA. Four-year follow-up on endovascular radiofrequency obliteration of great saphenous reﬂux. Dermatol Surg 2005; 31: 129–34. Pichot O, Kabnick LS, Creton D, et al. Duplex ultrasound scan ﬁndings two years after great saphenous vein radiofrequency endovenous obliteration. J Vasc Surg 2004; 39: 189–95. Lurie F, Creton D, Eklof B, et al. Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year follow-up. Eur J Vasc Endovasc Surg 2005; 29: 67–73. Merchant RF, DePalma RG, Kabnick LS. Endovascular obliteration of saphenous reﬂux: a multicenter study. J Vasc Surg 2002; 35: 1190–6. Zikorus AW, Mirizzi MS. Evaluation of setpoint temperature and pullback speed on vein adventitial temperature during endovenous radiofrequency energy delivery in an in-vitro model. Vasc Endovascular Surg 2004; 38: 167–74. Manfrini S, Gasbarro V, Danielsson G, et al. Endovenous management of saphenous vein reﬂux. J Vasc Surg 2000; 32: 330–42. Weiss RA, Weiss MA. Controlled radiofrequency endovenous occlusion using a unique radiofrequency catheter under duplex guidance to eliminate saphenous varicose vein reﬂux: a 2-year follow-up. Dermatol Surg 2002; 28: 38–42. Merchant RF, Frisbie JS, Kistner RL. Endovenous radiofrequency obliteration of saphenous vein reﬂux. In: Pearce WH, Matsumura JS, Yao JS, eds. Trends in Vascular Surgery 2006. Evanston, IL: Greenwood Academic, 2007: 429–42. Kistner RL. Endovascular obliteration of the greater saphenous vein: the Closure procedure. Jpn J Phlebol 2002; 13: 325–33. Merchant RF, Pichot O, for the Closure study group. Longterm outcomes of endovenous radiofrequency obliteration of saphenous reﬂux as a treatment for superﬁcial venous insufﬁciency. J Vasc Surg 2005; 42: 502–9. Rautio T, Ohinmaa A, Perälä J, et al. Endovenous obliteration versus conventional stripping operation in the treatment of primary varicose veins: a randomized controlled trial with comparison of costs. J Vasc Surg 2002; 35: 958–65. Lurie F, Creton D, Eklof B, et al. Prospective randomized study of endovenous radiofrequency obliteration (closure procedure) versus ligation and stripping in a selected patient population (EVOLVeS Study). J Vasc Surg 2003; 38: 207–14. Stötter L, Schaaf I, Bockelbrink A, et al. Radiowellenobliteration, invaginierendes oder Kryostripping. Welches Verfahren belastet den Patienten am wenigsten? [Radiofrequency obliteration, invagination or cryostripping: which is the best tolerated treatment by the patients?] Phlebologie 2005; 34: 19–24.

References 417

23. Hinchliffe RJ, Ubhi J, Beech A, et al. A prospective randomised controlled trial of VNUS closure versus surgery for the treatment of recurrent long saphenous varicose veins. Eur J Vasc Endovasc Surg 2006; 31: 212–18. 24. Perala J, Rautio T, Biancari F, et al. Radiofrequency endovenous obliteration versus stripping of the long saphenous vein in the management of primary varicose veins: 3-year outcome of a randomized study. Ann Vasc Surg 2005; 19: 669–72.

◆25.

Lumsden AB, Peden EK. Clinical use of the new ClosureFAST radiofrequency catheter. Endovasc Today 2007; Suppl: 7–10. 26. Kianifard B, Holdstock JM, Whiteley MS. Radiofrequency ablation (VNUS closure) does not cause neovascularisation at the groin at one year: results of a case controlled study. Surgeon 2006; 4: 71–4.

37 Laser treatment of the incompetent saphenous vein NICK MORRISON Introduction Scientiﬁc background Procedure Technology Outcomes

418 418 419 419 422

Discussion Summary Clinical practice guidelines References

INTRODUCTION

SCIENTIFIC BACKGROUND

Lower extremity varicose vein disease is most often associated with truncal venous insufﬁciency involving the saphenous system: the great saphenous vein, the small saphenous vein, and/or incompetent major tributaries or perforator veins. Management of varicose vein disease has historically been treated with stripping of the saphenous vein, and interruption/ligation and removal of the major tributary and perforator veins.1 Since 1999, endovenous ablation procedures have been reported to be safe and effective methods of eliminating the proximal portion of the great saphenous vein, the small saphenous vein, and even tributary and perforating veins from the venous circulation, with faster recovery and better cosmetic results than stripping.2–4 The three currently available methods used to achieve ablation of these diseased veins are: the Closure procedure using a radiofrequency (RF) catheter and generator (VNUS Medical Technologies, San Jose, CA, USA); the endovenous laser ablation procedure using a laser ﬁber and generator (various manufacturers); and endovenous chemical ablation with ultrasound-guided foam sclerotherapy (either catheter directed or injection). The ﬁrst two systems use electromagnetic energy whereas the last utilizes a foamed chemical detergent (polidocanol or sodium tetradecylsulfate). As with a stripping procedure, following these endovenous ablation procedures it is necessary to treat any remaining portion of the great and/or small saphenous vein, perforating veins, and varicose tributaries additionally, typically with either sclerotherapy and/or phlebectomy.5 This chapter will primarily concern itself with endovenous laser ablation.

Pathophysiologic effects of laser energy

424 426 426 427

ANIMAL STUDIES

There are no reports of animal testing of laser technology in saphenous vein ablation prior to initial publication of clinical case series. In 2002, Weiss6 described in vivo caprine jugular veins treated with RF and pulsed mode laser with ﬂuoroscopic and histologic examinations demonstrating extensive vein wall damage and frequent perforations with laser ablation compared with RF ablation. Min et al.7 recorded temperatures outside the porcine vein during laser ablation, with injected perivenous anesthetic (as is standard for human treatment), and demonstrated temperatures no higher than 40°C within 2 mm of the vein. Also Schmedt et al.8 treated freshly harvested bovine foot veins with laser and RF ablation, producing inconsistent thermal damage with laser ranging from minimal changes to extensive carbonization and perforation compared with the homogeneous vein wall damage seen following RF ablation. HUMAN STUDIES

Prior to the publication of single-center case series reports of endovenous laser ablation of the incompetent saphenous vein, and to date, no multicenter clinical trials of the safety and efﬁcacy of this procedure in humans have been published. Since the initial published case series, some analyses of the pathophysiologic effects of laser

Technology 419

ablation in humans have emerged. Proebstle et al.9 reported on the heat injury seen in a great saphenous vein removed following pulsed mode laser ablation and found damage along the entire vein, noting more severe damage with perforations at the site of the laser pulses. On the basis of experiments with heating heparinized blood in silicone tubes, the authors opine that the thermal damage in areas not subjected to direct laser energy was produced by heated blood and steam bubbles. Further evidence for the steam bubble-induced laser thermal damage theory was reported by Proebstle et al.10 wherein in vivo and ex vivo great saphenous veins were treated with laser ablation. The ex vivo veins were ﬁlled with blood, saline, and plasma, and then treated with laser ablation. Steam bubble thermal damage was detected in areas remote to direct laser energy in only the blood-ﬁlled veins. Corcos et al.11 described histopathologic changes in great saphenous veins treated by laser ablation without perivenous anesthesia, in combination with saphenofemoral interruption and excision of a portion of vein for histologic examination. Full-thickness intimal thermal damage was seen in threefourths of the veins, with transmural damage and/or perforation in one-fourth. However, several veins had been subjected to more than one ablation period during treatment, thus limiting the importance of the ﬁndings. And ﬁnally, in an attempt to quantify the risk of thermal damage to surrounding tissue during laser ablation, Beale et al.,12 after injection of perivenous anesthetic, measured maximum temperatures of approximately 43°C in tissue 3–5 mm from the great saphenous vein during laser ablation.

PROCEDURE

BOX 37.2 Absolute exclusion criteria ● ● ●

Arteriovenous malformation Restricted mobility Deep venous obstruction

Absolute exclusion criteria are arteriovenous malformations, restricted ambulation and deep venous obstruction (Box 37.2). As surgeons’ experience with endovenous ablation procedures increases, relative exclusion criteria may be relaxed, and patients with deep venous reﬂux, previous venous treatment, large-diameter veins, aneurysmal vein segments, vein tortuosity, or those on chronic anticoagulant therapy or hormone replacement therapy may be safely and successfully treated (Box 37.3). Strong consideration of a thrombophilia work-up should be given preoperatively to patients with a history of deep venous thrombosis, recurrent episodes of acute superﬁcial venous thrombophlebitis, multiple spontaneous abortions, or strong family history of deep vein thrombosis or clotting disorders. The physician should be aware of the guidelines produced by the American College of Physicians for risk assessment for deep vein thrombosis, as these guidelines may be helpful in choosing which patients should receive prophylactic anticoagulation before undergoing endovenous laser ablation. While the risk of deep venous thrombosis following these procedures is low, such a potentially life-threatening outcome following treatment of relatively benign disease could be catastrophic to all involved.

Patient selection Inclusion criteria consist of symptoms and physical signs of venous insufﬁciency; a duplex scan, performed by a fully qualiﬁed sonographer, showing a patent vein with reﬂux greater than 0.5 seconds; a patent deep venous system; a vein conducive to catheterization or injection; and full patient mobility (Box 37.1).

TECHNOLOGY Laser generators are available from various manufacturers, all of which appear to be effective in producing venous ablation (Table 37.1). Each generator utilizes a 600 μm bare-tipped ﬁber.

BOX 37.3 Relative exclusion criteria BOX 37.1 Clinical indications for laser ablation

● ●

● ● ● ● ●

Superﬁcial venous insufﬁciency Duplex scan with reﬂux >0.5 seconds Patent deep system Vein conducive to cannulation Adequate patient mobility

● ● ● ● ●

Deep venous reﬂux Previous treatment Large-diameter vein Anticoagulant therapy Hormone replacement therapy Vein tortuosity Aneurysmal vein segments

420

Laser treatment of the incompetent saphenous vein

Table 37.1 Laser generators Wavelength 810 nm 940 nm 980 nm 1319 nm 1320 nm

Name Diomed, Varilase, Angiodynamics Dornier Biolitec, Angiodynamics Sciton CoolTouch

Technique Initially, endovenous laser ablation was performed in the hospital surgical or radiologic suite under general anesthesia or conscious sedation. However, several factors, not the least of which was a signiﬁcant change in insurance reimbursement beginning in January 2005, have combined to shift these procedures to the ofﬁce setting under local anesthesia, with or without sedation. Furthermore, although the ablation procedure is often performed on veins other than the great saphenous vein, the technical details remain quite similar. The following description of the procedure for a saphenous vein (great or small) is given with the above in mind. After obtaining informed consent, patients may be given an oral or intravenous sedative prior to the procedure. The patient is placed on an adjustable operating table (with Trendelenburg capability), in a patient gown and undergarments. The course of the saphenous vein, from the saphenofemoral or saphenopopliteal junction to the insertion site, is mapped by ultrasound and marked with an indelible marker. An insertion site is chosen to maximize treatment length, minimize risk of thermal damage to perivenous structures, and assure facile access. Most physicians will utilize a site in the distal thigh or proximal calf for the great saphenous vein, and the mid-calf to distal calf for the small saphenous vein. The portion of the great saphenous vein below the knee is not routinely treated by most physicians with endovenous laser ablation because of the increased risk of paresthesia from damage to the saphenous nerve, which is in close proximity to the vein below the knee. Access to the saphenous vein may be gained using an ultrasoundguided, percutaneously placed needle, or via microincision and hooking of the saphenous vein for direct venipuncture. If the percutaneous method is used, 2% nitropaste is sometimes applied to the proposed insertion site prior to the sterile surgical preparation to increase the chance of successful venous cannulation by dilating the vein and preventing venospasm. It is sometimes appropriate to choose a primary access site and a higher, larger diameter, secondary (back-up) access site in case access at the primary site is unsuccessful. Perivenous or intramural

hematoma from unsuccessful attempts at cannulation may render that portion of the saphenous vein technically inaccessible, leading to the need for a secondary site. As the practitioner’s ultrasound-guided technical skills improve, even small-diameter saphenous veins can be successfully cannulated. The ﬁrst attempt at cannulation of the vein is the most likely to be successful, so the insertion site should be carefully chosen to make access as ergonomically feasible as possible. Just below the knee, the great saphenous vein is relatively anterior. With the patient’s operative leg externally rotated, this site becomes more advantageous than in the distal or mid-thigh (Fig. 37.1). Even though the saphenous nerve is closer to the vein in this area, the laser sheath will protect this portion of vein, and thus limit the risk of thermal nerve damage. The leg is cleansed from the most proximal treatment site to the insertion site with an antiseptic. The operative area is isolated with sterile drapes. After inﬁltration of local anesthetic at the insertion site, an introducer needle is inserted into the vein under ultrasound guidance; or a small incision is made and the vein is elevated through the skin incision with a phlebectomy hook. A microinsertion set can be used to gain access, and the caliber of sheath “stepped up” to accommodate a 600 μm laser ﬁber. Using the Seldinger technique, after placement of a guide wire into the vein, a sheath is advanced into the vein over the guide wire until it is identiﬁed by ultrasound to be 3–4 cm below the saphenofemoral junction, or just inferior to the deep penetration of the small saphenous vein where it will join the deep system. (Alternatively, the bare-tipped ﬁber may be advanced directly through the access needle, and carefully guided to the same position, without the use of the sheath and guide wire.) Occasionally, passage of the ﬁber may be impeded by vein tortuosity. Usually, straightening of the leg or guiding the ﬁber by external compression/manipulation of the thigh will allow

Leg externally rotated Insertion site with nitropaste

Figure 37.1 Leg externally rotated with the insertion site covered with nitropaste.

Technology 421

successful advancement. Segmental stenosis from previous sclerotherapy will also impede advancement of the ﬁber or guide wire. In this case, or if the vein is so tortuous as to not allow passage, a second cannulation, with another insertion kit, will allow treatment of ﬁrst the proximal and then the distal segments of the saphenous vein. Ultrasound-guided, high-volume, dilute anesthesia (0.1–0.25% xylocaine with epinephrine/bicarbonate) is then injected into the saphenous compartment (Fig. 37.2) from the insertion site up to 3 cm below the tip of the ﬁber, completely surrounding the target vein to ensure adequate anesthetic effect, compress the vein for better thermal effect, and to protect the perivenous structures from

Figure 37.2 Longitudinal ultrasound image of dilute local anesthesia injected into saphenous sheath. LA, local anesthesia; SS, saphenous sheath; DN, delivery needle; LF, laser ﬁber. Courtesy D Neuhardt: Compudiagnostics

Figure 37.3 Longitudinal ultrasound image of saphenofemoral junction area. SEV, superﬁcial epigastric vein; GSV, great saphenous vein; CFV, common femoral vein; FV, femoral vein. Courtesy D Neuhardt: Compudiagnostics

thermal damage. Alternatively, less precise, higher volume, dilute tumescent anesthetic can be injected into the entire thigh generally surrounding the vein, without the need for ultrasound guidance. In either case, it is always necessary to clearly identify several important anatomic landmarks (Fig. 37.3) near the saphenofemoral junction prior to treatment to effect safe and adequate treatment of the great saphenous vein. However, injection of the local anesthetic near the intended start of treatment will obscure these landmarks, severely limiting one’s ability to see the safe ﬁnal placement of the laser tip. The patient may be placed in a Trendelenburg position to further empty the vein of residual blood, with the ﬁnal position of the tip of the laser ﬁber conﬁrmed by ultrasound [just inferior to the entrance of the superﬁcial epigastric vein into the great saphenous vein for great saphenous vein treatment (Fig. 37.4), and just inferior to the deep penetration of the small saphenous vein]. The anesthetic solution is then injected into the tissue surrounding the proximal 3–4 cm of the saphenous vein. External hand compression may be applied to the leg over the tip of the ﬁber as it is withdrawn. The sheath and/or laser ﬁber are then withdrawn at a rate of 1–3 mm per second, more slowly for the proximal 10 cm and more quickly distally. The goal is to achieve successful ablation while at the same time minimizing the incidence of postoperative pain and bruising. Generally, delivering 60–100 J of laser energy per centimeter of vein treated will accomplish these goals. On conclusion of the procedure, Doppler conﬁrmation of the patency of the common femoral artery and vein, or popliteal artery and vein, as well as successful occlusion of the saphenous vein are recorded. Patients should then be placed in compression therapy, e.g., short-stretch bandages, and/or 30–40 mmHg compression hose (thigh high or panty – patient’s preference). Compression should be maintained

Figure 37.4 Longitudinal image of saphenofemoral junction area with appropriately-positioned laser tip in great saphenous vein. SEV, superﬁcial epigastric vein; CFV, common femoral vein; GSV, great saphenous vein; laser tip, tip of the laser ﬁber just inferior to the entrance of the superﬁcial epigastric vein into the great saphenous vein. Courtesy D Neuhardt: Compudiagnostics

422

Laser treatment of the incompetent saphenous vein

for at least several days, if not longer, to enhance successful ablation. Adjunctive ligation of the saphenofemoral or saphenopopliteal junction is not necessary.

Follow-up Because of the possibility of incomplete ablation or recurrent patency of the treated vein, and the need for adjunctive treatment of the distal great saphenous vein and/or small saphenous vein, and the reﬂuxing tributaries and perforators, color-ﬂow Doppler ultrasound, interviews, and physical examinations at appropriate intervals are needed to assure a successful outcome. At a minimum, patients should be examined at 1 week, 6 months, and 1 year following laser ablation of the saphenous vein. More frequent follow-up visits will often reveal the need for adjunctive treatment earlier in the postoperative course, and result in more complete treatment of the patient’s venous insufﬁciency with better resolution of the patient’s symptom complex. It is simply not appropriate to merely ablate the proximal saphenous vein, and expect longlasting resolution of the patient’s symptoms and varicosities. Unless one is committed to a program of meticulous follow-up and adjunctive treatment, the practitioner and the patient will be left with unsatisfactory results.

OUTCOMES (Table 37.2) Navarro et al.13 published the ﬁrst case series in 2001 on 40 veins treated with laser ablation under local perivenous anesthesia. They reported 100% complete ablation at a mean follow-up of 4.2 months, with no signiﬁcant complications. Proebstle et al.14 reported occlusion in all 41 small saphenous veins treated at a mean follow-up period of 6 months. Similar short-term reports of successful ablation with lasers of different wave lengths have been published.15–21 Few mid-term reports are available,22,23 but most demonstrate similar good results. In particular, Meyers et al.24 has reported his carefully collected and statistically well-analyzed data showing a secondary or assisted success of 88% at 3 years. Marston et al.25 reported improved CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology), Venous Clinical Severity Score (VCSS), and air plethysmography readings following RF or laser ablation. Mekako et al.26 has demonstrated the feasibility of carrying out laser ablation in concert with ambulatory phlebectomy. Neglen et al.27 demonstrated good outcomes combining laser ablation with deep vein stenting for superﬁcial venous insufﬁciency and concomitant deep vein obstruction. Proebstle et al.28,29 have reported that successful ablation is directly related to the amount of laser energy delivered to the vein wall. Puggioni et al.30 reported that segmental deep venous

Table 37.2 Outcomes following endovenous laser ablation Author

Number of veins

Follow-up period (months)

Successful ablation (%)

Signiﬁcant complications

Navarro et al.13 Proebstle et al.14 Chang and Chua15

40 41 252

4.2 6 19

100 100 96.8

Oh et al.16 Timperman et al.17

15 111

3 7

100 77.5

Goldman et al.18 Huang et al.19

24 230

6–12 6

100 100

Vuylsteke et al.20

118

9

94

Almeida and Raines21

819

5.3

98.3

Disselhof et al.22 Min et al.23 Meyers et al.24

93 121 404

29 24 36

84 93.4 80

None 6% thrombophlebitis 36.5% paresthesia 4.8% skin burn 1.6% thrombophlebitis None 1% deep vein thrombosis 1% skin burn None 1% skin burn 7% paresthesia 4% skin burn 14% paresthesia 0.2% deep vein thrombosis 0.2% paresthesia 2% thrombophlebitis None 0.2% severe pain 2.2% thromboembolism 0.3% nerve palsy

Outcomes 423

reﬂux will improve or resolve in one-third of patients following laser ablation. It has been reported that most incompletely ablated veins will be seen in the ﬁrst few months following treatment.23 However, we have identiﬁed recurrence in our own patients more than 6 years after apparently successful ablation, with recurrent symptoms and partially patent segments. Thus, it seems prudent to perform careful follow-up of these patients for 1 year, and then yearly, or certainly when recurrent symptoms occur.

Complications Complications may be divided into intraoperative and postoperative adverse events. Intraoperative adverse events include technical challenges and adverse patient events (Box 37.4).

BOX 37.4 Intraoperative adverse events ● ● ● ● ●

Difﬁcult access Difﬁcult ﬁber advancement Vagal reaction/dysrhythmia Nerve pain Transient heat

The technical challenges one may encounter are difﬁcult access (venospasm, access location); and problems threading the wire/sheath/ﬁber (vein tortuosity, aneurysmal segments, or sclerosis from previous sclerotherapy). Adverse patient events that may occur are dysrhythmia or vagal reaction (often because of anxiety); saphenous nerve pain; or transient heat (the last two occur with inadequate anesthetic inﬁltration). Postoperative adverse events include bruising, pain, paresthesia, infection, skin burn, superﬁcial thrombophlebitis, lymphedema, and deep vein thrombosis (Box 37.5).

BOX 37.5 Postoperative adverse events ● ● ● ● ● ● ●

Ecchymosis Pain Paresthesia Infection Cutaneous thermal injury Superﬁcial thrombophlebitis Deep vein thrombosis

Bruising is usually minimal, and of less than 2 weeks’ duration.14 The incidence of paresthesia has been reported as high as 7% with groin-to-ankle laser ablation without perivenous anesthesia.19 It has been reported by Pannier

and Rabe31 (and similar experience has been seen in our center) that, unlike after groin-to-ankle stripping, paresthesia following endovenous ablation is usually mild, short-lived, and limited to the distal thigh. It is our observation that the rate of paresthesia is inversely related to the practitioner’s experience with perivenous ultrasound-guided anesthesia. Infection is rare, but Dunst et al.32 reported a case of septic thrombophlebitis following laser ablation, requiring surgical drainage. Infection is generally avoidable with adequate sterile technique. Skin burns are rarely reported19 and are easily avoided with the perivenous anesthetic injected to separate the skin from the underlying vein to be treated. Superﬁcial thrombophlebitis is reported in 1–12%9,15 and responds to the usual clinical measures of anti-inﬂammatory medication, compression, and ambulation. Lymphedema has not been reported, but we have seen it in our own center, and it is believed to be caused from unrecognized impaired lymphatic drainage usually present prior to any procedures. Treatment of this complication will include therapeutic lymphatic massage, compression with multilayered low-stretch bandages and compression hose, and exercise. Deep vein thrombosis is the most signiﬁcant complication, and has rarely been reported in the laser literature. However, it has been our experience that there is a direct correlation between the discovery of deep vein thrombosis and the duplex scanning interval, as well as the quality and objectivity of the examination and examiner. Most deep vein thromboses develop in calf veins, and are of limited clinical signiﬁcance. More proximal deep thigh vein thromboses do occur, however, and should be aggressively searched for and treated. Treatment is usually outpatient, with compression, ambulation, anti-inﬂammatory medication or anticoagulation (short term with lowmolecular-weight heparin, or longer term with oral agents), and even percutaneous thrombolytic/ thrombectomy therapy for more proximal thromboses. A thrombophilia work-up should be considered in any patient who develops deep venous thrombosis in the postoperative period. Mozes et al.33 reported on thrombus extensions from the great saphenous vein into the common femoral vein, identiﬁed early in the postoperative period. We have seen a number of such thrombus extensions in our own center (Fig. 37.5), which were treated early in our experience with anticoagulation and frequent follow-up duplex examinations. With careful duplex follow-up, we concluded all of these thrombus extensions retract over the course of 7–10 days, and none produced clinical symptoms suggestive of pulmonary embolus. Because of this experience, and the fact that there have been no reports of pulmonary embolus in the laser literature, our current management is expectant duplex observation without anticoagulation. Other rare complications have been reported, such as arteriovenous ﬁstula,34 and cutaneous thermal injury to overlying tributary veins.35

424

Laser treatment of the incompetent saphenous vein

Figure 37.5 Thrombus extending from great saphenous vein into common femoral vein. CFV, common femoral vein; GSV, great saphenous vein. Courtesy D Neuhardt: Compudiagnostics

One complication, of great interest because of its relative absence following laser ablation, is neovascularization. Neovascularization is commonly seen after the traditional surgical high ligation procedure, wherein all tributaries of the great saphenous vein are carefully dissected and divided.36 This is thought to be secondary to “frustrated” venous drainage from the abdominal wall and perineum, and/or the neovascular stimulus created by the groin surgery itself. The ultrasound picture of neovascularization, seen as grape-like clusters of veins in the groin, is quite characteristic (Fig. 37.6). Whether this is actually

Figure 37.7 Transverse ultrasound image of infrainguinal groin near saphenofemoral junction following endovenous laser ablation of the great saphenous vein. Neo, neovascularization in the area of the saphenofemoral junction 3 years after endovenous laser ablation. Courtesy D Neuhardt: Compudiagnostics

the development of new veins or simply enlargement of previously existing veins, the result is recurrent reﬂux in thigh and leg veins. The endovenous laser ablation procedure deliberately leaves the superﬁcial epigastric vein intact, which, it is believed, has contributed to the lack of neovascularization reported thus far. However, we have seen one case of typical neovascularization in our own center discovered 3 years after laser ablation (Fig. 37.7).

DISCUSSION

Figure 37.6 Transverse ultrasound image of infrainguinal groin near saphenofemoral junction following traditional high ligation and stripping of the great saphenous vein. Neo, neovascularization in the area of the saphenofemoral junction 3 years after ligation/stripping, appearing as “grape clusters.” Courtesy D Neuhardt: Compudiagnostics

Considerable confusion in the literature has emerged regarding the deﬁnition of successful treatment, the means used to detect treatment failures, and the reporting of results. Recent advancements in the technology of ultrasound have resulted in more critical evaluation of clinical results than were possible in the past. Duplex ultrasound has replaced continuous wave Doppler, venography, and rheography in the diagnosis, treatment, and follow-up of patients with chronic venous insufﬁciency. However, shortcomings have come to light in regards to the use of duplex ultrasound, including the facts that duplex examination (and thus results obtained) are operator based, operator dependent, and that operator training in chronic venous insufﬁciency is lacking. The result is a plague of inconsistent information from vascular laboratories. Because of our concern when comparing our own outcomes with those published in the literature – and in an attempt to answer the questions does reﬂux detection depend on equipment; does Doppler sensitivity vary among equipment; and does this sensitivity variation alter

Discussion 425

Table 37.3 Inconsistencies in assessment of reﬂux using ﬁve different ultrasound equipments Patient no. 1 RGSV SFJ RGSV AK RGSV BK LGSV SFJ LGSV AK LGSV BK

Equipment A

Equipment B

Equipment C

Equipment D

Equipment E

– + + – + +

– – + – + +

– – + – + +

– + + – + +

– – – – + +

AK, above the knee; BK, below the knee; LGSV, left great saphenous vein; RGSV, right great saphenous vein; SFJ, saphenofemoral junction.

treatment options and reported results – we designed a study to gauge the effect of the sensitivity of different ultrasound machines. One registered vascular technologist, with extensive experience in the diagnosis and treatment of superﬁcial venous disease, examined the great saphenous veins at three sites: the saphenofemoral junction (SFJ), above the knee (AK), and below the knee (BK) in six patients with moderate reﬂux using ﬁve different ultrasound machines. The examination was conducted in the standing position, using the highest frequency available for the equipment, and each machine was set up to optimize Doppler scale and sensitivity. The studies were blindly graded by an interpreting MD. Table 37.3 illustrates the inconsistency of the presence or absence of reﬂux at various sites identiﬁed by the same sonographer in patient no. 1, using the ﬁve ultrasound machines. One can see that, comparing the most sensitive equipment D with the least sensitive equipment E, agreement was present only two-thirds of the time. Figure 37.8 demonstrates that, by comparing the most sensitive equipment D with the least sensitive equipment E in all patients at all anatomic sites, reﬂux was identiﬁed in every case with equipment D, whereas using equipment E

14 12

Number of reflux sites identified in all patients

100%

85% 77%

10

reﬂux was identiﬁed in only 62% of the sites at which it was present. This will result in misdiagnosis and undertreatment in over one-third of patients, using the least sensitive equipment. It can be reasonably assumed that, if the same equipment is used to conduct follow-up examinations on patients in whom the great saphenous vein has undergone laser thermoablation, partial patency or ﬂow can be expected to be missed as well. We have demonstrated in our own center that identiﬁcation of treatment failure is dependent on the sensitivity of the ultrasound equipment used for postoperative examination, the objectivity and expertise of the sonographer, and the vigor with which the examination is conducted. Duplex examination for successful ablation of a laserablated vein should include gray-scale, compression, and color-ﬂow Doppler. Interestingly, foam sclerotherapy has had an unexpected effect on critical analysis of successful laser ablation. Because foam is an excellent contrast medium with ultrasound, injection of foam into distal vein segments, tributaries, and incompetent perforators will sometimes reveal an incompletely treated vein, which by all other duplex ultrasound criteria is completely occluded (Figs 37.9–37.11). This further calls into question even the most critical examination techniques. Whether these minimally patent segments will become clinically signiﬁcant is unanswered at this time. But certainly patients who complain of localized pain in the area of a previously ablated vein deserve very careful examination to identify the incompletely ablated segment.

69% 62%

8 6 4 2 0 Equipment A

Equipment B

Equipment C

Equipment D

Equipment E

Figure 37.8 Percent of reﬂux sites identiﬁed using ﬁve different ultrasound equipments.

SUMMARY Endovenous laser ablation is generally safe. Intraoperative and postoperative complications are uncommon and generally are less frequently seen than with more traditional surgical procedures. Differences in methods of follow-up examination, and in deﬁnitions of successful ablation, may help explain variances of results between published reports and those seen in the surgeon’s own clinical setting. Only randomized controlled trials comparing endovenous laser ablation with other modalities, with long-term follow-up, will demonstrate

426

Laser treatment of the incompetent saphenous vein

Figure 37.9 Previously ablated great saphenous vein appears closed by gray scale and demonstrates incompressibility (arrow). Courtesy D Neuhardt: Compudiagnostics

Figure 37.11 Partial patency of a previously ablated great saphenous vein demonstrated using foam injected into a tributary, creating a column in the vein judged to be “closed” by all duplex ultrasound criteria (arrow). Courtesy D Neuhardt: Compudiagnostics

surgeons have expressed the view that none of these techniques has yet been shown to better conventional surgery in the long term,37 the patient’s perception has uniformly been that minimal invasion is better.

CLINICAL PRACTICE GUIDELINES ●

●

Figure 37.10 Color-ﬂow Doppler demonstrates no ﬂow in previously ablated great saphenous vein (arrow). Courtesy D Neuhardt: Compudiagnostics

where these minimally invasive methods belong in the therapeutic armamentarium for the treatment of chronic venous insufﬁciency of the lower extremity. While some

●

●

Endovenous laser ablation of the saphenous vein effectively removes the target vein from the venous circulation. Endovenous laser ablation is safe and well-tolerated, with a low incidence of signiﬁcant complications reported. Adjunctive therapy to permanently eliminate the saphenous vein and all other sources of reﬂux disease is integral to adequate control of superﬁcial venous insufﬁciency. Careful follow-up with the most sensitive ultrasound equipment available will ensure the best results.

Guidelines 4.10.0 of the American Venous Forum on laser treatment of the incompetent saphenous vein No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.10.1 Endovenous laser therapy of the great saphenous vein is safe and effective and we recommend it for treatment of saphenous incompetence

1

A

4.10.2 Clinical outcome after endovenous laser therapy up to 3 years is comparable to traditional stripping and ligation and we recommend it for treatment of the incompetent great saphenous vein

1

C

References 427

●

●

Long-term outcome reports are necessary to conclude that endovenous laser ablation is a durably effective method of treating superﬁcial venous insufﬁciency. Randomized controlled trials comparing endovenous laser ablation with other methods (including surgery, radiofrequency ablation, and chemical ablation) are lacking at this time.

★13.

14.

15.

REFERENCES ◆ ★

= Major review article = First formation publication of a management guideline

16.

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29. Proebstle T, Moehler T, Herdemann S. Reduced recanalization rates of the great saphenous vein after endovenous laser treatment with increased energy dosing: deﬁnition of a threshold for the endovenous ﬂuence equivalent. J Vasc Surg 2006; 44: 834–9. 30. Puggioni A, Lurie F, Kistner R, Eklof B. How often is deep venous reﬂux eliminated after saphenous vein ablation? J Vasc Surg 2003; 38: 517–21. ◆31. Pannier F, Rabe E. Endovenous laser therapy and radiofrequency ablation of saphenous varicose veins. J Cardiovasc Surg 2006; 47: 3–8. 32. Dunst K, Huemer G, Wayand W, Shamiyeh A. Diffuse phlegmonous phlebitis after endovenous laser treatment of the greater saphenous vein. J Vasc Surg 2006; 43: 1056–8. 33. Mozes G, Kalra M, Carmo M, et al. Extension of saphenous

34.

35.

36.

37.

thrombus into the femoral vein: a potential complication of new endovenous ablation techniques. J Vasc Surg 2005; 41: 130–5. Timperman P. Arteriovenous ﬁstula after endovenous laser treatment of the short saphenous vein. J Vasc Interv Radiol 2004; 15: 625–7. Sichlau M, Ryu R. Cutaneous thermal injury after endovenous laser ablation of the great saphenous vein. J Vasc Interv Radiol 2004; 15: 865–7. van Rij AM, Jiang P, Solomon C, et al. Recurrence after varicose vein surgery: a prospective long-term clinical study with duplex ultrasound scanning and air plethysmography. J Vasc Surg 2003; 38: 935–43. Soumian S, Davies A. Endovenous management of varicose veins. Phlebology 2004; 19: 163–9.

38 Phlebectomy LOWELL S. KABNICK Introduction History Deﬁnition of ambulatory phlebectomy Diagnostic methods and indications Technique

429 429 430 430 431

INTRODUCTION Hippocrates performed the ﬁrst phlebotomy to treat a varix about 2400 years ago. Since that time, procedures for removal of varicose veins have evolved with many modiﬁcations. It was Robert Muller, a Swiss dermatologist, who reﬁned the technique in 1956 and later discovered through surgical history and to his dismay that ambulatory phlebectomy was practiced by Aulus Celsus 2000 years earlier. Although Muller’s technique was adopted slowly, it is now considered the preferred method for the treatment of varicose veins. The procedure is performed for an ambulatory patient under local anesthesia with little, if any, recovery time. In short, a small hook-like instrument, together with ﬁne clamps, is employed to extract the varix from a small (~2 mm) incision made by an 18G needle or 15° ophthalmic blade. A dry sterile compression dressing or a compression hose is applied postoperatively to the limb. This chapter will cover the indications and contraindications of ambulatory phlebectomy. A detailed explanation of the procedure will be provided, as well as a description of potential complications and the regions where phlebectomy is difﬁcult to perform. For the reader to best gain expertise and shorten the learning curve, the author suggests not only reading this chapter but seeking out an expert in the ﬁeld of phlebectomy to observe the procedure.

HISTORY Hippocrates, in 400BC, was the ﬁrst to conceptualize phlebectomy; several sequential punctures in the vein would be used to get rid of the “bad blood” that fed an

Complications Powered phlebectomy Conclusions Clinical practice guidelines References

434 435 437 437 438

ulcer.1,2 However, it appears that Aulus Cornelius Celsus, 56BC to 40AD, was the ﬁrst surgeon to actually perform phlebectomy. According to historians who researched and wrote the history of ambulatory phlebectomy, most of Celsus’ writings disappeared or were destroyed. However, some of the documents that were discovered attributed and described Celsus’ venous contributions. Concerning phlebectomy, Celsus wrote, “The varicose veins were treated by exposure followed by avulsion with a blunt hook or by touch of the cautery.”3 Although he made large incisions, he used compressive bandages that allowed ambulation. The modern-day phlebectomy technique was ﬁrst described by Robert Muller, a dermatology-trained phlebologist from Neuchâtel, Switzerland, who reinvented and reﬁned the technique that we know today as ambulatory phlebectomy (Fig. 38.1). Disappointing results of large-vein sclerotherapy had prompted Dr. Muller to reevaluate and change his technique. He noticed that phlebitis developed in a number of cases after injection, followed by recanalization and recurrent thrombus. Because of the fragility of the venous wall and the difﬁculty of removing these treated veins, he eliminated sclerotherapy and went directly to removal. Muller began by using small hooks (made from broken forceps) to remove varicosities through small incisions. By 1956, he had perfected this technique, which he presented in 1967 to the French Society of Phlebology and in 1968 to the International Congress of Phlebology. These presentations were poorly received by most of the audience. Muller wrote, “It was a total ﬁasco. Everybody agreed that it was a ridiculous method, after which I could have buried myself together with the invention. However, a young colleague, Dr. Dortu, asked me to teach him the method.”4–6

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Phlebectomy

The objective of ambulatory phlebectomy is to provide deﬁnitive treatment for removal of the target vein after the highest point of reﬂux is treated and/or eliminated.

DIAGNOSTIC METHODS AND INDICATIONS Diagnostic methods A complete history should be taken and a physical examination performed for every patient, as well as, in most cases, a duplex ultrasound. Transillumination is very helpful for identifying reticular and feeding veins associated with telangiectasias. Common transilluminating devices include the Veinlite® (TransLite, Sugar Land, TX, USA) and VeinViewer™ by Luminetx (Memphis, TN, USA).

Indications Figure 38.1 Dr. Robert Muller.

Since that time, Muller and his disciples have taught this technique, which has spread slowly throughout the world. It was not until recently that Muller’s phlebectomy technique was adopted in the USA as the procedure of choice to remove segments of varicose and some reticular veins. Over the years, Dr. Muller’s technique and instrumentation have been imitated, given different names, reinvented using personal techniques, and perhaps improved.

DEFINITION OF AMBULATORY PHLEBECTOMY The term “ambulatory phlebectomy,” coined by Dr. Muller, refers to the technique in which varicose veins are extracted in an outpatient setting under local anesthesia using small punctures and hooks. This technique requires hemostatic compression and immediate ambulation. Ambulatory phlebectomy, stab avulsion, stab phlebectomy, microphlebectomy, and microextraction are synonymous terms that deﬁne this ambulatory, outpatient technique performed using local anesthesia. The author strongly recommends that the term ambulatory phlebectomy or microphlebectomy be used when discussing the procedure with a patient. Stab avulsion and stab phlebectomy should be avoided as patients really do not want to be stabbed. The Current Procedural Terminology (CPT) code book of the American Medical Association lists three codes for the billing of the procedure: (1) 37765, stab phlebectomy of varicose veins, one extremity, 10–20 stab incisions; (2) 37766, stab phlebectomy of varicose veins, one extremity, more than 20 incisions; and (3) 37799, for fewer than 10 incisions.7

Indications for ambulatory phlebectomy vary depending on the skill set and other techniques with which the phlebologist is comfortable. Patients of all ages are candidates for phlebectomy. The procedure may be medically indicated if the veins are symptomatic or cosmetic if the veins are asymptomatic. Ambulatory phlebectomy can be performed by itself or in conjunction with another procedure. Varicose veins of any size, in any location excluding the cephalad end of the great or small saphenous vein, are candidates for ambulatory phlebectomy. These include the epifascial great saphenous vein, collateral varicosities, and reticular veins. Also appropriate for ambulatory phlebectomy are regional venous networks, including accessory saphenous veins of the thigh, pudendal perineal veins, reticular veins of the lateral subdermic plexus and popliteal fossa, and foot and hand veins.8,9 Dilated veins in other parts of the body including the periorbital, abdominal, and chest areas, as well as medial thigh perforating veins and small lateral perforating veins, can be removed by this technique with success.10 Areas of difﬁculty for removing the veins by hook are the knee, tibial, and foot areas where the veins are tethered by connective tissue, making their removal somewhat difﬁcult. Areas of caution are the following: the distal great saphenous vein in the saphenous nerve distribution and the small saphenous vein in the sural nerve region. Lateral varicosities by the ﬁbular head are in the region of the peroneal nerve and should be approached with caution, as should many areas of the hand and foot.

Treatment strategies Accepted treatment strategies in phlebology include compression therapy, sclerotherapy, ambulatory phleb-

Technique 431

ectomy, endovenous thermal ablation, and topical laser. Each treatment modality has its advantages and indications; however, there is signiﬁcant overlap. Sclerotherapy is the closest alternative treatment strategy to ambulatory phlebectomy. At present, there is still a debate as to which is better and a paucity of evidenced-based literature to support the superiority of either procedure. A single randomized, controlled trial by de Roos et al.11 demonstrated the superiority of ambulatory phlebectomy over sclerotherapy for the treatment of the anterior thigh circumﬂex vein. However, there are ﬂaws in the study. The debates about the superiority of the procedures usually end in a tie. The phlebologist must know both procedures.

Staged versus unstaged procedures There is substantial controversy over whether ambulatory phlebectomy should be performed at the same time that truncal reﬂux is being abolished. Historically, the complete removal of any varicosities at the same time as great saphenous vein treatment has been dogma. Homans12 and Mayo,13 in the early twentieth century, published papers stating that complete removal of varicosities was encouraged to prevent recurrence. However, I have presented data demonstrating a signiﬁcant reduction in size and disappearance of varicosities after treating the truncal reﬂux.14 In reviewing the literature, the author identiﬁed one single-center, prospective study addressing the issue, from which Dr. Monahan15 concluded, “[Great saphenous vein] ablation resulted in subsequent resolution or regression of many lower-limb visible varicose veins. If proven durable, the advantage of this strategy is obvious.” I believe that the phlebologist must be selective when confronted with the treatment algorithm. Combined procedures are indicated if the varicose veins involve the zone of inﬂuence regarding the truncal reﬂux. Instead, staging is indicated if the varicose veins lie outside the zones of inﬂuence.

Contraindications There are a limited number of contraindications to ambulatory phlebectomy. The following conditions should be considered as relative contraindications: ● ● ● ● ● ● ●

infectious dermatitis or cellulitis in surrounding areas severe peripheral edema severe arterial insufﬁciency serious illness anticoagulated state, e.g., patient receiving warfarin hypercoagulable state pregnancy.

TECHNIQUE Preoperative preparation All target veins should be traced while the patient is standing as they may be difﬁcult or impossible to identify during recumbency. Surgical markers include those using gentian violet-colored solution, e.g., Vismark™ (Viscot Medical, East Hanover, NJ, USA) surgical skin markers. Use of a permanent marker to trace the veins should be avoided because of risk of tattooing. After the patient has been placed in the recumbent position, the vein marks are adjusted using a transilluminator such as the VeinLite® or VeinViewer™. Because veins tend to shift, this subsequent adjustment adds to the efﬁcacy and speed of extraction19 (Fig. 38.2).

Surgical plan The timing of ambulatory phlebectomy depends on the nature and type of other venous procedures being performed. When ambulatory phlebectomy is coupled with saphenectomy or endochemical or endothermal ablation of the great or small saphenous veins, phlebectomy below the knee should be performed ﬁrst. There

Benefits of ambulatory phlebectomy Ambulatory phlebectomy is an economical, cosmetic, and effective method to remove veins. Improvements in anesthetic technique, namely the use of tumescent anesthesia, have limited the amount of pain both intraoperatively and postoperatively. Patients can return to daily activities after the procedure and return to work the next day. Because of the paucity of reported complications, the procedure is considered safe.16–18 However, long-term results, although presumed excellent, have not been studied well to date.

Figure 38.2 The circle and dotted line tracing the vein were drawn with the patient in an erect position (blue arrows). The straight line was drawn with the patient in a recumbent position (red arrows).

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can be a transient increase in endoluminal pressure in caudal veins during saphenous treatment, which could result in bleeding if ambulatory phlebectomy is performed during the same stage. I often stage my procedures, treating the great or small saphenous vein ﬁrst, followed several weeks later by ambulatory phlebectomy. This method allows the existing truncal varicosities to decrease in size or disappear before further procedures.14,15

Anesthesia Local anesthesia with or without epinephrine was used historically, but rarely today, to provide a painless phlebectomy. Most operators now suggest using tumescent anesthesia for ambulatory phlebectomy. TUMESCENT ANESTHESIA

Tumescent Function: adjective Etymology: Latin tumescent-, tumescens, present participle of tumescere to swell up, inchoative of tumere to swell: somewhat swollen 20 J.A. Klein, a dermatologist, was the ﬁrst, in 1987, to describe tumescent anesthesia.21 His method utilized dilute local anesthesia as a way of creating a ﬁeld block. Tumescent anesthesia exploits the principles of pharmacokinetics to achieve anesthesia of the epidermis, dermis, and subcutaneous tissues. The subcutaneous inﬁltration of a large volume of dilute buffered lidocaine and epinephrine causes the targeted tissue to become swollen and ﬁrm, or tumescent. Because the subcutaneous tissue is relatively avascular, a large volume of diluted epinephrine injected into this area produces widespread and prolonged vasoconstriction. Vasoconstriction appears to diminish the rate of systemic lidocaine absorption, thus reducing the peak plasma lidocaine concentration, reducing potential toxicity, and permitting a much larger dose of lidocaine to be administered.21–24 According to Klein, “In fact tumescent technique permits safe lidocaine dosage of at least 35 mg/kg of body weight and provides effective local anesthesia for as long as ten hours. The widely accepted 5–7 mg/kg safe maximum dose for lidocaine with epinephrine when administered subcutaneously, as published in the PDR has never been substantiated by a published scientiﬁc study.”24 Klein and others observed that the pharmacokinetics of dilute lidocaine with epinephrine are different from those of 1–2% lidocaine. With undiluted lidocaine, a measurable plasma level appears in 15 minutes and peaks soon after; lidocaine is metabolized in a few hours. Absorption of the tumescent solution is slower, causing peak plasma levels to occur many hours later, and thus the anesthetic effect is longer. Patients receiving large volumes can have plasma

levels that peak in 4–14 hours and linger for longer than 24 hours. PROCEDURE FOR ADMINISTERING TUMESCENT ANESTHESIA

In 1995, Cohn and co-workers25 reported using the tumescent technique for local anesthesia while performing ambulatory phlebectomy. Three years later, Smith and Goldman26 reported the use of tumescent anesthesia for ambulatory phlebectomy. The inﬁltration of dilute anesthesia in a perivascular position, epidermal and dermal, serves several purposes: 1. The anesthetic effect is long lasting, and sensation returns slowly. 2. With the use of longer needles and dilute solution, fewer needle punctures and less pain upon administration are observed. 3. Tumescent technique causes more compression of surrounding tissues leading to less hematoma and ecchymosis. 4. Hydrodissection occurs around the vein, facilitating the removal. 5. Reduction of infection, usually limited to the incision site, is a result of the bacteriostatic and bacteriocidal properties of lidocaine concentration.27 The methods of delivering and mixing of ingredients of tumescent anesthesia vary among operators. I use the following solution: ● ● ●

445 mL of 0.9% saline 50 mL of 1% lidocaine with 1:100 000 epinephrine, and 5 mL of 8.4% sodium bicarbonate.

Presently, most operators use either a regular syringe, a self-ﬁlling syringe, or a pump to deliver tumescent anesthesia. The last two methods facilitate delivery of higher volumes of tumescent anesthesia. Microcannulas, 22G (author’s preference), or 25G needles are used for the delivery of the solution.

Procedural equipment Incisions or punctures can be made with various devices, including hypodermic needles and surgical blades. The most common instruments are 18G needles, number 11 blades, and 15° ophthalmologic blades. From my experience, the number 11 blade causes greater scarring. After phlebectomy is completed, 1.25 cm adhesive strips are placed to close the punctures. Several different hooks are available for purchase, varying in size, shape, and sharpness. The most widely known are the Muller, Oesch, Tretbar, Ramelet, Verady, and Dortu-Mortimbeau hooks.28 One particular phleb-

Technique 433

Figure 38.5 Kabnick phlebectomy instrument with the spatula end used as dissector. Figure 38.3 A typical surgical tray for phlebectomy.

ectomy instrument is not superior to another. It is important for the surgeon to be comfortable with a particular set of hooks, making the selection after trying the gamut. The clamps used for the vein extraction should have a ﬁne tip so that they can grip close to the skin. A serrated face is helpful in maintaining ﬁrm traction without slippage. The operator should have at least three ﬁne hemostat clamps available, but ﬁve or more are preferable (Fig. 38.3).

Procedure After the anesthetic has been injected into the perivenous tissues, a microincision or puncture is made near the vein (Fig. 38.4). Most are oriented vertically, except around the knee, where they should be oriented along the tension lines (Langer’s lines). A blunt-tip spatula may be inserted into the opening, although this is not mandatory (Fig. 38.5). It does, however, enable a hook to be inserted without

interference from surrounding tissues and without enlarging the entrance hole. Once the hook has been inserted, the vein is grasped blindly and brought up and out of the opening (Fig. 38.6a). The vein is then grasped between clamps and transected by small scissors (Fig. 38.6b,c). Using gentle traction on the hemostat in a “windshield wiper movement,” one end of the varix is teased out of the puncture site. Successive hemostats are applied to the varix as it is extracted from its position, keeping in mind that the vein will eventually tear (Fig. 38.6d). Very long segments can often be removed through a single puncture site. Once a segment has been extracted, the operator moves along the vein by a roughly equivalent distance and makes another incision, and the process is repeated. The operator is encouraged to remove all parts of the varix, without leaving isolated segments behind, to reduce a possible inﬂammatory response from thrombosis of the retained segment. However, as long as most of the segment is removed, the patient should have an excellent result. There is rarely cause to ligate a vessel except when a perforating vein, peripheral foot or hand vessel, or large varix (> 1 cm) is exposed (Fig. 38.6e). Perforating veins are recognized as branches in the vein, often with an orientation perpendicular to the skin and associated with a deep pulling sensation by the patient. The puncture sites are covered with adhesive strips, sterile dressings, and wrapped with a soft gauze roll and stretch bandages (Fig. 38.7a–d).

Discharge recommendations The patient can be safely discharged from the facility after ambulating. Discharge and follow-up recommendations are as follows:

Figure 38.4 Incision.

1. Provide a prescription for an oxycodone– acetaminophen combination tablet or capsule, with instructions to try acetaminophen initially (most patients take only acetaminophen).

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Phlebectomy

(a)

(c)

(b)

(d)

(e)

Figure 38.6 (a) Hook delivering the target vein above the skin surface. (b) Delivering a loop of vein and clamping proximally and distally. (c) Transection of the vein loop. (d) Gentle traction on the clamp. (e) Optional vein ligation.

2. Instruct the patient to return to the ofﬁce the following day for bandage removal and placement of a class 2 compression hose. 3. Have the patient wear compression hose (class 2, 30–40 mmHg) for at least 2 weeks. 4. Instruct the patient to return to activities of daily living, with no heavy aerobic exercise that would involve the lower extremities for 2 weeks. 5. Leave adhesive strips in place for 2 weeks. 6. Follow up in 2 weeks, 8 weeks, 6 months, and 1 year.

COMPLICATIONS Complications arising from ambulatory phlebectomy are quite rare but can occur, as listed in Table 38.1.14,17,18,29,30 I

have performed more than 60 000 phlebectomies and have experienced few complications. There have been two large retrospective studies looking at complications of phlebectomy. The ﬁrst was a multicenter French study that reviewed 36 000 phlebectomies.31 The second was a literature review by Ramelet16 in 1997. He republished the complication rates of several different authors. The rates of complications vary widely among the same listings, with skin blistering being the highest, ranging from 1.3% (1997 Olivencia report18) to 20% (1980 Gillet report32). Telangiectatic matting has varied in the different studies from 1.5% in the multicenter French review31 to 9.5% in Trauchessec and Vergereau’s report.33 Isolated authors have reported telangiectatic matting as high as 2.4%. However, if we look at modern-day reports, the common complications appear to change in frequency. Regardless, I

Powered phlebectomy

435

(b)

(a)

(c)

(d)

Figure 38.7 (a) Placement of adhesive strips over vein extraction sites. (b) Sterile gauze placement. (c) Gauze wrap. (d) Stretch bandage placement.

believe that the complication rates are minimal. In my experience, the most common complications are: development of telangiectasias, 2%; blistering, 0.5%; hyperpigmentation (limited), 0.01%; and missed varix, 0.3%. It is my observation that patients who are prone to telangiectasias have a higher incidence of developing this complication than patients who are not prone. The incidence of hyperpigmentation depends on the size of the veins being removed and the amount of blood shed. The incidence of skin blistering has decreased over time by proper bandage placement, as well as alternatives to skin tapes.

POWERED PHLEBECTOMY The proprietary name for the powered phlebectomy device is the TriVex System (Endoscopy Division, Smith & Nephew, Mississauga, ON, Canada). The development of this device began in 1966, when Greg Spitz, a surgeon, took an arthroscopic shaver and applied it for the removal of varicose veins. Through many derivations, including transillumination and a delivery method for tumescent anesthesia, the present system was complete. The system contains a modiﬁed arthroscopic shaver and a transilluminator coupled with an irrigator that can also deliver tumescent anesthesia. The concept was developed to

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Phlebectomy

Table 38.1 Potential complications arising from ambulatory phlebectomy* Anesthetic complications

Skin complications

Complications of compression bandage

Vascular complications

Lymphatic complications

Neurological complications

Allergic reaction, e.g., to preservative, lidocaine Emotionally labile patient Technique related, e.g., placement of injection Blister Dimpling Hypo- or hyperpigmentation (incision) Induration Infection Pigmentation, transitory or permanent Blisters Contact dermatitis Ischemia Skin necrosis Swelling Bleeding, seroma Deep venous thrombosis Matting Pulmonary embolism Superﬁcial thrombosis Telangiectasias Lymphocele Lymphorrhea Persistent edema Dysesthesia (temporary or permanent) Nerve damage: saphenous, sural, peroneal, etc. nerves Temporary hypoesthesia Traumatic neuroma

*This list is compiled from the experience of several physicians: Jose Olivencia, Robert Muller, Stefano Ricci, Lowell Kabnick, and Michael Ombrellino.14,17,18,29,30

decrease the time for ambulatory phlebectomy. Although there have been many modiﬁcations, the procedure still remains virtually the same. Varicose clusters are transilluminated, anesthetized, morcellated, and aspirated (Fig. 38.8a,b).

Study results

(a)

(b)

Studies of the TriVex System describe several modiﬁcations of the procedure to improve patient outcomes. Investigators have often compared manual phlebectomy

Figure 38.8 (a) Transillumination and instillation of tumescent anesthesia. (b) Removing vein placement of the TriVex Resector and Illuminator.

Clinical practice guidelines

with powered phlebectomy. Most authors indicate that the number of incisions are less with TriVex, and operating time is faster. Ray-Chaudhuri et al.34 compared postoperative pain scores, with the results after 14 days being 2.6 (manual) and 1.9 (TriVex); a difference that was not statistically signiﬁcant. Cosmetic scores were also equal. In two randomized trials, Aremu et al.35 and Scavée et al.36 demonstrated no difference in patient cosmetic scores or satisfaction. These conclusions were ﬁrst recognized by Spitz and co-workers37 in their original reported ﬁndings. At 52 weeks, in the TriVex cohort, there was a higher number of recurrences than in the ambulatory phlebectomy cohort of 21.2% and 6.2%, respectively.35 In the initial postoperative period of a 14-patient study (by the author) comparing consecutive ambulatory phlebectomy and TriVex, 100% of the patients would prefer ambulatory phlebectomy over TriVex if repeating the procedure in the future. The reasons listed for the preference for manual ambulatory phlebectomy were the difference in early recovery, pain, general anesthesia, and amount of bruising. Although TriVex is presently utilized, it will become obsolete unless the procedure can be modiﬁed to obviate general or regional anesthesia and become an ofﬁce-based procedure.

(a)

Ambulatory phlebectomy has now been adopted by surgeons as the standard procedure for the removal of varicose veins. This simple procedure has added a highly acceptable cosmetic dimension to the medical indication. Using accepted technique – ambulatory delivery, local anesthesia, 2 mm incisions, hook technique, and compression – patients will experience minimal recovery time and few if any complications (Fig. 38.9a,b).

(b)

Figure 38.9 (a) Preoperative photograph of varicose veins. (b) Postoperative phlebectomy (12 weeks).

CLINICAL PRACTICE GUIDELINES ●

CONCLUSIONS

●

●

●

●

Ambulatory phlebectomy should be staged and treated after truncal reﬂux (14, 15 [2C]). Local or tumescent anesthesia is recommended to be used when performing ambulatory phlebectomy (21, 22, 24 [1C]). Powered phlebectomy (TriVex) has been effective in multiple studies in treating varicose veins (34 [2B], 35 [2B], 36 [2B], 37 [2C]). Phlebectomy has been superior to sclerotherapy for varicose veins (11 [2B]). Preoperative mapping with transillumination in the recumbent position is accurate (19 [1C]).

Guidelines 4.11.0 of the American Venous Forum on phlebectomy No.

437

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.11.1 We recommend ambulatory phlebectomy, an outpatient procedure performed under local anesthesia, as an effective and deﬁnitive treatment for varicose veins. The procedure is performed after saphenous ablation, either during the same procedure or, as recommended by most experts, at a later stage

1

B

4.11.2 Powered phlebectomy (TriVex) has been effective in multiple studies for the treatment of varicose veins. We suggest it as an option

2

C

4.11.3 We suggest phlebectomy over sclerotherapy for treatment of varicose veins

2

B

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REFERENCES

◆18.

= Key primary paper = Major review article ★ = First formal publication of a management guideline

★19.

● ◆

1. Adams F. The Genuine Works of Hippocrates. Translated from the Greek with a preliminary discourse and annotations by Francis Adams. London: The Sydenham Society, 1849: 808–9. ◆2. Olivencia JA. Ambulatory phlebectomy turned 2400 years old. Dermatol Surg 2004; 30: 704–8. 3. Aulus Cornelius Celsus. Medicinae Libri Octo, Patavii. Typis Seminarii Apud Joannem Manfrè, Liber Septimus. 1749: 473–4. ◆4. Muller R. History of ambulatory phlebectomy. In: Ricci S, Georgiev M, Goldman MP (eds). Ambulatory Phlebectomy, 2nd edn. Boca Raton: Taylor Francis Group, 2005: xxxiii–xl. 5. Muller R. Treatment of varicose veins by ambulatory phlebectomy (in French). Phlebologie 1966; 19: 277–9. 6. Muller R. Clariﬁcation on ambulatory phlebectomy according to Muller. (A.P.M.) (in French). Phlebologie 1996; 49: 335–44. 7. Gordy T, et al. Current Procedural Terminology 2007. Chicago: American Medical Association, 2006: 175. ★8. Olivencia JA. Ambulatory phlebectomy of the foot. Review of 75 patients. Dermatol Surg 1997; 23: 279–80. 9. Constancias-Dortu I. Indications for ambulatory phlebectomy (in French). Phlebologie 1987; 40: 853–8. ★10. Weiss RA, Ramelet AA. Removal of blue periocular lower eyelid veins by ambulatory phlebectomy. Dermatol Surg 2002; 28: 43–5. ★11. de Roos KP, Nieman FH, Neumann HA. Ambulatory phlebectomy versus compression sclerotherapy: results of a randomized controlled trial. Dermatol Surg 2003; 29: 221–6. 12. Homans J. The operative treatment of varicose veins and ulcers, based upon a classiﬁcation of these lesions. Surg Gynecol Obstet 1916; 22: 143–58. 13. Mayo CH. Treatment of varicose veins. Surg Gynecol Obstet 1906; 2: 385–8. ★14. Kabnick L. Should we consider a paradigm shift for the treatment of GSV and branch varicosities? In: Proceedings of the UIP World Congress Chapter Meeting, August 27–31, 2003, San Diego, California. Abstract. ★15. Monahan DL. Can phlebectomy be deferred in the treatment of varicose veins? J Vasc Surg 2005; 42: 1145–9. 16. Ramelet AA. Complications of ambulatory phlebectomy. Dermatol Surg 1997; 23: 947–54. ◆17. Ricci S. Ambulatory phlebectomy. Principles and evolution of the method. Dermatol Surg 1998; 24: 459–64.

20.

●21.

★22.

23. ★24.

●25.

26. 27.

28. 29. 30. 31. 32. 33.

◆34.

●35.

●36.

★37.

Olivencia JA. Complications of ambulatory phlebectomy. Review of 1000 consecutive cases. Dermatol Surg 1997; 23: 51–4. Weiss RA, Goldman MP. Transillumination mapping prior to ambulatory phlebectomy. Dermatol Surg 1998; 24: 447–50. Merriam-Webster’s Online Dictionary. Available from: www.m-w.com/cgi-bin/dictionary?book=Dictionary&va= tumescent. Accessed 23 January 2007. Klein JA. The tumescent technique for liposuction surgery. Am J Cosmetic Surg 1987; 4: 263–7. Klein JA. Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermatol Surg Oncol 1990; 16: 248–63. Klein JA. Tumescent technique chronicles. Local anesthesia, liposuction, and beyond. Dermatol Surg 1995; 21: 449–57. Klein JA. Tumescent technique for local anesthesia. Epitomes. Dermatology 1996; 164: 51. Cohn MS, Seiger E, Goldman S. Ambulatory phlebectomy using the tumescent technique for local anesthesia. Dermatol Surg 1995; 21: 315–18. Smith SR, Goldman MP. Tumescent anesthesia in ambulatory phlebectomy. Dermatol Surg 1998; 24: 453–6. Schmidt RM, Rosenkranz HS. Antimicrobial activity of local anesthetics: lidocaine and procaine. J Infect Dis 1970; 121: 597–607. Dortu J, Raymond-Martimbeau P (eds). Ambulatory Phlebectomy. Houston: PRM Editions, 1993. Kabnick LS, Ombrellino M. Ambulatory phlebectomy. Semin Intervent Radiol 2005; 22: 218–24. Muller R. Ambulatory phlebectomy (in French). Phlebologie 1978; 31: 273–8. Gauthier Y, Derrien A, Gauthier O. Ambulatory phlebectomy (in French). Ann Dermatol Venereol 1986; 113: 601–3. Gillet F. Die Ambulante Phlebectomie. Schw Rundschau Med (PRAXIS) 1980; 69: 1398–404. Trauchessec J-M, Vergereau R. Outcomes after ambulatory phlebectomy (in French). J Med Esthet Chir Dermatol 1987; 14: 337–43. Ray-Chaudhuri SB, Huq Z, Souter RG, McWhinnie D. A randomized controlled trial comparing transilluminated powered phlebectomy with hook avulsions: an adjunct to day surgery? J One Day Surg 2003; 13: 24–7. Aremu MA, Mahendran B, Butcher W, et al. Prospective randomized controlled trial: conventional versus powered phlebectomy. J Vasc Surg 2004; 39: 88–94. Scavée V, Lesceu O, Theys S, et al. Hook phlebectomy versus transilluminated powered phlebectomy for varicose vein surgery: early results. Eur J Vasc Endovasc Surg 2003; 25: 473–5. Spitz GA, Braxton JM, Bergan JJ. Outpatient varicose vein surgery with transilluminated powered phlebectomy. Vasc Surg 2000; 34: 547–55.

39 Treatment algorithms for telangiectasias and varicose veins: current guidelines JOSE I. ALMEIDA AND JEFFREY K. RAINES Introduction and background C1 disease C2 disease

439 439 441

INTRODUCTION AND BACKGROUND Comprehensive treatment of most medical syndromes involves diagnostic algorithms, decision strategies prior to treatment, and procedural details associated with therapy. Diagnosis for telangiectasias, varicose veins, and venous ulcers were discussed in Chapter 29. In other sections of this handbook, procedural and therapeutic details for management of the saphenous vein, varicose tributaries, and telangiectasias are discussed. This chapter will concentrate on the algorithms for telangiectasias and varicose veins with reference to decision-making prior to treatment. As is customary for any medical condition, the physician must begin with a careful history and physical examination. The primary purpose of the clinical examination of the patient presenting with chronic venous disease (CVD) is to classify the subject using the popular CEAP system (Fig. 39.1).1,2 CEAP represents: C, clinical signs; E, etiology; A, anatomic distribution; P, pathophysiologic dysfunction. For each of these major classiﬁcations, there are subgroups. For the work described in this chapter, clinical signs emerge as the most important

History and physical examination

Clinical practice guidelines References

443 444

and are grouped as follows: C1, spider telangiectasias; C2, varicose veins; C3, edema; C4, lipodermatosclerosis; C5, healed ulcer; and C6, active ulcer. Regarding treatment, the class (C) is the most important parameter to establish during the initial encounter. Treatment algorithms for chronic venous insufﬁciency (CVI), i.e., patients with more severe disease (C3–C6), will be discussed in other sections of this handbook. This chapter will be limited to the processes involved when treating patients with the less advanced presentations of CVD (C1 and C2). Patients with CVD will usually present to a physician with concerns referable to both medical symptoms and cosmetic appearance of their disease. Patient satisfaction results from identifying and properly treating the patient’s primary concerns, which may include medical and/or cosmetic issues. Not all symptomatic patients are aware of their symptoms because the onset may be insidious. Symptoms may include leg heaviness, pain or tenderness along the course of a vein, pruritus, burning, restlessness, night cramps, edema, skin changes, and paresthesias. After treatment, patients are often surprised to realize how much discomfort they had accepted as normal. Pain caused by CVD is often improved by walking or by elevating the legs. The pain of arterial insufﬁciency, conversely, is worsened with ambulation and elevation. Pain and other symptoms of venous disease may intensify with the menstrual cycle, pregnancy, and in response to exogenous hormonal therapy (i.e. oral contraceptives).

CEAP

C1 DISEASE C1

C2

C3

C4

Figure 39.1 Clinical examination algorithm.

C5

C6

In our practice, approximately 90% of patients are women. When women seek medical attention for spider telangiectasias, they will sometimes report lower extremity

440

Treatment algorithms for telangiectasias and varicose veins: current guidelines

throbbing and discomfort during menstrual cycles. It is controversial whether spider telangiectasias actually cause pain. The majority of women are asymptomatic and have visited the ofﬁce to improve their cosmetic appearance. Asymptomatic patients who present with C1 disease will rarely have underlying saphenous venous incompetence; therefore, we will generally defer duplex imaging during their initial work-up and we will proceed to treatment. The presence of symptomatic spider veins should prompt an evaluation for reﬂux in order to rule out clinically unappreciated CVD. Some symptomatic patients with C1 disease will have reﬂux in their deep or superﬁcial systems that is not apparent on physical examination, but nevertheless causes the development of spider veins. In this group of patients, sclerotherapy of spider telangiectasias without treating the underlying venous reﬂux will result in spider vein treatment failure. For this reason, most patients complaining of leg symptoms will undergo an ultrasound examination in advance of treatment to assess for the presence of venous incompetence (Fig. 39.2). However, this evaluation is dependent upon local practice patterns. In most parts of the country, spider veins are considered cosmetic issues and treatment is often not covered by third-party payers.

C1 treatment options The C1 patient traditionally presents with reticular veins and spider telangiectasias localized to the lateral aspect of the thigh and leg. However, medial localization is not uncommon. Lateral disease of the limb is usually associated with incompetence of the lateral venous system; an extension of the veins in the lateral thigh and leg which represent a remnant of the embryonic vena marginalis lateralis (Fig. 39.3). Disease located on the medial aspect of

C1 disease Symptomatic Duplex ultrasound

Asymptomatic Treat

Observe

Deep reflux Compression GSV reflux GSV ablation? Normal Treat

Figure 39.2 Algorithm for spider telangiectasia treatment.

Figure 39.3 C1 disease, lateral venous complex.

the limb may or may not be secondary to the presence of great saphenous vein (GSV) reﬂux. In this setting physicians may face the difﬁcult decision between treating – or not treating – a reﬂuxing GSV in a patient with C1 disease. Historical information is important to determine whether the patient has a genetic predisposition for coronary artery disease, and thus be a candidate for GSV preservation for future consideration of coronary bypass surgery. The patient must be informed that an unsatisfactory cosmetic result may follow treatment of medial calf spider telangiectasias in the presence of untreated GSV incompetence. More often, spider telangiectasias located laterally are a cosmetic nuisance to patients, and are the reason they seek treatment. Patients should understand that spider veins pose no threat to their health and if left untreated generally do not progress to C2 disease. Spider veins do proliferate with time and therefore will require lifelong maintenance to counter disease progression. Sclerotherapy remains the most effective treatment for C1 disease. Transdermal lasers are available, but in our experience require careful patient selection. Sotradecol [sodium tetradecylsulfate (STS); Bioniche Pharma, Belleville, ON, Canada] is the only product approved by the Food and Drug Administration (FDA) and the only drug that will be discussed here. STS can be administered in liquid form or it can be mixed with air and delivered as foam. Foam is not approved by the FDA at the time of writing. The efﬁcacy of sclerosing agents is a function of concentration and vein diameter. If the target vein diameter is greater than 3 mm; the fact that liquid sclerosants lose potency secondary to dilution should be considered.3 It is important to note that treatment of reticular veins is controversial. Some investigators feel that they are sources of venous hypertension for the telangiectatic veins and, therefore, spider telangiectasias will be incompletely

C2 disease

treated if the reticular veins are not interrupted. Observation reveals that innumerable and often inconspicuous perforating veins are in continuity with reticular veins and transmit elevated venous pressures superﬁcially. We use 0.25% liquid STS for injection of spider teleangiectasias. For reticular veins less than 3 mm in diameter we use 0.5% STS liquid; if the vessels are greater than 3 mm in diameter, 0.5% STS foam is preferred. Transdermal laser is generally reserved for facial teleangiectasias, areas of telangiectatic matting, or if speciﬁcally requested by the patient (Fig. 39.4). Technical details for the aforementioned procedures are available in Chapters 32, 33, and 34.

form of venous insufﬁciency in symptomatic patients and is most frequently responsible for varicose veins of the lower extremity.4,5 The ﬁrst objective in the treatment of varicose veins is therefore elimination of GSV reﬂux by removing the vein from the circulation. The traditional intervention has been vein stripping surgery, although percutaneous saphenous thermal ablation is now the standard of care. The most common source of ambulatory venous hypertension is an incompetent superﬁcial system, usually the GSV. An incompetent GSV, in continuity with a bulging venous tributary, is a common scenario encountered in patients presenting with venous disease (Fig. 39.5). However, venous hypertension may also originate from deep veins, perforating veins, or any combination of superﬁcial, perforating, and deep system veins (Fig. 39.6). If a source of ambulatory venous hypertension is identiﬁed during the preoperative workup, it should be treated either prior to or at the same setting as treatment of bulging tributary veins. There are many techniques available to treat superﬁcial axial vein incompetence, perforating vein incompetence, and bulging tributaries; the technical details of which are beyond the scope of this chapter. As will be brieﬂy outlined below, superﬁcial axial vein reﬂux may be corrected by surgical, thermal, or chemical means (Fig. 39.7).

C2 DISEASE A fundamental principle in successful treatment of lower extremity CVD is the elimination of all sources of venous reﬂux. Great saphenous vein reﬂux is the most common

C1 Disease Spider telangiectasias Sclerotherapy

Laser

441

Reticular veins Sclerotherapy

Saphenous reflux

Liquid

In the USA, surgical high ligation and stripping is rapidly becoming senescent and will soon be extinct. Surgical stripping is covered in detail in Chapter 35. Endovenous

Foam

Figure 39.4 Algorithm for spider telangiectasia treatment.

(a) Figure 39.5 C2 disease, a) before and b) after treatment.

(b)

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Treatment algorithms for telangiectasias and varicose veins: current guidelines

C2 disease Duplex ultrasound

Saphenous reflux

Perforator reflux

Deep reflux

Figure 39.6 Algorithm for varicose vein evaluation.

Saphenous reflux Stripping

Thermal ablation Laser

Radio frequency

Chemical ablation Catheter

HSLW

Liquid

WSLW

Foam

years. Improvement of patients’ symptom persisted over 4 years. Endovenous lasers are available in different wavelengths. Hemoglobin-speciﬁc laser wavelengths (HSLWs) have been available since the 810 nm wavelength received FDA clearance in 2002. The 940 nm and 980 nm HSLWs are also available and FDA approved. Two water-speciﬁc laser wavelengths (WSLWs), 1320 nm and 1319 nm, are available and approved for use by the FDA. Reports with endovenous lasers demonstrate success rates of 98% at 1 year follow-up after treatment and 93% at 3 year followup.6 At this point studies comparing efﬁcacy between EVL wavelengths have not conclusively demonstrated a superior wavelength. Device choice is a matter of physician preference. Our center and other investigators have compared the efﬁcacy of RF and EVL. The ablation data are slightly better for EVL.8,9 We recently published our 3 year data showing 94% success with RF and 98% success with laser.10 Technical details referable to RF and EVL ablation are available in Chapters 36 and 37.

Syringe Liquid Foam

Figure 39.7 Algorithm for saphenous vein reﬂux treatment.

thermal ablation of the GSV is safe and effective with faster recovery and better cosmesis than surgical high ligation and stripping.6,7 THERMAL ABLATION

The two methods of thermal ablation presently in comprehensive vein centers are the Closure procedure, which uses a catheter to direct radiofrequency (RF) energy from a dedicated generator (VNUS Medical Technologies, Inc., Sunnyvale, CA, USA), and endovenous laser (EVL) ablation, which employs a laser ﬁber and generator to produce focused heat (multiple manufacturers). Both RF and EVL are catheter-based endovascular interventions which use electromagnetic energy to destroy the reﬂuxing saphenous system. Merchant et al.8 reported on 1078 limbs treated with RF ablation at 32 centers. Clinical and duplex ultrasound follow-up was performed at 1 week, 6 months, and 1, 2, 3, and 4 years. The vein occlusion rates were 91.0%, 88.8%, 86.2%, 84.2%, and 88.8%, respectively; the reﬂux-free rates were 91.0%, 89.3%, 86.2%, 86.0%, and 85.7%, respectively; and the varicose vein recurrence rates were 7.2%, 13.5%, 17.1%, 14.0%, and 21.4%, respectively, at each follow-up time point at 6 months and 1, 2, 3, and 4

CHEMICAL ABLATION

Sclerotherapy, or chemical ablation of the GSV, has reentered the arena since sclerosant in the form of foam has clearly improved results when compared with its liquid counterpart.11,12 Foam is more readily delivered with ultrasound imaging. Foam will expand and ﬁll a vein less than 12 mm diameter offering better contact with the vein wall. Foam loses efﬁcacy in veins greater than 12 mm in diameter because it ﬂoats in blood and leaves an inadequately treated posterior wall. Sclerosants may be delivered with a needle and syringe or via endoluminal catheters. Most available literature reports GSV chemical ablation using a needle and syringe. At the time of this writing two catheters for this purpose are under clinical investigation and are not commercially available. Incompetent saphenous veins may present with different morphologies, i.e., they may be straight or tortuous in appearance. In our experience, if the reﬂuxing vein is straight, we prefer thermal ablation. When tortuous veins are encountered, they are not easily navigated with endovenous devices, therefore ultrasound-guided foam sclerotherapy is our preference.

RESCUE

High levels of efﬁcacy for RF and EVL have been ﬁrmly established in published medical literature. The most important advantage of thermal and chemical ablation over surgical stripping is the ease associated with assisted closure. Speciﬁcally, failed (i.e., recanalized) treatment segments are easily rescued (i.e., closed) with a single session of ultrasound-guided sclerotherapy (UGS) (Fig. 39.8).

Clinical practice guidelines

Figure 39.8 Ultrasound-guided sclerotherapy.

Bulging vein treatments Elimination of an incompetent GSV reduces venous hypertension, relieves patient symptoms, and prevents or slows the progression of disease. However, GSV ablation alone is usually not sufﬁcient for elimination of all existing varicose veins.13 Varicose veins are frequently removed with phlebectomy at the time of the saphenous procedure or treated later by sclerotherapy. The three most popular modalities for eliminating bulges are ambulatory phlebectomy, sclerotherapy, and transilluminated powered phlebectomy(TriVex) (Fig. 39.9). Ambulatory phlebectomy is indicated for the removal of varicosed venous tributaries, when visible and palpable on the surface of the skin. Ambulatory phlebectomy is simple to perform, well tolerated, and can be used in conjunction with other treatment modalities. The most important concept for the practitioner treating varicose veins to understand is that simple vein removal, without proper work-up, will not yield good results. It is critical to recognize that bulging veins are usually associated with an underlying source of venous hypertension, and treatment of the source is as important as the vein removal itself. Prior to performing ambulatory

443

phlebectomy the treating physician must perform a thorough evaluation with duplex ultrasound imaging to identify the source of venous hypertension and its highest point of reﬂux. To prevent recurrence, the reﬂuxing source in continuity with the varicose veins should be eliminated prior to undergoing ambulatory phlebectomy. Technical details of ambulatory phlebectomy are available in Chapter 38. In a randomized clinical trial comparing ambulatory phlebectomy with compression sclerotherapy for the treatment of varicose veins, the recurrence rate with ambulatory phlebectomy at 1 year recurrence was 1 out of 48 for phlebectomy and 12 out of 48 for compression sclerotherapy (P < 0.001); at 2 years, six additional recurrences were found for compression sclerotherapy (P < 0.001).14 In a randomized clinical trial TriVex was compared with ambulatory phlebectomy in 188 limbs in 141 patients with varicose veins. At 6 and 12 months, there was no signiﬁcant difference in cosmesis (P = 0.955, P = 0.088, respectively) or recurrence (P = 0.27, P = 0.11, respectively).15 Ambulatory phlebectomy is the preferred technique of the author because it is performed rapidly using local anesthesia in the ofﬁce. Ambulatory phlebectomy is costeffective, durable, and gives superb cosmetic results. Ambulatory phlebectomy is easily performed in conjunction with saphenous vein ablation.

Perforating vein incompetence Bulging varicose veins are commonly the result of perforating vein (PV) incompetence alone or in combination with saphenous vein reﬂux.16,17 The majority of cases in which PV incompetence needs to be addressed are in those patients who present with the advanced syndrome of CVI, i.e., C3–C6 disease. Regardless of the indication for intervention, PV treatment has evolved and minimally invasive techniques are available and effective for their treatment18 (Fig. 39.10). Most of the literature referable to PV treatment involves subfascial endoscopic perforator surgery (SEPS).19 Contemporary vein centers reserve SEPS for failure of less invasive treatments such as ultrasound-

Bulging varicose vein Perforating vein incompetence Compression sclerotheraphy

Phlebectomy

Liquid

TriVex Ultrasound-guided sclerotherapy Foam

Figure 39.9 Algorithm for varicose vein treatment.

Figure 39.10

Thermal ablation

Subfascial endoscopic perforating vein surgery

Algorithm for perforating vein treatment.

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Treatment algorithms for telangiectasias and varicose veins: current guidelines

Guidelines 4.12.0 of the American Venous Forum on treatment algorithms for telangiectasias and varicose veins No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.12.1 For class 1 chronic venous disease we recommend treatment of symptomatic patients, but treatment can be considered in asymptomatic patients as well. We recommend sclerotherapy or laser for spider telangiectasias, and liquid or foam sclerotherapy for reticular veins

1

A

4.12.2 For treatment of the incompetent saphenous vein, we recommend either surgical stripping or thermal ablation (laser, radiofrequency)

1

B

4.12.3 For treatment of the incompetent saphenous vein, we suggest chemical ablation (catheter, syringe; liquid, foam)

2

C

4.12.4 For treatment of the incompetent perforating veins we recommend ultrasound-guided sclerotherapy, thermal ablation, or subfascial endoscopic perforating vein surgery

1

B

4.12.5 For treatment of bulging varicose veins we suggest phlebectomy or sclerotherapy (liquid, foam) or transilluminated powered phlebectomy (TriVex)

2

B

guided sclerotherapy (UGS) or thermal ablation. Technical details are available in Chapters 47 and 48.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

CLINICAL PRACTICE GUIDELINES ●

●

●

The material presented above may be considered in the light of treatment algorithms. Figure 39.1 depicts the history and physical examination and the determination of CEAP classiﬁcation. This takes place at initial patient presentation. Treatment algorithms for C1 disease are given in Figs 39.2 and 39.4. Figure 39.2 focuses on whether or not to treat, whereas Fig. 39.4 lists the treatment options available for C1 disease. In the opinion of the authors, the recommendations provided, as deﬁned by the American College of Chest Physicians Task Force,20 reach grade 1A. Figure 39.6 guides the reader through the identiﬁcation of the underlying source producing C2 disease (bulging varicose veins). If the saphenous vein is the source of venous hypertension, the available techniques to eliminate saphenous reﬂux are depicted in the algorithm in Fig. 39.7.21 If perforating veins are the source of venous hypertension, the techniques available for treatment are listed in Fig. 39.10. This information in the opinion of the authors is grade 1B. The therapeutic options for bulging varicose veins are displayed in Fig. 39.9 and are considered to be grade 1B.

◆1.

●2.

3. 4.

5.

6.

7.

Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248–52. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: 635–45. Guex J-J. Indications for the sclerosing agent polidocanol. J Dermatol Surg Oncol 1993; 19: 959–61. Labropoulos N, Delis K, Nicolaides AN, et al. The role of the distribution and anatomic extent of reﬂux in the development of signs and symptoms in chronic venous insufﬁciency. J Vasc Surg 1996; 23: 504–10. Evan CI, Allan PL, Lee AI, et al. Prevalence of venous reﬂux in the general population on duplex scanning: the Edinburgh vein study. J Vasc Surg 1998; 28: 767–76. Lurie, F, Creton, D, Eklof, B, et al. Prospective randomized study of endovenous radiofrequency obliteration (Closure Procedure) versus ligation and stripping in a selected patient population (EVOLVeS Study). J Vasc Surg 2003; 38: 207–14. Min RJ, Zimmet SE, Isaacs MN, Forrestal MD. Endovenous laser treatment of the incompetent greater saphenous vein. J Vasc Interv Radiol 2001; 12: 1167–71.

References 445

8. Merchant RF, Pichot O, Mayers KA. Four-year follow-up on endovascular radiofrequency obliteration of great saphenous reﬂux. Dermatol Surg 2005; 31: 129–34. 9. Min RJ, Khilnani N, Zimmet SE. Endovenous laser treatment of saphenous vein reﬂux: long-term results. J Vasc Interv Radiol 2003; 14: 991–6. 10. Almeida JI, Raines JK. Radiofrequency ablation and laser ablation in the treatment of varicose veins. Ann Vasc Surg 2006; 20: 547–52. 11. Hamel-Desnos C, Desnos P, Wollmann JC, et al. Evaluation of the efﬁcacy of polidocanol in the form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: initial results. Dermatol Surg 2003; 29: 1170–5. 12. Rao J, Wildemore JK, Goldman MP. Double-blind prospective comparative trial between foamed and liquid polidocanol and sodium tetradecyl sulfate in the treatment of varicose and telangiectatic leg veins. Dermatol Surg 2005; 31: 631–5. 13. Almeida JI, Raines JK. Radiofrequency versus laser versus chemical sclerotherapy for endoablation of the saphenous vein and when you do not need to do stab avulsions. Vascular 2005; 13: S16. 14. De Roos KP, Nieman FH, Neumann HA. Ambulatory phlebectomy versus compression sclerotherapy: results of a randomized controlled trial. Dermatol Surg 2003; 29: 221–6.

15. Aremu MA, Mahendran B, Butcher W, et al. Prospective randomized controlled trial: conventional versus powered phlebectomy. J Vasc Surg 2004; 39: 88–94. 16. Labropoulos N, Tassiopoulos AK, Bhatti AF, Leon L. Development of reﬂux in the perforator veins in limbs with primary venous disease. J Vasc Surg 2006; 43: 558–62. 17. Jeanneret C, Fischer R, Chandler JG, et al. Great saphenous vein stripping with liberal use of subfascial endoscopic perforator vein surgery (SEPS). Ann Vasc Surg 2003; 17: 539–49. 18. Masuda EM, Kessler DM, Lurie F, et al. The effect of ultrasound-guided sclerotherapy of incompetent perforator veins on venous clinical severity and disability scores. J Vasc Surg 2006; 43: 551–6. 19. Puggioni A, Kalra M, Gloviczki P. Superﬁcial vein surgery and SEPS for chronic venous insufﬁciency. Semin Vasc Surg 2005; 18: 41–8. 20. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest 2006; 129: 174–81. ★21. Bergan JJ. Surgery versus sclerotherapy in treatment of varicose veins. In: Veith FJ, ed. Current Critical Problems in Vascular Surgery. St. Louis: Quality Medical, 1989.

40 Recurrent varicose veins: etiology and management MICHEL PERRIN Introduction Deﬁnitions Epidemiology and socioeconomic consequences Mechanisms and physiopathology Pathology Classiﬁcations Diagnostic

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INTRODUCTION Recurrent varices after surgery (REVAS) are a common, complex, and costly problem both for the patients and the physicians who treat venous diseases. To deal with this problem, an international consensus meeting was held in Paris in 1998, which proposed guidelines for the deﬁnition and description of REVAS.1 At that time, only open surgery was performed; today, endoluminal obliteration, whose treatment principle is different, may be included in REVAS, but recurrence after sclerotherapy will be excluded.

DEFINITIONS According to Browse et al.,2 it is important to distinguish between residual veins and recurrent veins. Residual veins are varicose veins that were not treated at the original operation, because they were not detected preoperatively, not found during the operation or were deliberately left untreated. Recurrent varicose veins are veins which have become varicose after the initial treatment having been normal at the time of that treatment. This deﬁnition is true from a theoretical point of view, but for the patient any kind of varices after surgery are considered a failure and usually termed recurrence. Consequently, we decided at the REVAS consensus meeting to deﬁne REVAS as “The presence of varicose vein in a lower limb previously operated for varices with or

Treatments Results Indications for treating REVAS Guidelines for future studies Conclusions Clinical practice guidelines References

452 453 454 454 454 454 455

without adjuvant therapies.” This is a clinical deﬁnition, which includes true recurrences, residual veins, and varicose veins as a consequence of progress of the disease.

EPIDEMIOLOGY AND SOCIOECONOMIC CONSEQUENCES Prevalence and incidence of REVAS Neither is easy to determine as most studies are retrospective, analyzing patients who were not evaluated preoperatively by duplex scanning (DS) and usually the detailed operative report is not available. The presence of REVAS is stated to be between 20% and 80% depending on the duration of the follow-up assessment and the deﬁnition given to this status. In a 34 year follow-up,3 varicose veins were present in 77% of the lower limbs examined and were mostly symptomatic. Patients stated that the lower limbs were painful (58%), had a tired feeling (83%), and that edema had reappeared (93%). Three recently published prospective studies are available with a follow-up of 5 years.4–6 In two of them,4,5 the patients had preoperative DS and were treated by high ligation, saphenous trunk stripping, and stab avulsion. In the Kostas et al.4 series from Crete, 28 patients out of 100 had REVAS. True recurrent varices were present in eight limbs (8/28, 29%), primarily caused by neovascularization; new varicose veins as a consequence of disease progression were seen in seven limbs (7/28, 25%); residual veins were found in three limbs (3/28, 11%), mainly due to

Mechanisms and physiopathology

tactical errors [e.g., failure to strip the great saphenous vein (GSV)]; and complex patterns were identiﬁed in 10 limbs (10/28, 36%). This study among others showed that recurrence of varicose veins after surgery in a high-skilled center is common. However, the clinical condition of most affected limbs remains improved. Progression of the disease and neovascularization are responsible for more than half of the recurrences. In the van Rij et al. series5 from New Zealand, 127 limbs (C2–C6) were evaluated postoperatively by clinical examination, DS and air plethysmography (APG). Recurrence of clinical varices was progressive from 3 months onward (13.7%) to 5 years (51.7%). Corresponding to clinical changes there was a progressive deterioration in venous function measured by APG and recurrence of reﬂux evaluated by DS. The third study concerned recurrence after radiofrequency (RF) procedure. At 5 year follow-up recurrence was estimated at 22.7% (32/117).6

Socioeconomic consequences There are no available published socioeconomic data on REVAS. The incidence and the cost per patient are variable according to the different national health service politics. When “redo” surgery is performed, its cost is higher than ﬁrst-time surgery because of the number of peri- and postoperative complications. In one observational study, 40% of patients had complications.7

MECHANISMS AND PHYSIOPATHOLOGY Several possible mechanisms have been implicated in recurrence of varices, and their cause has been classiﬁed into four groups. 1. Tactical errors a Non-identiﬁed reﬂuxive connections between the deep and superﬁcial system, i.e., saphenofemoral junction (SFJ), saphenopopliteal junction (SPJ), and perforating veins that have not been treated continue to feed some veins that dilated progressively. b Identiﬁed or non-identiﬁed superﬁcial incompetent veins that have not been treated deliberately and remain reﬂuxive. Tactical errors are supposed to be less frequent since the preoperative DS is used as a matter of routine. 2. Technical errors a Identiﬁed reﬂuxive connections between the deep and superﬁcial system, i.e., SFJ, SFP, and perforating veins that were scheduled to be

447

treated, but surgery was incorrectly performed and reﬂux persists (Fig. 40.1). b Identiﬁed superﬁcial incompetent veins that were scheduled to be treated but surgery was incorrectly or incompletely performed. To recognize the technical errors a postoperative DS is strongly recommended. However, it must be kept in mind that both tactical or/and technical errors do not lead always to REVAS as: i some incompetent connections between the deep and superﬁcial system become competent after suppression of the incompetent superﬁcial system; this has been demonstrated mainly for perforating veins and less frequently at the SFJ and SPJ ii some incompetent veins become competent after suppression of the distal reservoir (Fig. 40.2). 3. Neovascularization Recurrence of varicose veins after surgery or endovenous obliteration cannot always be attributed to tactical errors or technical inadequacy. Many clinical studies have indicated that postoperative neovascularization may occur.8–11 Tiny new venous vessels developing in the granulation tissue mainly around the SFJ and/or/ the SPJ may enlarge and connect deep to superﬁcial veins, causing clinically obvious recurrence after a few years. As in some RF obliteration studies postoperative neovascularization is infrequent12 or absent,13 it has been suggested that the absence of high ligation can explain this phenomenon as far as neoangiogenesis is a normal process in tissue healing. Besides, the persistence of draining tributaries in the saphenous stump may play a role. But in another study,14 neovascularization has been identiﬁed at 1 week follow-up by DS both after RF and endovenous laser (EVL) respectively in 2.2% and 7.1% of cases. 4. Progression of the disease As varicose veins are a progressive disorder, new territories must be affected by the evolution of the disease. It must be highlighted that endovenous obliteration outcome treatment must lead to the dogmatic reassessment of the systematic highligation resection, including patients with a reﬂux at the SFJ or SPJ. In a very well-documented study, Pichot et al.15 assessed by DS after 2 years the fate of the SFJ in 63 limbs treated by RF without high-ligation resection, knowing that all patients had preoperatively had a GSV reﬂux; 82% presented with a < 5 cm patent terminal GSV segment conducting prograde tributary ﬂow through the SFJ. Despite the presence of a total of

448

Recurrent varicose veins: etiology and management

(b)

(c)

Incorrect saphenofemoral or saphenopopliteal ligation Loose connective tissue (scar) Previous ligation (clip) Stump

(a)

Tributaries

(d)

104 patent junctional tributaries, SFJ reﬂux was uncommon, affecting only ﬁve limbs. Unfortunately, we have no detailed preoperative information on the terminal valve competence at the SFJ that would have allowed the assessment of whether the absence or presence of an incompetent terminal valve made a difference in term of persistent reﬂux at the SFJ.

PATHOLOGY Two studies investigating the cause of the most frequent recurrence that occurs at the SFJ taking account of the pathology have been reported. Their conclusions are contradictory. In a German study,16 the most frequent pattern identiﬁed (68%) was a persistent stump related to a possible non-ﬂush high ligation, but surprisingly a valve was identiﬁed in only 18 out of 63 cases with a single channel.

Figure 40.1 Recurrent varices after surgery related to a nonﬂush resection of the saphenofemoral junction in a patient with an incompetent terminal valve. (a) View of patient. (b) Same patient; B mode ultrasound. The terminal valve (TV) is identiﬁed at the saphenofemoral junction. (c) Same patient; color duplex ultrasound. Massive reﬂux induced by a Valsalva maneuver. (d) Same patient; scheme: incorrect ligation. CFV, common femoral vein; SS, saphenous stump.

Conversely, van Rij et al.11 found multiple vessels in 94% at the stump site at the SFJ and concluded that neovascularization is the most frequent cause of recurrence (Fig. 40.3). This conclusion was in accordance with their previous clinical study.17 Geier et al.18 underlined that the only tool valid for the identiﬁcation of neovascularization remains the histologic and immunohistochemical work-up of the resected vein. Unfortunately, this work-up is rarely performed. Consequently, the real cause of recurrence remains debatable in many studies.

CLASSIFICATIONS Many classiﬁcations have been developed concerning REVAS, but they have not been widely used.2,19 One of their main goals was to identify whether redo surgery, particularly at the previous SFJ and SPJ, must be part of the REVAS treatment.

Classiﬁcations 449

(a)

(b)

(a)

(b) Neovascularization Heavy connective tissue (scar)

Figure 40.2 The reservoir capacity reduction may decrease or suppress the reﬂux. (a) The reﬂuxive main venous trunk drains off principally in a tributary. This “siphon effect” increases the reﬂux in the main trunk. (b) Compression of the reﬂuxive tributary suppresses or decreases the reﬂux in the main trunk.

At the consensus meeting1 it was decided to use both the previously reported CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) classiﬁcation20 and a speciﬁc classiﬁcation named the REVAS classiﬁcation. Of course, the revised CEAP classiﬁcation21 will now be used in combination with the REVAS one. The REVAS classiﬁcation was intended to serve everyday clinical practice as well as research studies into epidemiology, clinical status, and treatment of recurrent varicose veins. A survey was carried out in order to test its intraobserver and interobserver reproducibility.22 The conclusion of this study was that intraobserver reproducibility is quite satisfactory. However, the fact that interobserver reproducibility was inferior to intraobserver reproducibility reﬂects real life, especially interobserver

No stump

(c) Figure 40.3 Recurrent varices after surgery related to neovascularization in a patient who had a ﬂush resection of the saphenofemoral junction. (a) View of patient. (b) Same patient; duplex scanning. (c) Same patient; scheme: reﬂux induced by a Valsalva maneuver is identiﬁed in several small-caliber channels. CFV, common femoral vein.

differences. This ﬁnding emphasizes the need to validate a duplex scanning protocol and to standardize duplex scan reports.

450

Recurrent varicose veins: etiology and management

The REVAS classiﬁcation (Fig. 40.4) includes six items: T, topographic sites of REVAS; S, sources of reﬂux; R, degree of reﬂux; N, nature of sources (Nss for same site of previous surgery, and Nds for different sites); P, contribution from a persistent incompetent saphenous trunk; and F, possible contributory factors (Fg for general and Fs for speciﬁc factors). ●

●

●

Topographic sites of REVAS. Recurrent varices should be localized at ﬁve sites: g, groin; t, thigh; p, popliteal fossa; l, lower leg including ankle and foot; and o, other. Because more than one territory may be involved in the same limb, topography gives a degree of quantiﬁcation as to the extent of the recurrences. Sources of reﬂux. It is considered important to identify the sources of reﬂux from the deep system when it is

present: 0, no identiﬁed source of reﬂux; 1, pelvic and/or abdominal; 2, saphenofemoral junction; 3, thigh perforating veins; 4, saphenopopliteal junction; 5, popliteal perforating veins; 6, gastrocnemius veins; and 7, lower leg perforating veins. Several sources of reﬂux should be identiﬁed. Degree of reﬂux. Although it is recognized that there are limitations for quantifying the degree of reﬂux according to parameters (duration, volume, mean peak velocity) and that addition of present reﬂux is valuable, the clinician should estimate the clinical signiﬁcance of reﬂux. This estimate should be based on DS information and how the degree of reﬂux relates to the overall clinical situation. R+, clinical signiﬁcance probable; R–, clinical signiﬁcance unlikely; R?, clinical signiﬁcance uncertain.

REVAS Classification sheet

Date of examination Day

Month

• N ds is for different (new) site Only one box can be ticked

Year

Patient First name or given name Last name or family name

Persistent

New

Topographical sites of REVAS Since more than one territory may be involved, several boxes may be ticked Groin Thigh Popliteal fossa Lower leg including ankle and foot Other

2

(Known to have been absent at the time of previous surgery) 1 2 3 4 5

Uncertain/not known (Insufficient information at the time of previous surgery)

3

Contribution from persistent incompetent saphenous trunks Since more than one territory may be involved several boxes may be ticked

Sources(s) of recurrence Since more than one source may be involved, several boxes may be ticked No source of reflux For pelvic or abdominal Saphenofemoral juction Thigh perforator(s) Saphenopopliteal junction Popliteal perforator Gastrocnemius vein(s) Lower leg perforator(s)

1

(Known to have been present at the time of previous surgery)

0 1 2 3 4 5 6 7

Reflux Only one box can be ticked

AK great saphenous vein (above knee)

1

BK great saphenous vein (below knee) SSV small saphenous vein

2 3

Neither/other Comment:

4

Possible contributory factors Several boxes may be ticked General factors

PROBABLE Clinical significance R⫹ UNLIKELY Clinical significance R– UNCERTAIN Clinical significance R?

1 2 3

Nature of sources Only one box can be ticked N classifies the source as to whether or not it is the site of previous surgery and describes the cause of recurrence.

Specific factors Several boxes may be ticked

• N ss is for same site Only one box can be ticked Technical failure Tactical failure Neovascularization Uncertain Mixed

1 Family history Obesity 2 3 Pregnancy* 4 Oral contraceptive Lifestyle factors** 5 * Pregnancy since the initial operation ** Prolonged standing, lack of exercise, chair sitting

1 2 3 4 5

Primary deep vein reflux Post-thrombotic syndrome Iliac vein compression Angiodysplasia Lymphatic insufficiency Calf pump dysfunction

1 2 3 4 5 6

Figure 40.4 The recurrent varices after surgery (REVAS) questionnaire.

Diagnostic 451

●

●

●

It is worthy of note that in the international survey interobserver R reproducibility was moderate but the intraobserver R was reliable.22 Nature of sources. This classiﬁes the source as to whether or not it is the site of previous surgery and describes the cause of the recurrence. – Ss is for the same site, which means the recurrence occurred in an area where superﬁcial veins were previously operated on and one of the following ﬁve terms may be chosen for Nss: 1, technical failure; 2, tactical failure; 3, neovascularization; 4, uncertain or unknown; 5, mixed. – Ds is for a different (new) site. In other words, when varices are present in a territory not previously operated, one of the following three terms may be selected for Nds: 1, persistent (known to have been present at the time of the previous surgery and not treated); 2, new (known to have been absent at the time of previous surgery); 3, uncertain or not known (insufﬁcient information on the preoperative status before the previous surgery). As might be foreseen in a retrospective study using REVAS classiﬁcation, two-thirds of the patients were classiﬁed uncertain or not known and both the intraobserver and interobserver reproducibility was moderate.22 A precise answer to N in the REVAS classiﬁcation should be anticipated in a prospective study, and, if used by dedicated physicians looking at their own patients before and after treatment, it might work very well. Contribution. This is the contribution from persistent incompetent saphenous trunks. GSV AK, above the knee;, GSV BK, below the knee; small saphenous vein (SSV); O, other; N, neither. Possible contributory factors. These should be gathered and reported in the REVAS ﬁle: – Fg (general factors): family history, obesity, pregnancy, oral contraceptive, lifestyle factors (pregnancy since the initial operation, professional activity, other) – Fs (speciﬁc factors): primary deep venous incompetence, post-thrombotic syndrome, iliac vein compression, congenital vascular malformation, lymphatic abnormality, calf pump dysfunction, other.

DIAGNOSTIC Clinical presentation Patients who have previous surgical treatment or endovenous obliteration may consult their physicians for various reasons: unsightly recurrent varicose veins or related

emotional problems, which are especially common in female patients; discomfort (in other words venous-related symptoms); appearance of skin or subcutaneous changes; concerns about the health risk related to their veins; or limitation of activity. Also, REVAS may be found at routine follow-up.

Medical history FAMILY AND PERSONAL HISTORY

A family history of varicose veins and personal history including pregnancies, hormone therapy, superﬁcial venous thrombophlebitis, deep vein thrombosis, etc. should be recorded. PREVIOUS TREATMENT

The date of previous surgical treatment(s) for varicose veins and the age of the patient at the time of surgery; the name of the surgeon and the place of the operation in order to retrieve the operative record; postoperative surgical complications; date of the onset of recurrence and reappearance of symptoms have to be documented as does other treatment received after initial surgery, such as phlebotonic drugs, sclerotherapy, use of compression stockings, and leg elevation.

Physical examination Presence and intensity of the various vein-related symptoms have to be noted: pain, throbbing, heaviness, itching, feeling of swelling, night cramps, heat or burning sensations, or restless legs. In the REVAS survey, 76.7% of patients were symptomatic.23 Inspection and palpation allow the C of the CEAP classiﬁcation to be completed, but it must be kept in mind that some signs such as corona phlebectatica are not described in the CEAP. Edema should be quantiﬁed. The presence of scars on the lower limb must be noted, especially at the groin or/and popliteal fossa. Neurological abnormalities and particularly numbness have to be documented. Efﬁciency of the calf pump has to be assessed and particularly the degree of ankle motion. Arterial pulses should be checked and ankle brachial index calculated. A general examination including abdominal palpation should be performed, and possible obesity can be identiﬁed by body mass index calculation. Some data are available concerning leg symptoms4,23,24 and clinical disability scores24 in patients with REVAS. In the international REVAS survey, there was a statistical difference in terms of the presence or absence of symptoms between C2 and C3–C6 (P = 0.0001).23 Conversely in a Finnish series,24 there was no difference

452

Recurrent varicose veins: etiology and management

between the C2–C3 group and the C4–C6 group except itching (P < 0.001). In the latter series, disability scores were higher in C4–C6 group than in C2–C3 group (P < 0.005).24

TREATMENTS Methods COMPRESSION

Investigation Many investigations have been used in the past to assess REVAS. At present, there is a large consensus for recommending DS in all cases. This investigation provides anatomical and hemodynamic data including: ● ●

● ●

the topographical sites of REVAS that can be mapped the possible sources of reﬂux from the deep venous system to the superﬁcial the intensity or degree of reﬂux the nature of sources knowing that causes have to be classiﬁed differently if recurrence occurs in a site previously operated or not.

In addition, DS gives information on perforator and deep venous systems that must be assessed in patients with REVAS. A remaining problem is that the different investigators do not universally use a standardized DS investigation protocol. In very few cases, venography, including descending venogram and three-dimensional imaging, may give complementary valuable information. Numerous data are available concerning the pattern of reﬂux in patients with REVAS. Two points have to be underlined: (1) multiple sources of reﬂux are frequent23,25 and (2) the high prevalence of superﬁcial axial reﬂux in the main trunks of those legs with complicated (C4–C6) disease.24 With regard to the symptoms, only itching (P = 0.04) was more frequent in extremities with main trunk reﬂux than in those with reﬂuxive tributaries.24 Another point must be underlined: the presence of an associated primary deep vein reﬂux that is more frequent in patients with REVAS than in those with non-treated or treated varices without recurrence.26 Other studies have conﬁrmed this,27 and skin changes including ulcer are more frequent when deep reﬂux is present.25 Other investigations such as APG and ambulatory venous pressure may be useful for research studies but not for daily practice.

Compression in varicose veins is frequently recommended and improves both symptoms and signs, but it does not cure the disease. DRUGS

In varicose veins, phlebotonic drugs are prescribed mainly to improve edema and symptoms. The most commonly used are ﬂavonoids but others exist. INTERVENTIONAL PROCEDURES

They share the same goals: ●

● ●

to eliminate reﬂux from deep to superﬁcial systems when they exist to suppress varices in some speciﬁc cases to correct deep vein abnormality to prevent new recurrences.

The ﬁnal objectives are multiple: decrease the ambulatory venous pressure, prevent worsening of chronic venous disorders, avoid further recurrences, and, of course, improve patients’ cosmetic appearance, symptoms, and signs. Sclerotherapy This has been used for a very long time for treating REVAS, but currently ultrasound-guided sclerotherapy (UGS) has improved the technique efﬁcacy. Different protocols have been used but no comparative study is available. Recently, foam UGS has entered the arena, but no consensus exists on the techniques, doses, concentrations, or sclerosing agents. Nevertheless, one of the main advantages of sclerotherapy with or without foam is that the treatment is simple, cheap, less invasive, and repeatable. Surgery and endovenous obliteration Procedures can be classiﬁed into three groups according to their objective, and should be used in combination.

Quality of life questionnaires To determine whether REVAS affects patients’ quality of life, the health-related quality of life (HRQL) score can be used in different ways for clinical studies. Beresford et al.28 compared patients presenting with REVAS with patients with untreated varicose veins. These authors stated that varicose vein recurrence was associated with a signiﬁcantly worse HRQL.28 No survey has compared operated patients with or without REVAS.

1. The ﬁrst group are techniques that aim to eliminate reﬂux from deep to superﬁcial systems. At the saphenofemoral or saphenopopliteal junctions the site has usually been previously operated and, according to the extent of postoperative ﬁbrosis, redo surgery may be difﬁcult. It is recommended that the deep vein should be approached ﬁrst in order to avoid dissection of scar tissues, lymphatic nodes, and cavernoma (Fig. 40.5). The last does not need to be ablated. Flush

Results 453

Sclerotherapy c d

b

e

a

Figure 40.5 Redo surgery at the saphenofemoral junction (SFJ) after incomplete high-ligation resection of the SFJ. The femoral artery is exposed ﬁrst, then the anterior lateral and medial aspects of the common femoral vein and, ﬁnally, the SFJ is circumscribed without dissection of the cavernoma before ﬂush ligation. (a) Femoral artery; (b) inferior pudendal artery; (c) common femoral vein; (d) saphenofemoral junction; (e) cavernoma.

ligation of the stump is then performed and can be completed by patch interposition.29 The second procedure of this group consists of perforating vein ligation. When severe skin and subcutaneous changes are present, subfascial endoscopic perforator surgery (SEPS) is the favored technique. 2. The second group includes procedures that aim to eliminate or obliterate the reﬂuxing varices. According to the location and type of varicose veins various techniques can be used: stab avulsion and phlebectomy are the most used techniques, and stripping or endovascular obliteration (laser, RF) are usually reserved for treating the residual saphenous trunk. 3. The third group is represented by procedures whose goal is to suppress deep vein reﬂux (valvuloplasty, valve transfer), as several studies demonstrated that primary extended deep venous reﬂux is frequently identiﬁed in patients with REVAS as stated above.

The efﬁcacy of sclerotherapy using one protocol has been reported on a large series (253 legs) with a follow-up of 3.1 ± 1.7 years (range 1.5–5.7 years).30 The cumulative obliteration rate was sustained at > 90% and there was a signiﬁcant decrease in the venous dysfunction score. Unfortunately, the end-point of sclerotherapy sessions is not given. Thibault and Lewis31 reported early favorable results with UGS when treating recurrent varices fed by leg or thigh incompetent perforators.31 No data have yet been published with foam techniques. No randomized controlled trials (RCTs) comparing sclerotherapy with other interventional technique are available.

Surgery Very few data are available on the results provided by redo surgery in patients investigated preoperatively with DS. A retrospective series of 145 limbs with 5–6 years follow-up has been reported.32 All had major reﬂux from the deep system feeding recurrent varices that was treated by redo surgery. Postoperative sclerotherapy was performed in all patients during the ﬁrst 2 years. An external audit revealed a global objective improvement of 85%, but there was better improvement of signs and symptoms than cosmetic appearance. The results of two studies using an interposition patch for treating recurrence at the SFJ have been published, but Creton,33 using this procedure without resection of the groin cavernoma but with combined resection of varices (saphenous trunks and/or tributaries), had only 4.2% recurrences at the SFJ at 4.9 years mean follow-up (range 3–7 years) in 119 extremities. Nevertheless, 22.6% of patients had diffuse varices, with a new site of incompetence between the deep and femoral systems.33 De Maeseneer et al.29 compared the results at 5 years of two non-randomized groups with and without patch in a prospective study. All patients had recurrent SFJ incompetence. The results were signiﬁcantly better in terms of absence of recurrent thigh varicosities and neovascularization in the patch group.29

REVAS related to pelvic or gonadal veins reflux Two methods can be used: direct ligation or embolization and coils.

RESULTS Compression and drugs We have no speciﬁc data on the efﬁcacy of compression treatment and drugs in patients with REVAS.

Endovenous obliteration One RCT assessed the immediate postoperative outcome of RF and traditional redo groin surgery and GSV stripping in patients treated initially by isolated highligation resection of the SFJ and presenting a persistent reﬂux at the SFJ and in the patent GSV trunk.34 Radiofrequency caused less pain and bruising and was performed more quickly than traditional open surgery.

454

Recurrent varicose veins: etiology and management

Embolization At 6 month follow-up, 90% of 215 patients treated by embolization of gonadal and pelvic veins were signiﬁcantly improved in both signs and symptoms but relief of pelvic pain or lower limb symptoms or signs were not evaluated separately.35

INDICATIONS FOR TREATING REVAS Patients with REVAS can be roughly divided into two groups: 1. Patients complaining of symptoms or esthetic concerns, or presenting with signs of chronic venous disease (C2–C6). In all cases, these patients need to be investigated by DS. 2. Subjects attending a routine follow-up. The decision whether to undertake DS or not depends on the presenting complaint and physical ﬁndings. In practice, DS is almost always done.

GUIDELINES FOR FUTURE STUDIES In order to know the prevalence and annual incidence of REVAS we need prospective studies that are well documented from the outset of surgical treatment. These studies may give information on: ●

●

●

●

The preoperative duplex scanning and, particularly, information on the competence or incompetence of the terminal valve at the SFJ. This point is crucial in patients treated by endovenous obliteration as the SFJ is not ablated; we need to know whether the outcome is different in patients with competent or incompetent terminal valves. The value of routine postoperative duplex scanning in the early detection of persisting reﬂux. The relationship between hemodynamics and clinical recurrence. The possible role of compression therapy and/or complementary postoperative sclerotherapy in preventing recurrence.

To identify which is the best method, when REVAS has occurred, prospective randomized studies using different treatments are needed. These studies may use both the CEAP and REVAS classiﬁcations and a quality of life questionnaire.

CONCLUSIONS REVAS is a frequent condition that frustrates both patients and physicians and that has been poorly evaluated. In

order to build a scientiﬁcally convincing evidence base and to achieve a greater degree of comparability between studies, an international consensus on conformity is required.

CLINICAL PRACTICE GUIDELINES Asymptomatic patients When hemodynamic abnormalities are found in asymptomatic patients without severe signs who are not concerned by their minor varices as cosmetic problems the decision to treat depends on the severity of the noninvasive ﬁndings. In all cases, follow-up is required knowing that abnormal DS ﬁndings precede symptoms and signs.

Symptomatic patients In symptomatic patients presenting with recurrent varices and hemodynamic anomalies, treatment must be considered. At the REVAS conference in 1998 we agreed that there was no consensus for recommending sclerotherapy, surgery, or a combination of both when active treatment was needed. Seven years later, as only observational studies or cases series are available, one can only provide a grade 2C recommendation to treat patients either by redo surgery or by sclerotherapy.

Indications according to hemodynamic abnormality SOURCE OF REFLUX

Concerning the treatment of sources of reﬂux, surgery was considered the best option in patients where a major reﬂux was identiﬁed at the SFJ, but there is no evidence that UGS does not give the same results. If redo surgery is undertaken, a silicone or polytetraﬂuoroethylene (PTFE) patch on the common femoral vein may be used [grade 2C]. In the presence of recurrent reﬂux at the SPJ, sclerotherapy is generally undertaken as redo surgery is sometimes difﬁcult, but again there is no evidence that one method is better than the other. Concerning incompetent perforators, there is no RCT that suggests their treatment is recommended. Residual varicose veins below the knee after proximal GSV stripping are not related to incompetent perforating veins.36 When they are fed by an incompetent perforator, UGS is popular when dealing with recurrent varices without skin change. But in patients with ulcer, SEPS is usually preferred.

References 455

Guidelines 4.13.0 of the American Venous Forum on etiology and management of recurrent varicose veins No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.13.1 For clinical description of recurrent varicose veins, we recommend using the REVAS (Recurrent Varicose Veins After Surgery) classiﬁcation

1

B

4.13.2 For evaluation of recurrent varicose veins we recommend duplex scanning for venous mapping, for assessment of the source and duration of reﬂux, and to help establish the etiology of recurrence

1

B

4.13.3 For treatment of recurrent varicose veins, treatment with foam sclerotherapy, surgery, or endovenous thermal ablation or coil embolization is suggested, depending on the etiology and extent of varicosity

2

C

Major pelvic reﬂux is mainly treated by embolization and minor reﬂux by UGS. As only observational studies or case series are available only a grade 2C recommendation can be given to treat the reﬂux either by redo surgery or by foam sclerotherapy.

◆1.

2. 3.

THE VARICOSE NETWORK

When a persistent incompetent saphenous trunk is present, pin stripping or endovenous procedures (EVL, RF) or UGS are possible options according to the experience and habits of the practitioner. For other varices, UGS and stab avulsion are appropriate. As only observational studies or case series are available, only a grade 2C recommendation can be given to treat the varicose network either by redo surgery or by foam sclerotherapy.

●4.

●5.

6.

COMBINED PRIMARY DEEP VEIN REFLUX

In patients with combined primary deep vein reﬂux grade 4 and C4b–6, valvuloplasty must be considered in active patients reluctant to wear lifelong compression or with recurrent ulcer. As only observational studies or case series are available only a grade 2C recommendation can be given to treat the deep reﬂux when REVAS is combined with primary deep vein reﬂux.

7.

8.

●9.

REFERENCES = Key primary paper ◆ = Major review article ★ = First formal publication of a management guideline ●

10.

Perrin M, Guex, JJ, Ruckley CV, et al. Recurrent varices after surgery (REVAS), a consensus document. Cardiovasc Surg 2000; 8: 233–45. Browse NL, Burnand KG, Irvine AT, Wilson NM. Disease of the Veins, 2nd edn. London: Arnold, 1999: 191–248. Fischer R, Linde N, Duff C. Cure and reappearance of symptoms of varicose veins after stripping operation: a 34year follow-up. J Phleb 2001; 1: 49–60. Kostas T, Loannou CV, Toulouopakis E, et al. Recurrent varicose veins after surgery: a new appraisal of a common and complex problem in vascular surgery. Eur J Vasc Endovasc Surg 2004; 27: 275–82. van Rij AM, Jiang P, Solomon C, et al. Recurrence after varicose vein surgery: a prospective long-term clinical study with duplex ultrasound scanning and air plethysmography. J Vasc Surg 2003; 38: 935–43. Merchant RF, Pichot O for the Closure Study Group. Long-term outcomes of endovenous radiofrequency obliteration of saphenous reﬂux as a treatment for superﬁcial venous insufﬁciency. J Vasc Surg 2005; 42: 502–9. Hayden A, Holdsworth J. Complications following reexploration of the groin for recurrent varicose veins. Ann R Coll Surg Engl 2001; 83: 313–15. Jones L, Braithwaite BD, Selwyn D, et al. Neovascularisation is the principal cause of varicose vein recurrence: results of a randomised trial of stripping the long saphenous vein. Eur J Vasc Endovasc Surg 1996; 12: 442–5. De Maeseneer MG, Tielliu IF, Van Schil PE, et al. Clinical relevance of neovascularisation on duplex ultrasound in the long term follow up after varicose vein operation. Phlebology 1999; 14: 118–22. Fischer R, Chandler JG, De Maeseneer MG, et al. The unresolved problem of recurrent saphenofemoral reﬂux. J Am Coll Surg 2002; 195: 80–94.

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12.

13.

14.

15.

16.

●17.

18.

19.

20.

●★21.

22.

●23.

Recurrent varicose veins: etiology and management

van Rij AM, Jones GT, Hill GB, et al. Neovascularization and recurrent varicose veins: more histologic and ultrasound evidence. J Vasc Surg 2004; 40: 296–302. Lurie F, Creton D, Eklof B, et al. Prospective randomized study of endovenous radiofrequency obliteration(Closure) Versus ligation and Vein Stripping (EVOLVeS): two-year follow-up. Eur J Vasc Endovasc Surg 2005; 29: 67–73. Nicolini PH, and the Closure Group. Treatment of primary varicose veins by endovenous obliteration with the VNUS Closure system: results of a prospective multicentre study. Eur J Vasc Endovasc Surg 2005; 29: 433–9. Labropoulos N, Bhatti A, Leon L, et al. Neovascularization after great saphenous ablation. Eur J Vasc Endovasc Surg 2006; 31: 219–22. Pichot O, Kabnick LS, Creton D, et al. Duplex ultrasound scan ﬁndings two years after great saphenous vein radiofrequency endovenous obliteration. J Vasc Surg 2004; 39: 189–95. Stücker M, Netz K, Breuckmann F, et al. Histomorphologic classiﬁcation of recurrent saphenofemoral reﬂux. J Vasc Surg 2004; 39: 816–22. van Rij AM, Jiang P, Solomon C, et al. Recurrence after varicose vein surgery: a prospective long-term clinical study with duplex ultrasound scanning and air plethysmography. J Vasc Surg 2003; 38: 935–43. Geier B, Olbrich S, Barbera L, et al. Validity of the macroscopic identiﬁcation of neovascularization at the saphenofemoral junction by the operating surgeon. J Vasc Surg 2005; 41: 64–8. Stonebridge PA, Chalmers N, Beggs I, et al. Recurrent varicose veins: a varicographic analysis leading to a new practical classiﬁcation. Br J Surg 1999; 82: 60–2. Porter JM, Moneta GL. International consensus committee on chronic venous disease. Reporting standard in venous disease: a update. J Vasc Surg 1995; 21: 635–45. Eklöf B, Rutherford RB, Bergan JJ, et al. for the American Venous Forum’s International ad hoc committee for revision of the CEAP classiﬁcation. Revision of the CEAP classiﬁcation for chronic venous disorders. A consensus statement. J Vasc Surg 2004; 40: 1248–52. Perrin M, Allaert FA. Intra- and inter-observer reproducibility of the recurrent varicose veins after surgery (REVAS) classiﬁcation. Eur J Vasc Endovasc Surg 2006; 32: 326–32. Perrin M, Labropoulos N, Leon LR. Presentation of the patient with recurrent varices after surgery (REVAS). J Vasc Surg 2006; 43: 327–34.

24. Saarinen J, Suominen V, Heikinen M, et al. The proﬁle of leg symptoms, clinical disability and reﬂux in legs with previously operated varices. Scand J Surg 2005; 94: 51–5. 25. Jiang P, van Rij AM, Christie R, et al. Recurrent varicose veins: patterns of reﬂux and clinical severity. Cardiovasc Surg 1999; 7: 322–9. ●26. Almgren B, Eriksson I. Primary deep vein incompetence in limbs with varicose veins. Acta Chir Scand 1989; 155: 445–60. 27. Guarnera G, Furgiuele S, Di Paola FM, Camilli S. Recurrent varicose veins and primary deep venous insufﬁciency: relationship and therapeutic implications. Phlebology 1995; 10: 98–102. 28. Beresford T, Smith JJ, Brown L, et al. A comparison of health-related quality of life of patients with primary and recurrent varicose veins. Phlebology 2003; 18: 35–7. 29. De Maeseneer MG, Vandenbroeck CP, Van Schil PE. Silicone patch saphenoplasty to prevent repeat recurrence after surgery to treat recurrent saphenofemoral incompetence: long-term follow-up study. J Vasc Surg 2004; 40: 98–105. 30. McDonagh B, Sorenson S, Gra C, et al. Clinical spectrum of recurrent postoperative varicose veins and efﬁcacy of sclerotherapy management using the compass technique. Phlebology 2003; 18: 173–85. 31. Thibault PK, Lewis WA. Recurrent varicose veins. Part 2. Injection of incompetent perforating veins using ultrasound guidance. J Dermatol Surg Oncol 1992; 18: 895–900. 32. Perrin M, Gobin JP, Grossetete C, et al. Valeur de l’association chirurgie itérative: sclérothérapie après échec du traitement chirurgical des varices. J Mal Vasc 1993; 18: 314–19. 33. Creton D. Surgery for recurrent saphenofemoral incompetence using expanded polytetraﬂuoroethylene patch interposition in front of the femoral vein: long-term outcome in 119 extremities. Phlebology 2002; 16: 93–7. 34. Hinchliffe RJ, Uhbi J, Beech A, et al. A prospective randomised controlled trial of VNUS Closure versus surgery for the treatment of recurrent long saphenous varicose veins. Eur J Vasc Endovasc Surg 2006; 31: 212–18. 35. Leal Monedero J, Zubicoa Ezpeleta S, Castro Castro J, et al. Embolization treatment of recurrent varices of pelvic origin. Phlebology 2006; 21: 3–11. 36. van Neer P, Kessels A, de Haan Ed, et al. Residual varicose veins below the knee are not related to incompetent perforating veins. J Vasc Surg 2006; 44: 1051–4.

41 Local treatment of venous ulcers THOMAS F. O’DONNELL JR. Introduction Wound dressings Standard or usual care in the management of venous ulcers Evidence-based rationale for selection of wound dressings

457 458 461 462

INTRODUCTION Prevalent in 1–1.5% of the population, venous ulcers are associated with a signiﬁcant disability and socioeconomic impact.1 Since at least 50% of venous ulcers recur within 10 years, they are marked by an insidious component of chronicity, which compounds their economic impact. Venous ulcers also are painful and affect both the working and retired generations, but increase in incidence with age. The economic cost of treating venous ulcers approaches 1% of the healthcare budget of Western European countries, which in the UK is estimated to cost £300–400 million per year.2 Although most patients with venous ulcers are treated on an outpatient basis and are infrequently hospitalized except for complications, the direct cost of treating venous ulcers in the USA has been calculated to average $2500 per month. The direct cost of this care is related to: (1) personnel, i.e., reimbursement of physicians, nurses, and home health aids; (2) wound care treatments; (3) medications; (4) specialized wound dressings; and ﬁnally (5) compression garments. Compression either by multilayer bandages or by custom-ﬁtted elastic compression stockings is one of the essential components for promoting ulcer healing.3 In a systematic review of the effect of compression bandaging on the healing of ulcers, the Cochrane Review demonstrated that high levels of compression with a multilayered system is most effective and is associated with an ulcer healing rate of 60–80%.4 There are other modalities, however, which when applied to the venous wound may have an additive effect on ulcer healing. They will be reviewed in this chapter. Since Chapter 30 has addressed compression bandaging, this chapter will focus on local

Implications of this systematic review of wound dressings Local care of the wound Other newer wound treatment modalities Clinical practice guidelines References

465 466 467 468 469

wound care for venous ulcers and in particular the role of wound dressings.

Why is local wound care important? The advantages of any additional treatment modality which could improve the proportion of wounds healed as well as the healing time of venous ulcers would provide not only important beneﬁts to the patient – a shorter period of pain and wound care with an improved quality of life – but also a profound socioeconomic impact. There are a myriad of wound dressing products available for the care of chronic wounds, and claims for their efﬁcacy in the healing of venous ulcers sometimes ascribe miraculous results to their use. Currently, the putative beneﬁts of these modalities, however, may not be clearly deﬁned for clinicians, so that their adoption for wound care treatment should be validated by level I trials. This chapter will encompass not only what are the usual (customary) elements of local wound care for venous ulcers but also what are the “cutting edge” developments in this area and, most importantly, what is their real value. Recommendations for both of these areas generally will be derived from systematic reviews of randomized controlled trials (RCTs). Recent Cochrane Reviews have assessed the efﬁcacy of other less common treatment modalities such as laser, electromagnetic therapy, and ultrasound, so that these modalities will be only brieﬂy mentioned in this chapter.5 While every element essential to the treatment of venous ulcers will be reviewed, the principal focus of this chapter will be on wound dressings and, in particular, how complex modern wound dressings

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Local treatment of venous ulcers

Table 41.1 Basis for comparative studies Level Large RCT Small RCT Non-RCT Non-RCT Uncontrolled case series

Study type

Strength

Low risk of error High risk of error Contemporaneous control Historical control

Great Moderate Weak Weak Weak

RCT, randomized controlled trial.

for venous ulcers may or may not be beneﬁcial to promoting wound healing.

The importance of level I evidence The preponderance of wound treatment studies for venous ulcers can be classiﬁed as level V evidence derived from case series (Table 41.1). This chapter will rely on RCTs which provide level I evidence to recommend therapy. These trials have the greatest statistical power and can scientiﬁcally validate a new treatment modality (Table 41.1). Moreover, Centers for Medicare & Medicaid Services (CMS) and other third-party payors are greatly inﬂuenced by level I trials on whether to reimburse for a speciﬁc treatment. The ﬁrst section of this chapter will review what is the usual or customary care of venous ulcers, whereas the second part will examine recent level I RCTs on not only newer wound dressings for venous ulcers but also other elements of local wound care. There are several potential positive beneﬁts of a dressing or any modality which accelerates wound healing: shorter period of pain, drainage, and disability related to the open wound for the patient as well as a reduced cost of total treatment.

the past, it was common practice to leave a wound as dry as possible, where the function of the wound dressing became simply to keep infections out and reduce trauma to the wound. Winter7 and associates’ ground-breaking experiments carried out in both a porcine wound model and human volunteers, however, demonstrated that the healing rate of wounds was markedly increased if an occlusive dressing was employed. These investigators observed a 40% increase in epithelialization rate in wounds treated with occlusive dressings over those treated with dry non-occlusive dressings. While slow to occur in certain quarters, the shift to semi-occlusive or occlusive dressings in wound therapy has been characterized succinctly by Falanga8 as “the composition and properties of a dressing itself now play a major role in modifying the micro environment of the wound.” Semi/occlusive wound dressings provide both a warm and moist wound environment by reducing heat loss and water evaporation (Table 41.2). In addition, a new class of dressings, the biologic dressing, has emerged. This dressing type is based on the principle of stimulating or providing important growth factors which are necessary in promoting wound healing.

The biology of wound healing

Classification of wound dressing types

A chronic venous ulcer can be deﬁned as a wound that has “failed to proceed through the orderly and timely series of events which should occur to produce a durable structural and cosmetic closure.”6 Chapter 7 has discussed the microcirculatory and subcellular pathophysiology of venous ulcer. Although the mechanisms may be different for each type of chronic wound, the biology is basically similar. The biologic phases of wound healing have traditionally been divided into three progressive segments: the inﬂammatory phase, the proliferative phase, and the maturational phase. Chronic wounds, such as a venous ulcer, appear to be stuck in the inﬂammatory phase.

Figure 41.1 demonstrates a convenient general classiﬁcation of wound dressing types: passive, interactive, and active dressings.7 These types are further subdivided into four classes: (1) non-occlusive, (2) semi-occlusive, (3)

WOUND DRESSINGS

Woven gauze Impregnated gauze Moist wound Hydrocolloid

Over the last several decades there has been a major transformation in the type of dressing used for wounds. In

Table 41.2 Examples of the effects of semi-occlusive and occlusive dressings on water loss from a wound Dressing type

Moisture vapor transmission rate (g/m2/h) 68 57 < 35 8

Wound dressings

Passive

Non-occlusive

Interactive

Active

Semi-occlusive and occlusive

Biologic

(a) Interactive Semi-occlusive and occlusive Moist and warm wound environment

Hydrocolloids

Alginates

Foams

Films

(b) Active Biologic

Living human dermal equivalent (LHDE)

Platelet products – growth factors

Other growth factors

(c) Figure 41.1 (a) Overall classiﬁcation of wound dressings. (Reproduced from Winter.7) (b) Interactive or semiocclusive/occlusive dressing types are subdivided into four types dependent on the unique properties of each subtype. (c) Biologic wound dressings are subdivided into living human dermal equivalent or human skin equivalent, platelet products, and other growth factors.

occlusive that are based on the evaporative water loss, and ﬁnally (4) biologic. The basic principles of wound care recognize that no single wound dressing may be ideal for all wounds and the type of dressing that is employed may change as wound healing and other local wound factors progress.6 Nonocclusive dressings such as topical antibiotics covered with dry gauze simply protect the wound from trauma and potential infection and are classiﬁed as a passive dressing. By contrast, the interactive types of wound dressings – semi-occlusive or occlusive dressings – maintain a moist warm wound environment and, dependent on the dressing’s properties, help to control the amount and composition of wound exudate.7 The old standby dressing – “saline wet-to-dry gauze dressing” – functions as a semi-occlusive dressing when wet. Saline wet-to-dry dressings have been the subject of

459

considerable criticism, but this dressing is still the most widely used form of wound dressing in certain areas of medicine. This dressing can facilitate healing in a moist environment, if the gauze is kept wet, but when the gauze is dried out the dressing assumes a non-occlusive characteristic. When these sponges are moist, they may be marginally occlusive, thereby permitting some water vapor loss, but as the gauze sponges dry they probably promote vapor and heat loss from the wound by evaporative cooling. It is a commonly held tenet that removal of the gauze dressing serves to debride the wound, so that many physicians employ this dressing for this speciﬁc purpose. Unfortunately, the dry gauze may also remove cells which are important in wound healing. In addition, removal of the dry sponge with its adherent debris, however, usually results in pain for the patient. To obviate the pain, clinicians “rewet” the sponge and thereby lower its principal function of debridement. In addition to the production of pain as a major drawback, saline wet-to-dry dressings have other disadvantages: (1) slowing the healing process by inducing inﬂammatory response, (2) desiccating and cooling the wound, (3) retarding angiogenesis, and (4) macerating the per-wound skin.6

Common types of semi-occlusive/occlusive dressings This class of dressings (Fig. 41.1b) will be discussed brieﬂy based on the dressing properties and mechanisms of action, as shown in Table 41.3. HYDROCOLLOIDS

Hydrocolloid dressings are composed of two layers: an inner hydrocolloid layer and an outer water-impermeable layer, which usually contains pure polyurethane.9 While maintaining a moist, warm environment this dressing also has properties of debridement and absorption of wound drainage. Hydrocolloid dressings are less permeable than ﬁlm dressings. Some common examples of this wound dressing are DuoDerm (Convatec, Princeton, NJ, USA), Comfeel (Coloplast, Peterborough, UK), and Signadress (Convatec, Princeton, NJ, USA). HYDROGELS

Hydrogel dressings are semi-transparent non-adherent hydrogels which are customarily constructed in sheets, but can be supplied in other forms such as a gel. These dressings have a moderate absorptive capacity owing to their composition of insoluble polymers with hydrophilic substitutes.10 Like other occlusive dressings, a particular advantage of hydrogel dressings is to promote debridement by inducing autolysis. An example of this dressing type is Tegagel (3M, Bracknell, UK).

460

Local treatment of venous ulcers

Table 41.3 Individual dressing types in non-occlusive/semi-occlusive dressing classes5,8 Subtype

Non-occlusive Wound dressing pads Tulle gras Non-adherent

Composition

General properties

Capacity for wound ﬂuid absorption

Commercial example

Gauze

Protects wound; dry → adheres to wound

Limited

Dry sterile dressing

Protects wound; less adherent Protects wound; permits drainage

None None

Transmits H2O, O2 and CO2; protects and insulates Less permeable than ﬁlms; protects and insulates

None

Woven fabric Impregnated with parafﬁn Various synthetic; conﬁgured in pores

Semi occlusive/occlusive Film Transparent and adherent polyurethane Hydrocolloid Water-impermeable outer layer → polyurethane; hydrocolloid inner layer Hydrogels Semi-transparent, nonadherent hydrogels → insoluble polymers with hydrophilic subtitles Foam Silastic or polyurethane foam sheets or liquids; hydrophobic layer Alginate Derived from brown seaweed

Tegapore polyamide Mepitel silicone Adaptic synthetic

Moderate

Tegaderm Opsite DuoDerm, Comfeel

Protection

Moderate

Tegagel

Permeable to gases and H2O prevents penetration of liquid

Moderate

Allevyn

Insoluble alginate converted Greatest to soluble salt → hydrophilic gel

Sorbsan

FILM

ALGINATES

Film dressings are composed of a transparent and adherent polyurethane which permits transmission of water vapor, oxygen, and carbon dioxide from the wound. While this dressing protects and insulates the wound, it also provides autolytic debridement of the eschar.11 There are several drawbacks to the ﬁlm dressings: (1) their lack of signiﬁcant absorption capabilities and (2) pooling of drainage under the dressing with the resultant maceration of the surrounding skin. Examples of this type of dressing are Opsite (Smith & Nephew Healthcare Ltd, Hull, UK) and Tegaderm (3M, Bracknell, UK).

Sodium alginate derived from brown seaweed is the major component of this dressing. Alginates’ great absorptive capabilities as well as its use in infected wounds are its chief advantages.13 Sorbsan is an example of this dressing type.

FOAM

Foam dressings have the potential for absorbing considerable quantities of wound exudate and are a composite of two materials, sialastic and polyurethane foam. The hydrophobic properties of the dressing’s outer layer prevent penetration of liquid, but the dressing is permeable to gases and water vapor.12 Allevyn (Smith & Nephew Healthcare Ltd, Hull, UK), is an example of this dressing type.

Biologic dressings This class of dressings has been characterized by some critics as “miracle dressings” and can be subdivided into: (1) human skin or dermal equivalent (HSE), (2) platelet products, either autologous or recombinant (DNA technology), and (3) other growth factors (Fig. 41.1c). Currently, there are two types of human skin equivalent dressings. The ﬁrst type, which mimics the layers of skin, is composed of keratinocytes (cells occupying the outer layer of the skin or epidermis) as well as ﬁbroblasts (the dermis) on a bovine type I collagen matrix.14 The keratinocytes are derived from cultured neonatal foreskin cells and differentiate to simulate the anatomy of human skin. Blood vessels, melanocytes, hair follicles, and sweat glands,

Standard or usual care in the management of venous ulcers 461

however, are not present in this skin substitute. Apligraf (Organogenesis, Canton, MA, USA), which is approved by the Food and Drug Administration (FDA), is an example of this type. The second type of human dermal equivalent, Dermagraf (Smith & Nephew Healthcare Ltd, Hull, UK), contains only the dermal elements with ﬁbroblasts alone on a collagen matrix, and this dressing does not have an epithelial layer of keratinocytes.15 Although HSE dressings provide temporary epithelial coverage of the wound, their main mechanism of action is through the secretion and stimulation of wound growth factors. Endogenous cells migrate into the wound to promote healing. Clinical studies with Apligraf have shown an approximately 40% “take” of the fetal-derived keratinocytes. The ﬁrst commonly employed topical biologic “growth factor” was a platelet-derived growth factor, Regranex (becaplermin; Janssen-Cilag, High Wycombe, UK), which is synthesized through recombinant DNA technology. This product is provided as a topical gel and is applied to the wound, so that it promotes chemotactic recruitment and proliferation of cells as well as increasing angiogenesis.16 This wound dressing is widely used, particularly in diabetic foot ulcers, but has been employed quite frequently for venous ulcers. Other growth factors such as autologous platelet thrombin, epidermal growth factor, ﬁbroblast growth factor, granulocyte–macrophage colony-stimulating factor have also been explored recently in small trials.

STANDARD OR USUAL CARE IN THE MANAGEMENT OF VENOUS ULCERS To determine what is the customary care provided for venous ulcers, authoritative texts or clinical guidelines provide some information. We sought a different method, however, and one possibly based on a higher level of evidence. Therefore, we carried out an analysis of all RCTs published since 1997 which described the treatment of venous ulcers by wound dressings as well as other chronic wounds.6 This start date was chosen because it coincided with the completion (end date) of a previous systematic review conducted by the National Health Services Health Technology Assessment Survey (NHS-TAS).17 Only RCTs were assessed because these level I trials characteristically have the most extensive description of the background care provided compared with other less rigorous study designs. The control arm of the RCT was designated as the “usual care group.” To identify modalities employed in the range of venous ulcer treatment, clinical care guidelines and standard authoritative textbooks were reviewed. In addition, both the National Guidelines Clearing House and MedLine were searched for clinical practice guidelines and were assessed for information containing this standard of care.

Identification of randomized controlled trials MedLine, CINAHL, and the Cochrane Control Trials Registry were used as the search engines for a review of all English language studies published through July 1, 2004. This literature search was limited to those articles published since 1997, the year of publication of the ﬁrst UK NHS-TAS Wound Assessment. Through this method a total of 2762 unique citations were retrieved. After preliminary screening of the titles and abstracts, 277 articles on chronic wounds were retrieved for review. Studies that included different types of ulcers other than venous ulcers or those did not provide clear delineation of subgroups and wound types were not included in this review of usual care for venous ulcers, but are reported elsewhere. Sixty-six RCTs examining wound dressings for venous ulcer were available for interview.

Usual care treatment modalities We categorized speciﬁc treatment modalities in the control arms of the RCT into: (1) debridement, (2) cleansing, (3) dressing type, (4) compression bandage, and (5) antibiotics. Methods of debridement were further categorized into surgical debridement and non-surgical debridement. We reviewed RCTs of venous ulcer dressings to determine how frequently a speciﬁc modality was used in the control arm. A limitation of this study was the possibility that some authors might have taken certain basic treatment modalities for granted and not reported them, e.g., antibiotic treatment for an infected wound. Thus, the information and the frequency of various treatment modalities were employed as a proxy for standard of care and must be interpreted accordingly.

Eligible studies Sixty-six venous ulcer trials with 6335 patients were identiﬁed. Seventeen venous ulcer trials had a sample size larger than 100 patients, but only one study reported a sample size of more than 300 patients. Among the venous ulcer trials, almost one-third were conducted in the UK and one-ﬁfth in the USA. The trials were usually conducted in an outpatient setting and were multicenter in six of these trials. The average age of the patients in the venous ulcer trials was older than expected, nearly 70.

Treatment modalities for usual care (Table 41.4) Approximately 30% of the trials reported either surgical (18%) or non-surgical (9%) debridement as an element of care. Wound cleansing was employed in over half of the RCTs and antibiotics were used in only 15%. The

462

Local treatment of venous ulcers

Table 41.4 Number and proportion of 66 venous ulcer RCTs reporting various usual care treatment modalities Treatment modality

An overwhelming number of the venous ulcer trials were conducted over 24 weeks of treatment. Only two trials had a study duration of less than 12 weeks.

Number (%)

Surgical debridement Non-surgical debridement Cleansing Dressing Compression Antibiotics

12 (18) 6 (9) 34 (52) 57 (86) 55 (83) 10 (15)

Conclusion Wound dressings were employed in 85% of RCTs, of which two-thirds were a semi-occlusive/occlusive type. Wound cleansing or debridement was described less frequently.

preponderance of RCTs (> 85%) reported that both a wound dressing and some form of compression bandage were used.

Dressing types Table 41.5 shows that approximately one-fourth of the RCTs employed non-occlusive dressings in their control arm with the majority being a dry gauze bandage (15%). Semi-occlusive dressings were used in 16% of the RCTs, which was relatively evenly distributed among the various types. Occlusive dressings constituted the greatest proportion of dressings used (55%), in which the predominant dressing type was hydrocolloid. An additional 20% either failed to specify clearly that a dressing was used or did not report the dressing type used.

Frequency of dressing changes Dressings for venous ulcers were changed on a once- or twice-weekly basis in the majority of trials (28/38 RCTs) that reported this information. In seven trials, dressings were changed every 2 days, while in only three trials they were changed once or twice per day.

Table 41.5 Number and proportion of venous ulcers RCTs reporting speciﬁc types of wound dressings Wound dressing Non-occlusive Ointment/cream Dry sterile dressing Semi-occlusive Saline wet to dry Wet dressing Medicated gauze Occlusive Unna Boot Hydrocolloid

Trial length

Number

%

6 10

9 15

}

24%

3 2 5

5 3 8

}

16%

10 25

15 40

}

55%

EVIDENCE-BASED RATIONALE FOR SELECTION OF WOUND DRESSINGS As an extension of our analysis to determine the usual and customary care of venous ulcers, we analyzed the experimental treatment arm of these RCTs for efﬁcacy.18 The date of inclusion of these trials, however, was extended to September 1, 2005. Those chronic venous ulcer RCTs were reviewed that included ulcers that failed to heal completely after receiving standard medical treatment for at least 30 days. In addition, occult arterial occlusive disease was ruled out by the use of non-invasive vascular laboratory studies.

Treatment criteria As shown in Fig. 41.2 only those RCTs that clearly used some form of compression were included. The use of this treatment modality was essential because it permitted our review to isolate the effect of an additive modality, a new wound dressing, on the healing of venous ulcers. As recommended by two authoritative publications the primary outcome criterion was complete wound healing,17,19 while a secondary outcome criterion was the rate of wound healing, preferably determined by Kaplan–Meier analysis. The following study types were eliminated from our review: those that (1) failed to report complete wound healing, (2) reported partial wound healing, and (3) focused solely on change in wound size. Finally, the incidence of ulcer recurrence was also examined, but was not an inclusion criterion for a speciﬁc RCT. Twenty studies were identiﬁed (Fig. 41.3) through this selection process: ﬁve human skin equivalent RCTs; seven growth factor RCTs; and eight semiocclusive/occlusive (inter-active) RCTs.

Additional elements of wound care While 80% of patients in the HSE group reported wound debridement, it was reported in only 50% of studies

Evidence-based rationale for selection of wound dressings 463

Medline, CINAHL Search 1997–2005 20 RCTs

Wound dressing types 68 RCTs on venous ulcer Biologic

Semi-occlusive and occlusive

Elastic compression Wound care Human skin equivalent: 5 studies

33 RCTs

Valid outcomes

Proportion of wounds healed Healing rate Recurrence

Growth factors 7 studies

Interactive: 8 studies

Figure 41.3 Twenty randomized controlled trials (RCTs) were identiﬁed and subdivided by wound dressing type.

20 RCTs

Figure 41.2 Process for selection of randomized controlled trials (RCTs) dependent upon the inclusion of compression as an element of treatment as well as primary outcomes of the proportion of ulcers healed.

overall. The greater use of debridement may be related to wound bed preparation in the HSE group. One study used an Unna Boot as its sole means of compression, whereas the majority of studies used forms of compression that

have been deﬁned as being within the class III category (British National Formulary20). As detailed in Table 41.6, the type of dressings employed in the control group most likely was inﬂuenced by the experimental type of dressing being examined. Non-adherent (n = 7), hydrocolloid (n = 4), and foam (n = 3) dressings were the most frequently used dressings in the control group. A zinc bandage was used in three trials. Hydrocolloid or foam dressings were used in six of the eight studies in the semi-occlusive/occlusive group, while non-adherent dressings were used in half of the

Table 41.6 Five comparative randomized controlled wound dressing trials which demonstrated statistically improved ulcer healing Dressing type

Population (no.) and [no. of sites]

Control dressing [% healed]

Experimental dressing [% healed]

Study length (weeks)

Compression type

Time to healing (median days) Control

Semi-occlusive/occlusive Stacey et al.13 113 [single]

Limova and 31 [two] Troyer-Caudle9 Growth factor DaCosta et al.22 60 [single]

Mostow et al.23

120 [12]

Human skin equivalent Falanga et al.24 309 [15]

Zinc oxide paste bandage [79%] Tegasorb [59%]

Calcium alginate [56%]; zinc oxide stockinette [59%] DuoDerm [15%]

Placebo injections Perilesional and gauze [19%] injection of GM-CSF [57%] Allevyn [34%] Porcine collagen small intestine submucosa [55%] Tegapore [48%]

Apligraf [63%]

36

Experimental

8

Two elastocrepe bandages; tubigrip stockinette Coban medicopaste

Zinc oxide paste (P < 0.001) (by Cox regression) Not provided

13

Four layer

112

54

12

Four-layer “Profore”

70

70 (P < 0.023)

24

Coban

181

61 (P < 0.003)

GM, CSF, granulocyte–macrophage colony-stimulating factor. Studies in bold print show efﬁcacy.

464

Local treatment of venous ulcers

growth factor studies. Two studies in the HSE group resorted to a form of skin graft in their control group, which more than likely was similar in effect to the experimental dressing.

a foam dressing (Allevyn). In the Oasis group, 55% of the wounds healed compared with 34% in the control (P = 0.02). In another trial of an advanced dressing type, Falanga et al.24 demonstrated in over 300 participants that Apligraf was superior to the semi-occlusive dressing Tegapore (3M, Bracknell, UK). Of the limbs treated with Apligraf over the rather long study period of 6 months 63% of the ulcers healed compared with 49% in the Tegapore-treated control group (P < 0.02).

Primary outcome: proportion of wounds healed Five of the 20 RCTs (25%) reported statistically signiﬁcant improvement in the proportion of ulcers healed (Table 41.6). This outcome has been deﬁned as a totally epithelialized wound within the time frame of the study. Stacey et al.13 conducted a trial comparing their standard dressing in their venous ulcer clinic – Viscopaste (Smith & Nephew Healthcare Ltd, Hull, UK), which is a zinc oxideimpregnated bandage – with both a zinc oxideimpregnated stockinette and a calcium alginate dressing. This study was conducted over the longest trial period of all the RCTs – 9 months – and found superiority for Viscopaste. In a smaller study with 31 patients carried out over 8 weeks, Limova and Troyer-Caudle9 observed a fourfold greater proportion of wounds healed in those wounds treated with Tegasorb (3M, Bracknell, UK) than in those treated with DuoDerm, both of which are hydrocolloids. Three studies showed signiﬁcantly improved healing in the growth factor group; however, two of these were with complex wound treatment regimens. One with vasoactive intestinal peptide, delivered by iontophoresis, subsequently was found not to be signiﬁcant on our statistical analysis and therefore was dropped from the overall number of signiﬁcant studies.21 In an RCT of 60 patients which compared granulocyte colony-stimulating factor with a non-adherent dressing, DaCosta et al.22 showed that the proportion of ulcers healed was three times greater in the experimental group (57%) than in the control group (18%). In a recently ﬁnished multicenter 12 week trial Mostow and colleagues23 found that a xenograft composed of collagen derived from porcine small intestinal submucosa (Oasis, Healthpoint, TX, USA) was superior to

Risk ratios To provide an analysis of the effect of the various wound ulcer treatments, the data are displayed in a risk ratio and conﬁdence interval format for the individual studies in the semi-occlusive/occlusive and HSE groups (Figs 41.4 and 41.5). By contrast, both the results of a meta-analysis and the individual studies are provided for the growth factor trials in Fig. 41.6. In these ﬁgures the black circle and the horizontal line provide the risk ratio of treatment failure and their respective 95% conﬁdence intervals (CIs). In each analysis, the vertical line through the center of the ﬁgure represents a risk ratio of 1, in which there was no difference in the outcome between the experimental and the control groups. A CI that crosses this center “no difference line” indicates that the results of this study are not statically signiﬁcant. In Fig. 41.4 both zinc paste13 and Tegasorb9 show an advantage over their comparator, while a similar result is observed for Apligraf in Fig. 41.5.24 By contrast, a meta-analysis of the growth factor group showed superiority for this dressing class as a whole as well as for the individual dressings, granulocyte colonystimulating factor22 and Oasis.23

Additional outcomes: ulcer healing rates Only 50% of the RCTs reported healing rates (in median days to complete healing): 3/8 in the semi-occlusive/ occlusive group, 4/7 in the growth factor group, and 3/5 in

Risk ratio 95% CI No. of patients

Study 40

Vin

5 Dressing B

Zinc paste

31

Duo Derm

Tegasorb

53

Comfeel

Unna’s boot

91

Cutinova foam

Comfeel

Polyurethane foam

Allevyn foam

Hydropolymer

Hydrocolloid

Hydrocellular foam

Foam composite

41

42

2

Adaptic

9

Charles12

1

Dressing A

Calcium alginate

133

Koksal

0.5

Promogran

73

Stacey13 Limova

0.2

Anderson

99

Thomas43

100

Van Scheidt44 107

Favors dressing A

Favors dressing B

Figure 41.4 Plot of risk ratios for the semi-occlusive/occlusive group of dressings. The black circles and the horizontal lines represent the risk ratio of the treatment failures and their respective 95% conﬁdence intervals (CIs).

Implications of this systematic review of wound dressings 465

Risk ratio 95% CI Study

No. of patients

Human skin equivalent

Omar45

18

Dermagraf

Non-adherent

27

0.2

1

0.5

2

5 Comparator

Keratinocytes

Mepitel

Falanga24

275

Apligraf

Tegapore

Tausche47

77

Epidex

Mesh splitthickness graft

Cultured epidermal allografts

Cryopreserved keratinocytes

Lindgren

46

Navratilova48 50

Favors human skin equivalent

Favors comparator

Figure 41.5 Risk ratio for individual studies in the human skin equivalent group. (See the legend to Fig. 41.4 for further explanation.)24,45–48

Risk ratio 95% CI No. of patients Growth factor

Study Robson49

0.2

0.5

1

2

5 Comparator

94

Repifermin

Non-adherent Visco paste

75

Platelet Iysate

DaCosta22

60

Granulocyte-CSF

Gauze pad

Gheradini21

65

Vasoactive intestinal peptide

Non-adherent

Wieman-1

16

68

Becaplermin

Wieman-2

16

64

Becaplermin

Adaptic

Stacey

50

Adaptic

Harding51

140

Keratinocyte Iysate

Hydrocolloid

Mostow23

120

Oasis

Allevyn (foam)

Overall 686

Favors growth factor

the HSE group. Limova et al.9 failed to provide this outcome measurement. In the remaining studies which showed signiﬁcance for the proportion of ulcers healed, the outcome of time to complete wound healing paralleled the ﬁndings for proportion of ulcers healed as shown in Table 41.6. In the growth factor group, Mostow et al.23 observed a signiﬁcantly reduced time to complete wound healing: 70 days in the Oasis-treated arm versus 95 days in the control arm. DaCosta et al.22 also demonstrated an improved healing rate, with the experimental group healing in onehalf the time of the control group (54 days versus 112 days). In the only HSE trial to report signiﬁcantly improved proportion of wounds healed, Falanga et al.24 noted that the time to complete closure was cut to onethird with the application of Apligraf (61 days) versus the control arm (181 days) P < 0.003.

Quality of study design The overall quality of the study design had improved since the last systematic review, in which the weakness of study design for wound trials had been criticized heavily.17 Of the 20 studies 40% performed an a priori calculation and 35% employed an intention-to-treat analysis.18 Except for

Favors comparator

Figure 41.6 Meta-analysis and individual risk ratios and conﬁdence intervals (CIs) for the growth factor group. The overall value favored the growth factor form of wound dressing. (See the legend to Fig. 41.4 for further explanation.)22–23, 49–51

the study by Limova et al.,9 the four other studies which showed signiﬁcance for wound healing included key elements of proper study design.13,22–24

Recurrence It was striking that very few wound dressing trials reported the incidence of ulcer recurrence and, if reported, the RCT usually had a short follow-up period. This may be related to funding limitations because the primary sponsor for the majority of the RCTs was industry.

IMPLICATIONS OF THIS SYSTEMATIC REVIEW OF WOUND DRESSINGS The treatment of chronic venous ulcers relies on some time-honored principles which have been validated by RCTs: (1) external compression with a device that preferably achieves a compression pressure of 40 mmHg at the ankle region and (2) proper care of the wound. This systematic review of available RCTs of wound dressings shows that some of the more sophisticated wound dressings can improve the results of wound healing beyond that observed with standard adequate compression

466

Local treatment of venous ulcers

and a simple wound dressing. It is interesting to note that only 10% of the original RCTs of wound dressings identiﬁed in this review showed a statistically improved proportion of ulcers healed. Each of these trials used optimal compression with four-layer bandages or class III stockings, so that the results in the treatment arm should represent the additive effect of a wound dressing combined with an adequate compression regimen.

Selection of a wound dressing for venous ulcers The type of dressing chosen for a venous ulcer will depend on many factors, a number of which are related to the wound: (1) wound drainage, (2) potential infection, i.e., bacterial burden, (3) eschar formation, and (4) amount and type of granulation tissue present. Other important considerations are the patient’s acceptance of the dressing and the pain relief or exacerbation provided by the dressing. Finally, the choice of a wound dressing is also inﬂuenced by the complexity of the application process for the dressing, its cost, and the frequency of dressing applications. A basic principle of wound dressings is that no dressing truly ﬁts all wound types. Dressing types may be changed as the character of the wound changes. Hydrocolloids and other occlusive dressings are adequate “all around dressings,” while advanced therapy dressings, such as Oasis and Apligraf, are usually reserved for ulcers that are resistant to standard care. These dressings require that certain conditions be present in the wound bed. For example, two occlusive dressings shown to improve the proportion of wounds healed as well as their rates – Tegasorb, a hydrocolloid, and Viscopaste, a zinc paste dressing – can be easily applied and have a relatively low product and application/maintenance cost. A more sophisticated dressing such as Oasis is generally applied by or under the physician’s direction and is moderately priced, but should be used when the wound is at a particular stage of healing with some granulation tissue present. Similarly, Apligraf, a more complex wound dressing, has shown statistically improved wound healing, particularly in “hard to heal” ulcers.25 This artiﬁcial skin graft is placed on the wound by a physician in a sterile environment so that it becomes a minor surgical procedure and is reimbursed as such. The cost of the Apligraf is signiﬁcantly greater than the other dressings discussed and certain wound conditions must be met.

LOCAL CARE OF THE WOUND Wound bed preparation The elements of wound treatment identiﬁed in our review and recommended in most guidelines include: (1) debride

the non-vital tissue from the wound, which provides a nidus for bacterial infection, (2) cleanse the wound, (3) control bacterial colonization with wound care, while treating true wound infection aggressively with antibiotics, (4) provide optimal moisture and temperature balance, usually by the wound dressing, (5) optimize general nutrition, and (6) employ mechanical measures that favorably alter local hemodynamics (discussed in other chapters).6

Wound debridement (surgical and nonsurgical) To accomplish surgical wound debridement, the use of a scalpel is most expeditious. Surgical debridement requires some degree of skill to differentiate between normal and abnormal tissue – the detritus of cells and devitalized tissues which is located predominantly on the surface and margins of the wound. Debridement of necrotic tissue is generally performed to reduce the potential for delayed wound healing by the accumulation of these breakdown products as well as gross bacterial infection, which in itself leads to persistent inﬂammation. Although most wounds are colonized by bacteria, Williams and colleagues26 have shown in a concurrent controlled prospective cohort study of 45 patients that debridement of a venous ulcer is an independent factor which promotes wound healing. Mean surface area reduced by 6 cm2 at 4 weeks and 7.4 cm2 at 20 weeks versus a 1 cm2 decrease and an actual 1.3 cm2 increase in the control group at the same respective time periods. A fourfold greater proportion of ulcers in the debrided group achieved complete healing than in the control group. Thus, sharp scalpel debridement of the periwound eschar and/or the eschar covering the wound should be performed because it is postulated that it retards granulation and epithelialization of the wound. Enzymatic debridement softens necrotic material, but there is little level I evidence to show that it improves wound healing.27 Autolytic debridement occurs under moist occlusive dressings so that the tissue separates out into viable and non-viable portions. Mechanical debridement can be carried out with wet to dry dressings, which if they are truly allowed to dry remove debris but are indiscriminate in the type of cells removed. A variety of wound products have been developed that promote debridement based on the chemical properties of the agent. Enzymatic debriding compounds such as Accuzyme (Healthpoint, Fort Worth, TX, USA), which contains the proteolytic enzyme papain, digest the complex wound detritus, which is usually composed of collagen and proteins. Hydrophilic beads or particles, such as dextranomer polysaccharide or cadexomer iodine, absorb ﬂuid from the wound and trap the necrotic material from within the wound on the surface of the beads. When the wound is washed with saline this debris is removed along with the beads. Finally, hydrogels, either as

Other newer wound treatment modalities

a gel or in sheets, promote autolysis because of their high water content and are customarily used with an overlying highly absorbent dressing. The NHS-HTA systematic review of 35 RCTs of wound debridement revealed that there is no advantage for enzymatic agents over usual care; mixed results for beads versus customary dressings; and one of four RCTs showed an advantage over controls for hydrogels.27

Wound cleansing The patient can cleanse the wound and especially the surrounding skin while taking a bath or shower with a mild soap such as Dove and have the wound dressed afterwards, depending on the speciﬁc dressing’s frequency of changes. A skin lotion is applied to the skin of the leg, such as water-based poly-sorb hydrate, which has the advantage of not interacting with the rubber in the elastic bandage or stocking. Contact dermatitis of the affected limb is a common complication which is encountered in the local treatment of venous ulcer. The intense pruritus can lead to further injury of the skin around the ulcer and secondary ulcers as a result of the excoriations created by the patient’s scratching of the itchy skin. Topical corticosteroids can alleviate this pruritus. Wound cleansing is based on the principle of reducing the bacterial involvement of the wound (bioburden), which can be separated into three classes: (1) contaminated, in which there are non-replicating bacteria within the wound and no injury to the host, (2) colonized, in which there are replicating bacteria within the wound, and, ﬁnally, (3) infected, in which replicating bacteria within the wound are found to have invaded healthy tissue and caused injury to the host.28 When the results from animal and human studies are assessed for the value of topical antiseptics, it is clear that Dakin’s solution, acetic acid, hydrogen peroxide, and even povidone-iodine interfere with wound healing. By contrast, malenide acetate (sulfamylon) achieved the best overall result.29 The management of a wound’s bioburden depends on the type of bacterial involvement, as previously presented. In colonized wounds appropriate dressings and debridement are effective. However, in critically colonized wounds not only is debridement required but also topical antimicrobials. Finally, for infected wounds systemic antibiotics are generally required. Systemic antibiotics for venous ulcers are used for the following indications: (1) when the infection extends beyond the wound margin, (2) if the patient is immunosuppressed, and (3) the patient has systemic signs of infection with fever, crepitus in the wound, or an elevated white count. Bacteria contaminate over threefourths of leg ulcers, with Staphylococcus aureus and Pseudomonas aeruginosa being the most common isolates.30 Anaerobic bacteria are less common in venous ulcers than in diabetic foot ulcers.

467

Antimicrobials The NHS-HTA performed a systematic review of both systemic and topical antimicrobials, which included RCTs of two systemic antibiotics and seven topical antibiotic for venous ulcers.31 Neither of the two RCTs of systemic antibiotics showed improvement in ulcer healing. There has been a great deal of enthusiasm for silver-based wound dressings because of their purported activity against a wide range of bacteria. Three RCTs using this type of dressing focused on the primary end-point of complete wound healing. While an activated charcoal dressing impregnated with silver showed an early advantage in reduction of wound size, as did another RCT in which silver sulfadiazine was used, neither trial showed superiority of wound healing over the control group at the end of the trial.

Management of pain A frequent problem with venous ulcers is the complication of pain, which may be worsened with dressing changes or certain treatments such as debridement. The Cochrane Review performed a meta-analysis of six trials, which showed a signiﬁcant advantage for a eutectic mixture of a local anesthetic and a cream in the reduction of pain at the time of wound debridement.32

Compression bandaging Finally, compression bandaging and/or elastic stockings as demonstrated in Chapter 30 are the essential element to favorably modify local hemodynamics.4

OTHER NEWER WOUND TREATMENT MODALITIES Vacuum-assisted closure therapy This mechanical method of wound care induces a local subatmospheric pressure on the wound. The putative advantages of this technique are: increased growth factor production, control of wound exudates, removal of bacteria, and increased blood ﬂow.33 The wound is sealed with a foam dressing, which is placed directly over the area of the wound. The vacuum device – a non-collapsible tube with multiple fenestrations – is then placed over the wound and an adhesive drape is applied over the foam to fashion a closed environment. The suction tube is then connected up to a collection device, which is set to exert a continuous negative pressure of 125 mmHg.

468

Local treatment of venous ulcers

In 2004, Samson et al.34 performed a systematic review of vacuum-assisted closure (VAC) therapy which evaluated six RCTs for a total of 135 limbs at risk and commented on the poor quality of these trials. They observed that these studies were insufﬁciently powered to detect differences and concluded at that time that we must await the results of ongoing trials. One such recently published trial is that of Vuerstaek and colleagues,35 which has an interesting study design and was carried out in hospitalized patients with a mixed etiology for their ulcers. A major drawback of the study was that only 43% of the limbs had venous ulcers and an equal proportion had ulcers of “arteriosclerotic origin.” The primary outcome was preparation of the wound bed for eventual split thickness skin grafting by pinch grafts and not complete wound healing. Vacuum-assisted closure therapy showed an advantage over the conventionally treated wounds both in time to achieve an adequately prepared wound bed for pinch grafts and in time to complete healing once the skin graft was applied. Estimates of cost and quality of life were less meaningful because all patients were hospitalized – a situation that is impractical in the USA. Moreover, the application and maintenance of the VAC occurred in an ideal situation, a hospital, in contrast to the usual outpatient setting, where equipment-based problems are inevitable. A high rate of ulcer recurrence (approximately 50%), however, was observed in both groups.

Physical measures Various techniques such as laser, therapeutic ultrasound, electrotherapy, and electromagnetic therapy have been explored in a limited number of small poorly designed RCTs.5 One small study showed a slight advantage for limbs treated with laser and infrared light, but its sample size limits ﬁrm conclusions. Of seven RCTs on therapeutic ultrasound and three for electromagnetic therapy no clearcut superiority was observed for either modality.

CLINICAL PRACTICE GUIDELINES This chapter has relied on RCTs, usually the level I type, to develop recommendations for the local care of venous ulcers. The primary outcome of these modalities has been complete ulcer healing. This outcome differs from the prevention of ulcer recurrence, which is less with nonsurgical care than with superﬁcial venous surgery, even with optimal compression and ideal wound care.39 ●

●

Other forms of local treatment Surgical procedures directly aimed at the venous ulcer itself can be considered local wound treatment. Following tangential excision of the ulcer base, which provides a receptive area upon which to place a skin graft, a meshed split skin graft is placed over the defect. Some investigators had theorized that the preparation of the base with radical surgical debridement including fasciectomy interrupts important local incompetent perforating veins and may have a signiﬁcant additive effect to the placement of the skin graft.36 Burnand and Abis37 reported their experience with 62 patients with 100 leg ulcers, the majority of which were venous (72%). Although 28% had an ulcer recurrence within 2 months postoperatively, 55% remained healed at 5 years. They saw no difference in recurrence between large ulcers (> 10 cm) and small ulcers. Obviously, this is level V evidence and would have to be validated by a RCT. Toward that end the Cochrane Review identiﬁed only two RCTs that employed split thickness skin grafts and observed no signiﬁcant advantages for the treatment group.38 It has been this author’s experience that split thickness skin grafts should be reserved for large ulcers, once the ulcer bed has appropriate granulation tissue. The successful take of a skin graft can reduce the amount of time that the patient will require wound dressings and incur pain.

●

●

●

Wound cleansing. The ulcer should be washed with tap water (there appears to be no advantage to sterile saline) and the surrounding skin should be washed with a mild soap [1B]. Debridement. Sharp debridement of periwound or wound eschar should be carried out, if tolerated by the patient (26 [1A]). Alternatively, a hydrogel or an enzymatic dressing can be applied to reduce the necrotic material and bioburden, which impede wound healing (27 [1B]). Antibiotics. Systemic antibiotics should be limited to the treatment of obvious infections of the ulcer or the surrounding skin, as manifest by systemic signs, periwound cellulitis, or gross purulence [1B]. For localized infections, topical antimicrobials, such as silver-based wound dressings, are indicated and can be conveniently combined as a form of an occlusive wound dressing (31 [1A]). Wound dressings. Our systematic review clearly showed the superiority of ﬁve wound dressings which when combined with adequate compression should improve the proportion of wounds healed and the speed with which they heal. The condition of the wound bed will dictate the type of dressing. For uncomplicated venous ulcers occlusive dressings, such as Tegasorb, can be used, while Viscopaste provides the concomitant advantages of mild rigid compression and a decreased frequency of dressing changes. Non-infected wounds with some degree of granulation tissue can beneﬁt from the xenograft Oasis, while hard to heal and large ulcers without infection but with supportive granulation tissue are candidates for Apligraf (9, 13, 18, 23, 24 [1A]). Split thickness skin/pinch grafts. Large ulcers, which will require an extended period of time to heal by secondary

References 469

Guidelines 4.14.0 of the American Venous Forum on local treatment of venous ulcers No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1

B

4.14.2 We recommend sharp debridement of venous ulcers if tolerated by the patient 1

A

4.14.3 As an alternative to debridement we recommend a hydrogel or an enzymatic dressing to reduce the necrotic material and bioburden, which impede wound healing

1

B

4.14.4 Routine use of antibiotics for venous ulcers is not recommended. We recommend systemic antibiotics for treatment of obvious infections as manifested by systemic signs, periwound cellulitis, or gross purulence

1

B

4.14.5 For localized infections we recommend topical antimicrobials, such as silver-based wound dressings

1

A

4.14.6 For uncomplicated venous ulcers we recommend compression treatment with occlusive dressings, such as Tegasorb, while Viscopaste provides the concomitant advantages of mild rigid compression and a decreased frequency of dressing changes

1

A

4.14.7 For non-infected wounds with some degree of granulation tissue we recommend the xenograft Oasis, while for hard to heal and large ulcers without infection but with supportive granulation tissue we recommend Apligraf

1

A

4.14.8 For large ulcers, which will require an extended period of time to heal by secondary intention, we suggest skin grafting. Pinch grafts have the advantage over split thickness skin grafts because they can be performed in an ambulatory setting and avoid hospitalization

2

B

4.14.1 For local wound cleansing of venous ulcers we recommend tap water and the surrounding skin should be washed with a mild soap

intention, are candidates for skin grafting. Pinch grafts have the advantage over split thickness skin grafts because they can performed in an ambulatory setting and avoid hospitalization (38 [2B]).

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25. Falanga V, Sabolinski M. A bi-layered living skin construct (Apligraf) accelerates complete closure of hard to heal venous ulcers. Wound Repair Regen 1999; 7: 201–7. 26. Williams E, Enoch S, Miller D, et al. Effect of sharp debridement using curette or recalcitrant non-healing venous leg ulcers: a currently controlled, prospective cohort study. Wound Repair Regen 2005; 13: 138–47. ◆27. Lewis R, Whiting P, ter Riet G, et al. A rapid and systematic review of the clinical effectiveness and cost effectiveness of debriding agents in treating surgical wounds. Health Technol Assess 2001; 5 (14): 1–131. 28. Halbert AR, Stacey MC, Rohr JB, Jopp-McKay A. The effect of bacterial colonization on venous ulcer healing. Aust J Dermatol 1992; 33: 75–80. 29. Wilson JR, Mills JG, Prather ID, et al. A toxicity index of skin and wound cleansers used on in vitro ﬁbroblasts and keratinocytes. Adv Skin Wound Care 2005; 18: 373–8. 30. Gilchrist B, Reed C. The bacteriology of chronic venous ulcers treated with hydrocolloid dressings. Br J Dermatol 1989; 121: 337–44. 31. O’Meara S, Cullum N, Majid M, Sheldon T. Systematic review of wound care management: (3) antimicrobial agents for chronic wounds. Health Technol Assess 2000; 4: 1–52. 32. Briggs M, Nelson EA. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database Syst Rev 2003; Issue 1. Art. No.: CD001177. ●33. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg 1997; 38: 562–76. ◆34. Samson DJ, Lefeure F, Aronson N. Wound-healing technologies: low level laser and vacuum assisted closure evidence report. Evidence Report/Technology Assessment No. 111. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center, under Contract No. 290-02-0026.) AHRQ Publication No. 05-E005-2. Rockville, MD: Agency for Healthcare Research and Quality, 2004. 35. Vuerstaek JDD, Vainas T, Wuite J, et al. State-of-the-art treatment of chronic leg ulcers: a randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg 2006; 44: 1029–38. 36. Beckert S, Coerper S, Becker HD. The role of a radical surgical debridement and mesh graft tissue transfer for treatment of venous ulcers. Zentralbl Chir 2003; 128: 680–4. 37. Burnand K, Abis S. Treatment of venous ulcers by excision and split thickness skin grafting. Vascular 2006; 14: 108–109. 38. Jones JE, Nelson EA. Skin grafting for venous ulcers. Cochrane Database Syst Rev 2005; Issue 1. Art. No.: CD001737. ●39. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomized controlled trial. Lancet 2004; 363: 1854–9.

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40. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. Wound Care 2002; 11: 335–41. 41. Koksal C, Bozkurt AK. Combination of hydrocolloid dressing and medical compression stockings versus Unna’s Boot for the treatment of venous leg ulcers. Swiss Med Weekly 2003; 133: 364–8. 42. Andersen KE, Franklin CP, Gad P, et al. A randomized, controlled study to compare the effectiveness of two foam dressings in the management of lower leg ulcers. Ostomy Wound Manage 2002; 48: 34–41. 43. Thomas S, Banks V, Bale S, et al. A comparison of two dressings in the management of chronic wounds. J Wound Care 1997; 6: 383–6. 44. Vanscheidt W, Sibbald RG, Eager CA. Comparing a foam composite to a hydrocellular foam dressing in the management of venous leg ulcers: a controlled clinical study. Ostomy Wound Manage 2004; 50: 42–55. 45. Omar AA, Mavor AI, Jones AM, HomerVanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg 2004; 27: 666–72. 46. Lindgren C, Marcusson JA, Toftgard R. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Br J Dermatol 1998; 139: 271–5.

47. Tausche AK, Skaria M, Bohlen L, et al. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as splitthickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Regen 2003; 11: 248–52. 48. Navratilova Z, Slonkova V, Semradova V, Adler J. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. European Academy of Dermatology and Venereology. J Eur Acad Dermatol Venereol 2004; 18: 173–9. 49. Robson MC, Phillips TJ, Falanga V, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001; 9: 347–52. 50. Stacey MC, Matas AD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg 2000; 20: 296–301. 51. Harding KG, Krieg T, Eming S, et al. Efﬁcacy and safety of the freeze-dried cultured human keratinocyte lysate, LyphoDermTM 0.9%, in the treatment of hard-to-heal venous leg ulcers. Wound Repair Regen 2005; 13: 138–47.

42 Surgical repair of deep vein valve incompetence SESHADRI RAJU Introduction Indications and selection of patients Preoperative assessment Surgical pathology Surgical techniques Identiﬁcation of valve attachment lines Strip test Speciﬁc valve reconstruction techniques Internal valvuloplasty External valvuloplasty Angioscopic repair

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INTRODUCTION The description of the ﬁrst successful repair of the deep vein valve by Kistner1,2 was a seminal event. Though initially controversial, it sparked a resurgence of interest in venous disease, leading to important advances. Today vein valve reconstruction is an established option in the treatment of deep venous insufﬁciency. While the ﬁeld has broadened from worldwide contributions, the concepts and techniques developed by the Straub Clinic team3 continue to inﬂuence its practice.

Transcommissural valvuloplasty Prosthetic sleeve Neovalve Segment transfer Axillary vein transfer Anticoagulation Morbidity Outcome Controversies New developments References

475 476 476 476 477 478 478 478 478 480 480

without other clinical features is an important consideration in case selection. Recurrent cellulitis and recurrent superﬁcial or deep venous thromboses are less common indications. As most patients with deep venous reﬂux have other system involvement,4 simpler procedures such as saphenous ablation and/or perforating vein interruption might have been carried out already. It is well known that venous disease often responds to partial correction at least initially. Deep valve repair is indicated only when the initial approach fails. Since chronic venous disease in general poses little risk to limb or life, this graduated approach makes sense.

INDICATIONS AND SELECTION OF PATIENTS PREOPERATIVE ASSESSMENT Deep valve repair should be reserved for patients who have exhausted other less intensive therapeutic options. Typically, a course of compression therapy would have been tried for a reasonable period, say 6 months. However, certain socioeconomic factors and special situations such as occupation or comorbidities may render long-term compression therapy impractical or impossible. Potential candidates for deep valve reconstruction should have symptoms with CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) clinical class 3 or higher. Pain is not adequately covered by the CEAP classiﬁcation. About 10% of patients with deep valve reﬂux will have severe [visual analog scale (VAS) > 5] pain unaccompanied by other clinical manifestations. The severity of pain with or

Prospective candidates should undergo a general as well as a detailed venous evaluation. The latter should employ the CEAP classiﬁcation system, with venous severity scoring. Current medications including hormones and anticoagulants are relevant. Adequacy of arterial perfusion should be ascertained. A comprehensive set of investigations is necessary for initial assessment and follow-up. These include duplex, a global test such as ambulatory venous pressure or air plethysmography, and contrast studies, typically ascending and transfemoral (ascending and descending) venograms. The last are no longer used to quantify reﬂux as the test has been found to be not very speciﬁc.4–6 It is, however, useful

Identiﬁcation of valve attachment lines 473

in detecting iliac outﬂow obstructions and in delineating relevant anatomy before undertaking deep valve repair. Currently, there are no techniques to precisely quantify reﬂux at a single valve station or system; targeted intervention is therefore not possible. Valve closure times have poor clinical correlation.7,8 Some crude estimation of reﬂux severity can be estimated by counting the number of reﬂuxive venous segments (segment score) or the distal extent of uninterrupted reﬂux in the limb (Kistner reﬂux grades).4,9 “Axial reﬂux” is frequently (in about 40%) but not exclusively associated with severe clinical presentation.7 Venous ﬁlling time (VFT) in ambulatory venous pressure and venous ﬁlling index (VFI90) measured by air plethysmography have been shown to correlate with global severity of reﬂux and are useful outcome monitors.4,8,10–17 Several quality of life measures speciﬁc for venous disease have become available recently. A few of these18,19 are easy enough to be employed on a routine basis in venous practice. A routine hypercoagulability work-up is recommended to provide proper guidance for the duration and extent of postoperative anticoagulation.

SURGICAL PATHOLOGY Roughly half the patient population undergoing valve repair will be found to have “primary” valve reﬂux and the other half secondary or post-thrombotic disease.20,21 Very rarely congenital anomalies such as tricuspid valves, absent valves, duplicated reﬂuxive conduits involving one or both limbs may be found. In “primary” valve reﬂux the valve station appears normal and free of apparent disease; the caliber is normal or slightly enlarged. Often, valve attachment lines can be easily seen and traced on the surface of the vein from the outside. The valve angle where the two valve attachment lines come together at the commissure is widened and often obtuse (normally acute).20 This may be seen at only one or both of the two commissures. The adventitia may be thick, in some cases obscuring the valve attachment lines. Internally, the valve cusps are redundant with excessive pleats and folds, thus failing to coapt properly and allowing reﬂux. The texture of the valve cusps themselves appears normal and translucent. Perivenous and wall ﬁbrosis are the hallmarks of a postthrombotic valve. This may be extensive, sometimes apparent even before the fat layer is traversed. In others, ﬁbrosis is microscopic and the vein appears to be ostensibly normal on gross inspection. Neovascularization induced by prior thrombosis is seen to inﬁltrate the vein wall and valve remnants on microscopy.22 The extent of valve damage is variable; in some, the valve cusps are preserved but they are secondarily redundant from postthrombotic ﬁbrosis encasing the valve station. These valves are amenable to direct repair. In others, perforation or adhesion of the valve cusps may be present rendering the

valve non-functional and non-repairable; a valve substitution or transplantation technique (indirect repair) is required. In advanced cases, the valve cusps have disappeared altogether and the valve station houses only trabeculae. In a subset of patients, distal deep vein thrombosis is seen below a “primary” reﬂuxive valve.12,23 It is not clear whether the thrombotic process is the result (from reﬂux stasis) or cause of the reﬂux. In the post-thrombotic series followed in Dr. Strandness’s laboratory, new reﬂux develops in valves remote from the thrombus site for unknown reasons.24–27

SURGICAL TECHNIQUES Exposure and preparation of the valve station for repair/transplantation is the same. This will be outlined ﬁrst followed by descriptions of individual repair techniques. The patient is positioned supine with the femoral or popliteal (medial approach preferred) areas prepared. One arm is abducted on an arm board with the axilla prepared, in case an axillary vein transfer is found to be required. A femoral valve is invariably present below the take-off of the profunda femoris vein. This is the main target for repair. A second inconstant femoral valve may be found 2–5 cm below the ﬁrst valve; a common femoral valve may also be present in some cases. When present, these extraneous valves provide convenient alternative or additional sites for repair through the same incision. A profunda femoris valve is commonly present (in about 85%) at the origin; in its absence, a more distal valve can be found 2–3 cm more distally. In the popliteal vein, a valve is present in about 70% at the adductor tubercle level. A valve at the mid- or distal popliteal vein is found less frequently (in about 50%) in non-thrombotic cases. However, one or more valves are invariably present in the adjoining posterior tibial vein. Guidance to repairable valve station locations may be obtained from preoperative venography or duplex but not always.

IDENTIFICATION OF VALVE ATTACHMENT LINES Once the target vein is exposed, the valve station may become readily apparent, particularly in “primary” cases; in others, particularly post-thrombotic cases, the valve station may have to be identiﬁed by a preliminary adventitial dissection. By a combination of sharp and blunt dissection the adventitia is peeled away (Fig. 42.1). Diamond jaw forceps are useful tools in this task. It is essential to expose and identify the valve attachment lines in their entirety. Commissural apices should be clearly visible. Intact valve lines indicate the presence of valve cusps and a direct repair is almost always possible.

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Surgical repair of deep vein valve incompetence

clamp in place, the infravalvular segment is emptied upwards through the valve. If the valve is competent, the segment will remain collapsed. A reﬂuxive valve will allow the segment to ﬁll from above. The supravalvular segment may also be gently squeezed towards the valve to test its competence.

SPECIFIC VALVE RECONSTRUCTION TECHNIQUES

Figure 42.1 Adventitial dissection to expose valve attachment lines.

Interrupted or absent valve attachment lines denote valve dissolution. This sign is so reliable that further time and effort do not need to be wasted in performing a venotomy to search for non-existent valve cusps. About 4 cm of the valve station and adjoining venous segments should be cleared of branches in preparation for both direct and indirect types of repairs.

STRIP TEST Once the valve station is identiﬁed, a strip test is performed to conﬁrm valve incompetence. With a bulldog

Descriptions of numerous techniques of valve reconstruction can be found in the literature. Most direct valve repair techniques in current use are variations/modiﬁcations of the basic internal or external techniques originally described by Kistner. Axillary vein transfer is the most frequently used indirect repair technique. A brief outline of the more common techniques in current use is provided below. The source manuscript should be consulted for ﬁner details.

INTERNAL VALVULOPLASTY The original description by Kistner1 utilized a longitudinal incision between the two valve cusps cutting through the anterior commissural apex (Fig. 42.2). The incision is started 10–15 mm below the valve attachment lines and extended upwards through the commissural apex keeping the cusps in view to avoid damage (the valves can droop or even prolapse down in some cases). The incision allows the valve station to be laid open like pages in a book, providing excellent exposure of redundant cusps. Frequent irrigation with saline is necessary to visualize the translucent valve cusps and their free edges. Using 7° polypropylene sutures

Figure 42.2 Internal valvuloplasty through longitudinal venotomy: Kistner technique. Transverse and “T” venotomy exposure of the valve cusps are shown on the far left.

Transcommissural valvuloplasty

the valve edges are gathered like the pleats of a curtain and tacked to the commissural apex with the knot placed outside. A single double-needled suture can be used at the undivided posterior commissure. Separate sutures will be necessary at each half of the divided anterior commissure. Approximately 20% of the valve edges at each commissure will need to be tacked in this fashion. Some subjective judgment is required in deciding when enough valve tightening has been achieved as valve competency cannot be tested till after the venotomy had been closed. Closure has to be meticulous with everting sutures and good intimal apposition minimizing the chances of a potential nidus site for thrombus formation. The valve can also be exposed through a supravalvular transverse incision28 placed about 5 mm above the commissural apex. Half a dozen or so stay sutures are placed through the lower cut edge for retraction; the same sutures can be used later for closure. This transverse incision is comparatively short, reducing suture line length but at the cost of somewhat reduced exposure. The annulus is not traversed, minimizing the chance of cusp damage during the venotomy; tightening of the valve cusps can be continuously monitored as the repair progresses and the end-point can be gauged before the venotomy is closed. Exposure can be further increased by converting the transverse incision into a “T”29 towards the valve cusps. Extension into the valve sinus where there is relative stasis should be avoided. The “trapdoor” incision30 provides even greater exposure than the longitudinal incision, but if the incision length is much greater this increases the effort at faultless closure. Despite the cited pros and cons, all of the described incisions seem to work well in the hands of their proponents, and the choice seems to be one of personal preference. After completing the closure, the valve should be tested for competency by the strip test. With some experience, valve competency is readily achieved. However, there should be no hesitation to reopen the venotomy for placement of additional sutures if the valve is not completely competent. If total competence cannot be achieved even then, one should proceed with axillary vein transfer. Precision, faultless technique and a mindset that accepts nothing less than a perfect repair/transplantation are essential for success. Botched reconstructions can seldom be salvaged by reoperation at later date at the same site because of edema, inﬂammatory response, and cicatrix formation in the wound.

EXTERNAL VALVULOPLASTY This technique31 brings the two valve attachment lines together by externally placed sutures at each commissural end. The valve redundancy itself is not directly addressed. Starting at the commissural apex continuous or interrupted transmural sutures are placed along the valve attachment lines covering about 20% of attachment line

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length at each end. This is usually at the point where the attachment lines curve sharply away from each other. Additional sutures may be required at one or both commissural sides to achieve competence. It is remarkable how a single additional suture would restore competence to a valve that had remained reﬂuxive after a row of prior sutures. Creation of valve station stenosis during repair should be avoided; a relative stenosis of 10–20% is occasionally necessary to achieve valve competence and is probably acceptable. If more lumen narrowing is required to achieve valve competence, the technique should be abandoned in favor of axillary vein transfer. Some modiﬁcations of the external technique with supporting clinical series have appeared in the literature.17,32

ANGIOSCOPIC REPAIR First described by Gloviczki et al.33 from the Mayo Clinic the technique has gained many adherents.34–36 It is an enhancement of the external repair technique; transluminal instead of transmural sutures are used along the valve attachment lines (Fig. 42.3). Visualizing the valve apparatus with an angioscope introduced through a small venotomy above the valve station, the transluminal sutures not only appose the valve attachment lines but also tighten the valve cusps. Angioscopic irrigation is required for proper visualization of the valve apparatus; a watertight purse string suture around the venotomy is required. Some extravasation of the irrigant into the vein wall at the venotomy site is common and minor intimal trauma from manipulation of the tip of the angioscope is unavoidable. It is actually quite difﬁcult to direct the sutures under angioscopic visualization to catch the valve cusps. More often, angioscopic inspection merely conﬁrms that the valve has been traversed by the sutures after they had been placed. It appears that transluminal sutures placed along the valve attachment lines usually tack or tether the redundant valve cusps; the angioscope is conﬁrmatory but not an aid in the actual placement of sutures. This insight led to the development of transcommissural valvuloplasty described below.

TRANSCOMMISSURAL VALVULOPLASTY In this technique,37 the valve attachments are clearly delineated ﬁrst as described. Transluminal sutures are placed as in the angioscopic technique but “blindly” without the aid of the angioscope or venotomy. Initial sutures near the commissural apex are shallow as the free edges of the valve cusps do not extend very far into the lumen at this point. Farther down they do extend further into the lumen, crossing it to the opposite commissure. Each subsequent suture should, therefore, be placed slightly deeper into the lumen than the previous one to

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Surgical repair of deep vein valve incompetence

Figure 42.4 Prosthetic sleeve valvuloplasty.

Figure 42.3 Angioscopic valvuloplasty. Transluminal sutures bring the valve attachment lines together while tightening the valve cusps internally.

stations that remained overtly incompetent even after surgical exposure. Because of its relative simplicity, this technique has attracted lot of clinical interest. Several short-term series have appeared with good clinical results.40–43 Substituting a stenosis or occlusion (which improves symptoms initially) for reﬂux with this technique is a major concern particularly in postthrombotic cases where there are no valve cusps to coapt with prosthetic constriction. Long-term results should be monitored.

NEOVALVE catch the cusp edges. As each repair suture is tied the slack valve cusps will tighten progressively. Despite the “blind” nature of the technique, valve competency can be routinely achieved which can be continuously monitored after each suture is placed.

PROSTHETIC SLEEVE Prosthetic sleeves wrapped around a reﬂuxive valve station can restore valve competence.38 Our use of the technique28 arose as an extension of its use around axillary vein transplants23 and was prompted by the observation that reﬂuxive valves sometimes became competent with venospasm induced by surgical manipulation (Fig. 42.4). A suitably sized prosthetic sleeve of Dacron or polytetraﬂuoroethylene (PTFE) was wrapped around the slightly constricted valve station to maintain competence. Jessup and Lane39 have used the technique more aggressively using a prosthetic device to constrict valve

There have been numerous experimental and clinical attempts20,44–49 to create new valve cusps at valve stations where native valves had become destroyed beyond repair. These techniques have obvious appeal for use in postthrombotic cases. Few long-term successes have been reported however. A recent technique described by Maleti and Lugli50 has drawn widespread interest; neovalves are fashioned out of the intima by sharp dissection. Shortterm results with this technique are promising.

SEGMENT TRANSFER First described by Ferris and Kistner,2 the femoral vein is divided below the incompetent valve and anastamosed to the adjacent saphenous or profunda femoris vein (Fig. 42.5). The receiving veins should have adequate caliber and have competent valve(s) for a successful reconstruction. Such favorable anatomy is not always found. Saphenous and profunda valves are shallower than the

Axillary vein transfer 477

Figure 42.6 Exposure of the axillary vein through an incision along the axillary skin crease.

Figure 42.5 Kistner vein segment transfer. Anastomosis to the adjacent saphenous vein is shown. The profunda femoris vein could also be used for segment transfer (dashed lines).

femoral and are prone to reﬂux with dilatation.51 Longterm competence of this repair after redirection of additional ﬂow is therefore a concern. Perhaps for this reason, published results12,52,53 with this technique appear to be somewhat inferior.

AXILLARY VEIN TRANSFER Axillary vein transfer for femoral reconstructions in the ﬁrst 20 patients from our center was brieﬂy reported in 1981.54 Simultaneously, Taheri et al.55 reported using the brachial vein valve transfers to the femoral vein changing later to the popliteal vein56 because of size considerations. Later reports from us and others have followed since.14,20,21,28,57–59 The axillary valve is a better size match for the femoral vein and has become the standard in valve transfer. A deceptively simple technique on the surface, it is in fact technically quite demanding.10,20,51 The axillary valve cusps are shallow and even mild torsional or tensional defects during the transfer procedure can result in incompetence. About 40% of axillary valves are incompetent in situ even before harvest for unknown reasons; and a few more become reﬂuxive after transfer despite meticulous technique. A large number of these potential technical failures can be salvaged by performing a valvuloplasty on the donor valve before or after transfer. The axillary vein is exposed through a transverse incision along the skin crease in the axilla (Fig. 42.6). One

or more valves at the distal or mid-portion of the vein may readily come into view. If not, a valve is nearly always found near the ﬁrst rib that can be exposed by retracting the pectoralis muscles. A 3–4 cm length of axillary valve segment should be harvested after clearing tributaries. The valve should be strip tested and repaired if necessary by using an external or transcommissural technique before harvest. After harvest, the cut ends of the donor vein are simply ligated. After harvest, arm symptoms are extremely rare (< 2%) and transient. The harvested vein segment is dropped into cold balanced salt solution. After heparinization, the recipient vein is divided allowing the cut ends to retract. The axillary valve is now anastomosed in proper orientation using interrupted sutures, the upper end ﬁrst. Continuous sutures, howsoever carefully placed, will result in postoperative suture line stenosis after intraoperative venospasm is relieved. The upper clamp can come off at this stage and the transferred valve tested for competence (Fig. 42.7). If reﬂuxive, the valve can be quickly repaired by an external or transcommissural technique before completing the lower anastomosis. The transplanted segment should be placed under optimal tension trimming the lower cut end of the host vein as necessary. Both over- and undertension can cause reﬂux of the transferred valve. Leaving the upper clamp off during the lower anastomosis allows for early detection and correction of any reﬂux inducing torsional or tensional defects. A prosthetic sleeve of Dacron or PTFE can be wrapped around the transplanted wall to prevent late dilatation and incompetence of the transferred valve. The technique is feasible even in post-thrombotic veins with trabeculae.10 The trabeculae are excised at cut ends of the host vein to create a single lumen for anastomosis (Fig. 42.8). The transplant maintains surprisingly very high long-term patency despite the advanced post-thrombotic pathology of the host vein. The axillary–basilic complex can be used to reconstruct the entire femoral–profunda conﬂuence in severe postthrombotic cases.10,51 Valve transfer using cryopreserved allografts has had very poor results possibly related to immune rejection.60

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Surgical repair of deep vein valve incompetence

patients with known thrombophilia or other risk factors for thrombosis.

MORBIDITY Wound complications, commonly hematoma or seroma, occur in about 10% of patients. These should be aggressively drained early to avoid compression and thrombosis of the repair. Postoperative (6 weeks) thrombotic complications occur in about 4% of primary cases20 and the incidence is no different in post-thrombotic cases10 after valve reconstruction. But the latter subset is prone to interval recurrent thromboses (about 6% cumulative over 10 years) from the underlying disease and unrelated to the surgery. In early or late thromboses after valve surgery, the valve repair itself is usually spared, the thrombus occurring at a remote location in the same or opposite limb. Pulmonary embolism and mortality are rare after valve reconstruction. Figure 42.7 Axillary vein transfer. The upper anastomosis has been completed. With the upper vascular clamp removed the valve is seen to be competent.

Figure 42.8 Axillary vein transfer in trabeculated veins.

ANTICOAGULATION Prophylactic or bridge low-molecular-weight heparin (LMWH) started before surgery should be continued at least for 4 or 5 days afterwards along with pneumatic compression and early ambulation. Primary cases with external repair may not need warfarin anticoagulation beyond perioperative LMWH.61 Most others will require postoperative warfarin anticoagulation for at least 8–12 weeks. Operative endothelial injury is healed by 6 weeks.62 Longer term anticoagulation may be considered in

OUTCOME Several long-term clinical results have been published.8,12,21,63,64 In primary disease, long-term cumulative ulcer healing of about 60–80% can be expected. Resolution of pain and swelling are excellent as well. Results in postthrombotic disease have been mixed (see below). Most patients are able to discard or limit stocking use after successful valve reconstruction. Hemodynamically, signiﬁcant improvement in VFI90 (air plethysmography) can be expected following valve reconstruction.14,15,37,65 Ambulatory venous pressure improves signiﬁcantly after valve reconstruction and may even normalize in some “primary” disease cases.12,17,57,66 Clinical failures are associated with non-improvement in ambulatory venous pressure parameters after valve reconstruction. Preoperative venous ﬁlling times (VFT) are typically lower in post-thrombotic disease; ulcers seldom heal if VFT persists below 5 seconds after surgery.10 Ambulatory venous pressure is inﬂuenced by multiple aspects of venous dynamics including vein wall compliance.67 Reﬂux is but one component, though a dominant one. Therefore, only improvement, not total normalization, is to be expected following a single valve reconstruction in a multifocal disease, particularly in post-thrombotic cases.

CONTROVERSIES Single versus multiple valve reconstructions In symptomatic primary disease, multisystem, multilevel disease is often present. Whether a single valve repair is enough and whether multiple valve repairs at more than

Controversies

one location (e.g., femoral, popliteal, tibial, profunda femoris) would yield better clinical and hemodynamic outcome has long been a subject of controversy. Clinical experience indicates that a single valve repair at the femoral location provides durable clinical relief in about 70% (cumulative) of patients; however, hemodynamic improvement is often only partial, though signiﬁcant. Multivariate analysis of our valve reconstruction database (all cases) showed no advantage for multiple reconstructions.8 The situation may be different with regard to a speciﬁc post-thrombotic subset. Eriksson and Almgren68 ﬁrst drew attention to the increasing outﬂow function assumed by the profunda femoris in post-thrombotic disease. They performed profunda femoris valve repairs with good clinical results. The association of profunda femoris reﬂux adversely affects ambulatory venous pressure and clinical outcome after femoral valve reconstructions.12 In a selected series from our center combined femoral and profunda femoris repairs were shown to yield 65% cumulative ulcer healing at 5 years.51

Preferred site for valve repair The popliteal valve is often considered the “gatekeeper” of the calf venous pump. Attractive in theory, there is no evidence for this concept in hemodynamic data7 or from any comparative clinical series. In our own material,8 femoral repairs had a better clinical outcome than repairs at other sites, including the popliteal location. All valve repairs show a steady functional deterioration with duplex over time.8 One notable exception is a subset of posterior tibial valve repairs that were remarkably durable in function and clinical outcome for unknown reasons beyond 5 years of follow-up. This ﬁnding has not been tested by others. The femoral valve showed less deterioration than other repair locations including the popliteal.

Choice of technique A direct valve repair technique should be used ﬁrst if the valve structure is repairable. Indirect techniques such as axillary vein transfer should be used only if the direct repair fails or is not feasible. Internal valvuloplasty is a precise direct technique with proven long-term efﬁcacy. Even though internal valvuloplasty too deteriorates in duplex competence over time, it decays less in relative terms than other valve reconstruction techniques.8 However, there was no difference in clinical outcome between the various valve reconstruction techniques including those that deteriorated more or less rapidly. Clinical outcome appears to be roughly similar in a number of other clinical series utilizing various different direct valve reconstruction techniques. Internal valvuloplasty is a time-consuming technique and may not be

479

feasible in small-caliber veins. External or transcommissural techniques are fast and can be carried out in small-caliber veins; because of their speed, they will be preferred in multiple valve reconstruction or when repairing a reﬂuxive axillary vein transplant. All things being equal, the choice of technique is largely governed by personal preference and the experience gained with a certain technique. This is as it should be as there is a considerable learning curve in mastering valve reconstruction techniques.

Valve reconstruction in post-thrombotic cases Valve reconstruction in post-thrombotic veins is controversial. Many do not even consider reconstruction in this subset for fear of thrombosis. Venographic appearance can be daunting because of the presence of extensive trabeculae. In some patients, the deep veins may not visualize at all on venography, giving a “wiped out” appearance. However, almost all such cases are due to anomalous contrast ﬂow and not due to absence of deep venous elements.10 Our own experience with valve reconstruction in a large cohort of post-thrombotic cases,20,22,51 even those with trabeculated veins,10 has been surprisingly good. There is faster duplex deterioration and a lesser degree of hemodynamic improvement in postthrombotic cases than in primary disease but clinical outcome is similar. Cumulative ulcer healing in postthrombotic cases without trabeculae (n = 51) and with trabeculae (n = 59) was 69% and 61% respectively at 12 years.10 Thrombotic complications are nominal and repair loss from them is negligible with proper anticoagulation protocols. Counterintuitively, trabeculated veins appear resistant to thrombosis after surgical trauma and direct surgical intervention appears to be safe.69 Similar good clinical results have been reported by numerous other groups in post-thrombotic disease14,41,50,55–57,68,70 using a variety of valve reconstruction techniques. In contrast, Masuda and Kistner12 noted cumulative good results of 50% at 5 years and 43% at 10 years in 16 post-thrombotic cases; 14 of these utilized segment transfer technique, and axillary vein transplants were used in only two patients. Thus, these below par outcomes compared with their primary cases (73% at 10 years) could have been related to the choice of segment transfer technique rather than the post-thrombotic disease itself, as the authors themselves noted. Perrin21 also noted somewhat inferior results in post-thrombotic cases compared with primary cases, but his long-term cumulative good results in the former group was still > 50%. Valve reconstruction in advanced postthrombotic cases is a “last ditch” salvage effort. Having exhausted other forms of therapy, many are consigned to “life-long” compression therapy with persistent ulcers. Deep venous reconstruction as a salvage effort would seem to be worthwhile in this group even if the results are not quite as good as in primary disease.

480

Surgical repair of deep vein valve incompetence

Guidelines 4.15.0 of the American Venous Forum on surgical repair of deep vein valve incompetence No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.15.1 Valve reconstruction is recommended in primary valvular incompetence after less invasive therapies had failed

1

A

4.15.2 Valve reconstruction or valve transfer procedures is suggested in post-thrombotic cases after other available forms of therapy had failed

2

B

NEW DEVELOPMENTS The advent of venous stenting has resulted in a signiﬁcant change in our approach to deep venous reﬂux. It has been well known that post-thrombotic cases often had combined obstruction/reﬂux. Use of intravascular ultrasound in primary cases has revealed that an obstructive non-thrombotic iliac vein lesion (NIVL) was present in over 90% of these patients as well.71 Present as a silent lesion in over 60% of the general population, NIVL is thought to play a permissive role resulting in symptoms when additional pathology such as reﬂux, trauma, or cellulitis is superimposed. Symptoms of pain and swelling abate and about 60% of venous ulcers heal with venous stenting of NIVL even when the coincident reﬂux remains uncorrected. Venous stenting is a minimally invasive outpatient procedure. This has resulted in a paradigm shift in our treatment approach. Whether primary or postthrombotic, the obstructive component is ﬁrst corrected through stent placement. Simultaneous percutaneous laser ablation of a reﬂuxive saphenous vein may be added as well in a single stage.72 Open deep valve reconstruction will be needed only in those who do not respond to the initial less invasive approach. Valve reconstruction capability has remained restricted to very few specialty centers. Because of the much wider availability of stent technologies, patients are expected to beneﬁt in terms of greater access to effective therapy.

◆3.

4.

5.

6.

7.

●8.

9.

●10.

11.

REFERENCES ●12.

= Key primary paper ◆ = Major review article ●

13. ●1.

Kistner RL. Surgical repair of a venous valve. Straub Clin Proc 1968; 34: 41–3. ●2. Ferris EB, Kistner RL. Femoral vein reconstruction in the management of chronic venous insufﬁciency. A 14-year experience. Arch Surg 1982; 117: 1571–9.

14.

Kistner RL, Eklof B, Masuda E. Deep venous valve reconstruction. Cardiovasc Surg 1995; 3: 129–40. Neglen P, Raju S. A rational approach to detection of signiﬁcant reﬂux with duplex Doppler scanning and air plethysmography. J Vasc Surg 1993; 17: 590–5. Masuda EM, Kistner RL, Eklof B. Prospective study of duplex scanning for venous reﬂux: comparison of Valsalva and pneumatic cuff techniques in the reverse Trendelenburg and standing positions. J Vasc Surg 1994; 20: 711–20. Masuda EM, Kistner RL. Prospective comparison of duplex scanning and descending venography in the assessment of venous insufﬁciency. Am J Surg 1992; 164: 254–9. Neglen P, Egger III JF, Raju S. Hemodynamic and clinical impact of venous reﬂux parameters. J Vasc Surg 2004; 40: 303–19. Raju S, Fredericks RK, Neglen PN, Bass JD. Durability of venous valve reconstruction techniques for “primary” and postthrombotic reﬂux. J Vasc Surg 1996; 23: 357–66; discussion 366–7. Neglen P, Raju S. A comparison between descending phlebography and duplex Doppler investigation in the evaluation of reﬂux in chronic venous insufﬁciency: a challenge to phlebography as the “gold standard”. J Vasc Surg 1992; 16: 687–93. Raju S, Neglen P, Doolittle J, Meydrech EF. Axillary vein transfer in trabeculated postthrombotic veins. J Vasc Surg 1999; 29: 1050–62; discussion 1062–4. de Souza GG, Pereira AH, Costa LF, et al. Hemodynamic results of femoral vein valve repair. Cardiovasc Surg 2001; 9: 127–32. Masuda EM, Kistner RL. Long-term results of venous valve reconstruction: a four- to twenty-one-year follow-up. J Vasc Surg 1994; 19: 391–403. Gillespie DL, Cordts PR, Hartono C, et al. The role of air plethysmography in monitoring results of venous surgery. J Vasc Surg 1992; 16: 674–8. Bry JD, Muto PA, O’Donnell TF, Isaacson LA. The clinical and hemodynamic results after axillary-to-popliteal vein valve transplantation. J Vasc Surg 1995; 21: 110–19.

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15. Sakuda H, Nakaema M, Matsubara S, et al. Air plethysmographic assessment of external valvuloplasty in patients with valvular incompetence of the saphenous and deep veins. J Vasc Surg 2002; 36: 922–7. 16. Abidia A, Hardy SC. Surgery for deep venous incompetence. Cochrane Database Syst Rev 2000; Issue 3. Art No. CD001097. 17. Belcaro G, Nicolaides AN, Ricci A, et al. External femoral vein valvuloplasty with limited anterior plication (LAP): a 10-year randomized, follow-up study. Angiology 1999; 50: 531–6. 18. Comerota AJ. Quality-of-life improvement using thrombolytic therapy for iliofemoral deep venous thrombosis. Rev Cardiovasc Med 2002; 3 Suppl 2: S61–7. 19. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufﬁciency (CIVIQ). Qual Life Res 1996; 5: 539–54. ◆20. Raju S, Hardy JD. Technical options in venous valve reconstruction. Am J Surg 1997; 173: 301–7. 21. Perrin M. Reconstructive surgery for deep venous reﬂux: a report on 144 cases. Cardiovasc Surg. 2000; 8: 246–55. ●22. Raju S, Fredericks RK, Hudson CA, et al. Venous valve station changes in “primary” and postthrombotic reﬂux: an analysis of 149 cases. Ann Vasc Surg 2000; 14: 193–9. 23. Raju S. Venous insufﬁciency of the lower limb and stasis ulceration. Changing concepts and management. Ann Surg 1983; 197: 688–97. 24. Meissner MH, Manzo RA, Bergelin RO, et al. Deep venous insufﬁciency: the relationship between lysis and subsequent reﬂux. J Vasc Surg 1993; 18: 596–605; discussion 606–8. 25. Caps MT, Manzo RA, Bergelin RO, et al. Venous valvular reﬂux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg 1995; 22: 524–31. 26. Killewich LA, Bedford GR, Beach KW, Strandness DE Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vasc Surg 1989; 9: 89–97. 27. Meissner MH, Caps MT, Zierler BK, et al. Deep venous thrombosis and superﬁcial venous reﬂux. J Vasc Surg 2000; 32: 48–56. ●28. Raju S, Fredericks R. Valve reconstruction procedures for nonobstructive venous insufﬁciency: rationale, techniques, and results in 107 procedures with two- to eight-year follow-up. J Vasc Surg 1988; 7: 301–10. 29. Sottiurai VS. Technique in direct venous valvuloplasty. J Vasc Surg 1988; 8: 646–8. 30. Tripathi R, Ktenidis KD. Trapdoor internal valvuloplasty: a new technique for primary deep vein valvular incompetence. Eur J Vasc Endovasc Surg 2001; 22: 86–9. ●31. Kistner RL. Surgical technique of external valve repair. Straub Found Proc 1990; 55: 15–16. 32. Wu ZQ. Valvuloplasty and ﬁxation of the femoral vein for valvular incompetence of deep veins of the lower extremity. Zhonghua Wai Ke Za Zhi 1991; 29: 110–12, 143.

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Gloviczki P, Merrell SW, Bower TC. Femoral vein valve repair under direct vision without venotomy: a modiﬁed technique with use of angioscopy. J Vasc Surg 1991; 14: 645–8. Jing ZP, Cao GS, Zhou YI. Superﬁcial femoral vein valvuloplasty under direct angioscopic vision. Zhonghua Wai Ke Za Zhi 1994; 32: 376–9. Hoshino S, Satakawa H, Iwaya F, et al. [External valvuloplasty under preoperative angioscopic control]. Phlebologie 1993; 46: 521–9. Welch HJ, McLaughlin RL, O’Donnell TF Jr. Femoral vein valvuloplasty: intraoperative angioscopic evaluation and hemodynamic improvement. J Vasc Surg 1992; 16: 694–700. Raju S, Berry MA, Neglen P. Transcommissural valvuloplasty: technique and results. J Vasc Surg 2000; 32: 969–76. Hallberg D. A method for repairing incompetent valves in deep veins. Acta Chir Scand 1972; 138: 143–5. Jessup G, Lane RJ. Repair of incompetent venous valves: a new technique. J Vasc Surg 1988; 8: 569–75. Belcaro G, Nicolaides AN, Errichi BM, et al. Expanded polytetraﬂuoroethylene in external valvuloplasty for superﬁcial or deep vein incompetence. Angiology 2000; 51 (8 Pt 2): S27–32. Akesson H, Risberg B, Bjorgell O. External support valvuloplasty in the treatment of chronic deep vein incompetence of the legs. Int Angiol 1999; 18: 233–8. Guarnera G, Furgiuele S, Mascellari L, et al. External banding valvuloplasty of the superﬁcial femoral vein in the treatment of recurrent varicose veins. Int Angiol 1998; 17: 268–71. Camilli S, Guarnera G. External banding valvuloplasty of the superﬁcial femoral vein in the treatment of primary deep valvular incompetence. Int Angiol 1994; 13: 218–22. Wilson NM, Rutt DL, Browse NL. In situ venous valve construction. Br J Surg 1991; 78: 595–600. Psathakis ND. The substitute “valve” operation by technique II in patients with postthrombotic syndrome. Surgery 1984; 95: 542–8. Magomedov MG, Diuzhikov AA, Ramazanov MR. Surgical method for correction of absolute valvular insufﬁciency in post-thrombophlebotic disease of the lower limbs. Angiol Sosud Khir 2005; 11: 77–82. Plagnol P, Ciostek P, Grimaud JP, Prokopowicz SC. Autogenous valve reconstruction technique for postthrombotic reﬂux. Ann Vasc Surg 1999; 13: 339–42. Labas P, Svec R. Long-term results of anti-reﬂux surgery of the popliteal vein. Rozhl Chir 1997; 76: 502–5. Jones JW, Elliott F, Kerstein MD. Triangular venous valvuloplasty. A new procedure for correction of venous incompetence. Arch Surg 1982; 117: 1250–1. Maleti O, Lugli M. Neovalve construction in postthrombotic syndrome. J Vasc Surg 2006; 43: 794–9. Raju S, Fountain T, Neglen P, Devidas M. Axial transformation of the profunda femoris vein. J Vasc Surg 1998; 27: 651–9.

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52. Cardon JM, Cardon A, Joyeux A, et al. Use of ipsilateral greater saphenous vein as a valved transplant in management of post-thrombotic deep venous insufﬁciency: long-term results. Ann Vasc Surg 1999; 13: 284–9. 53. Johnson ND, Queral LA, Flinn WR, et al. Late objective assessment of venous value surgery. Arch Surg 1981; 116: 1461–6. 54. Raju S. Discussion after: Late objective assessment of venous value surgery. Arch Surg 1981; 116: 1466. 55. Taheri SA, Lazar L, Elias S, et al. Surgical treatment of postphlebitic syndrome with vein valve transplant. Am J Surg 1982; 144: 221–4. 56. Taheri SA, Elias SM, Yacobucci GN, et al. Indications and results of vein valve transplant. J Cardiovasc Surg (Torino) 1986; 27: 163–8. 57. Nash T. Long term results of vein valve transplants placed in the popliteal vein for intractable post-phlebitic venous ulcers and pre-ulcer skin changes. J Cardiovasc Surg (Torino) 1988; 29: 712–16. 58. Rai DB, Lerner R. Chronic venous insufﬁciency disease: its etiology. A new technique for vein valve transplantation. Int Surg 1991; 76: 174–8. 59. Jamieson WG, Chinnick B. Clinical results of deep venous valvular repair for chronic venous insufﬁciency. Can J Surg 1997; 40: 294–9. ●60. Dalsing MC, Raju S, Wakeﬁeld TW, Taheri S. A multicenter, phase I evaluation of cryopreserved venous valve allografts for the treatment of chronic deep venous insufﬁciency. J Vasc Surg 1999; 30: 854–64. ◆61. Kistner RL, Masuda E, Lurie F. Valvuloplasty in primary venous insufﬁciency: development, performance and long term results. In: Bergan JJ, ed. The Vein Book. New York: Elsevier, 2006: 579–92. 62. Raju S, Perry JT. The response of venous valvular

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endothelium to autotransplantation and in vitro preservation. Surgery 1983; 94: 770–5. Tripathi R, Sieunarine K, Abbas M, Durrani N. Deep venous valve reconstruction for non-healing leg ulcers: techniques and results. ANZ J Surg 2004; 74: 34–9. Sottiurai VS. Surgical correction of recurrent venous ulcer. J Cardiovasc Surg (Torino) 1991; 32: 104–9. Wang SM, Hu ZJ, Li SQ, et al. Effect of external valvuloplasty of the deep vein in the treatment of chronic venous insufﬁciency of the lower extremity. J Vasc Surg 2006; 44: 1296–300. Huse JB, Nabseth DC, Bush HL Jr, et al. Direct venous surgery for venous valvular insufﬁciency of the lower extremity. Arch Surg 1983; 118: 719–23. Raju S, Neglén P, Carr-White PA, et al. Ambulatory venous hypertension: component analysis in 373 limbs. Vasc Surg 1999; 33: 257–67. Eriksson I, Almgren B. Inﬂuence of the profunda femoris vein on venous hemodynamics of the limb. Experience from thirty-one deep vein valve reconstructions. J Vasc Surg 1986; 4: 390–5. Puggioni A, Kistner RL, Eklof B, Lurie F. Surgical disobliteration of postthrombotic deep veins – endophlebectomy – is feasible. J Vasc Surg 2004; 39: 1048–52; discussion 52. Taheri SA, Heffner R, Meenaghan MA, et al. Vein valve transplant. Indications and results. Int Angiol 1985; 4: 425–8. Raju S, Neglen P. High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 2006; 44: 136–43; discussion 144. Neglén P, Hollis KC, Raju S. Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 2006; 44: 828–33.

43 Artificial venous valves MICHAEL C. DALSING Introduction Data

483 483

INTRODUCTION The need for an artiﬁcial venous valve becomes evident when no other option exists or has been successful in managing the venous reﬂux associated with chronic deep venous valvular insufﬁciency. External compression can successfully heal venous ulceration but the recurrence rate is 70–100% in non-compliant patients and 30–40% in those faithfully compliant in its use.1 The proper diagnosis of superﬁcial, perforator, and deep venous disease has been well discussed and sets the stage for appropriate interventions. Isolated superﬁcial or perforator disease has been observed to cause the advanced stages of venous disease. However, in approximately two-thirds of advanced stage disease, the deep system is insufﬁcient alone or in association with superﬁcial and/or perforator disease.2,3 Removal of pathologic superﬁcial and/or perforator venous incompetence can eliminate the majority of venous reﬂux in such patients.4,5 In about 30% of patients with associated primary deep venous insufﬁciency and 70% of those with associated postthrombotic syndrome, recurrent ulceration will occur and emphasizes the impact of the deep system in the adequate control of venous hypertension in such patients.4 Venous obstruction was once thought a minor factor (2–20%) in the pathophysiology of deep venous disease.6,7 This teaching is being questioned by at least one group of investigators.8 Obstructive deep disease is being sought and treated aggressively; nevertheless, deep venous reﬂux must be dealt with in patients with unresolved symptoms. The majority of such patients will have a lower extremity venous valve available for repair or a valve for transplantation or transposition. Such repairs are not universally successful, with valvuloplasty having the best track record (~ 70% long-term success); the other repairs realize a less impressive patency and clinical success rate of 40–50% over a 3–5 year period of follow-up.6,7,9–11 In that ﬁnite number of patients remaining with life style-limiting

Conclusions References

488 489

symptoms (generally ulceration) not relieved by all other measures, an artiﬁcial venous valve is critical. A dictionary deﬁnition for “artiﬁcial” is “not arising from natural growth.” Therefore, in this manuscript, an artiﬁcial venous valve is any venous valve substitute not originally a “de novo” autologous venous valve. Therefore, all standard options mentioned above are not further considered in this chapter. All other options are considered and fall into two general categories: nonautologous and autologous options. Percutaneously placed valve/stent designs have been investigated and will be noted.

DATA Non-autologous artificial venous valves Many potential off-the-shelf venous valve substitutes have been studied over the years and have been made of allograft, xenograft, or synthetic tissue. Most have performed poorly in animal studies and, therefore, have not been pursued further. Unless otherwise speciﬁcally stated, all allograft and xenograft venous valve transplants consist of a segment of vein in which lay a venous valve. Fresh canine allograft transplants ignoring blood compatibility concerns have fared poorly. Even providing an initial 24 hours of full systemic anticoagulation, only 7% of 14 transplants were patent and none competent during a 4 week study.12 Supported by a continuously functioning distal arteriovenous ﬁstula (dAVF), glutaraldehyde-preserved canine allograft transplants remained patent (80%) but rarely competent (25%) during a 7 week study.13 One interesting allograft allowed prolonged storage by virtue of lyophilization (freeze drying). Following rehydration, the mechanical properties of the valve were essentially the same as a native valve.14 The valve cusps could withstand at least 350 mmHg

484

Artiﬁcial venous valves

retrograde pressure without insufﬁciency and the valve closure time was 0.31 ± 0.03 seconds. This allograft has not advanced to either animal or clinical trials. One allograft valve substitute has reached clinical trial. The initial animal experiment involved dog erythrocyte antigen (DEA)-matched and cryopreserved allografts transplanted into recipient dogs with pre-established lower limb venous insufﬁciency. Following ligation of a high-ﬂow dAVF which was allowed to function for 3–6 weeks, all four transplants remained patent and competent for a subsequent 3 weeks. The animals were killed and the histologic evaluation demonstrated what appeared to be endothelial cells present on the luminal surface in addition to thrombus-free cusp sinuses.15 These promising data and some fortunate aspects of the commercially available cryopreserved valve allograft (cryovalve; CryoLife, Inc, Kennesaw, GA, USA) allowed an initial multicenter feasibility study.16 Unfortunately, this study suggested that a low-grade rejection was negatively affecting valve function over time. The primary patency and valve competency rate at 6 months was 67% and 56% respectively. A 2 year clinical study of 27 cryovalves reported a disappointing 27% patency and competency rate.17 These two negative studies demonstrated that a standard cryovalve does not function sufﬁciently well over time to be considered a reliable valve substitute in the treatment of patients with chronic deep venous insufﬁciency. The observation that a low-grade chronic rejection might explain the failures noted in the above-mentioned cryovalve studies suggests that ridding the cryovalve of immunogenic cells might provide an answer to the failure noted. Furthermore, clinical experience demonstrated that a cryopreserved and decellularized allograft, when used as an arteriovenous ﬁstula conduit, incited very little antigenic response as determined by panel reactive antibody (PRA) testing and appeared to function well over time.18 Similarly, this tissue demonstrated a lack of antigenic response and acceptable valve function when used as a heart valve substitute.19 However, a decellularized external jugular valve allograft, when implanted into the venous system of a recipient sheep without supportive systemic anticoagulation, demonstrated a 100% (four of four tested) occlusion rate at 6 weeks.20 Although the only animal study reported to date using a decellularized venous valve allograft in the venous system had a negative result, clinical data using this material in other settings would support the need for further study. Such studies have not yet taken place to my knowledge. A cryopreserved superﬁcial femoral vein containing valve allograft (cryovalve) remains available from CryoLife. It will maintain valve competency when tested by 125 mmHg of retrograde valve pressure. It may require primary valvuloplasty post-thaw for optimal competency at the time of implant.17 Without modiﬁcation, it does not perform adequately to be recommended for the long-term treatment of patients with chronic deep venous

insufﬁciency but, if one could modify the apparent rejection issues experienced by the valve, it might be useful.16,17 The immunosuppression would have to be minimal, well-tolerated, and not risk systemic infection since the standard patient with a venous ulcer is not systemically infected but certainly does possess an obvious portal for infection. Cytotoxic T cells to foreign endothelium may be the primary cause of rejection such that azathioprine or cyclosporine A would be potential immunosuppressive agents to consider. There are no clinical trials available investigating such a modiﬁed protocol for the use of the cryovalve in the treatment of patients with chronic deep venous insufﬁciency. Xenograft transplantation was initially investigated in a somewhat reverse fashion in that human tissue was used as the valve material and implanted into an animal model. Frozen and cleaned human umbilical vein was ﬁtted over an aluminum mandrel and ﬁxed with glutaraldehyde to construct a bicuspid valve for implantation.21 All 10 transplants into the canine model failed in 3 days, demonstrating neither patency nor competence. Glutaraldehyde-preserved bovine tissues have been used as human valve substitutes for cardiac surgery with success and the technology exists to construct glutaraldehyde-preserved bovine venous valves of appropriate size for use in the human lower extremity. A percutaneously placed glutaraldehyde-preserved bovine venous valve substitute implanted in a swine model demonstrated acceptable early results.22 The xenograft was patent and competent at 2 weeks in the three surviving animals. These and other unpublished data were sufﬁciently compelling to initiate human trials. Early thrombosis in the clinical setting resulted in a streamlined design construction, but the new design obviously did not solve the clinical problem since the parent venture company is no longer in existence. The most recent venture into the use of xenograft tissue also uses a non-vascular tissue with which to construct the valve substitute. A bioprosthetic, bicuspid, square, stentbased venous valve has been developed and percutaneously placed in the external jugular vein of sheep in a feasibility study.23 The valve was made of processed small intestinal submucosa (SIS; essentially collagen with remaining growth factors) stretched between a square metal frame with a slit cut in the middle of the SIS sheet to form the valve opening. The square metal frame bends with slit up to form relative cusps when placed in the venous system. The valve was resistant to thrombosis and did become repopulated with recipient endothelial cells after implantation.23,24 Placed in the sheep external jugular vein it demonstrated an 88% patency and competency rate; however, tilting led to occlusion or valve insufﬁciency in three animals.23 A change in the metal cage aimed at preventing misalignment within the vein was tested; six of eight valves were competent at 5 weeks.25 A third design change has taken place to improve the venous hemodynamics around the valve cusps and thereby to prevent

Data 485

cusp thickening. A recent report suggests that the SIS may ultimately experience ﬁbrosis in the clinical arena and, therefore, a change in material used for the valve construction is being investigated.26 Completely synthetic designs have also been investigated. Using the same aluminum rod design to fashion a bicuspid valve as that noted in the umbilical vein experiment, liquid pellethane valves were made. All 10 canine implants experienced a thrombotic occlusion in 8 days.21 Platinum- or pyrite-carbon-covered titanium, centerhinged, bileaﬂet valves have been implanted into the femoral vein of three dogs with a reported 100% patency and competency at approximately 3 months of followup.27 However at 2 years, the valves were rendered nonfunctional by extensive neointimal hyperplastic ingrowth.28 Although a long-term negative study in the canine model, early results were quite promising for such a completely non-autologous, metal valve design. Therefore, the results do hold some promise that modiﬁcations could extend the life of the valve sufﬁciently for clinical use.

Autologous artificial venous valves A venous valve can be made by invaginating a length of vein into itself in the fashion of Eiseman and Malette.29 The basic technique intussuscepts a segment of vein into itself with an appropriate bicuspid valve made by two sutures placed at 180° from each other to hold the inner vein wall in the correct position (Fig. 43.1).29,30 The base tissue is autologous vein, but the valve structure is artiﬁcial since the vein wall is not a natural valve cusp. In experimental studies, operative systemic heparin to therapeutic levels was administered, but no long-term anticoagulation was provided. The short-term patency was excellent and 90–100% of valves were competent at physiologic pressures. The valve is thicker than a native valve on gross and histologic study.29 When transplanted into the femoral vein of a chronic lower limb deep venous insufﬁciency canine model, the 90% venous reﬁll time was modestly improved but not the venous ﬁlling time, suggesting that the valve was not as hemodynamically responsive as a native valve.29 A modiﬁcation of this valve

Figure 43.1 A means of constructing the Eiseman–Malette valve.

involved thinning the adventitia and part of the media to result in a thinner valve cusp after intussusception. This design was investigated experimentally in the canine model.31 The valve closed with a retrograde pressure of only 3–5 cm of water and opened rapidly with minimal antegrade pressures (< 3 cm of water). Furthermore, it could withstand physiologic pressure without reﬂux. However, a thin layer of thrombus formed along the cusp wall, resulting in early valve incompetence. These studies suggested that the invagination method of constructing a venous valve from a length of autologous vein could function as a native valve substitute tempered with the knowledge that these valves may be more thrombosis prone and possibly less hemodynamically responsive than a native valve. No clinical trials have blossomed from these experimental studies possibly because a signiﬁcant length of vein is required for its construction and patients with chronic venous disease often have little to spare. Repopulating a decellularized external vein containing valve allograft with recipient smooth muscle cells and endothelial cells would make for a transplant which is essentially autologous with only a remaining allograft infrastructure of non-viable extracellular matrix materials. One author has done this experiment in a sheep model with excellent results.20 The seeded valve autologous/ allograft was transplanted into the external jugular vein of the sheep that provided the cells for seeding. Even without chronic anticoagulation, nine of 12 seeded transplants (75%) were patent and competent at 12 weeks. One transplant had occluded and two others demonstrated frozen valve cusps from neointimal ingrowth.20 The technique seems promising and outperformed allograft valves without seeding (100% failure in 6 weeks). However, the seeded transplants did not fare as well as the eight autografts since the autografts demonstrated a 100% patency and competency rate at 6 weeks. This promising experimental valve design has not been evaluated in the clinical situation. Several clinical studies report the use of autologous venous tissue to make venous valve cusps. It is my personal feeling that this approach sprang for an intraoperative need for a valve in a situation where preoperatively the presence of an autogenous valve was expected but at operation there was none present. The impromptu solution worked and, therefore, became a viable option in other patients devoid of more standard options. Raju and Hardy32 have a small series of patients who received a de novo valve made of autologous vein. The procedures involved the use of a piece of saphenous vein, a tributary of the saphenous vein, or the axillary vein as the donor valve cusp tissue. Semilunar cusps were fashioned from the donor vein after trimming away the adventitia and part of the media. The thinned vein was sutured into the recipient vein with the non-endothelial surface directed toward the lumen to decrease the risk of thrombosis.32 Five of seven patients (71%) healed their venous ulcers in less than 4 months without recurrence

486

Artiﬁcial venous valves

during 15–24 months of follow-up. Two others healed after 1 year but one required a skin graft. There was no associated mortality or signiﬁcant complications noted following these repairs. The ﬁne clinical results reported in this small series have not been substantiated by other investigators as yet. Invaginating a stump of the long saphenous vein into the femoral vein and then fashioning a bicuspid valve by tacking the invaginated end to the opposite side of the femoral vein has been described.33 The opening in the femoral vein at the site of saphenous invagination was closed along its length to reconstruct a closed, circular femoral vein. Both experimental and clinical results have been reported. Nineteen of 20 clinical reconstructions were reported patent and competent at a mean of 10 months. One valve demonstrated reﬂux from what was thought a poor reconstruction owing to insufﬁcient size of the invaginated saphenous stump. All ulcers healed within 1–6 months and no recurrences were reported. There were no signiﬁcant complications reported or mortality in this small series. The invagination of an adventitial surface into the venous lumen is concerning, but a concern not substantiated by the excellent results reported. No collaborative study has been reported to date. Most recently, an Italian vascular surgeon34 has reported a technique for constructing a bicuspid or monocusp venous valve by dissecting the intimal/medial wall of the thickened post-thrombotic vein to form the cusp(s). The technique of delicately cutting the postphlebitic vein into two sheets is shown in Fig. 43.2. Often, an ophthalmic knife is used to divide the vein wall into two sheets to fashion the valve cusps. The initial seven cases did quite well.34 A more robust report was given at a American Venous Forum meeting in 2005,35 with follow-up in

Figure 43.2 The Italian neovalve is made by cutting the postthrombotic wall into two sleeves to form bicuspid valves in the case shown. A probe holds one of the leaﬂets open for better visualization.

2006.36 Eighteen venous valves were constructed in 16 patients with recurrent or non-healing venous ulcers to treat chronic deep venous insufﬁciency due to the postthrombotic process. The patients received anticoagulation for 6 months. Early thrombosis below the valve occurred in two patients and there was one late occlusion shortly after starting oral contraceptives. Therefore, 83.3% of treated segments remained primarily patent with signiﬁcantly improved duplex and air plethysmographic results at a mean 22 months of follow-up; 88.8% of ulcers healed at a median of 12 weeks without recurrences noted.35 There was no associated mortality. This technique certainly seems promising if others can duplicate these impressive results.

Percutaneous designs: the artificial components Our personal experience was of using a Z-type stent with autologous vein containing valve lining the entire lumen of the metal exoskeleton. Slight oversizing of the diameter of the stent to that of the recipient vein appeared to be the best design for stable positioning and for valve function.37 The addition of metal barbs to prevent migration also added trauma to the vein wall and negatively affected transplant patency.37 The conﬁguration of the Z-stent allows for a moderate expansion in the area of the valve cusps, hopefully providing an area for valve sinus function that appears important to proper valve cleansing considered essential for long-term function.38 Rejection issues were not of concern since all the tissue exposed to blood ﬂow was autologous. No metal was exposed since the vein overlapped the ends of the metal stent prior to implantation (Fig. 43.3) and, therefore, a metal/ endothelial reaction was not introduced. However, the

Figure 43.3 The vein ends overlap the metallic struts so that there is no exposed metal at the time of implantation.

Data 487

presence of the metal exoskeleton did lead to local scarring and thrombus formation in the non-perfused native vein containing the valve/stent (Fig. 43.4a,b). Ultimately, the presence of a rigid metal cage could introduce unexpected compliance issues which may negatively affect patency or valve function by virtue of scarring external to the enclosed valved vein segment per se. Using a different self-expanding stent (Wallstent, Schneider, Inc., Minneapolis, MN, USA), the researcher attached an autologous valve-bearing segment of vein to its midsection with portions of the metal stent protruding at each end. Overexpansion held the stent/valve device in place. At 1 week in a canine study, non-occlusive thrombus lined the exposed metal struts on the downstream end of the transplant in all ﬁve animals.39 The animals were anticoagulated for the entire ﬁrst week of the

(a)

(b) Figure 43.4 (a) This post-implant radiograph demonstrates some narrowing at the site of implantation. (b) This was conﬁrmed at the time of explant as local thrombus formation between the valve/stent exterior and native valve interior (area within which the valve/stent lays) with scarring.

study. The donor valve and vein wall were normal in appearance and function during the study, suggesting that the exposed metal was of concern. At 6 weeks, all valves (n = 6) were patent and ﬁve were competent by the manual strip test. These valves/stents were now fully incorporated without thrombus formation present. The one incompetent valve appeared to have been recanalized by multiple small channels, suggesting that the threat of thrombus is present until full incorporation. This makes it very desirable to minimize clot formation as much as possible and, since the exposed metal is where clot seemed to invariably form, it would appear that the less exposed metal the better. If one views the histologic images, the vein’s wall is thickened with metal struts impeded within it at ﬁnal healing. This would imply that, to incorporate the metal struts in the venous system, a hyperplastic response of some source does take place. This could ultimately affect long-term function as well. Nevertheless, the early animal results are promising. No clinical paper has been published with this valve/stent design to date. A much more challenging arrangement was studied by Boudjemline and his associates.40 A glutaraldehyde xenograft valve, with inherent challenges to patency and competence noted above when not mounted within a stent, was secured to a balloon-expandable stent for percutaneous deployment. This valve containing metal stent was implanted into the inferior vena cava, a high ﬂow and therefore more favorable circuit than the femoral system, but the results were poor with all six implants occluded at 2 months.40 Since all were occluded at explant, one cannot be certain where the thrombotic process began and, therefore, what components of the design were most detrimental to functional venous incorporation. Certainly, the presence of xenograft material, any exposed metal, a compliance mismatch or possibly the trauma of balloon expansion either to the recipient vein wall or to the donor valve could have been factors in the poor outcome. Probably, each factor contributed to some degree, and this particular valve/stent arrangement is unlikely to be the focus of investigation in the near future. Percutaneously place valve/stents reaching clinical trials have allowed some observations that might be helpful for future valve/stent designs. As mentioned above, the glutaraldehyde-preserved xenograft which had reached clinical trial was being continually redesigned to decrease the bulk of xenograft present and to streamline it.22 The optimal design was never reached or at least reported in the literature to my knowledge. The sequence of reports would suggest that the less foreign material exposed to the venous circulation the better, whether xenograft or metal. Thrombosis, ﬁbrosis, and scarring may all have been active in the short term in the analysis of this valve/stent’s function. The “Portland” (or SIS) valve uses a minimum of metallic exoskeleton, when compared with the previously mentioned designs, with promising early results.23 However, several design changes have taken place; ﬁrst, to

488

Artiﬁcial venous valves

(a)

Figure 43.5 An autologous valve-containing venous segment has been attached by ﬁne prolene sutures to the unique metal exoskeleton design by Pavcnik and colleagues.25,26

aid in proper centering of the valve, which resulted in an increase in exposed metal components. These changes seemed to have been tolerated well in animal experimentation.25 A ﬁnding of cusp thickening suggested that an improvement could be realized by lengthening the valve cusps, thereby changing the ﬂow hemodynamics to improve self-cleansing and realize less turbulent ﬂow. However, more recent reports note that the SIS used to construct the valve cusps was experiencing ﬁbrosis in the clinical arena.26 The experimental use of an autologous valve-containing venous segment on a unique metal stent is now being investigated (Fig. 43.5). At 3 months, the valve will open with a normal gross appearance in vivo (Fig. 43.6a) and in vitro (Fig. 43.6b). One will have to wait to see what new information this experimental path will provide. The ﬁeld of endovascular treatment for chronic deep venous valvular disease is just beginning but some lessons have been learned. Autologous vein valves function best in the venous system to date. The presence of a permanent metal exoskeleton risks an increased risk of clot formation if exposed, and of local scarring in any case, which might still affect valve function over time. This begs the question as to whether an absorbable exoskeleton never exposed to the venous circulation might not be a more promising idea. Clariﬁcation of this ﬁeld of endovenous surgery awaits those sufﬁciently adventurous to choose to follow this line of investigation.

CONCLUSIONS Autologous vein or post-thrombotic venous media/intima can be used to design a venous valve cusp, have been used clinically, and early results would suggest that such valves

(b) Figure 43.6 (a) This endoscopic image conﬁrms the opening of the autologous Pavcnik valve within stent design in vivo. (b) On explant, the valve is thin and of normal gross appearance.

function well to prevent reﬂux in the patient with endstage chronic deep venous valvular pathology of the lower extremity. All non-autologous venous valves to reach clinical investigation have failed in early or mid-term analysis. Some non-autogenous valves do hold promise based only on animal experimentation or unrelated clinical uses. The quest for a percutaneous option is active and early studies would suggest that autologous venous valves are preferred in addition to as little retained or exposed metal components as possible. In the ﬁnal analysis, no option presented in this review is an equivalent substitute for a well-functioning native venous valve in the treatment of chronic deep venous valvular incompetence. For those unfortunate individuals who require surgical intervention to treat signiﬁcant life style- or limb-threatening venous reﬂux and have no standard option available, use of one of the non-standard but autologous options reported above may be reasonable. The search continues for a purely off-the-shelf venous valve alternative. Percutaneous options are also being actively sought but as yet have not demonstrated sustained clinical success.

References 489

Guidelines 4.16.0. of the American Venous Forum on artiﬁcial venous valves No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.16.1 For patients with venous ulcer and isolated deep vein valvular incompetence, who fail standard treatment modalities, we suggest the procedure of venous valve leaﬂet construction from autologous vein

2

C

4.16.2 We recommend that non-autologous venous valve substitutes currently not be used in the treatment of patients with symptomatic chronic deep venous insufﬁciency

1

C

REFERENCES ●

= Key primary paper

1. Erickson CA, Lanza DJ, Karp DL, et al. Healing of venous ulcers in an ambulatory care program: the roles of chronic venous insufﬁciency and patient compliance. J Vasc Surg 1995; 22: 629–36. 2. Labropoulos N, Leon M, Geroulakos G, et al. Venous hemodynamic abnormalities in patients with leg ulceration. Am J Surg 1995; 169: 572–4. 3. Hanrahan LM, Araki CT, Rodriguez AA, et al. Distribution of valvular incompetence in patients with venous stasis ulceration. J Vasc Surg 1991; 13: 805–11. 4. Kalra M, Gloviczki P. Surgical treatment of venous ulcers: role of subfascial endoscopic perforator vein ligation. Surg Clin North Am 2003; 83: 671–705. 5. Adam DJ, Bello M, Hartshorne T, London NJ. Role of superﬁcial venous surgery in patients with combined superﬁcial and segmental deep venous reﬂux. Eur J Endovasc Surg 2003; 25: 469–72. 6. O’Donnell TF. Chronic venous insufﬁciency: an overview of epidemiology, classiﬁcation, and anatomic considerations. Semin Vasc Surg 1988; 1: 60–5. 7. Eklöf BG, Kistner RL, Masuda EM. Venous bypass and valve reconstruction: long-term efﬁcacy. Vasc Med 1998; 3: 157–64. 8. Raju S, Neglen P. High prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. J Vasc Surg 2006; 44: 136–43. 9. Masuda EM, Kistner RL. Long-term results of venous valve reconstruction: a four to twenty-one year follow-up. J Vasc Surg 1994; 19: 391–403. 10. Raju S, Fredericks RK, Neglen PN, et al. Durability of venous valve reconstruction techniques for “primary” and postthrombotic reﬂux. J Vasc Surg 1996; 23: 357–67.

11. Tripathi R, Ktenidis KD. Trapdoor internal valvuloplasty: a new technique for primary deep vein valvular incompetence. Eur J Vasc Endovasc Surg 2001; 22: 86–9. 12. McLachlin AD, Carroll SE, Meads GE, et al. Valve replacement in dogs. Ann Surg 1965; 162: 446–52. 13. Kaya M, Grogan JB, Lentz D, et al. Glutaraldehydepreserved venous valve transplantation in the dog. J Surg Res 1988; 45: 294–7. 14. Reeves TR, Cezeaux JL, Sackman JE, et al. Mechanical characteristics of lyophilized human saphenous vein valves. J Vasc Surg 1997; 26: 823–8. 15. Burkhart HM, Fath SW, Dalsing MC, et al. Experimental repair of venous valvular insufﬁciency using a cryopreserved venous valve allograft aided by a distal arteriovenous ﬁstula. J Vasc Surg 1997; 26: 817–22. ●16. Dalsing MC, Raju S, Wakeﬁeld TW, Taheri S. A multicenter, phase I evaluation of cryopreserved venous valve allografts for the treatment of chronic deep venous insufﬁciency. J Vasc Surg 1999; 30: 854–66. ●17. Neglén P, Raju S. Venous reﬂux repair with cryopreserved vein valves. J Vasc Surg 2003; 37: 552–7. 18. Madden R, Lipkowitz G, Benedetto B, et al. Decellularized cadaver vein allografts used for hemodialysis access do not cause allosensitization or preclude kidney transplantation. Am J Kidney Dis 2002; 40: 1240–3. 19. Elkins RC, Dawson PE, Goldstein S, et al. Decellularized human valve allografts. Ann Thorac Surg 2001; 71: S428–32. 20. Teebken OE, Puschman C, Aper T, et al. Tissue-engineered bioprosthetic venous valve: a long-term study in sheep. Eur J Vasc Endovasc Surg 2003; 25: 305–12. 21. Hill R, Schmidt S, Evancho M, et al. Development of a prosthetic venous valve. J Biomed Mater Res 1985; 19: 827–32. 22. Gomez-Jorge J, Venbrux AC, Magee C. Percutaneous deployment of a valved bovine jugular vein in the swine venous system: a potential treatment for venous insufﬁciency. J Vasc Interv Radiol 2000; 11: 931–6.

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23. Pavcnik D, Uchida BT, Timmermans HA, et al. Percutaneous bioprosthetic venous valve: a long-term study in sheep. J Vasc Surg 2002; 35: 598–602. 24. Brountzos E, Pavcnik D, Timmersmans HA, et al. Remodeling of suspended small intestinal submucosa venous valve: an experimental study in sheep to assess the host cells’ origin. J Vasc Interv Radiol 2003; 14: 349–56. 25. Pavcnik D, Kaufman J, Uchida B, et al. Second-generation percutaneous bioprosthetic valve: a short-term study in sheep. J Vasc Surg 2004; 40: 1223–7. ●26. Pavcnik D. Update on venous valve replacement: long-term clinical results. Vascular 2006; 14 (Suppl 1): S106. 27. Taheri SA, Rigan D, Wels P, et al. Experimental prosthetic vein valve. Am J Surg 1988; 156: 111–14. 28. Taheri SA, Schultz RO. Experimental prosthetic vein valve. Long-term results. Angiology 1995; 46: 299–303. 29. Dalsing MC, Lalka SG, Unthank JL, et al. Venous valvular insufﬁciency: inﬂuence of a single venous valve (native and experimental). J Vasc Surg 1991; 14: 576–87. 30. Wilson NM, Rutt DL, Browse NL. In situ venous valve construction. Br J Surg 1991; 78: 595–600. 31. Rosenbloom MS, Schuler JJ, Bishara RA, et al. Early experimental experience with a surgically created, totally autogenous venous valve: a preliminary report. J Vasc Surg 1988; 7: 642–6. ●32. Raju S, Hardy JD. Technical options in venous valve reconstruction. Am J Surg 1997; 173: 301–7.

●33.

●34.

35.

36.

37.

●38.

39.

40.

Plagnol P, Ciostek P, Grimaud JP, Prokopowicz SC. Autogenous valve reconstruction technique for postthrombotic reﬂux. Ann Vasc Surg 1999; 13: 339–42. Maleti O. Venous valvular reconstruction in postthrombotic syndrome. A new technique. J Mal Vasc 2002; 27: 218–21. Maleti O, Lugli M. Neovalve construction in postthrombotic syndrome. Presented at American Venous Forum, 17th Annual Meeting, San Diego, CA, February 9–13, 2005, also J Vasc Surg 2006; 43: 794–9. Lugli M, Maleti O. The Italian neovalve: who would have thought? Presented at American Venous Forum Postgraduate Course, 18th Annual Meeting, Miami, FL, February 22, 2006. Dalsing MC, Sawchuk AP, Lalka SG, Cikrit DF. An early experience with endovascular venous valve transplantation. J Vasc Surg 1996; 24: 903–5. Lurie F. Kistner RL. Eklöf B. Kessler D. Mechanism of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg 2003; 38: 955–61 Ofenloch JC, Chen C, Hughes JD, Lumsden AB. Endoscopic venous valve transplantation with a valve-stent device. Ann Vasc Surg 1997; 11: 62–67. Boudjemline Y, Bonnet D, Sidi D, Bonhoeffer P. Is percutaneous implantation of a bovine venous valve in the inferior vena cava a reliable technique to treat chronic venous insufﬁciency syndrome? Med Sci Monitor 2004; 10: BR61–6.

44 Endovascular reconstruction for chronic iliofemoral vein obstruction PETER NEGLÉN Introduction Chronic post-thrombotic obstruction Non-thrombotic “primary” obstruction Miscellaneous etiology Symptoms Hemodynamically signiﬁcant venous obstruction Morphological venous obstruction Technique

491 491 492 492 492 493 493 495

INTRODUCTION Percutaneous endovenous stenting has emerged during the last decade as the “method of choice” for the treatment of chronic obstruction of the femoro-ilio-caval venous outﬂow. It has replaced bypass surgery as the primary treatment. Open surgery is presently used only in selected cases of failed stent procedures or reocclusion of stents. Availability of a relatively simple and effective endovenous treatment with low morbidity and mortality has also led to a reappraisal of the role of venous outﬂow obstruction in the pathophysiology of chronic venous disease (CVD). The awareness of the possible presence of iliofemoral obstruction is increasing, and consequently the venous outﬂow is now evaluated more carefully and stenting more frequently considered.

CHRONIC POST-THROMBOTIC OBSTRUCTION Poor recanalization following acute deep vein thrombosis is presently thought to be the most common cause of chronic venous blockage.1 Most symptomatic outﬂow obstruction occurs following deep vein thrombosis involving the iliac segment. It may be limited to the iliofemoral segment or contiguous from the calf to the iliac veins. Only approximately 20% of these iliac veins will completely recanalize on anticoagulation treatment, while the remaining veins recanalize only partially and develop varying degrees of obstruction and collateral formation.2,3

Complications and thrombotic events Stent outcome In-stent recurrent stenosis Clinical outcome Hemodynamic results Clinical practice guidelines References

496 497 498 498 499 500 500

In the 1960s, Cockett and his associates4–8 performed groundbreaking studies and published numerous “classic” reports on venous outﬂow obstruction, compression of the iliac veins and its relationship to thrombosis. They observed that the obstructive lesion that precipitated the thrombosis impeded its resolution and the postthrombotic perivenous ﬁbrosis appeared to develop excessively at the site of the initiating lesion. Recently, this observation has been conﬁrmed by serial spiral CTvenography studies, which showed inhibited and incomplete recanalization in the presence of an external compression, e.g., left iliac vein compression.9 This ﬁnding is of great importance, since it has been reported that 80% of limbs with iliofemoral deep vein thrombosis (DVT) have underlying extrinsic iliac compression-type lesions revealed by the same technique (67% and 84%, right and left iliofemoral veins, respectively).10 The typical post-thrombotic iliofemoral lesion often involves both common and external iliac veins with irregular stenosis or occlusions and axial, transpelvic and ascending lumbar collaterals are present. Infrequently a diffusely narrowed long segment of the iliac vein with no collateral formation is found (Fig. 44.1). We have designated this entity a “Rokitansky” stenosis, from the nineteenth century pathologist, who described the phenomenon.11 As the severe inﬂammation of the wall (phlebitis) subsides, a ﬁbrotic cylinder is formed, which impedes any collateral development and expansion of the vein. Thus, signiﬁcant outﬂow obstruction cannot be excluded because of lack of collaterals.

492

(a)

Endovascular reconstruction for chronic iliofemoral vein obstruction

(b)

Figure 44.1 Transfemoral ascending venograms. (a) The typical image of a chronically occluded post-thrombotic vein with axial and transpelvic collaterals. (b) A less frequently seen extensive iliac vein narrowing, a so-called “Rokitansky” stenosis, with a post-thrombotic perivenous ﬁbrotic cylinder, which impedes any collateral development and expansion of the vein.

(a)

(b)

(c)

Figure 44.2 Transfemoral ascending venograms. (a) Typical compression of the left common iliac vein in an elderly woman with slight ﬁlling of the ascending lumbar and internal iliac veins. (b) Distal compression of the proximal external iliac vein in the sagittal plane (see also Fig. 44.4). (c) Compression of the right distal common iliac and external iliac veins by the right iliac artery gradually traversing those veins.

NON-THROMBOTIC “PRIMARY” OBSTRUCTION Even without thrombosis, the existence of iliac vein compressions are in themselves more pathogenic than previously thought, although they have been considered a common ﬁnding of little clinical importance. Previous studies have established the frequent ﬁndings of intraluminal and varying degrees of external compression of the iliac vein in the general population (22–33%12–14 and 66–88%,6,8,15 respectively). Symptomatic nonthrombotic iliac vein obstructive lesions (NIVL) have previously been described as May–Thurner syndrome12 or Cockett’s or “iliac vein compression” syndrome.8 Why a silent lesion should suddenly become signiﬁcant in the pathophysiology is not fully understood. It has been suggested that the NIVL is a so-called permissive lesion, which does not become clinically signiﬁcant until other components of the venous circulation of the lower limb fail. Correction of a permissive lesion alone often results in cure, which may explain the surprisingly good results of venous stenting in CVD even in the presence of untreated reﬂux. Compression of the common iliac vein was seen in 36%, external iliac vein in 18%, and both sites in 46% of limbs.16 Typically, a stenosis of the left proximal common iliac vein is caused by compression of the right common iliac artery with secondary band or web formation, but may involve both the common and the external iliac veins.5,16 The prevailing concept is that iliac vein compression syndrome is clinically expressed only in the left lower extremity of predominantly young women of childbearing age. This limitation is not true since compression lesions are not uncommon in men and in elderly patients and may

involve the right limb (Fig. 44.2). In our experience, in the treatment of iliofemoral obstruction in 938 limbs in 879 patients, 53% of limbs had non-thrombotic compression lesions (deﬁned as absent history of DVT, no venographic or ultrasound ﬁndings indicating previous DVT); 40% had post-thrombotic obstruction; and 7% had a combined etiology. The ages of the patients with non-thrombotic blockage ranged from 18 to 90 years (median 54 years), 20% of the patients were men, and 25% of the symptomatic lower limbs were on the right side.16

MISCELLANEOUS ETIOLOGY Less common causes of chronic blockage of the iliocaval vein include benign or malignant tumors, retroperitoneal ﬁbrosis, iatrogenic injury, irradiation, cysts, and aneurysms. Relief of symptoms is immediate following successful stenting of malignant obstructions. The longterm outcome appears to depend largely upon the progress of the tumor.17 Iliocaval stenosis due to retroperitoneal ﬁbrosis has been successfully treated by stenting.18

SYMPTOMS Symptoms of obstruction may be any of those associated with CVD, ranging from moderate swelling and pain to discoloration and stasis ulcer. Venous outﬂow obstruction plays an important role in the clinical expression of CVD, especially of pain.19 Remaining obstruction is the principal cause of symptoms in approximately one-third of post-

Morphological venous obstruction

thrombotic limbs.1,20 The iliac vein is the common outﬂow tract of the lower extremity, and chronic obstruction of this segment appears to result in more severe symptoms than does lower segmental blockage. Femoropopliteal venous obstruction appears to be better compensated for by collateral formation than obstruction of the iliac and common femoral veins.21,22 The clinical expression is inﬂuenced by any concomitant deep or superﬁcial reﬂux. In addition, it has been demonstrated that persistent obstruction of proximal veins is associated with progressive distal vein incompetence.23,24 It is well recognized that the combination of reﬂux and obstruction results in the highest levels of venous hypertension and the most severe symptoms as compared with either alone.25,26 Negus and Cockett5 suggested that limb swelling and pain were related to the obstructive component whereas limb ulceration resulted from valve reﬂux. It has been shown that ulcers occur rarely in the presence of isolated iliofemoral obstruction (4%), but more often when obstruction is associated with reﬂux (30%).19 A substantial number of patients with CVD complain of disabling pain and swelling of the lower limbs without skin changes. It is possible that these symptoms are mainly attributable to obstruction rather than reﬂux. Five years after iliofemoral DVT treated conservatively with anticoagulation, 90% of patients suffer symptoms of CVD. Debilitating “venous claudication” is found in 15–44% of patients and venous ulcer has developed in 15% of limbs.2,27 “Venous claudication” is a dramatic condition described as an exercise-induced “bursting” pain, which requires several minutes of rest and sometimes leg elevation to achieve relief. Certainly, patients with signiﬁcant outﬂow obstruction may also have less distinct lower extremity pain and discomfort with decreased quality of life and moderate disability.

HEMODYNAMICALLY SIGNIFICANT VENOUS OBSTRUCTION The degree of hemodynamic venous obstruction depends on multiple factors, e.g., the number, location, degree of narrowing, and length of the lesions; development of collaterals; and the volume ﬂow varying at rest and during exercise. Any test to measure venous outﬂow obstruction must be identiﬁed as to whether it evaluates anatomic or functional aspects. The concept of a hemodynamically signiﬁcant vessel obstruction being a stenosis of more than 70–80% is derived from observations on the arterial system. These conclusions are probably not applicable in the venous system since there are many fundamental differences. The venous circulation is a low-pressure, lowvelocity, large-volume, and low-resistance converging vascular system (“sewage draining system”) compared with the high-pressure, high-velocity, small-volume, and high-resistance diverging arterial system (“water supply system”).28 The major obstacle in diagnosis of venous

493

obstruction is that it is presently not known at what degree a venous stenosis is hemodynamically signiﬁcant. Consequently, there is no accurate hemodynamic test (“gold standard”) available to properly assess venous outﬂow obstruction and its improvement after stenting in individual limbs. Plethysmographic outﬂow fraction determination and pressure tests (hand–foot pressure differential, hyperemia-induced dorsal foot venous pressure increase) are global hemodynamic tests and may suggest obstruction to the venous outﬂow at any anatomic site and level, but signiﬁcant blockage may exist in the presence of a normal result.29–31 Positive tests may support further investigation and intervention, but a negative test does not exclude clinically signiﬁcant venous outﬂow obstruction. Femoral venous pressure is a test for focal outﬂow obstruction. A pull-through pressure differential over a lesion or a pressure increase peripherally to the lesion with augmentation of venous inﬂow may be indicative of a signiﬁcant stenosis.4,32,33 The venous pressure is not only a function of resistance to the ﬂow, but is also dependent to a high degree on the ﬂow velocity and magnitude of volume ﬂow. It is not known to what degree the resting venous ﬂow must be increased to detect a functionally signiﬁcant stenosis, nor a method to reproduce this ﬂow rate consistently. Pressure gradients recorded in the venous system are much lower than in the arterial system and only small pressure differentials may indicate signiﬁcant obstruction. Studies suggest that a pre-stenotic pressure rise in the supine position greater than 2– 4 mmHg on provocation, a slow return to base level (> 30 s), or a gradient compared with the contralateral femoral pressure exceeding 2–5 mmHg indicate a hemodynamically signiﬁcant obstruction.4,32,33 It has been suggested that a pressure differential on exercise should be at least 5 mmHg to warrant intervention, but none of these pressure limitations has been validated. Good clinical results have been obtained treating morphologic obstruction with normal pressure ﬁndings.34 The accuracy of these tests is insufﬁcient to detect borderline obstructions. Thus, they play only a limited role in the management of obstructive disease, as a positive hemodynamic test may indicate hemodynamic signiﬁcance but a normal test does not necessarily exclude it.

MORPHOLOGICAL VENOUS OBSTRUCTION In lieu of an adequate hemodynamic test, morphological tests must be utilized. Ascending venography after injection of contrast dye in a foot vein or antegrade transfemoral venography reveals the distribution and nature of the morphologic changes, including occlusion, stenosis and the presence of collateral circulation, but is unable to show any hemodynamic impact of visualized lesions. Ascending venography usually insufﬁciently visualizes the iliac vein to permit assessment of any

494

Endovascular reconstruction for chronic iliofemoral vein obstruction

obstruction of that segment. It is mainly used today as a preoperative mapping tool to delineate the inﬂow to a post-thrombotic iliac vein segment considered for stenting. To increase accuracy, all antegrade transfemoral venograms should be performed using arterial angiographic techniques with subtraction imaging, multiple oblique projections and pressure injectors. With this technique the quality of the images will improve and the contrast medium load will be minimal. A single-plane venogram was actually considered “normal” in at least one-fourth of limbs despite the fact that intravascular ultrasound (IVUS) showed > 50% obstruction.35 Interestingly, Cockett and colleagues5,6,8 made similar observations. Venography was diagnostic in only 65% of obstructed limbs in their experience and collaterals were visualized in only 63%. It was noted that in 54% of symptomatic patients, transfemoral venography appeared “normal” with smooth contours of contrast in the iliac vein and without collaterals. The authors noted that absence of collateral formation should not negate consideration of the pathology. Although the formation of collaterals is classically regarded as a compensatory mechanism to bypass and thus alleviate an obstruction, the precise mechanism and inducement of collateral formation are unknown. Collateral circulation shown prior to stenting is often not visualized following stenting of a venous stenosis (Fig. 44.3). The ﬂow through the stent is obviously favored. Limbs with collateral formation have been shown to have a signiﬁcantly tighter stenosis than limbs with no collaterals, as measured by IVUS.36 The rate of limbs with femoral pressure increase on intra-arterial injection of papaverine was three times more common in patients with collaterals. These observations support the concept of pelvic collateralization as an indicator of obstruction and

(a)

(b)

Figure 44.3 Chronic post-thrombotic occlusion of the left iliac vein (a) before and (b) after stenting. Note the non-visualization of the pre-stent collaterals.

that collaterals poorly compensate for the blockage in symptomatic patients. Ultrasound scanning of the iliac vein is under development but still lacks the adequate accuracy to detect partial or complete chronic obstruction and to separate axial collaterals from main stem veins. It can be used to evaluate patency of inserted stents. Spiral CT imaging and magnetic resonance venography (MRV) are under evaluation and may replace transfemoral venograms for screening in the future. Like ultrasound scanning, none of these tests has been validated. Intravascular ultrasound is superior to single- and multiplane venography in detection of the extent and type of morphologic lesion of the vein.36–40 It is the most accurate test in this aspect and should be used to validate ﬁndings of other morphological imaging methods. Intravascular ultrasound has proven superior in showing intraluminal details, e.g., trabeculations and webs, which may be hidden in the contrast medium. Venous wall thickness, neointimal hyperplasia and movement can be adequately assessed. An external compression with the resulting deformity of the venous lumen or postthrombotic remodeling can be directly visualized (Figs 44.4 and 44.5). The degree of stenosis can be precisely

(a)

(b)

(c)

(d)

Figure 44.4 Images obtained by intravascular ultrasound (IVUS). The black circle inside the vein (V) represents the inserted IVUS catheter. (a) The distal inferior vena cava is compressed by a high aortic bifurcation at the conﬂuence of the iliac veins. (b) Same anatomic site post-stent. (c) The internal iliac artery is seen crossing the external iliac vein entering the pelvis. No compression of the vein. (d) Signiﬁcant compression of the external iliac vein, a distal compression lesion.

Technique 495

(a)

(b)

(c)

(d)

Figure 44.5 Images obtained by intravascular ultrasound (IVUS). The black circle inside the vein represents the inserted IVUS catheter. (a) Chronic post-thrombotic occlusion with hyperechogenic heterogeneous thrombus with poor delineation to surrounding tissue. (b) Chronic recanalized post-thrombotic vein with formation of trabeculae. (c) Acute thrombus with homogeneous clot with well-deﬁned wall. (d) Patent vein after lysis of the thrombus. The peripheral “double” contour may represent inﬂammatory edema of the vein wall or a remaining ﬁbrin layer.

through the popliteal vein is preferred. This access facilitates recanalization of occlusions from below, evaluation of the inﬂow, and precise placement of the stent caudal to the inguinal ligament when necessary. In contrast to arterial access at the thigh level, control of the venipuncture site is not a problem because of the low venous pressure and the routine use of tamponade devices (Vasoseal; Datascope Corp., Montvale, NJ, USA). After a sheath is inserted into the femoral vein, a guidewire is placed, and a transfemoral antegrade venography and IVUS are performed. The extent and degree of obstruction are measured by IVUS (Fig. 44.4). Partial obstruction of the post-thrombotic iliofemoral vein is usually fairly simple to traverse. Contrarily, occluded vein segments require guide-wire recanalization and often sequential balloon dilation of the tract with increasing balloon sizes before ﬁnal stent placement (Figs 44.6 and 44.7). The entire tract is ultimately dilated with 14–18 mm balloons. In contrast to the artery, the vein seems to accept extensive dilation without clinical rupture. No clinical rupture of the vein has as yet been reported, even when a total occlusion is recanalized, dilated, and stented up to 14–16 mm width. Only self-expanded stents should be inserted. Owing to size and radial strength requirements braided stainlesssteel stents (Wallstent, Boston Scientiﬁc, Natick, MA, USA) are most frequently used, but 14 mm Nitinol stents have also been placed. Stenting of a stenosis adjacent to the conﬂuence of the common iliac veins using Wallstents requires that the stent be placed well into the inferior vena cava (IVC) to avoid early caudal migration and restenosis

calculated by measurement of the cross-cut areas and diameters of the normal and compressed or diseased veins using the software built into the IVUS apparatus. In addition to being a diagnostic tool, it is also a crucial aid to guide stent insertion. Morphologic obstruction > 50% as measured by IVUS has arbitrarily been chosen for stenting.41,42

TECHNIQUE The technical details of percutaneous endovenous stenting of the venous outﬂow tract have been described elsewhere.36,38,41,43 The technique is outlined below, emphasizing a few important points. The procedure should be performed under local or general anesthesia in a fully equipped endovascular or angiographic suite and availability of IVUS and external ultrasound for cannulation guidance is preferred. Access to the iliac segment can be achieved retrogradely through the jugular or contralateral femoral vein, but an antegrade approach through an ultrasound-guided access distal to the obstruction in the thigh portion of the femoral vein or

(a)

(b)

(c)

Figure 44.6 Recanalization of an occluded left iliofemoral vein. (a) Transfemoral venogram showing occlusion of the common iliac vein and obstruction of external iliac and common femoral veins with axial and transpelvic collaterals. (b) Traversing the occlusion by creation of a pushing loop of the guide wire supported by guiding catheters. Interestingly, the guide wire will follow within the original vein although occluded. (c) After breakthrough to the inferior vena cava, the position is checked by injection of contrast dye.

496

(a)

Endovascular reconstruction for chronic iliofemoral vein obstruction

(b)

(c)

(d)

(a)

(b)

(c)

Figure 44.7 Dilation and stenting of an occluded left iliofemoral vein. (a) Often, initial dilation is performed with a low-proﬁle smaller balloon (6–10 mm diameter) to allow passage of larger catheters. Note the severe waisting. (b) Final balloon before dilation with 14–16 mm balloons. (c) The stents are covering the entire lesion. The stenting is carried into the common femoral vein to ensure an adequate inﬂow to prevent later occlusion. (d) Termination venography showing good inﬂow and outﬂow, no remaining obstruction, and no ﬁlling of the previously shown collaterals.

Figure 44.8 Stenting of a compression lesion. (a) Transfemoral venogram showing a typical non-thrombotic vein lesion with prestent translucency at the vessel crossing and transpelvic collaterals. (b) Waisting of balloon during inﬂation by the stenosis at pre-dilation prior to stent placement. (c) Post-stent venogram revealing no stenosis or collaterals. Note that the Wallstent is placed well into the inferior vena cava to prevent retrograde migration. The stent is carried into the external iliac vein since a signiﬁcant stenosis was found on intravascular ultrasound at the external and internal iliac vein conﬂuence.

(Fig. 44.8). With multiple focal stenoses two or more stents are inserted, overlapped by at least 2 cm to avoid any skipped areas between stents. Uninterrupted venous outﬂow and sufﬁcient inﬂow from below are vital for longterm patency and symptom relief just as in open bypass surgery. It is therefore important to stent the entire diseased area, even if the stent extends below the level of the inguinal ligament. The profunda femoris vein is easily identiﬁed by IVUS, and extension of the stent across the groin crease into the common femoral vein just above the profunda oriﬁce has not been found to jeopardize stent patency. Intravascular ultrasound should be an integral part of the stenting technique. The perioperative thrombosis prophylaxis may vary, but is fairly standardized in our hands. The patient receives 2500 units of dalteparin subcutaneously preoperatively. During the procedure, 5000 units of unfractionated heparin and 30 mg ketorolac are administered intravenously. All patients are admitted for less than 23 hours. Postoperatively, a foot compression device is applied, dalteparin 2500 units administered subcutaneously in the recovery room, and a ketorolac injection and dalteparin 5000 units repeated in the morning before discharge. Lowdose aspirin (81 mg p.o. daily) was started immediately postoperatively and continued. Most patients did not have additional anticoagulation. Only patients already on warfarin preoperatively owing to prior recurrent deep vein thrombosis and/or thrombophilia or those with signiﬁcant thrombophilia discovered preoperatively were anticoagu-

lated postoperatively. These were a minority, often on lifelong anticoagulation. Warfarin was routinely discontinued prior to surgery, and dalteparin (5000 units) was injected during the days warfarin had been discontinued. Patients with recanalization procedure and stenting were given dalteparin 5000 units daily for 7 days and we now consider full anticoagulation for these patients after successful intervention.

COMPLICATIONS AND THROMBOTIC EVENTS Venous stenting is performed with low morbidity and no mortality.35,42,44 The non-thrombotic complication rate related to the endovascular intervention is minimal and usually related to the cannulation site, although a few cases of retroperitoneal hematoma requiring blood transfusions have been described.38,42 After introduction of ultrasoundguided access of the femoral vein, the morbidity is virtually nil. Early thrombotic events (< 30 days) after iliofemoral stenting varies. The rate was found to be 11% in the Creighton University45 experience following stenting after thrombolysis of an acute DVT and 15% in the National Registry.46 The early thrombosis rate was found to be considerably lower when stenting was performed for chronic iliofemoral venous obstruction without prior thrombolysis.44 Early thrombotic events occurred in only 15 of 982 stented limbs (1.5%). All thrombi involving iliac

Stent outcome 497

STENT OUTCOME Although there are numerous small case reports in the literature, only a few larger series with acceptable short- to mid-term follow-up have been published. The majority of these reports mix limbs stented for chronic obstruction with those stented following clot removal. O’Sullivan et al.47 reported a 1 year patency of 79% in a retrospective analysis of 39 patients. Only half the patients presented with chronic symptoms. When initial technical failures are removed, the stented patients had a 1 year patency of 94%. In 2001 a similar group of 18 patients were reported by Hurst et al.31 Six limbs were stented after lysis of an acute deep vein thrombosis. The primary patency rates at 12 and 18 months were 79% and 79%, respectively. Recently, the same institution reported an update with a retrospective analysis of 50 stented patients. Nearly half the patients had lysis before stenting and more than 90% had thrombotic obstruction. Cumulative primary, assisted-primary, and secondary patency rates at 48 months were 58%, 71%, and 83%, respectively.48 Hartung et al.42 reported results of iliocaval stenting in 44 patients with chronic obstruction of primary, secondary, and congenital etiologies in 32, 10, and 2 limbs, respectively. Stenting was not preceded by thrombolysis. Overall cumulative primary, assistedprimary, and secondary patency rates at 36–60 months

were 73%, 88%, and 90%, respectively, with intention to treat. We have followed 982 limbs stented under IVUS guidance for chronic non-malignant obstructive lesions of the femoro-ilio-caval vein between 1997 and 2005.44 The obstructive lesion was considered thrombotic (464 limbs) when the patient had a known history of previous DVT or when post-thrombotic changes in the lower extremity were found on venogram, duplex, or IVUS. The remaining 518 limbs had NIVL. Venography or iliofemoral venous ultrasound was performed once or several times in 610 of these limbs. The overall cumulative primary, assistedprimary, and secondary patency rates found in this study at 72 months were 67%, 89%, and 93%, respectively (Fig. 44.9). The stent-related outcome in this study was related mainly to presence and severity of thrombotic disease. Primary and secondary patency rates dropped markedly from NIVL limbs to thrombotic limbs with obstruction, and to thrombotic limbs with occlusion (79% and 100%, 57% and 86%, and 54% and 74%, respectively) (Figs 44.10 and 44.11). Further analysis of possible associated factors conﬁrmed that tight long lesions of thrombotic etiology requiring multiple stents reaching distally into the common femoral vein were of greatest risk to occlude. Even though these associations with stent occlusion were found, the absolute numbers were low, and the stent length should not be limited for those reasons. This ﬁnding should not be misconstrued to conclude that these techniques should be avoided. Stents placed in the artery below the inguinal ligament often fracture and occlude. Fractures of the venous stent placed in this position have never been reported and were not observed during this study, nor are they related to venous stent occlusion at this site. Stent occlusions will be seen more frequently if the venous lesions are incompletely covered.

100 90 80 Patency rates (%)

veins (12/982, 1.2%) were found in limbs stented for chronic thrombotic obstruction (12/464, 2.6%). Thrombolysis of the newly formed clot should be attempted in initially technically successful limbs to reveal and treat unknown additional obstructions. Overall post-stent rate of thrombotic events was found to be 4–5%.42,44 Late thrombosis of the 982 stented iliac veins occurred in 3% of limbs 2–77 months after stenting, and, interestingly, only in limbs treated for thrombotic obstruction. These thrombi were difﬁcult to dissolve and thrombolysis was successful in only approximately onethird, leaving the majority occluded. Stenting of primary iliac vein compression lesions (NIVL) with the technique presented has very favorable long-term results with no thrombotic occlusions. The extension of the stent into the IVC has raised concerns about relative obstruction to the venous outﬂow of the contralateral limb and subsequent thrombosis. The thrombosis rate was, however, low (1%) and three-fourths of patients were stented for thrombotic obstruction. This should be compared with the approximately 40% rate of proximal restenosis when a braided stent (Wallstent) was not extended into the IVC.38 Probably because of acute onset of signiﬁcant symptoms, the patients sought immediate treatment and the success rate of thrombolysis or mechanical thrombectomy was high (82%). Thus, contralateral iliac vein thrombosis related to the IVC stent extension was benign and occurred infrequently.

70 60 50 Secondary Assisted-primary Primary

40 30 20

603 603 605

10

290 287 267

195 195 176

139 139 113

12

24

36

88 88 68

53 53 39

23 22 15

9 8 6

48

60

72

84

0 0

96

Months

Figure 44.9 Cumulative primary, assisted-primary, and secondary patency rates of 603 limbs after iliofemoral stenting. The lower numbers represent limbs at risk for each time interval (all SEM < 10%).

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Endovascular reconstruction for chronic iliofemoral vein obstruction

IN-STENT RECURRENT STENOSIS

100 90

Patency rates (%)

80 70 60

Assisted-primary/secondary Primary

50 40 30 20

302 302

10

143 135

96 87

65 54

34 36

24 18

11 8

12

24

36

48

60

72

0 0

Months

Figure 44.10 Cumulative primary, assisted-primary, and secondary patency rates for stented limbs with non-thrombotic iliac vein lesions. The lower numbers represent total limbs at risk for each time interval (all SEM < 10%).

In our study, cumulative severe (> 50%) in-stent recurrent stenosis (ISR) rate was assessed in 464 limbs and remained low in the long-term, 5% at 72 months (Fig. 44.12).44 Factors associated with ISR are similar to those associated with stent occlusion, except for age. The presence of thrombotic disease is the dominating factor. The cumulative rate of ISR was higher in thrombotic limbs than in non-thrombotic limbs (10% and 1%, respectively). Despite this observation, it has not been conclusively proven that progressive ISR results in occlusion.49 Stent occlusion appears to be caused by a recurrent thrombotic event rather than slowly evolving narrowing of the stent. Hartung et al.42 reported a 13% restenosis rate, but these authors appear to have included stenosis at the lower stent–vein border area, which is not considered true ISR. The nature and mechanism of development of ISR is not yet known.

CLINICAL OUTCOME

100 90

Patency rates (%)

80 70 60 50 Secondary Assisted-primary Primary

40 30 20

301 301 303

10

147 144 132

99 99 89

74 74 59

45 45 32

29 29 21

14 13 9

12

24

36

48

60

72

0 0

Patients with CVD are younger, will live longer, and have a better prognosis than patients with arterial atherosclerotic disease. Chronic venous disease rarely threatens the survival of limb or patient so the goal is to improve symptoms and the quality of life. Hurst et al.31 showed resolution or substantial improvement in 72% of limbs and Hartung et al.42 reported a marked improvement of Venous Clinical Severity and Venous Disability Scores (median score decreased from 8.5 to 2.0, and from 2 to 0, respectively). In addition to ulcer healing and ulcer

Months

Despite the fact that the thrombotic state was such a high-risk factor and thrombophilia was more frequent in limbs with thrombotic disease, the presence of thrombophilia in itself was not signiﬁcantly associated with occlusion. The operation side and sex did not inﬂuence stent outcome in this study, but younger age appeared to do so. Knipp et al.48 found that sex, recent trauma, and age under 40 years of age were predictive of decreased primary patency. This different ﬁnding may be explained by selection of patients, since half of the patients were enrolled with acute DVT in that study. Only 10% of the limbs presented without current or previous DVT, possibly too few to detect the thrombotic state as being predictive.

30

Rate of in-stent re-stenosis (%)

Figure 44.11 Cumulative primary, assisted-primary, and secondary patency rates for stented limbs with thrombotic iliac vein lesions. The lower numbers represent total limbs at risk for each time interval (all SEM < 10%).

Thrombotic All limbs Non-thrombotic

20

10

0 0

12

24

36

60

48

60

72

Months 224 494 270

97 216 119

65 141 76

45 93 48

26 56 30

17 32 16

7 14 7

Figure 44.12 Cumulative rates of severe in-stent recurrent stenosis (> 50% narrowing) in the entire study group, for limbs stented for post-thrombotic lesions (thrombotic), and for limbs stented for obstruction caused by non-thrombotic iliac vein lesions. The lower numbers represent total limbs at risk for each time interval (all SEM < 10%).

Hemodynamic results

recurrence rate, we have followed patients’ clinical result by quality of life (QoL) questionnaires; degree of swelling assessed by physical examination (grade 0, none; grade 1, pitting, not obvious; grade 2, ankle edema; and grade 3, obvious swelling involving the limb); and level of pain measured by the visual analog scale (VAS).50 Our clinical results following stenting in 982 patients were recently reported.44 Post-interventional clinical follow-up ranged up to 8 years 9 months (mean, 24 months; range, 1–107). Information was available in 918 of 982 limbs (93%). The incidence of ulcer healing after stent placement in 148 limbs with active ulcer was 68% and the cumulative ulcer recurrence-free rate at 5 years was 58%. Ulcers recurred in only eight limbs of 101 healed ulcers during the follow-up period. Thus, if healing of the ulcer was achieved after this intervention, ulcer recurrence was rare within the study period. Frequently, these limbs had remaining reﬂux, which was untreated during the observation period. Despite the presence of reﬂux the stasis ulcers stayed healed. Long-term ulcer healing was the same in limbs with primary (NIVL) and thrombotic obstruction (62% and 55%, respectively; P = 0.2819). The pre- and postoperative mean pain and swelling scores improved substantially (3.7, range 0–9, and 0.8, range 0–10; 1.7, range 0–3, and 0.8, range 0–3, respectively; P < 0.0001). The rate of limbs with severe pain (≥ 5 on VAS) fell from 41% to 11% after intervention; gross swelling (grade 3) in limbs decreased from 36% to 18%. After 5 years overall 62% and 32%, respectively, remained completely free of pain and swelling. This analysis was based on complete relief of swelling and pain (grade 0 swelling and 0 level of pain) and does not reﬂect partial improvement. It has previously been shown that both primary CVD with “simple” varicose veins and secondary CVD with development of post-thrombotic stigmata signiﬁcantly reduce quality of life.51–53 Speciﬁcally, previous iliofemoral DVT may cause clinically pertinent iliac outﬂow obstruction resulting in a marked compromise of QoL.27 A validated health-related QoL questionnaire (CIVIQ)54 assessing subjective leg pain, sleep disturbance due to leg problems, work-related leg problems, and the effect of leg symptoms on morale and social activities were ﬁlled out by patients prospectively before and after stent intervention (mean follow-up 5 months, range 1–79 months, n = 381).44 There was signiﬁcant improvement in all ﬁve problem categories after stenting of both NIVL and thrombotic outﬂow obstructions. Chronic venous disease regardless of etiology affects QoL adversely, and stenting in patients with chronic venous outﬂow obstruction frequently markedly improved it.

HEMODYNAMIC RESULTS As previously discussed, there is no accurate hemodynamic test available to properly assess venous outﬂow

499

obstruction and its improvement after stenting in individual limbs. The ultimate result of stenting is, therefore, better assessed by the clinical outcome as outlined above. Changes of conventional tests, such as ambulatory venous pressure (AVP, % drop) with venous ﬁlling time (VFT, s), air plethysmography [venous ﬁlling index (VFI90, mL/s); venous volume (VV, mL); outﬂow fraction at 1 s (OF1s, %)] and arm–foot pressure differential/hyperemia-induced pressure increase, have been found to be relatively minor compared with the clinical improvement.44 Signiﬁcant decrease of the mean hand–foot pressure differential was found in stented limbs and occurred with and without remaining reﬂux and no adjunct procedures, and AVP improved in most subsets of limbs in that study. Although numerically small, these changes were statistically signiﬁcant, and indicated that the outﬂow obstruction was alleviated and the global hemodynamics improved after stenting.43 After successful stenting of 23 selected limbs with iliofemoral post-thrombotic obstruction and reﬂux, Delis et al.55 reported a signiﬁcant increase in reﬂux matched by a greater outﬂow fraction and decrease of residual venous volume measured by strain-gauge plethysmography. There is a contention that alleviation of proximal obstruction by stenting would increase distal reﬂux, a “protection” against reﬂux would be lost, and would perhaps worsen the clinical condition. We found that better reﬂux-related parameters (VFT, VFI90, VV) after treatment were observed only when adjunct saphenous procedures were combined with the stenting.44 In no subset of patients was there observed a deterioration of venous reﬂux. The analysis of stented limbs with reﬂux and no adjunct procedure showed neither deterioration nor improvement of these parameters in this study. The presence of axial deep reﬂux pre-stent did not worsen the global reﬂux measurably after stenting. Although increased retrograde ﬂow measured by VFI90 may increase in individual patients, in this larger stented group of limbs it was not found to be a dominant or constant phenomenon. Prior to stenting, limbs with thrombotic obstruction clearly had more extensive venous disease with more severe obstruction and reﬂux more frequently involving multiple systems and levels than did limbs with NIVL.44 Despite this observation, stenting improved clinical symptoms and QoL substantially and similarly in both groups of patients. The positive clinical outcome was achieved with an improvement of the calf muscle pump function in the NIVL limbs, whereas the thrombotic limbs had no measurable hemodynamic improvement in these parameters. The hemodynamic response in patients who became completely free of pain and swelling or healed their ulcers was no different than in those with residual pain or swelling or non-healing ulcers.

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Guidelines 4.17.0. of the American Venous Forum on endovascular reconstruction for chronic iliofemoral vein obstruction No.

Guideline

4.17.1 For chronic iliac vein obstruction we recommend endovenous stenting to improve symptoms and the quality of life of the patients

●

●

●

Stenting of the venous outﬂow obstruction of the lower extremities can be performed with low morbidity, no mortality, long-term high patency rate, and a low rate of in-stent restenosis. Endovenous stenting is the current “method of choice” to treat chronic venous obstruction (grade 1A). Stenting of the venous outﬂow tract of limbs with CVD speciﬁcally alleviates pain and swelling and promotes sustained ulcer healing. Most importantly the QoL of the patients is signiﬁcantly improved (grade 1A). Stenting is a minimally invasive outpatient procedure and results in marked clinical improvement whether or not an adjunct procedure to control superﬁcial reﬂux is performed. In the presence of combined iliac vein obstruction and superﬁcial or deep reﬂux, therefore, the emerging course of treatment is to primarily correct

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1

A

the obstructive component. When signiﬁcant great saphenous vein reﬂux is present, the great saphenous vein has increasingly been obliterated by percutaneous technique at the time of the stenting.56

CLINICAL PRACTICE GUIDELINES The major obstacle to improving the selection of patients for venous outﬂow stenting is the lack of a reliable test to measure a hemodynamically signiﬁcant stenosis. The key for the physician is to be aware of the importance and possibility of venous blockage combined with increased suspicion in patients with history and clinical signs and symptoms suggestive of outﬂow obstruction. Patients with previous DVT; patients with limb symptoms, especially pain, out of proportion to detectable pathology; patients not improving on conservative treatment; and patients with no other detectable pathology to explain their symptoms are speciﬁcally targeted. Although a positive non-invasive or invasive test may support further studies, a negative test should not exclude it. The diagnosis and treatment must presently be based on invasive morphological investigations of the iliac venous outﬂow, although hemodynamic criteria would be preferred. Intravenous ultrasound investigation is the ultimate test and should be generously utilized in symptomatic patients with a suspicion of outﬂow obstruction. Limiting work-up of patients with signiﬁcant CVD to only duplex ultrasound will not sufﬁce, especially not when restricted to the infrainguinal vein segments.

Grade of recommendation (1, we recommend; 2, we suggest)

REFERENCES ●

= Key primary paper 1. Johnson BF, Manzo RA, Bergelin RO, Strandness DE Jr. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995; 21: 307–12. ●2. Akesson H, Brudin L, Dahlstrom JA, et al. Venous function assessed during a 5-year period after acute ilio-femoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 1990; 4: 43–8. 3. Plate G, Akesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arteriovenous ﬁstula. Eur J Vasc Surg 1990; 4: 483–9. ●4. Negus D, Cockett FB. Femoral vein pressures in postphlebitic iliac vein obstruction. Br J Surg 1967; 54: 522–5. ●5. Negus D, Fletcher EW, Cockett FB, Thomas ML. Compression and band formation at the mouth of the left common iliac vein. Br J Surg 1968; 55: 369–74. ●6. Cockett FB, Thomas ML, Negus D. Iliac vein compression: its relation to iliofemoral thrombosis and the postthrombotic syndrome. BMJ 1967; 2: 14–9. 7. Cockett FB. The iliac compression syndrome alias “iliofemoral thrombosis” or “white leg”. Proc R Soc Med 1966; 59: 360–1. ●8. Cockett FB, Thomas ML. The iliac compression syndrome. Br J Surg 1965; 52: 816–21. 9. Fraser DG, Moody AR, Morgan PS, Martel A. Iliac compression syndrome and recanalization of femoropopliteal and iliac venous thrombosis: a prospective study with magnetic resonance venography. J Vasc Surg 2004; 40: 612–19.

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28.

29. 30.

31.

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33.

34.

35.

36. 37.

●38.

39.

40.

41.

●42.

●43.

●44.

on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004; 239: 118–26. Strandness DE Jr, Sumner DS. The Effect of Geometry on Arterial Blood Flow. Hemodynamics for surgeons. New York: Grune & Stratton, 1975: 96–119. Neglén P, Raju S. Detection of outﬂow obstruction in chronic venous insufﬁciency. J Vasc Surg 1993; 17: 583–9. Labropoulos N, Volteas N, Leon M, et al. The role of venous outﬂow obstruction in patients with chronic venous dysfunction. Arch Surg 1997; 132: 46–51. Hurst DR, Forauer AR, Bloom JR, et al. Diagnosis and endovascular treatment of iliocaval compression syndrome. J Vasc Surg 2001; 34: 106–13. Albrechtsson U, Einarsson E, Eklöf B. Femoral vein pressure measurements for evaluation of venous function in patients with postthrombotic iliac veins. Cardiovasc Intervent Radiol 1981; 4: 43–50. Rigas A, Vomvoyannis A, Giannoulis K, et al. Measurement of the femoral vein pressure in oedema of the lower extremities. Report of 50 cases. J Cardiovasc Surg (Torino) 1971; 12: 411–16. Raju S, Owen S Jr, Neglén P. The clinical impact of iliac venous stents in the management of chronic venous insufﬁciency. J Vasc Surg 2002; 35: 8–15. Neglén P, Berry MA, Raju S. Endovascular surgery in the treatment of chronic primary and post-thrombotic iliac vein obstruction. Eur J Vasc Endovasc Surg 2000; 20: 560–71. Neglén P, Raju S. Intravascular ultrasound scan evaluation of the obstructed vein. J Vasc Surg 2002; 35: 694–700. Forauer AR, Gemmete JJ, Dasika NL, et al. Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May–Thurner) syndrome. J Vasc Interv Radiol 2002; 13: 523–7. Neglén P, Raju S. Balloon dilation and stenting of chronic iliac vein obstruction: technical aspects and early clinical outcome. J Endovasc Ther 2000; 7: 79–91. Ahmed HK, Hagspiel KD. Intravascular ultrasonographic ﬁndings in May–Thurner syndrome (iliac vein compression syndrome). J Ultrasound Med 2001; 20: 251–6. Satokawa H, Hoshino S, Iwaya F, et al. Intravascular imaging methods for venous disorders. Int J Angiol 2000; 9: 117–21. Neglén P, Raju S. Proximal lower extremity chronic venous outﬂow obstruction: recognition and treatment. Semin Vasc Surg 2002; 15: 57–64. Hartung O, Otero A, Bouﬁ M, et al. Mid-term results of endovascular treatment for symptomatic chronic nonmalignant iliocaval venous occlusive disease. J Vasc Surg 2005; 42: 1138–44. Raju S, McAllister S, Neglén P. Recanalization of totally occluded iliac and adjacent venous segments. J Vasc Surg 2002; 36: 903–11. Neglén P, Hollis KC, Olivier J, Raju S. Stenting of the venous outﬂow in chronic venous disease: long-term stent-related outcome, clinical and hemodynamic results. J Vasc Surg 2007; 46; 979–90.

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45. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheterdirected thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999; 211: 39–49. 46. Thorpe PE. Endovascular Therapy for Chronic Venous Obstruction. Chronic Venous Insufﬁciency. New York: Springer, 1999: 179–219. 47. O’Sullivan GJ, Semba CP, Bittner CA, et al. Endovascular management of iliac vein compression (May–Thurner) syndrome. J Vasc Interv Radiol 2000; 11: 823–36. ●48. Knipp B, Ferguson E, Williams D, et al. Factors predictive of outcome following interventional treatment of iliac vein compression syndrome. J Vasc Surg 2007; 46: 743–9. 49. Neglén P, Raju S. In-stent recurrent stenosis in stents placed in the lower extremity venous outﬂow tract. J Vasc Surg 2004; 39: 181–7. 50. Scott J, Huskisson EC. Accuracy of subjective measurements made with or without previous scores: an important source of error in serial measurement of subjective states. Ann Rheum Dis 1979; 38: 558–9.

51. Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med 2002; 162: 1144–8. 52. Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med 1995; 155: 1031–7. 53. MacKenzie RK, Paisley A, Allan PL, et al. The effect of long saphenous vein stripping on quality of life. J Vasc Surg 2002; 35: 1197–203. 54. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufﬁciency (CIVIQ). Qual Life Res 1996; 5: 539–54. ●55. Delis KT, Bjarnason H, Wennberg PW, et al. Successful iliac vein and inferior vena cava stenting ameliorates venous claudication and improves venous outﬂow, calf muscle pump function, and clinical status in post-thrombotic syndrome. Ann Surg 2007; 245: 130–9. ●56. Neglén P, Hollis KC, Raju S. Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 2006; 44: 828–33.

45 Endovascular reconstruction of complex iliocaval venous occlusions HARALDUR BJARNASON Introduction Evaluation of patients before endovascular reconstruction Technique of endovenous recanalization

503 503 505

INTRODUCTION Management of atherosclerotic coronary artery disease and subsequently of peripheral arterial disease has moved in signiﬁcant degree from surgical intervention to endovascular treatment in the past 20–30 years. It is now generally accepted that coronary artery stenosis, iliac artery stenosis and renal artery stenosis should be treated with angioplasty and stent placement and the outcomes have been very satisfactory. At the same time, surgical management of venous disease was never much applied, mainly because of complexity of the operations and relatively poor outcomes. However, the endovascular treatment of venous disease appears to be quite successful even though it has taken a signiﬁcantly longer time to develop than that for arterial disease and several reports of successful treatment of venous disease treated with an endovascular approach have been published.1–6 Obstruction or occlusion of the common femoral vein (CFV), iliac vein (IV) or inferior vena cava (IVC) are associated with signiﬁcant morbidity.7,8 In the past, the treatment options for such chronic obstructions have mainly been conservative, based on compression therapy and leg elevation with or without the use of anticoagulation.9 Surgical options are available but have inconsistent outcomes and not all patients are candidates for such a treatment.10–12 It has been estimated that 1 in every 1000 of the general population will develop deep vein thrombosis (DVT) annually. In only 10% of those patients will the thrombus extend to the iliac veins. Simple calculation leads to an estimated annual incidence of thrombosis of the IV close to 1 in 10 000 of the population. The treatment for

Stent selection Outcomes Clinical practice guidelines References

509 510 512 513

thrombosis of the IV is the same as for general DVT, which is anticoagulation for 6 months or longer. Many patients will be left with persistent long-term occlusion, and these patients may be at considerable risk of developing severe post-thrombotic syndrome. Although the standard treatment for acute iliofemoral thrombosis is anticoagulation, catheter-directed thrombolysis with or without mechanical thrombectomy has been shown to be effective to resolve acute iliofemoral DVT. Even with thrombolytic treatment a large proportion of these patients will still have endovascular stents placed in conjunction with the thrombolytic procedure.13,14 There are now many signiﬁcant publications on the use of endovascular stents for the treatment of venous obstruction or occlusion in the iliac veins and IVC.2,6,15–18 Occlusion of the IVC is present in approximately 6% of patients who undergo treatment with endovascular stents for chronic venous obstruction according to Raju et al.6

EVALUATION OF PATIENTS BEFORE ENDOVASCULAR RECONSTRUCTION Ultrasound is, as a general rule, the best imaging study available for evaluation of the venous system of the lower extremities (Fig. 45.1a). On ultrasound one can easily visualize the veins of the leg, popliteal vein, femoral vein, and the CFV. When ultrasound is combined with Doppler (duplex) and color Doppler the information obtained is signiﬁcantly improved. The added functional component with Doppler can be of signiﬁcant clinical beneﬁt. These methods are used together for diagnostic evaluation in most centers for image evaluation of the lower extremity

504

Endovascular reconstruction of complex iliocaval venous occlusions

(a)

(b)

(c)

(d)

(e)

Figure 45.1 (a) Ultrasound of the left common femoral vein (CFV) in a 49 year old woman with chronic occlusion of the left iliac veins and deep veins of the left lower extremity. Note partial compressibility of the left CFV (arrow). (b) Computed tomography (CT) of the abdomen. Normal inferior vena cava at the renal vein level (arrow). (c) A CT at the inferior vena cava bifurcation level. Note narrowing of the left common iliac vein (IV) where the right common iliac artery crosses it (arrow). (d) A CT at the mid-pelvic level demonstrates the small left external IV (arrow) compared with the right counterpart. (e) A CT at the level of the CFV level. The left CFV is smaller but still reasonably large (arrow). Note large collaterals in the pubic area.

veins. For imaging of the iliac veins and, in particular, the distal end of the IVC, ultrasound becomes signiﬁcantly less dependable and sensitive. In these areas, ultrasound can in most cases indicate whether or not the vein is open. The Doppler waveform from the CFV will also give an indication of the status of the proximal iliac veins.19 Other alternative modalities such as ascending venography, computed tomography (CT) and magnetic resonance imaging (MRI) can be helpful in the evaluation

of the iliac veins and the IVC. These imaging methods are discussed in detail in Chapters 13 and 16. Ascending venography gives a very good anatomic image of the deep veins in the leg, knee, and thigh. The CFV is also well visualized, but the iliac veins and the IVC are often poorly opaciﬁed because of the diluted contrast and because the blood is often diverted away by collaterals in the case of central obstruction. The great saphenous vein can also be well evaluated, which is another important

Technique of endovenous recanalization 505

point in the evaluation of the possible candidate for IV recanalization. Contrast-enhanced CT is often very helpful in the evaluation of a patient with obstruction of the IV or IVC (Fig. 45.1). CT can reveal underlying lesions such as a tumor, iliocaval compression syndrome (also called May–Thurner syndrome), retroperitoneal ﬁbrosis,20 or an aneurysm21 compressing the vein. Acute thrombosis of the pelvic veins or IVC can also be diagnosed with contrastenhanced CT. Contrast mixture artifacts may mimic thrombus in the veins. Therefore, caution is needed when diagnosing acute venous thrombosis based on a CT because non-opaciﬁed blood mixes with the enhanced blood, which can resemble thrombosis. The same type of artifacts can also be seen on MRI. MRI can be used to evaluate the iliac veins and the IVC. There is less experience with MRI than with the other modalities. MRI sequence has been reported that can directly demonstrate acute thrombus (6 months or less).22 Non-invasive tests such as air plethysmography have been used to diagnose venous disorders and for follow-up. These functional tests can be used to follow patients after intervention. There are mixed reports on the usefulness of these tests when it comes to documenting obstruction,18 and some reports have indicated that there might not be good correlation with hemodynamic improvement after successful endovascular stent procedures.4

TECHNIQUE OF ENDOVENOUS RECANALIZATION Successful recanalization of chronically occluded iliac veins and/or IVC depends on many factors. Experience in managing catheters and guide wires is needed. Selection of the correct access site is one of the most important parts. For recanalization of an IV occlusion, the contralateral femoral vein approach is not recommended. The steep angle around the IVC bifurcation directs much of the forward energy up into the IVC rather than into the contralateral IV. This makes it difﬁcult to pass balloon catheters and stents across into the contralateral vein. Therefore, most operators use the ipsilateral femoral or CFV access and/or access from the right internal jugular vein (RIJV). Common femoral or mid- to distal femoral vein access is usually easy using ultrasound guidance.4 The superﬁcial femoral artery is usually superﬁcial to the vein in the thigh, making access somewhat difﬁcult. The relatively small femoral vein (FV) and CFV compared with the IVC and right atrium, which have to be traversed from the RIJV, give extra support to catheters and guide wires. This helps a great deal with advancing wires and catheters through the chronically occluded and often tight iliac veins. On the other hand, if access is gained from the RIJV the guide wire and catheters can get looped in the right atrium and even in the IVC bifurcation, sometimes

causing arrhythmias.1 This can be partially averted by using long introducer sheaths. The CFV often has postthrombotic changes in it as well as the inﬂow vessels, the FV, profunda femoral vein, and the great saphenous vein.15 These veins can be dilated if RIJV access is used by guiding the catheter into the branches from above, but this cannot be easily done coming from below such as from the femoral vein. Also, if the femoral vein access is high, introducer sheaths may be too close to the diseased area to be treated with stents or balloon angioplasty.4,5 For the procedure an introducer sheath should be used. Coming from the jugular vein a 45 cm long introducer sheath will usually extend to the level of the IVC bifurcation. Having the introducer at that level will, in addition to the support, allow simultaneous pressure measurement in the IVC and in the open distal vein. This gives the pressure gradient across the obstructed segment before the procedure and it can then be measured again after stent placement. If access has been gained from the CFV, FV, or the popliteal vein, an introducer of a sufﬁcient length to extend to the distal landing zone should be selected. If a long segment of partially recanalized femoral vein is crossed on the way to the distal landing zone (CFV) the long introducer will ease repeated exchange of balloons and catheters. A hydrophilic (glide) wire such as the stiff-angled glide wire from Terumo (Terumo Medical Corporation, Somerset, NJ, USA) combined with a 5 Fr angiographic catheter with hydrophilic coating (Glidex; Terumo Medical Corporation, Somerset, NJ, USA) works well to traverse the chronically occluded iliac veins. Often, the ﬁbrotic veins are quite tough to pass through. Spinning the guide wire or rolling it between one’s ﬁngers as it is slowly advanced works well. The glide catheter is then advanced over the wire with a spinning forward motion. As soon as the occluded segment has been passed and the catheter has reached the normal venous segment, pressures should be measured on both ends of the obstructed segment to obtain the pressure gradient (Fig. 45.2). At this point, the glide wire can be exchanged for a stiffer wire. We have preferred a braided guide wire such as the Amplatz Super Stiff guide wire (Medi-Tech, Boston Scientiﬁc Corporation, Natick, MA, USA). For the iliac veins and CFV pre-dilation is always performed prior to stent delivery. The iliac veins and the CFVs can be dilated to 14 mm (12 mm for smaller patients) and even to 16 mm in the common iliac vein (CIV). The IVC can be dilated to the same diameter prior to stent placement (Figs 45.3–45.5). Passing the balloon through the occluded veins can be quite difﬁcult, so pre-dilation with a smaller proﬁle balloon such as a 4–8 mm balloon may be needed in order to be able to pass the larger balloons through. If a catheter or balloon still cannot be passed through the vessel, but the wire has been passed, a puncture can be made into the vessel distally and the wire pulled through that puncture site. By applying tension to both ends, the catheter and balloons can now be pulled through.

506

Endovascular reconstruction of complex iliocaval venous occlusions

(a)

(b)

(d)

(c)

(e)

Figure 45.2 (a) Same patient as in Fig. 45.1. A catheter has been negotiated into the left common iliac vein (IV) from the right internal jugular vein. A venogram demonstrates narrowing and irregularity of the vein. Note reﬂux into the normal right common IV. (b) The catheter/wire combination has now been negotiated through the occluded/obstructed IV system to the left common femoral vein (CFV). The CFV has post-thrombotic changes in it but there is good inﬂow from the profunda femoral vein. (c) A 14 mm angioplasty balloon is used to dilate the common femoral, external iliac, and common IV. Here, it is being inﬂated in the CFV. Note severe waist in the balloon. (d) A 14 mm wide stent has now been placed from the mid-CFV up (arrow). (e) The 14 mm stents extend to the proximal common IV and into the inferior vena cava (IVC). There is controversy among experts on how far the stent into the IVC should extend.

When the occluded segments have been dilated the stents are placed. Self-expandable stents are generally used for this purpose. A variety of self-expandable stents are available. When placing the stents it is important not to leave behind uncovered diseased space in between the stents. In other words, the stents should overlap a few millimeters rather than leaving uncovered space in between them.6 There are mixed opinions on how to place the stents towards the IVC (Fig. 45.2e). We place the proximal stent such that it extends just barely into the IVC overriding the contralateral IV just slightly. Juhan et al.23 describe a contralateral thrombosis in a single case out of ﬁve where the stents were placed overriding the contralateral IV. This

thrombosis occurred 3 years after the initial procedure. Others advocate placing the stents into the IVC overriding the contralateral IV and have not reported a high incidence of contralateral IV thrombosis.4 It is still unclear whether this causes a higher rate of contralateral IV thrombosis or other related issues such as increased venous pressure. The placement of stents into the CFV has caused considerable debate; however, this is a common practice and accepted by operators (Fig. 45.2d). Of the 35 patients in the series from O’Sullivan et al.,15 12 received an infrainguinal (CFV) stent, and the patency rate at 1 day, 1 month, and 1 year was 91.3%, 81.7%, and 81.7%, respectively. The authors reported no fractures or

Technique of endovenous recanalization 507

(a)

(b)

(c)

(d)

Figure 45.3 (a) A computed tomography (CT) from a middle-aged man with chronic occlusion of the inferior vena cava (IVC). The intrahepatic IVC is normal (arrow). (b) A CT from the renal vein level. The IVC is atretic (arrow). The renal veins drain into retroperitoneal collaterals. (c) A CT from the level of the IVC bifurcation. Atretic IVC bifurcation (arrow). (d) A CT at the common femoral vein (CFV) level. The right CFV is atretic (arrow). The left is quite large.

mechanical failures in this group. Andrews et al.24 demonstrated that, in swine in which metallic stents were placed across the hip, no fractures were noted. There have, however, been anecdotal reports of fracture in the CFV in humans with Nitinol-type self-expandable stents. The renal veins are commonly occluded or partially occluded when the IVC is involved in the chronically occluded or obstructed IVC (Fig. 45.3). When stents are placed across the renal vein, one of the concerns is to further affect the venous drainage from the kidney, which subsequently could lead to decline in renal function. This has, however, not been reported or been our experience. Raju et al.6 did not ﬁnd any indication of impaired renal function that could be attributed to stent placement, even though they had one case of elevated creatinine thought to be due to contrast load in a patient who did not have stents placed.

Recanalization of a chronically occluded IVC bifurcation poses a technical challenge (Figs 45.4, 45.5). When the IVC occlusion extends to the bifurcation, which it most often does, both CIVs are usually involved as well. That means that the bifurcation has to be reconstructed. There are no bifurcated stents similar to an abdominal aortic endograft. A combination of the available stents has to be used to build a bifurcation. We prefer to perform a single-barrel recanalization of the IVC using a largediameter Gianturco (20–25 mm) (Cook Incorporated, Bloomington, IN, USA) or Wallstent (22–24 mm) (Boston Scientiﬁc Corp., Natick, MA, USA). At the bifurcation we simultaneously bring stents across the CIVs such that the inferior edges of the CIV stents just touch at the bifurcation rather than bringing the stents parallel into the IVC.

508

(a)

Endovascular reconstruction of complex iliocaval venous occlusions

(b)

(c)

(d)

Figure 45.4 (a) Same patient as in Fig. 45.3. Access from the right internal jugular vein. Catheter in the intrahepatic inferior vena cava (IVC) demonstrating the normal intrahepatic portion but bird beak obstruction inferior to that. (b) The catheter has now been advanced into the atretic portion of the IVC. The lumen is very small. (c) The catheter is in the right common femoral vein (CFV). Note very poor inﬂow. (d) The left CFV has much better inﬂow than the right and a good landing zone.

Raju et al.6 use Wallstents for the iliac veins and form an inverted Y within the distal portion into the IVC, forming a double barrel there. One of the stents will then continue up to the proximal healthy segment of the IVC while the shorter stent will end at the side of the longer stent. The blood from the contralateral side will ﬂow through the sidewall into the longer and parallel IVC stent. Intravascular ultrasound (IVUS) may have been underutilized as a tool in endovascular therapy in the past and at present. This may be due to the relatively high cost of the ultrasound unit and the ultrasound catheters, which are single-use items. Hurst et al.18 used IVUS in 12 of 18 patients who had IV stents placed and found that IVUS changed the management in ﬁve patients. Raju et al.4–6 used IVUS to guide accurate stent placement and as a diagnostic tool. These authors indicated that IVUS was invaluable as both a diagnostic and intraoperative tool and thought that venography, even with the injection close to the diseased and treated area, did not provide adequate information about the severity and location of the lesion. Intravascular ultrasound may be even more important on the venous side than on the arterial side because pressure measurements have not been found to reliably conﬁrm hemodynamic signiﬁcance of narrowed segments. O’Sullivan et al.15 did not ﬁnd that intravascular pressure measurements, measuring gradients across obstructed or narrowed segments, were useful for determination of the severity of an obstruction. Instead, they relied on the presence or absence of collaterals. Raju et al.4 found that of 36 patients with documented

collaterals on initial venography, the collaterals disappeared following successful recanalization and stenting in 33 patients. In three patients, the collaterals were signiﬁcantly diminished, but no change was noted in the remaining three patients. They did not rely on intravascular pressure measurements but mainly used IVUS to determine which stenoses were severe and needed stent placement as discussed above.4 Most if not all venous recanalizations can be performed with the patient under conscious sedation and local anesthesia. Because angioplasty of a chronically occluded vein is often painful, stronger analgesia (fentanyl) in combination with sedatives such as midazolam is used. Others prefer to use general anesthesia for the procedure, but in these cases the recanalization procedure is often combined with an open surgical procedure such as venous stripping or other peripheral venous operation.4,16,17,23,25 Inferior vena cava recanalization and stent placement often require signiﬁcantly more sedation. We carry out many of these procedures with propofol anesthesia administrated intravenously. Others use general anesthesia for these procedures.6 Generally, it has not been common practice to give antibiotics prophylactically prior to endovascular stent placement. Stent infections have been reported but are rare.26 We have recently started giving prophylactic antibiotic as a single dose before stent placement and Hartung et al.27 did give antibiotics at the beginning of the procedure to all their patients. This has not been the practice of other sites.

Stent selection 509

(a)

(b)

(c)

(d)

(e)

Figure 45.5 (a) Same patient as in Figs 45.3, 45.4. Two guide wires from the right internal jugular vein. The inferior vena cava (IVC) and both iliac veins were dilated to 14 mm. Note the IVC lumen compared with that in Fig. 45.4b. (b) Injection into the right external iliac vein (IV). Surgical endphlebectomy was performed on the right common femoral vein (CFV) (not shown). (c) Stents have now been placed in the IVC and both IV systems. Simultaneous dilation of both common IVs using two 14 mm balloons. (d) The IVC now has 20 mm stents which have been dilated to 20 mm. (e) The iliac veins were stented with 14 mm diameter stents dilated to 14 mm. Good ﬂow seen at this right IV venogram. Creating bifurcation is difﬁcult.

During the procedure full anticoagulation with unfractionated heparin is given with a goal of activated clotting time around 280–300 seconds. After the procedure, the patient is observed in the hospital overnight. The introducers can be removed with the patient fully anticoagulated but bed rest has to be requested for at least 2–4 hours following the procedure. Full anticoagulation, usually low-molecular-weight heparin followed by oral anticoagulation, is started immediately after the procedure. The length of anticoagulant therapy depends on risk factors such as hypercoagulability, which may require indeﬁnite anticoagulation. However, if reversible factors were the cause of the thrombosis or if there was not a thrombotic component and a good endovascular outcome was achieved after stent placement, only 2–6 months of anticoagulation may be needed. Generally, Raju et al.4,6 do not prescribe anticoagulation unless the patient clearly has a hypercoagulable state and particularly if there is evidence

of previous venous thrombosis. Ultrasound can be performed the next day to verify patency, but we do not practice that unless the patient’s symptoms indicate so. The leg is wrapped with elastic bandage immediately after the procedure and the patient can usually ambulate as soon as the sedation has worn off (2–4 hours). Raju et al.’s patients are discharged with instructions to take aspirin, 81 mg/day. We have begun to prescribe a regimen of clopidogrel, 75 mg/day for 4–6 weeks, and aspirin, 81 mg/day indeﬁnitely, from the time of the procedure. There are no studies to support this practice.

STENT SELECTION Endovascular stents can be divided into two general groups based on their metal properties. The two groups are self-

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Endovascular reconstruction of complex iliocaval venous occlusions

expanding and balloon-expanding stents. The balloonexpanding stents are mounted on a balloon and then brought to the site on the balloon through an introducer sheath, which has been brought across the area to be treated. The balloon is then inﬂated with the stent on it, and as the balloon is deﬂated the stent stays in place at the diameter the balloon expanded it to. That is to say, the diameter of the balloon determines the diameter of the stent. When the stent is dilated with the balloon, most stents will shorten to some degree, many signiﬁcantly, especially if they are dilated over their recommended range. Because balloon-expandable stents tend to have a higher radial force than self-expandable stents, they are used when extra radial force is needed. This property makes this type of stent useful in areas with high recoil force, which is sometimes encountered in the venous system. On occasions, balloonexpandable stents are placed within self-expandable stents in which the recoil force has been too high for the selfexpandable stent to withstand. A typical example of a balloon-expandable stent is the Palmaz stent (Cordis Corporation, Miami, FL, USA). Because balloon-expandable stents are malleable, they do not re-expand if bent or crushed. Juhan et al.23 described a case of a Palmaz stent that had been placed in the common IV for a left iliocaval stenosis. The patient became pregnant, the stent became crushed and the treated venous segment thrombosed. The lesson from this is that balloonexpandable stents can be used only in locations protected from external physical forces such as in the pelvis, preferable in women past reproductive age. On the other hand, self-expandable stents will re-expand if compressed or crushed. Other beneﬁts which self-expandable stents have over balloon-expandable stents are that selfexpandable stents are available in longer lengths and they conform better to curved vessels, and deployment is generally easier.3,28 The ﬁrst self-expandable stent in general use was the Gianturco stainless-steel stent. This stent is still commercially available and in clinical use. In treatment of venous obstructions this stent is especially useful because of its large diameter (up to 25 mm) and the distance between the interstices. The Gianturco stent has large spaces between the interstices which allow inﬂow from side branches into the stent lumen, making it possible to stent across side-branches without compromising ﬂow. Most other stents, both self-expandable and balloonexpandable, have tighter interstices and thus have the potential to hinder inﬂow through the sidewalls. The Wallstent endoprosthesis was one of the ﬁrst selfexpandable stents following the Gianturco stent. It is available in a variety of diameters and lengths. The sizes pertinent for the iliac veins and the IVC are 12 mm, 14 mm, 16 mm, 18 mm, 20 mm and 22 mm and then there are several different lengths. Because of its unique design it will shorten signiﬁcantly as it is deployed and dilated. Predilation to at least the recommended stent diameter will reduce foreshortening upon dilation of the stent itself

following deployment. This makes it less precise when deployed, as it may be difﬁcult to predict exactly where it will end on each end. On the other hand, it is very resistant to compression when it ﬁrst has been placed and dilated. The Wallstent is made of stainless steel. Then there is a large category of stents that are made of Nitinol. Included in this group are the Smart stent (Cordis Endovascular, Warren, NJ, USA), Protégé stent (ev3, Plymouth, MN, USA), Luminex (Angiomed/Bard, Karlsruhe, Germany), and the Silver stent (Cook Inc., Bloomington, IN, USA). There are other similar Nitinol-based stents on the market and most of these stents come in diameters of 12 mm, 14 mm, and 16 mm. The Nitinol stents can be placed accurately as they will not foreshorten signiﬁcantly upon deployment and dilation. On the other hand, they can be deformed by external forces such as the overlying right common iliac artery taking on a ﬁsh mouth appearance which limits the luminal size and can cause hemodynamically signiﬁcant narrowing. Stent visibility is one of the limitations of Nitinol-based stents. Placing multiple small radiopaque particles on the ends of the stents enabling better visualization has solved this problem to some extent. The Wallstent, made of stainless steel, is reasonably radiopaque and generally is well visualized with ﬂuoroscopy.

OUTCOMES It is important to make a distinction between stent placement in a previously thrombosed venous segment and a segment of a vein narrowed by external force (or other causes) without previous thrombosis. This is particularly important as successful recanalization depends on good inﬂow, which requires a near healthy vein distally where the stents can be landed into. It has been estimated that up to 88% of patients with IV occlusion will also have post-thrombotic changes in any or all of the following veins: common femoral, deep femoral, femoral, popliteal, or infrapopliteal veins.1

Technical success The technical outcomes as well as patency rates are listed in Table 45.1. Technical success for IV recanalization has been reported in 87–100% of cases.4,18,29 Failures have been attributed to inability to cross the occluded segment. Following successful recanalization and stent placement the collaterals will no longer be ﬁlled in 92% of patients and in 47% of the patients previously measured pressure gradient improved, as reported by Raju et al.4 Recanalization of an occluded IVC seems to be more complicated. Raju et al.6 found that in all patients with stenosis of the IVC the success rate was 100%, but when the IVC was occluded the success rate was 66% (14 of 21 patients). They were unable to identify factors which could

Outcomes 511

Table 45.1 Technical outcomes and patency rates Author

O’Sullivan et al.15 Nazarian et al.2 Blattler and Blattler16 Neglen and Raju17 Hurst et al.18 Hartung et al.20 Raju et al.6

No.

20 56 14 5 18 44 97

Technical success

92% 85.7% 100% 95.5% 100%*/66%**

PP at 12 months 93.0% 50% 79% 79% 83.6%

Late PP

Late SP

50% at 48 months

75% at 48 months

75% at 36 months

93% at 36 months

73.2% at 36 months 58% at 24 months

89.9% at 36 months 82% at 24 months

PP, primary patency rate; SP, secondary patency rate; *, for obstructed inferior vena cava; **, for occluded IVC. Modiﬁed from Hartung et al.20

help to predict whether or not recanalization would be successful. Factors which they considered included length of the occluded segment or other venographic ﬁndings.

Clinical success Raju et al.5 have reported that 74% of the patients were free of pain following the procedure and that 66% had improvement in leg swelling. In a series of 304 patients with venous insufﬁciency who were treated for IV stenosis, Raju et al.5 reported that 68% had healed ulcers at 2 year follow-up. In a similar manner, Hurst et al.18 reported clinical improvement in 47% of patients treated with iliac stents and angioplasty for iliocaval compression syndrome. Heijman et al.29 also reported improvement in ﬁve out of six patients. Patients with IVC obstruction or occlusion had very signiﬁcant improvement in symptoms. Swelling disappeared in 51% of patients with swelling prior to the procedure, and 74% of patients who indicated pain as a symptom prior to the procedure were pain free 3.5 years following the procedure. Of the 19 patients with active ulcers 12 (63%) healed and remained healed at 2 years. Overall, there was 70% excellent or good clinical outcome in a group of 97 patients who underwent stent placement including the IVC.6

Patency The primary patency rates reported ranged from 49% to 100%.4,18 In the report from Raju et al.4 the primary patency rate was 49%, the primary-assisted patency rate 62%, and a secondary patency rate of 76%. In their larger material5 in which they reported on patients whose main problem was venous insufﬁciency, the primary patency rate was 71%, and secondary- and primary-assisted patency rates were 97% at the 2 year follow-up. The reported primary patency rates by Hurst et al.18 were 89% at 6 months and 79% at 12 and 18 months. O’Sullivan et al.15 had a primary patency rate of 93.6% at 1 year.

A recent report from the Mayo Clinic presented outcomes from recanalization and endovascular stent placement in 63 patients (66 limbs).30 This retrospective review included all patients treated with recanalization for chronic thrombosis of the iliac veins, CFVs, and IVC from April 1, 1998, to December 31, 2003. Cumulative primary, primary-assisted, and secondary patency rates as determined by duplex ultrasound at 12 months were 53%, 68%, and 83% respectively. In nine patients an occlusion occurred during followup. In all cases, this had occurred by the ﬁrst follow-up (mean 2.4 months ± 0.5 months). In ﬁve cases, the occluded segments were successfully opened up, and of those none required a second reintervention during the remaining 12 month follow-up. The remaining four patients did not have an attempt at reintervention. Two were asymptomatic, one received a femoral–femoral bypass, and the fourth died soon after follow-up from unrelated causes.30 In this material, 30 CFVs were stented, six on the right and 24 on the left. There have been no reports of stent fractures, but the majority of the stents were Wallstents. Four patients with very poor inﬂow into the CFV did undergo endophlebectomy in the CFV and of the ostium of the inﬂow vessels. During the same procedure the IV proximally was recanalized and stents were placed. All four patients had poor inﬂow into the CFV. Three patients returned for follow-up at 2, 12, and 13 months and all had patent IVs.30 Raju et al.6 had a cumulative primary and primaryassisted stent patency of 58% and 82% respectively at 2 years for IVC stent procedures. Almost all venous stents will develop in-stent stenosis. Neglén et al.17 did look at the risk factors associated with in-stent stenosis and found that several factors were associated with increased incidence. The three main factors were presence of thrombotic disease, positive thrombophilia test results, and stent extending below the inguinal ligament or just long stents. These factors can actually all go in hand, and the common factor appears to be thrombosis. Longer stents are usually needed for

512

Endovascular reconstruction of complex iliocaval venous occlusions

thrombosed segments than for non-thrombosed segments. Overall, at 42 months 15% limbs had more than 50% diameter reduction, 61% had more than 20% reduction and only 23% had no in-stent stenosis. It appears as if in-stent stenosis may level off at 2–3 years.

syndrome which were noted to have migrated almost 1 year following the procedure. These stents were removed from the heart surgically.31

Complications

Treatment of chronic IV occlusions by using endoluminal stents has become a therapeutic alternative for symptomatic patients. The technical success rate of IV stenting is very good, and both clinical outcomes and patency rates are satisfactory. Patency depends to a large extent on the inﬂow into the stented area and outﬂow towards the inferior vena cava. Adjunctive procedures such as the combination of surgical endovenectomy and intraoperative stenting may expand the number of patients who are offered this type of treatment.

If re-thrombosis is excluded as a complication, complications are relatively rare. One could expect bleeding into the perivenous space to be a frequent complication. This is actually a rare complication. Hurst et al.18 reported on a retroperitoneal hematoma which was treated successfully with blood transfusion without any further intervention. Nazarian et al.2 reported two stent fractures, both Gianturco stents. Those were noted incidentally without any obvious clinical effect. There is one report of an infected stent in the common IV after thrombolysis and stent placement for May–Thurner syndrome.26 In the Mayo Clinic series of 63 patients, only two developed a post-procedural hematoma. In one patient this was associated with thrombolysis of an occluded stent. The other patient developed a hematoma at a puncture site just following an angioplasty and stent procedure. There were no deaths reported (30 days). The Mayo report had no retroperitoneal hematoma.30 Recanalization of the IVC appears to be very safe. Raju et al.6 had no mortality. No clinically apparent bleeding complications and no negative effect on renal function or liver function in patients who had stents placed across the hepatic vein or renal vein level. Mild back pain was frequently noted, but this was easily controlled with nonsteroidal anti-inﬂammatory drugs. Stent migration has been reported in association with iliac and IVC stent procedures.20,31 Hartung et al.27 reported migration of two stents during deployment. One stent had to be snared from the right atrium and surgically removed from the CFV after being pulled there. The other stent migrated into the perihepatic IVC and was pulled into the infrarenal IVC where it was left without sequel.27 There is a report of stents placed for May–Thurner

Conclusions

CLINICAL PRACTICE GUIDELINES ●

●

●

●

●

●

●

Ultrasound is a very helpful diagnostic tool for evaluation of venous disease but has limitations with regards to the iliac veins and IVC. Computed tomography is an excellent tool for evaluation of anatomic distribution of IV and IVC pathology. Intravascular ultrasound has turned out to be a very important tool for better understanding of the pathology in venous disease and is helpful for decisionmaking during stent placement. Iliac and IVC recanalization often requires more than one access site. The most common access sites are the right internal jugular vein and the ipsilateral femoral vein. Self-expandable stents are usually used. The stents have large diameter: 14–16 mm for the iliac veins and up to 20 mm for the IVC. Patency rates are high (secondary) and clinical improvement is signiﬁcant following treatment of IV and IVC obstructions. Complications are rare and not life-threatening.

Guidelines 4.18.0. of the American Venous Forum on endovascular reconstruction of complex iliocaval venous occlusions No.

Guideline

4.18.1 We suggest endovascular stents for reconstruction of complex iliocaval venous occlusions

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

2

B

References 513

REFERENCES ●

= Key primary paper

1. Semba CP, Dake MD. Iliofemoral deep venous thrombosis: aggressive therapy with catheter-directed thrombolysis. Radiology 1994; 191: 487–94. 2. Nazarian GK, Bjarnason H, Dietz CA Jr, et al. Iliofemoral venous stenoses: effectiveness of treatment with metallic endovascular stents. Radiology 1996; 200: 193–9. 3. Sawada S, Fujiwara Y, Koyama T, et al. Application of expandable metallic stents to the venous system. Acta Radiol 1992; 33: 156–9. ●4. Raju S, McAllister S, Neglén P. Recanalization of totally occluded iliac and adjacent venous segments. JAMA 2002; 36: 903–11. ●5. Raju S, Owen SJ, Neglén P. The clinical impact of iliac venous stents in the management of chronic venous insufﬁciency. JAMA 2002; 35: 8–15. ●6. Raju S, Hollis K, Neglén P. Obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. JAMA 2006; 44: 820–7. 7. Strandness DE Jr, Langlois Y, Cramer M, et al. Long-term sequelae of acute venous thrombosis. JAMA 1983; 250: 1289–92. 8. O’Donnell TJ, Browse NL, Burnand KG, Thomas ML. The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res 1977; 22: 483–8. 9. Nicoloff A, Moneta GL, Porter JM. Compression treatment of chronic venous insufﬁciency. In: Gloviczki P, Yao JST, eds. Handbook of Venous Disorders. New York: Arnold, 2001: 303–8. 10. Gruss J, Hiemer W. Bypass procedures for venous obstruction: Palma and May–Husmi bypasses, Raju perforator bypass, prosthetic bypasses, and primary and adjunctive arteriovenous ﬁstulae. In: Raju S, Villavicencio J, eds. Surgical Management of Venous Disease. Baltimore: Williams & Wilkins, 1997: 289–305. 11. Jost CJ, Gloviczki P, Cherry KJ Jr, et al. Surgical reconstruction of iliofemoral veins and the inferior vena cava for nonmalignant occlusive disease. JAMA 2001; 33: 320–8. ●12. Raju S. Experience in venous reconstruction in patients with chronic venous insufﬁciency. In: Bergan J, Yao J, eds. Venous Disorders. Philadelphia: Saunders, 1991: 296–305. 13. Bjarnason H, Kruse JR, Asinger DA, et al. Iliofemoral deep venous thrombosis: safety and efﬁcacy outcome during 5 years of catheter-directed thrombolytic therapy. J Vasc Intervent Radiology 1997; 8: 405–18. 14. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheterdirected thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999; 211: 39–49. 15. O’Sullivan GJ, Semba CP, Bittner CA, et al. Endovascular management of iliac vein compression (May–Thurner) syndrome. J Vasc Intervent Radiology 2000; 11: 823–36.

16. Blattler W, Blattler IK. Relief of obstructive pelvic venous symptoms with endoluminal stenting. JAMA 1999; 29: 484–8. ●17. Neglén P, Raju S. In-stent recurrent stenosis in stents placed in the lower extremity venous outﬂow tract. JAMA 2004; 39: 181–8. 18. Hurst DR, Forauer AR, Bloom JR, et al. Diagnosis and endovascular treatment of iliocaval compression syndrome. JAMA 2001; 34: 106–13. 19. Dorfman G, Cronan J. Venous ultrasonography. Radiol Clin North Am 1992; 30: 879–94. 20. Hartung O, Alimi YS, DiMauro P, et al. Endovascular treatment of iliocaval occlusion caused by retroperitoneal ﬁbrosis: late results in two cases. JAMA 2002; 36: 849–52. 21. Rosenthal D, Matsuura JH, Jerius H, Clark MD. Iliofemoral venous thrombosis caused by compression of an internal iliac artery aneurysm: a minimally invasive treatment. J Endovasc Surg 1998; 5: 142–5. 22. Fraser DGW, Moody AR, Morgan PS, et al. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002; 136: 89–98. 23. Juhan C, Hartung O, Alimi Y, et al. Treatment of nonmalignant obstructive iliocaval lesions by stent placement: mid-term results. Ann Vasc Surg 2001; 15: 227–32. 24. Andrews RT, Venbrux AC, Magee CA, Bova DA. Placement of a ﬂexible endovascular stent across the femoral joint: an in vivo study in the swine model. J Vasc Interv Radiol 1999; 10: 1219–28. 25. Irving JD, Dondelinger RF, Reidy JF, et al. Gianturco selfexpanding stents: clinical experience in the vena cava and large veins. Cardiovasc Intervent Radiol 1992; 15: 328–33. 26. Dosluoglu HH, Curl GR, Doerr RJ, et al. Stent-related iliac artery and iliac vein infections: two unreported presentations and review of the literature. J Endovasc Ther 2001; 8: 202–9. 27. Hartung O, Otero A, Bouﬁ M, et al. Mid-term results of endovascular treatment for symptomatic chronic nonmalignant iliocaval venous occlusive disease. JAMA 2005; 42: 1138–44. 28. Carrasco CH, Charnsangavej C, Wright KC, et al. Use of the Gianturco self-expanding stent in stenoses of the superior and inferior venae cavae. J Vasc Interv Radiol 1992; 3: 409–19. 29. Heijmen RH, Bollen TL, Duyndam DA, et al. Endovascular venous stenting in May–Thurner syndrome. J Cardiovasc Surg 2001; 42: 83–7. 30. Paulsen S, Misra MD, Sabater MD, et al. Iliac vein and inferior vena caval obstruction. Outcome of treatment with endovascular stents. Poster at the 16th Annual Meeting of the American Venous Forum in Kissimmee, Florida, 2004. 31. Mullens W, De Keyser J, Van Dorpe A, et al. Migration of two venous stents into the right ventricle in a patient with May–Thurner syndrome. Int J Cardiol 2006; 110: 114–15.

46 Open surgical reconstructions for non-malignant occlusion of the inferior vena cava and iliofemoral veins PETER GLOVICZKI AND GUSTAVO S. ODERICH Introduction Patient selection Preoperative evaluation Adjuncts to improve graft patency

514 514 515 516

INTRODUCTION Open surgical reconstructions of the inferior vena cava (IVC) and the iliofemoral veins now are reserved for those symptomatic patients who are not candidates for, or who failed attempts at, endovascular reconstructions. Catheterbased endovenous reconstructions using thrombolysis, mechanical thrombectomy, angioplasty, and stents have become the ﬁrst line of treatment in patients with venous thrombosis due to non-malignant disease. In this chapter we review patient selection, diagnostic evaluation, techniques, and results of open venous reconstructions for chronic non-malignant occlusion of the iliofemoral veins and the inferior vena cava. Chapter 51 in this volume discusses venous reconstructions for trauma whereas Chapter 52 presents venous bypasses in patients with malignant tumors.

PATIENT SELECTION Post-thrombotic iliac or iliocaval obstruction has been the most frequent cause for open reconstruction of large veins in patients with non-malignant disease.1,2 Compression of the left common iliac vein by the overriding right common iliac artery (May–Thurner syndrome) has been recognized now as the most frequent cause of left iliofemoral venous thrombosis.3,4 Primary compression of the left iliac vein without deep venous thrombosis has also emerged as

Surgical procedures Graft surveillance References

517 521 521

etiology of symptomatic venous outﬂow obstruction, and in a recent series on venous stenting 53% of 982 nonmalignant femoro-ilio-caval lesions were of primary and not of post-thrombotic etiology.5 A study from Northwestern University used computed tomography to evaluate the frequency of left iliac vein compression in asymptomatic patients. Kibbe et al.6 reported that 24% had > 50% compression of the left common iliac vein, and 66% had > 25% compression. It is likely that some degree of left iliac vein compression is an anatomic variant in the population. Venous occlusion requiring reconstruction may also develop as a result of iatrogenic or blunt trauma,7 irradiation, or as a result of external compression of deep veins by retroperitoneal ﬁbrosis,8 by benign or malignant tumors,9,10 by cysts, iliac aneurysm, ﬁbrous bands or ligaments.11 Congenital anomalies, such as membranous occlusion of the suprahepatic IVC, with or without associated thrombosis of hepatic veins (Budd–Chiari syndrome),12 or hypoplasia of the iliofemoral veins as in Klippel–Trenaunay syndrome,13 can also cause outﬂow obstruction. Failure of medical management with compression garments and life style modiﬁcations in patients with nonmalignant venous occlusion is an indication for venous reconstruction. Those patients who are not candidates for endovascular repair or those who failed after attempts at venous stenting are selected for open reconstruction using autologous or prosthetic bypasses.

Preoperative evaluation 515

PREOPERATIVE EVALUATION Preoperative evaluation of the patients should reveal the etiology and functional signiﬁcance of deep venous obstruction and the extent and severity of associated venous incompetence. Of note, in at least two-thirds of the patients with venous outﬂow obstruction, distal reﬂux due to incompetent valves will contribute to development of chronic venous insufﬁciency.

History and physical examination History and physical examination, complemented by a hand-held Doppler examination, should reveal signs and symptoms typical of venous congestion. Patients with venous occlusion have swelling and develop exerciseinduced pain in the thigh muscles known as venous claudication. This pain is described as a bursting pain in the thigh and sometimes in the calf that develops after exercise and is relieved by rest and leg elevation. The swollen leg has a cyanotic hue with distended varicose veins even in supine position. Bilateral swelling indicates bilateral iliofemoral or caval occlusion or systemic disease. Collateral veins in the suprapubic and abdominal wall usually indicate pelvic venous occlusion. Bleeding from high-pressure varicosities is not infrequent. In some patients, venous congestion results in hyperhidrosis and signiﬁcant ﬂuid loss through the skin. Associated chronic lymphedema may also develop. Patients with mem-

(a)

(b)

branous occlusion of the IVC frequently will have evidence of hepatic failure and portal hypertension as well.12 For details of clinical and diagnostic evaluation of the patients with chronic venous insufﬁciency the readers are referred to Chapters 13, 14 and 29.

Non-invasive evaluation A complete evaluation to establish the clinical class of venous disease is necessary. Duplex scanning and plethysmography are used to establish deep venous occlusion and to determine the extent of valvular incompetence and calf muscle pump failure. It is also important to exclude any abdominal or pelvic pathology (tumor, cyst, retroperitoneal ﬁbrosis) with computed tomography (CT) or magnetic resonance imaging (MRI). Outﬂow plethysmography is useful to conﬁrm functional venous outﬂow obstruction, and to document improvement following treatment.

Contrast, computed tomographic and magnetic resonance venography Detailed contrast phlebography is performed in patients in whom venous reconstruction is being considered. Both ascending and descending phlebography should be employed to evaluate obstruction and any associated valvular incompetence (Fig. 46.1a–c).1,14 Iliocavography

(c)

Figure 46.1 (a) Ascending venogram of a 36 year old woman conﬁrms left iliac vein thrombosis. (b) Venogram 1.6 years after implantation conﬁrms widely patent left femorocaval expanded polytetraﬂuoroethylene (ePTFE) graft. (c) Venogram at 11.7 years after graft placement. The patient has excellent clinical result. (With permission from the Mayo Foundation.)

516

Open surgical reconstructions for non-malignant occlusion of the inferior vena cava and iliofemoral veins

and abdominal cavography through a brachial approach may also be necessary in some patients to visualize the IVC proximal to the occlusion. The femoral access is useful not only for descending phlebography and iliocavography but also for measuring femoral venous pressures. Magnetic resonance venography has the advantage of avoiding the use of intravenous contrast, but details are less clear than contrast or CT venography. Three-dimensional CT venography has been used with increasing frequency to document the extent of deep vein obstruction (Fig. 46.2).

Venous pressure measurement The functional or hemodynamic effects of an obstruction can be ascertained by venous pressure measurement. Normal pressure at that level is 2–4 mmHg, while in patients with hemodynamically signiﬁcant proximal obstruction it is 6–8 mmHg.15 However, in the presence of well-developed collateralization, venous pressure may be normal at rest and manifest hemodynamic signiﬁcance only under the conditions of exercise. For the purpose of testing, exercise consists of 10 dorsiﬂexions of the ankle or

Figure 46.2 Three-dimensional computed tomographic venography conﬁrms occluded left iliac stent with large suprapubic venous collaterals.

20 isometric contractions of the calf muscle, which should increase the pressure by twofold in the setting of signiﬁcant obstruction.15 A pressure difference of at least 5 mmHg between the femoral and the central pressures or a twofold increase in femoral vein pressure after exercise also indicates hemodynamically signiﬁcance of a lesion.1,15 Venous pressure measurement following reactive hyperemia is another means of assessing hemodynamic signiﬁcance. With the transducer in the dorsum of the foot in the supine position, a thigh cuff is inﬂated to 300 mmHg for 2 minutes and the pressure measured 5 seconds after cuff deﬂation. The increase in pressure up to 30 mmHg indicates the functional signiﬁcance.15 However, in cases of severe post-thrombotic syndrome, the increase in pressure either does not take place or is only very small. Intravascular ultrasound is used frequently today to assess the degree of iliac vein stenosis before stenting.5

ADJUNCTS TO IMPROVE GRAFT PATENCY Arteriovenous fistula Multiple experiments conﬁrmed that a distal arteriovenous ﬁstula (AVF), ﬁrst suggested by Kunlin and Kunlin in 1953,16 improves patency of grafts placed in the venous system.17–19 An AVF increases ﬂow and decreases platelet and ﬁbrin deposition in prosthetic grafts placed in the venous system.17 Prosthetic grafts have signiﬁcantly higher thrombotic threshold velocity than autologous grafts and require higher ﬂow to maintain patency. Disadvantages of an AVF include an increased operating time and the inconvenience of a second procedure to ligate the ﬁstula at a later date. A potential side-effect is a high cardiac output caused by high ﬁstula ﬂow, which may also defeat the purpose of the operation by increasing femoral venous pressure and, thus, causing venous outﬂow obstruction. Experimental work in our laboratory revealed that, to avoid venous hypertension, the optimal ratio between the diameters of the ﬁstula and the graft should not exceed 0.3.19 Elevated intraoperative pressure in the femoral vein after placement of a ﬁstula is a warning sign and ﬁstula diameter should be decreased by banding the conduit. Several conﬁgurations and locations for a ﬁstula have been suggested.1,20,21 The authors prefer placement of the venous end of the AVF right onto the hood of the graft at the distal anastomosis, with either a 4 mm vein [great saphenous vein (GSV) or a large tributary thereof] or a 4 or 5 mm expanded polytetraﬂuoroethylene (ePTFE) graft. The arterial anastomosis is usually made to the superﬁcial femoral artery. A small silastic sheet and a 2-0 prolene suture is loosely tied around the ﬁstula and its end positioned in the subcutaneous tissue, close to the incision, to help with identiﬁcation and dissection of the ﬁstula during a second procedure. Percutaneous closure of the ﬁstula with transcatheter embolization or placement of

Surgical procedures

an endovascular plug is also an option. The use of an AVF is recommended for all prosthetic grafts anastomosed to the femoral vein and all longer (> 10 cm) iliocaval prosthetic grafts to help maintain patency. The ﬁstula is kept open for at least 6 months postoperatively, but in patients without any side-effects it is kept open for as long as possible to help maintain patency. For patients with saphenous vein grafts, take-down of a ﬁstula at 3 months is needed.

Thrombosis prophylaxis Intravenous heparin (5000 units) is given before crossclamping and anticoagulation is maintained during and after the procedure in most patients. Low-dose heparin (500–800 units/hour) can be administered locally through a small polyethylene catheter (Fig. 46.3) and continued until complete systemic heparinization is achieved with twice the normal partial thromboplastin time by 48 postoperative hours. The use of subcutaneous low-molecular-weight heparin to shorten hospitalization is suggested. The catheter is then removed and the patient converted to oral anticoagulation. The use of an intermittent pneumatic compression pump, leg elevation, elastic bandages, and early ambulation are recommended. The patients are ﬁtted with 30–40 mmHg compression stockings before discharge. Warfarin is usually continued indeﬁnitely.

517

SURGICAL PROCEDURES Femorofemoral saphenous vein transposition (Palma procedure) Patients with unilateral iliac vein obstruction are candidates for saphenous vein transposition (Palma procedure) (Fig. 46.4a–d). During the operation the contralateral saphenous vein is dissected and divided distally; the vein is then transposed in a subcutaneous tunnel above the pubis to the affected side. If there is a kink in the vein at the saphenofemoral junction after tunneling, sometimes it is necessary to disconnect the saphenous vein with a 2 mm cuff from the common femoral vein and reanastomose it, after rotating it upwards 180°. If the vein is less than 5 mm in size or the pressure difference between the two femoral veins is less than 3 mmHg, we add a femoral arteriovenous ﬁstula. This is performed between the superﬁcial femoral vein and the hood of the saphenous vein, using usually a separate reversed segment of the right GSV or using a small PTFE graft. Although few large series have been reported, overall patency of saphenous vein Palma grafts in nine series including 412 operations ranged between 70% and 83% at 3–5 years.1,2,22–24 Results were better in patients with good inﬂow, with no infrainguinal venous disease, and in those with May–Thurner syndrome without previous deep vein thrombosis. Gruss and Hiemer15 reported 71% patency of 20 Palma vein grafts at 5 years. In the Mayo Clinic series1 primary and secondary patency rates of 18 saphenous vein Palma grafts at 4 years were 77% and 83%, respectively. Halliday et al.24 reported a large series of 34 patients with saphenous Palma grafts in 1985; 5 year patency was 75%.

Crosspubic prosthetic bypass In the absence of a suitable saphenous vein, crosspubic venous bypass with ePTFE graft is a good alternative.15 An 8 or 10 mm PTFE graft is pulled into the suprapubic tunnel and the ends are anastomosed to the femoral veins bilaterally and a femoral arteriovenous ﬁstula is added to improve patency (Fig. 46.5a–e). RESULTS

Figure 46.3 A right iliac vein–inferior vena cava externally supported ePTFE graft. Note the arteriovenous ﬁstula at the right groin and a 20 gauge catheter which is introduced through a tributary of the saphenous vein for perioperative heparin infusion. (From Gloviczki et al.14 with permission.)

Variable patency rates of ePTFE grafts in this location have been reported. Eklöf21 observed patency in only two of seven grafts at 2 years while Comerota et al.25 reported patency in two of three grafts at 40 and 63 months. Sottiurai26 reported on a 100% (19/19) patency rate at follow-up that ranged from 11 to 139 months. Gruss and Hiemer15 have large experience with ePTFE; they observed 77% patency at 5 years in 27 PTFE Palma grafts. They now recommend using externally supported ePTFE grafts with AVF for all crosspubic venous bypasses.

518

Open surgical reconstructions for non-malignant occlusion of the inferior vena cava and iliofemoral veins

(a)

(b)

(c)

(d)

Figure 46.4 (a) Preparation of the right great saphenous vein before a suprapubic saphenous vein transposition (Palma procedure). Bilateral groin incisions were performed to expose the left common femoral vein and the right saphenofemoral junction. The right saphenous vein is harvested through short incisions in the thigh and a clamp is placed to occlude the saphenous vein and partially the common femoral vein as well. The vein is distended with heparinized papaverine solution before being tunneled to the left side for anastomosis with the femoral vein. (b) The right saphenofemoral junction after tunneling the vein to the left side in the suprapubic space. Note excellent inﬂow without kinks in the saphenous vein. (c) Anastomosis of the saphenous vein with the left common femoral vein. (d) Postoperative venography conﬁrms patent saphenous vein graft. (With permission of the Mayo Foundation.)

Femoro-ilio-caval bypass

TECHNIQUE

Anatomic in-line reconstruction can be performed for unilateral disease when an autologous conduit for suprapubic graft is not available, or for bilateral iliac, iliocaval, or IVC occlusion.21 Extensive venous thrombosis (not infrequently following previous placement of an IVC ﬁlter), failure of iliac vein stenting, or iliocaval occlusion caused by tumors or retroperitoneal ﬁbrosis are potential indications. Failure of previous endovascular attempts and occlusion following placement of multiple stents have also been indications for bypass.

The femoral vessels are exposed at the groin through a vertical incision. The iliac vein or the distal segment of the IVC is exposed retroperitoneally through an oblique ﬂank incision. The IVC at the level of the renal veins is best exposed through a midline or a right subcostal incision. The infrarenal IVC is reconstructed with a 16–20 mm graft, the iliocaval segment usually with a 14 mm graft and the femorocaval segment with a 10 or 12 mm ePTFE graft. Short iliocaval bypass with signiﬁcant pressure gradient or reconstruction of the IVC with a straight ePTFE graft, in the presence of good inﬂow, can be performed without an

Surgical procedures

(a)

(b)

(d)

519

(c)

(e)

Figure 46.5 (a) Partially recanalized femoral vein found after venotomy. Endophlebectomy was performed to remove the organized thrombus and improve inﬂow into a femorofemoral crossover venous polytetraﬂuoroethylene (PTFE) bypass. (b) A PTFE arteriovenous ﬁstula was performed between the superﬁcial femoral artery and the hood of the crossfemoral PTFE graft. (c) A small silastic sheath is placed around the ﬁstula and marked with metal clips for easy identiﬁcation at reoperation when the ﬁstula is closed. (d) Completed left-to-right femoral crossover PTFE graft with an arteriovenous ﬁstula. (e) Computed tomographic venography of the crossfemoral PTFE graft with a patent arteriovenous ﬁstula 8 months after surgery. (With permission of the Mayo Foundation.)

AVF, but long iliocaval PTFE grafts beneﬁt from a femoral arteriovenous ﬁstula. RESULTS

Only a few centers have reported larger experience with femorocaval or iliocaval bypass. Alimi and colleagues27 reported results of eight iliac vein reconstructions with femorocaval or iliocaval bypass grafting for both acute and chronic obstructions, four patients with each. At a mean follow-up of 20 months seven out of eight grafts were patent. Sottiurai26 noted long-term patency in 16 of 19 ePTFE grafts at last follow-up ranging from 80 to 113 months following femorofemorocaval (ﬁve), femoroiliac (six) and femorocaval (eight) bypass grafting with the aid of AVF.26 Ulcer healing was noted in 10 of 13 (77 %)

patients and improvement of limb edema in 16 of 19 patients. Results of the Mayo Clinic series of 44 large vein reconstructions in 42 patients were reported by Jost et al.1 All patients underwent surgical treatment for benign iliocaval or femoral venous thrombosis. Seventeen patients had ePTFE grafts placed (femorocaval, eight; iliocaval, ﬁve; crossfemoral, three; cavoatrial, one), six had spiral vein grafts (ﬁve iliofemoral and one cavoatrial) and one femoral vein patch angioplasty was performed. Clinical follow-up averaged 3.5 years (median 2.5), and graft follow-up with imaging studies averaged 2.6 years (median 1.6). Secondary 3 year patency rate of ilio/femorocaval ePTFE bypasses at 2 years was 54% (Figs 46.1 and 6–8). Secondary patency was lower in patients with an arteriovenous ﬁstula (P = 0.023), although these data

520

Open surgical reconstructions for non-malignant occlusion of the inferior vena cava and iliofemoral veins

100 Palma graft (n⫽18) 9 9

13 80 Patency (%)

11

8

83%

10

60 9 llio/femorocaval (n⫽ 13)

54% 7

40

20

0 0

0.5

1

1.5

2

Years

Figure 46.8 Cumulative secondary patency rates of expanded polytetraﬂuoroethylene (ePTFE) ilio-femoro-caval bypasses and saphenous vein crossover bypass grafts (Palma procedure). (From Jost et al.1)

Figure 46.6 Patent right iliocaval polytetraﬂuoroethylene (PTFE) graft 4.5 years after placement for iliocaval occlusion caused by retroperitoneal ﬁbrosis (arrows indicate anastomosis).

Suprarenal inferior vena cava reconstruction The most common reason to reconstruct the suprarenal IVC for benign disease is membranous occlusion of the IVC, which is frequently associated with occlusion of the hepatic veins (Budd–Chiari syndrome) and consequent portal hypertension and liver failure. Occlusion of the suprahepatic IVC usually does not cause signiﬁcant congestion of lower extremity veins, although leg edema and venous claudication may still develop in affected patients. If percutaneous balloon angioplasty, stenting, or transatrial dilatation of the membranous occlusion fails and portosystemic shunting is not required, cavoatrial bypass using an externally supported PTFE prosthesis is an effective technique to decompress the IVC.

(a)

(b)

Figure 46.7 (a) Right iliocaval occlusion (arrow) with a remarkable lack of collateral circulation. (b) Patent iliocaval polytetraﬂuoroethylene (PTFE) graft 3 months later. The patient had patent graft and excellent clinical result 5 years later (arrows indicate proximal and distal anastomosis) (With permission of the Mayo Foundation.)

probably reﬂected the more extensive disease in those requiring a ﬁstula to maintain patency. Femorofemoral saphenous vein grafts (Palma procedure) had a patency of 83% (P = NS). Early patency of caval reconstruction performed in patients together with excision of primary or secondary malignant disease is excellent and it is discussed in detail in Chapter 44.

TECHNIQUE

The retrohepatic segment of the vena cava and the right atrium are exposed through a right anterolateral thoracotomy, extending the incision across the costal arch such that the peritoneal cavity is entered through the diaphragm. The liver is retracted anteriorly and the paravertebral gutter exposed together with the suprarenal segment of the IVC. The pericardium is opened anterior to the right phrenic nerve and the right atrium isolated. The IVC is controlled with a partial occlusion clamp above the renal vein, and a 16 or 18 mm externally supported ePTFE graft is sutured end-to-side with a running suture of either 5-0 or 6-0 prolene. The graft is then passed parallel to the IVC up to the right atrium or to the suprahepatic IVC. The central anastomosis is performed after placement of a partial occlusion clamp on the IVC or the right atrium. Before completion of the anastomosis, the graft is de-aired to prevent air embolization.

References 521

Guidelines 4.19.0. of the American Venous Forum on open surgical reconstructions for nonmalignant occlusion of the inferior vena cava and iliofemoral veins No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.19.1 For symptomatic patients with unilateral iliofemoral venous occlusions who fail attempts at endovascular reconstruction we recommend open surgical bypass using saphenous vein as a crosspubic bypass (Palma procedure)

1

B

4.19.2 For symptomatic patients with iliac vein or inferior vena cava obstruction we suggest open surgical bypass using an externally supported polytetraﬂuoroethylene prosthesis, if endovascular options fail or they are not possible

2

B

An anterior approach was suggested by Kieffer28 for replacement of a short segment of the suprahepatic IVC with a ringed ePTFE graft. Tunneling of a long cavoatrial graft in front of the liver or under the left lobe was also reported. RESULTS

Reported clinical success rate with cavoatrial grafts is about 77%, with a perioperative mortality of 3% and 2, 5 and 10 year patency rates of 86%, 78%, and 57%, respectively. Wang and associates12 reported on clinical improvement at 1.5 years in 10 of 12 patients who underwent cavoatrial bypass grafting for Budd–Chiari syndrome. Kieffer’s group28 reported on long-term patency in ﬁve of six grafts placed for membranous occlusion of the vena cava. Victor and co-workers29 reported patent grafts at 21 months to 6 years after the operation in ﬁve patients. Three cavoatrial grafts placed for non-malignant disease were reported by our group: the patient with an ePTFE graft was asymptomatic at 10 years, the long Dacron graft failed at 3 years and the spiral vein graft occluded within 1 year.14

phlebography is obtained through the catheter, which is positioned at the distal anastomosis of the graft (Fig. 46.3). Any stenosis or thrombosis should be revised. Postoperatively duplex surveillance imaging is obtained at 3 and at 6 months and twice yearly thereafter. Outﬂow plethysmography is also performed to objectively document hemodynamic changes following the bypass procedure.

REFERENCES ● ◆

= Key primary paper = Major review article ●1.

◆2.

3.

GRAFT SURVEILLANCE 4.

Intraoperative duplex scanning is now performed in most patients to assure patency, good ﬂow, and lack of thrombus deposition. Direct pressure measurements are carried out before closure in every patient with and without graft ﬂow to document hemodynamic beneﬁt. In vein or polyethylene conduits ﬁstula ﬂow can be measured and calibrated using an electromagnetic ﬂow meter. If ﬂow exceeds 300 mL/min, banding of the ﬁstula should be considered. On the ﬁrst postoperative day contrast

●5.

●6.

Jost CJ, Gloviczki P, Cherry KJ Jr, et al. Surgical reconstruction of iliofemoral veins and the inferior vena cava for nonmalignant occlusive disease. J Vasc Surg 2001; 33: 320–7. Gloviczki P, Cho JS. Surgical treatment of chronic occlusions of the iliac veins and the inferior vena cava. In: Rutherford RB, ed. Vascular Surgery, 6th edn. Philadelphia: Saunders, 2005: 2303–20. May R, Thurner J. The cause of predominantly sinistral occurrence of thrombosis of the pelvic veins. Minerva Cardioangiol 1957; 3: 346–9. Cockett FB, Thomas ML, Negus D. Iliac vein compression: its relation to iliofemoral thrombosis and the postthrombotic syndrome. BMJ 1967; 2: 14–19. Neglén P, Hollis KC, Olivier J, Raju S. Stenting of the venous outﬂow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. J Vasc Surg 2007; 46: 979–90. Kibbe MR, Ujiki M, Goodwin AL, et al. Iliac vein compression in an asymptomatic patient population. J Vasc Surg 2004; 39: 937–43.

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7. Schanzer H, Skladany M. Complex venous reconstruction for chronic iliofemoral vein obstruction. Cardiovasc Surg 1996; 4: 837–40. 8. Rhee RY, Gloviczki P, Luthra HS, et al. Iliocaval complications of retroperitoneal ﬁbrosis. Am J Surg 1994; 168: 179–83. ●9. Dzsinich C, Gloviczki P, van Heerden JA, et al. Primary venous leiomyosarcoma: a rare but lethal disease. J Vasc Surg 1992; 15: 595–603. ●10. Bower TC, Nagorney DM, Cherry KJ Jr, et al. Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 2000; 31: 270–81. 11. Gullmo A. The strain obstruction syndrome of the femoral vein. Acta Radiol 1957; 47: 119–37. ●12. Wang Z, Zhu Y, Wang S, et al. Recognition and management of Budd–Chiari syndrome: report of one hundred cases. J Vasc Surg 1989; 10: 149–56. 13. Gloviczki P, Stanson AW, Stickler GB, et al. Klippel–Trenaunay syndrome: the risks and beneﬁts of vascular interventions. Surgery 1991; 110: 469–79. ●14. Gloviczki P, Pairolero PC, Toomey BJ, et al. Reconstruction of large veins for nonmalignant venous occlusive disease. J Vasc Surg 1992; 16: 750–61. ◆15. Gruss JD, Hiemer W. Bypass procedures for venous obstruction: Palma and May–Husmi bypasses, Raju perforator bypass, prosthetic bypasses, and primary and adjunctive arteriovenous ﬁstulae. In: Raju S, Villavicencio JL, eds. Surgical Management of Venous Disease. Baltimore: Williams & Wilkins: 1997: 289–305. 16. Kunlin K, Kunlin A. Experimental venous surgery. In: May R, ed. Surgery of the Veins of the Leg and Pelvis. Philadelphia: W.B. Saunders, 1979: 37–75. 17. Gloviczki P, Hollier LH, Dewanjee MK, et al. Experimental replacement of the inferior vena cava: factors affecting patency. Surgery 1984; 95: 657–66. 18. Plate G, Hollier LH, Gloviczki P, et al. Overcoming failure of venous vascular prostheses. Surgery 1984; 96: 503–10. 19. Menawat SS, Gloviczki P, Mozes G, et al. Effect of a femoral arteriovenous ﬁstula on lower extremity venous hemodynamics after femorocaval reconstruction. J Vasc Surg 1996; 24: 793–9.

20. Eklöf B. The temporary arteriovenous ﬁstula in venous reconstructive surgery. Int Angiol 1985; 4: 455–62. ◆21. Eklöf B. Temporary arteriovenous ﬁstula in reconstruction of iliac vein obstruction using PTFE grafts. In: Eklöf B, Gjores JE, Thulesius O, Berquist D, eds. Controversies in the Management of Venous Disorders. London: Butterworths, 1989: 280–90. 22. Plate G, Einarsson E, Eklöf B, et al. Iliac vein obstruction associated with acute iliofemoral venous thrombosis. Results of early reconstruction using polytetraﬂuoroethylene grafts. Acta Chir Scand 1985; 151: 607–11. 23. AbuRahma AF, Robinson PA, Boland JP. Clinical, hemodynamic, and anatomic predictors of long-term outcome of lower extremity venovenous bypasses. J Vasc Surg 1991; 14: 635–44. ●24. Halliday P, Harris J, May J. Femoro-femoral crossover grafts (Palma operation): a long-term follow-up study. In: Bergan JJ, Yao JST, eds. Surgery of the Veins. Orlando: Grune & Stratton, Inc., 1985: 241–54. 25. Comerota AJ, Aldridge SC, Cohen G, et al. A strategy of aggressive regional therapy for acute iliofemoral venous thrombosis with contemporary venous thrombectomy or catheter-directed thrombolysis. J Vasc Surg 1994; 20: 244–54. ●26. Sottiurai VS. Venous bypass and valve reconstruction: indication, technique and results. Phlebology 1997; 25: 183–8. 27. Alimi YS, DiMauro P, Fabre D, Juhan C. Iliac vein reconstructions to treat acute and chronic venous occlusive disease. J Vasc Surg 1997; 25: 673–81. 28. Kieffer E, Bahnini A, Koskas F, et al. Nonthrombotic disease of the inferior vena cava: surgical management of 24 patients. In: Bergan JJ, Yao JST, eds. Venous Disorders. Philadelphia: W.B. Saunders, 1991: 501–16. 29. Victor S, Jayanthi V, Kandasamy I, et al. Retrohepatic cavoatrial bypass for coarctation of inferior vena cava with a polytetraﬂuoroethylene graft. J Thorac Cardiovasc Surg 1986; 91: 99–105.

47 The management of incompetent perforating veins with open and endoscopic surgery JEFFREY M. RHODES, MANJU KALRA AND PETER GLOVICZKI Introduction Surgical anatomy of perforating veins Signiﬁcance of perforating veins Indications for perforator interruption Preoperative evaluation Open surgical techniques

523 523 524 524 525 525

INTRODUCTION Perforating veins connect the superﬁcial to the deep venous system, either directly to the main axial veins (direct perforating veins) or indirectly through muscular tributaries or soleal venous sinuses (indirect perforating veins). Incompetent perforating veins were ﬁrst linked to chronic venous insufﬁciency (CVI) and its most severe manifestation, venous ulceration, nearly one and a half centuries ago by John Gay.1 Since then interest in their treatment has waxed and waned with the development of each new surgical method or ablative technique. Surgical interruption of these veins to treat and prevent venous ulcers was ﬁrst suggested by Linton in 1938.2 Linton’s operation was championed over the next several decades by Cockett3 and Dodd4 and, through the mid-twentieth century, was considered the gold standard for the surgical treatment of refractory venous ulcers. The classic Linton procedure was ultimately abandoned because of major wound complication rates of up to 24%.5,6 Although several authors made modiﬁcations to Linton’s original technique to decrease wound complications, a major change in practice did not occur until the development of subfascial endoscopic perforator surgery (SEPS). It was not until 1985 when Hauer7 ﬁrst described a minimally invasive endoscopic approach to perforating vein ablation that these wound-healing issues were overcome. Using an endoscope, inserted subfascially into the superﬁcial posterior compartment through a small incision remote from the area of ulceration and lipodermatosclerosis, the perforating veins could be ligated under direct

Endoscopic surgical techniques Ultrasound-guided techniques Results of perforator ablation Conclusions References

525 528 528 533 533

visualization. In contrast to the Linton procedure, wound complication rates with SEPS, including minor wound problems, are of the order of only 5%.8 Subfascial endoscopic perforating vein surgery quickly became the surgical technique of choice for their ablation over the next two decades. In the past few years, further minimally invasive, percutaneous techniques of perforating vein ablation have continued to develop with the emergence of ultrasound-guided catheter ablation of perforating veins and ultrasound-guided foam sclerotherapy, both of which are now being performed in the ofﬁce setting.9–11 The emergence of these minimally invasive surgical techniques has led to increasing interest and much debate about appropriate surgical therapy for the treatment of severe chronic venous insufﬁciency and venous ulcers. However, the efﬁcacy of perforator ablation, regardless of which technique is used, remains intensely debated. This chapter will review the relevant surgical anatomy of perforating veins, the evidence to support the contribution of incompetent perforating veins to the pathophysiology of chronic venous disorders, and the techniques and results of both open and endoscopic perforating vein ablation. These data will then serve as the benchmark against which the newer techniques will be compared as they continue to evolve.

SURGICAL ANATOMY OF PERFORATING VEINS Important details on the anatomy of the perforating veins are outlined in Chapter 2. A few observations pertinent to

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The management of incompetent perforating veins with open and endoscopic surgery

the surgical techniques to be discussed need to be mentioned here. Perforating veins are those that connect the superﬁcial venous system to the deep veins. Valves within the calf and thigh perforating veins prevent blood from reﬂuxing from the deep system into superﬁcial veins, although in some normal limbs reversal of ﬂow in the perforating veins can be demonstrated. The most signiﬁcant calf perforating veins, termed the posterior tibial perforating veins (Cockett perforating veins), connect the posterior accessory great saphenous vein (Leonardo’s vein) to the paired posterior tibial veins. This observation is extremely important as, although the posterior accessory great saphenous vein (GSV) does connect to the great saphenous vein just below the knee, stripping of the GSV will not affect ﬂow through incompetent medial calf perforating veins. The perforating veins encountered during SEPS include the upper, middle, and lower posterior tibial perforating veins and the paratibial and Boyd’s perforating veins which connect the GSV to the posterior tibial and popliteal veins in the calf.12 Certain anatomic considerations speciﬁc to the endoscopic interruption of medial calf perforating veins need to be emphasized. In cadaver dissections, Mozes et al.12 noted that only 63% of all medial perforating veins were directly accessible from the superﬁcial posterior compartment. These constitute 32% of the mid-posterior tibial, 84% of the upper posterior tibial, and 43% of lower paratibial perforating veins; the remaining traverse the intermuscular septum dividing the deep and superﬁcial compartments or reside solely within the posterior deep compartment itself.12 In order to gain access to these, a paratibial fasciotomy must be performed, incising the entire length of the fascia of the posterior deep compartment.

perforator) incompetence, involving at least two of the three venous systems. Incompetent calf perforating veins in conjunction with superﬁcial or deep reﬂux have been reported in 56–73% of limbs with venous ulceration.8,14 A correlation between the number and size of incompetent perforating veins, as detected by duplex, and the severity of CVI was demonstrated by Labrapoulos and co-workers.14 In patients with advanced disease more incompetent perforating veins were found, and their diameters were also larger. In spite of this evidence the contribution of incompetent perforating veins to the hemodynamic derangement in limbs with CVI remains a topic of debate. However, functional studies cannot reliably differentiate perforating veins from deep vein incompetence in most patients, so the task of documenting hemodynamic problems related directly to perforator incompetence, even if conﬁrmed with duplex scanning, remains difﬁcult. The question that remains at the heart of the debate is not so much of the hemodynamic signiﬁcance but rather the relative clinical signiﬁcance of these perforating veins; speciﬁcally, do they independently contribute to the severity of CVI or are they merely a secondary effect of advanced superﬁcial and/or deep incompetence. A statistically signiﬁcant decrease in perforator incompetence over 12 months was seen in 261 patients in the ESCHAR study15 following superﬁcial venous reﬂux ablation alone, although the absolute reduction was only from 51% to 42%. Mendes et al.16 similarly found reversal of perforator incompetence in 71% limbs free of deep incompetence treated with superﬁcial surgery alone, while the Edinburgh group17 found that 72% of limbs with signiﬁcant deep venous involvement will have persistent perforating vein incompetence after isolated superﬁcial venous surgery.

SIGNIFICANCE OF PERFORATING VEINS

INDICATIONS FOR PERFORATOR INTERRUPTION

There is a consensus of opinion that venous hypertension in the erect position and during ambulation is the most important factor responsible for the development of skin changes and venous ulceration in CVI. The relationship between venous ulceration and ambulatory venous pressure was ﬁrst described by Beecher et al.13 in 1936. Subsequent studies have conﬁrmed that ambulatory venous pressure has not only diagnostic but also prognostic signiﬁcance in CVI. Negus and Friedgood5 described pressures in the supramalleolar network well above 100 mmHg during calf muscle contraction. The importance of incompetent perforating veins is also supported by the observation that skin changes and venous ulcers almost always develop in the gaiter area of the leg (the area between the distal edge of the soleus muscle and the ankle), where large incompetent medial perforating veins are located. Evidence is increasing that the majority of patients with venous ulcers have multisystem (superﬁcial, deep, and/or

The presence of incompetent perforating veins in patients with advanced CVI (clinical classes 4–6, i.e., lipodermatosclerosis, healed or active ulceration) and low operative risk constitute potential indications for surgical intervention. These include patients with isolated perforating vein incompetence as well as those with combined superﬁcial, deep, and perforating vein incompetence. In the last group, combined superﬁcial and perforating vein reﬂux ablation is a reasonable approach to provide maximum beneﬁt; however, the procedures may be staged in selected patients with limited perforating vein involvement reserving perforator interruption for persistent problems. Patients with varicose veins (C2–3) should be considered for perforating vein ligation only if varices recur following treatment of superﬁcial incompetence. An open ulcer is not a contraindication for SEPS. Contraindications include associated arterial occlusive disease (ankle–brachial index < 0.8), infected ulcer and a

Endoscopic surgical techniques 525

non-ambulatory or a medically high-risk patient. Diabetes, renal failure, liver failure, morbid obesity, or ulcers in patients with rheumatoid arthritis or scleroderma are relative contraindications. Presence of deep venous obstruction at the level of the popliteal vein or higher on preoperative imaging is also a relative contraindication. Patients with extensive skin changes, circumferential large ulcers, recent deep venous thrombosis, severe lymphedema, or large legs may not be suitable candidates. Subfascial endoscopic perforating vein surgery has been performed for recurrent disease after previous perforating vein interruption; however, it is technically more demanding in this situation. Owing to limitations of space in this subfascial compartment, limbs with lateral ulcerations should be managed by open interruption or percutaneous ablation of lateral or posterior perforating veins where appropriate.

PREOPERATIVE EVALUATION Preoperative evaluation includes imaging studies to document superﬁcial, deep, and/or perforating vein incompetence and to guide the operative intervention. The preferred test is duplex scanning. Ascending and descending phlebography is reserved for patients with underlying occlusive disease or recurrent ulceration after perforating vein division in whom deep venous reconstruction is being considered. Preoperative duplex mapping assists the surgeon in identifying all incompetent perforating veins at the time of operation. Duplex scanning is performed with the patient on a tilted examining table with the affected extremity in a near upright non-weight-bearing position. Perforating vein incompetence is deﬁned by retrograde (outward) ﬂow lasting longer than 0.3 seconds or longer than antegrade ﬂow during the relaxation phase after release of manual compression. Duplex scanning has 100% speciﬁcity and the highest sensitivity of all diagnostic tests to predict the sites of incompetent perforating veins.18 All identiﬁed perforating veins are marked on the skin with a non-erasable marker. In addition to duplex scanning, a functional study such as strain gauge or air plethysmography is performed before and after surgery to quantitate the degree of incompetence, identify abnormalities in calf muscle pump function, aid in the exclusion of outﬂow obstruction, and assess hemodynamic results of surgical intervention.

OPEN SURGICAL TECHNIQUES Open surgical techniques of perforating vein ablation are discussed here to serve as historical background. Linton’s initial description of subfascial perforator ligation included long incisions not only medially but also anteroand posterolaterally. This approach was soon abandoned by Linton owing to the high rate of wound

complications.19 Linton modiﬁed the original approach in 1953 to include only the medial incision through which all medial and posterior perforating veins were ligated. The modiﬁed Linton procedure also included stripping of both the great and small saphenous veins and excision of a portion of the deep fascia. The medial incision continued to be placed through the most diseased, lipodermatosclerotic skin and wound complications remained high. When studied in a prospective manner, the signiﬁcant wound complication rate was documented at 53%.18 In attempts to decrease these wound complications several authors have attempted further modiﬁcations such as extrafascial ligation proposed by Cockett.3 This approach can potentially miss perforating vein branches that occur subfascially but branch extensively on exiting the fascia.12 Moving the incision further posterolateral (stocking seam incision) has also been described, but when extensive skin changes are present this does not solve the problem and the subfascial dissection is still extensive.3,20 DePalma21 limited wound complications by using parallel incisions along the natural skin lines to create bipedical ﬂaps though which he could access the perforating veins. To decrease wound complications further, a technique to ablate incompetent perforating veins from sites remote from diseased skin was ﬁrst reported by Edwards in 1976.22 He designed a device, called the phlebotome, which is inserted through a medial incision just distal to the knee, deep to the fascia, and advanced to the level of the medial malleolus. Resistance is felt as perforators are engaged and subsequently disrupted with the leading edge. Other authors have subsequently reported successful application of this device, passed in either the subfascial or extrafascial plane. Interruption of perforating veins through stab wounds and hook avulsion is another possibility, and accuracy of this blind technique will improve if duplex scanning is used for mapping. Suture ligation of perforators without making skin incisions is another reported technique. With the widespread use of ultrasound-guided techniques some phlebologists will localize perforators and do a small, direct cut-down, thus minimizing the extent of the operation.

ENDOSCOPIC SURGICAL TECHNIQUES Since its introduction, two main techniques for SEPS have been developed. The ﬁrst, practiced mostly in Europe, is a reﬁnement of the original work of Hauer7 with further development by Bergan et al.23 and by Wittens et al.18 and Pierik.24 In the early development of the “single port” technique available light sources such as mediastinoscopes and bronchoscopes were used. With time a specially designed instrument was devised which uses a single scope with two channels for the camera and working instruments, which sometimes makes visualization and dissection in the same plane difﬁcult (Fig. 47.1). Recent

526

The management of incompetent perforating veins with open and endoscopic surgery

Insufflation port Skin seal with lock ring

Obturator handle

Balloon cover handle 10/11 mm Trocar Balloon cover

Balloon inflation fittings

Tunneling dilator with preloaded balloon

Olive-tipped guide rod

(a)

Figure 47.1 Olympus endoscope for the subfascial perforating vein interruption. The scope can be used with or without carbon dioxide insufﬂation. It has an 85° angle ﬁeld of view, and the outer sheath is either 16 or 22 mm in diameter. The working channel is 6 × 8.5 mm, with a working length of 20 cm. (From Bergan JJ, Ballard JL, Sparks S. Subfascial endoscopic perforator surgery: the open technique. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer Verlag, 1998: 141–9.)

developments in instrumentation for this technique now allow for carbon dioxide (CO2) insufﬂation into the subfascial plane. The second technique, the “ two-port” technique utilizes standard laparoscopic instrumentation and two ports, one for the camera and another for dissection. O’Donnell25 initially described this approach in the USA, and it was then simultaneously developed by our group at the Mayo Clinic26 and by Conrad27 in Australia. To provide a bloodless operative ﬁeld the limb is ﬁrst exsanguinated with an Esmarque bandage, and a pneumatic tourniquet placed on the proximal thigh is then inﬂated to 300 mmHg. Two 10 mm diameter endoscopic ports are placed in the medial aspect of the calf 10 cm distal to the tibial tuberosity and about 10–12 cm apart, proximal to the diseased skin. It is now routine to perform the procedure with a 5 mm distal port, since the availability of 5 mm harmonic scalpel and excellent 5 mm instruments (scissors, dissecting instruments). The distal port is placed half-way between the ﬁrst port and the ankle, for easier dissection. The 10 mm camera withstands the torque better than a 5 mm device and reaches all the way to the medial malleolus. We are now routinely using balloon dissection to widen the subfascial space and facilitate access after port placement (Fig. 47.2).28 Carbon dioxide is insufﬂated into the subfascial space and pressure is maintained around 30 mmHg to improve visualization and access to the perforators. Using laparoscopic scissors inserted through the second port, the remaining loose connective tissue between the calf muscles and the superﬁcial fascia is sharply divided.

(b) Figure 47.2 (a) Components of balloon dissector (General Surgical Innovations, Palo Alto, CA, USA) for creation of a large subfascial working space. An integral 10 mm endoscopic port is included. (b) The balloon dissector device before (top) and after (bottom) balloon cover removal. Note the degree of radial and distal balloon expansion that occurs when fully inﬂated with saline solution. Balloon inﬂation is performed with 200–300 mL of saline. The balloon expands both radially and distally with minimal trauma to surrounding tissue, thus creating a large bloodless working space. (From Allen RC, Tawes RL, Wetter A, Fogarty T. Endoscopic perforator vein surgery: creation of a subfascial space. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer Verlag, 1998: 153–62.)

The subfascial space is widely explored from the medial border of the tibia to the posterior midline and down to the level of the ankle. All perforators encountered are divided with the harmonic scalpel, electrocautery, or sharply between clips (Fig. 47.3). A paratibial fasciotomy is next made by incising the fascia of the posterior deep compartment close to the tibia to avoid injury to the posterior tibial vessels and nerve (Fig. 47.3b). The Cockett II and Cockett III perforating veins are located frequently within an intermuscular septum, and this has to be incised before identiﬁcation and division of the perforating veins

Endoscopic surgical techniques 527

can be accomplished. The medial insertion of the soleus muscle on the tibia may also have to be exposed to visualize proximal paratibial perforating veins. By rotating the ports cephalad and continuing the dissection up to the level of the knee, the more proximal perforating veins can also be divided. While the paratibial fasciotomy can aid in distal exposure, reaching retromalleolar Cockett I perforating vein endoscopically is usually not possible, and, if incompetent, may require a separate small incision over it to gain direct exposure. After completion of the endoscopic portion of the procedure the instruments and ports are removed, the CO2 is manually expressed from the limb and the tourniquet is deﬂated. Twenty milliliters of 0.5% marcain solution is

instilled into the subfascial space for postoperative pain control. Stab avulsion of varicosities in addition to ablation/stripping of the great and/or small saphenous vein, if incompetent, is performed. The wounds are closed and the limb is elevated and wrapped with an elastic bandage. Elevation is maintained at 30° postoperatively for 3 hours, after which ambulation is permitted. Unlike the in-hospital stay after an open Linton procedure, this is an outpatient procedure and patients are discharged the same day. Restrictions are the same as with great saphenous stripping. Patients are allowed to return to work in 10 days to 2 weeks. Proebstle and Herdemann have reported performing SEPS successfully under tumescent local anesthesia alone in 78% of patients.

(a)

(b)

(d)

(c) Figure 47.3 (a) Endoscopic perforator division is performed in a bloodless ﬁeld. A pneumatic tourniquet is placed on the thigh, and the extremity is exsanguinated with an Esmarque bandage. The tourniquet, inﬂated to 300 mmHg, is used to create a bloodless ﬁeld. (From Gloviczki P, Canton LG, Cambria RA, Rhee RY. Subfascial endoscopic perforator vein surgery with gas insufﬂation. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer Verlag, 1998: 125–38.) (b) Balloon dissection is used to widen the subfascial space. (c) Subfascial endoscopic perforator surgery is performed using two ports: a 10 mm camera port and a 5 or 10 mm distal port inserted under video control. Carbon dioxide is insufﬂated through the camera port into the subfascial space to a pressure of 30 mmHg to improve visualization and access to perforators. (From Gloviczki et al.26) (d) The subfascial space is widely explored from the medial border of the tibia to the posterior midline and down to the level of the ankle. Division of the perforator with endoscopic scissors after placement of vascular clips or harmonic scalpel placed through the second port. (From Gloviczki et al.26)

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The management of incompetent perforating veins with open and endoscopic surgery

(f)

(e) Figure 47.3 (contd) (e) A paratibial fasciotomy is routinely performed to identify perforators in the deep posterior compartment. (From Gloviczki P, Canton LG, Cambria RA, Rhee RY. Subfascial endoscopic perforator vein surgery with gas insufﬂation. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London: Springer Verlag, 1998: 125–38). (f) Full view of the superﬁcial posterior compartment after clipping and division of the medial perforating veins. (From Gloviczki et al.26)

ULTRASOUND-GUIDED TECHNIQUES Although these will be covered in more detail in other chapters, the emerging ofﬁce-based therapies of endovenous perforator vein ablation and ultrasound-guided sclerotherapy deserve mention here to place them in context of the natural evolution in the treatment of perforator incompetence. Endovenous perforating vein ablation arose from the treatment of superﬁcial saphenous reﬂux with both radiofrequency ablation and endovenous laser ablation of the saphenous veins. The procedure is technically much more demanding because of the short and often tortuous nature of these perforating veins.10,11 Ultrasound-guided foam sclerotherapy (UGS) is another ofﬁce-based procedure for the treatment of perforator incompetence. There are many different agents and techniques for this and the reader is referred to Chapter 33 for further details of these agents, although liquid sclerotherapy has also been used for the treatment of perforators with good results.9

RESULTS OF PERFORATING VEIN ABLATION Clinical results The need for perforating vein interruption remains a subject of debate as the signiﬁcance of incompetent perforating veins and their contribution to the severity of CVI remains in question. The controversy is whether the incompetent perforating veins are the cause or the effect of the global venous incompetence in the limb and, if they are contributing to the disease process, whether their relative

contribution is enough to warrant speciﬁc treatment of it. This debate continues because of the lack of direct comparative studies in large enough patient samples to make conclusions. In their seminal papers, Linton2 and Cockett3 reported the initial clinical beneﬁts of open perforator ligation. Table 47.1 summarizes the results from 10 reports of open perforating vein ablation in nearly 600 limbs performed since the 1970s. The ulcer healing rate was excellent at 89%. Ulcer recurrence was 23% over 2–5 years but most of these reports originated prior to the present-day reporting standards and the patient populations are likely heterogeneous. Burnand et al.29 brought the utility of open perforating vein ablation into question with the report of a 55% ulcer recurrence rate in their surgical patients. Although the post-thrombotic subset (Es) rate was 100%, the mere 6% recurrence rate in those patients with primary valvular insufﬁciency (Ep) was obscured by the high recurrence. Despite the apparent beneﬁt in the Ep subset, both the long recovery period after open perforating vein ablation combined with a signiﬁcant wound complication rate of 25% on average led to abandonment of open perforating vein ligation, interest in it now being for historical purposes only. This was solidiﬁed by Pierek et al.18 in their randomized trial comparing open and endoscopic perforating vein ablation that had to be terminated early because of the high (53%) wound complication rate in the open group compared with 0% in the SEPS group with no ulcer recurrence in either group over a mean follow-up of 21 months. With the advent of SEPS, the wound complication rate of perforating vein ablation and prolonged recovery period seen with the modiﬁed Linton procedure were no longer major concerns as documented by multiple reports

Results of perforating vein ablation

529

Table 47.1 Clinical results of open perforator interruption for the treatment of advanced chronic venous disease Author, year

Silver et al.,42 1971 Thurston and Williams,43 1973 Bowen,44 1975 Burnand et al.,29 1976 Negus and Friedgood,5 1983 Wilkinson and Maclaren,6 1986 Cikrit et al.,45 1988 Bradbury et al.,46 1993 Pierik et al.,18 1997 Sato et al.,30 1999 Total

No. of limbs treated

No. of limbs with ulcer

31 102 71 41 108 108 32 53 19 29 594 (100)

19 0 8 0 108 0 30 0 19 19 203 (34)

Wound complications, no. (%) 4 (14) 12 (12) 31 (44) – 24 (22) 26 (24) 6 (19) – 10 (53) 13 (45) 126/497 (25)

Ulcer healing, no. (%)

Ulcer recurrence, no. (%)*

Mean follow-up (years)

– † – †

– (10) 11 (13) 24 (34) 24 (55) 16 (15) 3 (7) 5 (19) 14 (26) 0 (0) 13 (68) 110/471 (23)

1–15 3.3 4.5 – 3.7 6 4 5 1.8 2.9 –

91 (84) † 30 (100) † 17 (90) 19 (100) 157/176 (89)

*Recurrence calculated where data available and percentage accounts for patients lost to follow-up. †Only class 5 (healed ulcer) patients admitted in study.

from centers in both Europe and North America.8,18,23,30,31 These series also documented the safety and efﬁcacy of SEPS with rapid ulcer healing and early low recurrence rates. With extended follow-up, however, ulcer recurrence rates seen with SEPS have proven to be similar to those seen historically with open ablation. In reporting late results of their prospective randomized study comparing SEPS with open perforator ligation Sybrandy et al.32 noted no signiﬁcant difference in ulcer recurrence: 22% vs 12% respectively. The mid-term (24 months) results of the North American (NASEPS) registry, reporting on SEPS performed in 17 US centers, demonstrated an 88% cumulative ulcer healing rate at 1 year (Fig. 47.4).8 The median time to ulcer healing was 54 days. Cumulative rate of ulcer recurrence was signiﬁcant: 16% at 1 year, 28 % at 2 years (Fig. 47.5). In the largest series from a single institution, Nelzen31 reported on prospectively collected

(a)

data from 149 SEPS procedures in 138 patients. During a median follow-up of 32 months, 32 of 36 ulcers healed, more than half (19/36) within 1 month. Three ulcers recurred, one of which subsequently healed during followup. Table 47.2 summarizes data from 13 separate reports in over 800 limbs during a 12 year period. The ulcer healing rate of 90% is indistinguishable from that seen in open perforating vein ablation. The crude ulcer recurrence rate is also comparable at 11%, although the follow-up was slightly less in the SEPS series ranging from just under 1 year to almost 4 years. TenBrook and colleagues33 did a systematic review and a combined statistical analysis of the reported series on SEPS that included a total of 1140 limbs. They found similar results as listed in Table 47.2 but identiﬁed that presence of a large ulcer (> 2 cm), secondary etiology of the venous disease (Es), and presence of persistent

(b)

100

80

80 78%

Percentage

Percentage

100

93%

88%

60 40

71%

60 40 41% 20

20

Median 35 days

Median 54 days 0

0 0

3

6

9

12

15

0

18

2

4

Limbs at risk 101

52

34

25

21

15

6

8

10

12

Months

Months

(a)

89%

85%

80%

9

7

5

Limbs at risk 42

24

12

8

5

3

(b)

Figure 47.4 (a) Cumulative ulcer healing in 101 patients after subfascial endoscopic perforator vein surgery. The 90 day, 1 year, and 1.5 year healing rates are indicated. The standard error is less than 10% at all time points. (From Gloviczki et al.8) (b) Cumulative ulcer healing in 42 patients after subfascial endoscopic perforator surgery. The 90 day and 1 year healing rates are indicated. The standard error is less than 10% at all time points. (From Kalra et al.34)

The management of incompetent perforating veins with open and endoscopic surgery

100

100

80

80

Percentage

Percentage

530

60 39%

40

28% 16%

20

60 27%

40

20%

20 4% 0

0 0

1

2

0

3

1

2

Limbs at risk 106

74

63

57

3

4

5

Years

Years 33

22

13

(a)

Limbs at risk 72

64

46

18

34

(b)

Figure 47.5 (a) Cumulative ulcer recurrence in 106 patients after subfascial endoscopic perforating vein surgery (SEPS). The 1, 2, and 3 year recurrence rates are indicated. All class 5 limbs at the time of SEPS and class 6 limbs that subsequently healed are included. The start point (day 0) for time to recurrence in class 6 patients was the date of initial ulcer healing. The standard error is less than 10% at all time points. (From Gloviczki et al.8) (b) Cumulative ulcer recurrence in 72 patients after SEPS. The 1, 3, and 5 year recurrence rates are indicated. All class 5 limbs at the time of SEPS and class 6 limbs that subsequently healed are included. The start point (day 0) for time to recurrence in class 6 patients was the date of initial ulcer healing. The standard error is less than 10% at all time points. (From Kalra et al.34)

Table 47.2 Clinical results of subfascial endoscopic perforator surgery for the treatment of advanced chronic venous disease Author, year

Jugenheimer and Junginger,47 1992 Pierek et al.,48 1995 Bergan et al.,23 1996 Wolters et al.,49 1996 Padberg et al.,40 1996 Pierek et al.,50 1997 Gloviczki et al.,8 1999 Illig et al.,51 1999 Sato et al.,30 1999 Nelzen,31 2001 Kalra et al.,34 2002 Iarati et al.,52 2002 Baron et al.,53 2004 Total no. of limbs (%)

No. of limbs treated

103 40 31 27 11 20 146 30 27 149 103 51 98 836 (100)

No. of limbs with ulcer*

17 16 15 27 0 20 101 19 20 36 42 29 53 395 (47)

Concomitant saphenous ablation, no. (%) 97 (94) 4 (10) 31 (100) 0 (0) 11 (100) 14 (70) 86 (59) – 17 (63) 132 (89) 74 (72) 33 (65) 36 (42) 535/789 (68)

Wound Ulcer complications, healing, no. (%) no. (%)

3 (3) 3 (8) 3 (10) 2 (7) – 0 (0) 9 (6) – 2 (7) 11 (7) 7 (6) 3 (6) – 50/680 (7)

16 (94) 16 (100) 15 (100) 26 (96) ‡ 17 (85) 85 (84) 17 (89) 18 (90) 32 (89) 38 (90) 22 (76) 53 (100) 355/395 (90)

Ulcer recurrence, no. (%)†

0 (0) 1 (2.5) (0) 2 (8) 0 (0) 0 (0) 26 (21) 4 (15) 5 (28) 3 (5) 15 (21) 6 (13) 0 (0) 62/580 (11)

Mean follow-up (months)

27 46 – 12–24 16 21 24 9 8 32 40 38 – –

*Only patients with class 6 (active ulcer) are included. †Only patients with class 5 (healed ulcer) were admitted in this study. ‡Recurrence calculated for classes 5 and 6 limbs only, where data available and percentage accounts for patients lost to follow-up.

incompetent perforating veins postoperatively were all risk factors for non-healing of the ulcers. Interestingly, the presence of deep venous incompetence was not an identiﬁable risk factor for non-healing of the ulcers or recurrence. Kalra et al.34 for the Mayo Clinic speciﬁcally examined their results in these post-thrombotic patients. Although the 5 year ulcer recurrence was signiﬁcantly higher in this subgroup (Ep 15% vs Es 56%) they still gained clinical beneﬁt as measured by improved venous

clinical severity scores as well as an apparent ease in treating the smaller, superﬁcial ulcers compared with their preoperative state (Figs 47.6 and 47.7). The Dutch SEPS trial was the ﬁrst of its kind – a randomized multicenter trial prospectively comparing surgical treatment (SEPS with or without superﬁcial reﬂux ablation) with medical treatment (ambulatory venous compression) in patients with venous ulcers.35 The study included 200 patients, 97 randomized to medical treatment and 103 in the surgical

Results of perforating vein ablation

100

Percentage

P = 0.001

Primary valvular incompetence Post-thrombotic syndrome

80

56%

60 47% 40 20

16%

0

0% 0

1

15% 8% 2

3

4

5

Years

Limbs at risk PVI 51

49

34

28

14

9

PT 21

16

12

7

5

3

Figure 47.6 Ulcer recurrence based on cause of chronic venous insufﬁciency. Limbs were separated into primary valvular incompetence (n = 51) and post-thrombotic syndrome (n = 21). The 1, 3, and 5 year recurrence rates are indicated. The dashed line represents a standard error of greater than 10%. Primary valvular incompetence versus post-thrombotic syndrome (P < 0.05). (From Kalra et al.34)

14 Median Mean

12

Clinical score

10

attributed to SEPS alone. Patients undergoing SEPS and accessory vein avulsion without saphenous stripping have been shown to have signiﬁcant clinical improvement as measured by venous clinical severity scores (VCSS).37 The NASEPS registry demonstrated improved ulcer healing in limbs that underwent SEPS with saphenous vein stripping compared with limbs that underwent SEPS alone: 3 and 12 month cumulative ulcer healing rates of 76% and 100% vs 45% and 83%, respectively (Table 47.2).8 Ulcer recurrence at 3 years was not signiﬁcantly different among the two groups. Although this is indirect evidence, it does support the clinical beneﬁt of addressing perforating vein incompetence. We attempted to study this in our analysis of 103 limbs.34 Ulcer healing was signiﬁcantly delayed in limbs undergoing SEPS alone compared with limbs that underwent SEPS with superﬁcial reﬂux ablation: 90 day cumulative ulcer healing rate was 49% vs 90%, respectively. Cumulative ulcer recurrence at 5 years was also higher in limbs that underwent SEPS alone (53%) than those undergoing SEPS with superﬁcial reﬂux ablation (19%) (Fig. 47.8). However, all limbs in the SEPS alone group had recurrent or persistent ulcers after previously having undergone saphenous vein ligation and stripping, and there was a relative predominance of Es limbs in this group.

9.5

8

P = 0.001 6

6

3 1.5

0 Preop

Hemodynamic results

P = 0.0001

4 2

531

Postop

Primary valvular incompetence

Preop

Postop

Post-thrombotic syndrome

Similar to the debate over clinical effectiveness, there is ongoing controversy about hemodynamic improvement that can be attributed to perforator interruption. Because perforator incompetence is frequently treated together with ablation of superﬁcial reﬂux, postoperative hemodynamic measurements reﬂect results of a combined operation. Akesson et al.38 demonstrated a signiﬁcant

Figure 47.7 Preoperative and postoperative clinical scores based on the etiology of chronic venous insufﬁciency. Limbs were separated into primary valvular incompetence (n = 73) and limbs with post-thrombotic syndrome (n = 30). (From Kalra et al.34)

100

Percentage

group. The ulcer healing rate of 83% and recurrence in the surgical group of 22% at 29 months in this trial are comparable to previously reported results. In the conservative group, ulcers healed in 73% and recurred in 23%. Ulcer size and duration were independent factors adversely affecting ulcer healing and recurrence. On extended follow-up the authors reported that the ulcerfree rate was signiﬁcantly greater in the surgical group (72% vs 53%) as was the ulcer-free period.36 It must be emphasized that the majority (more than two-thirds) of patients reported in the above studies underwent concomitant saphenous vein stripping and branch varicosity avulsion (Table 47.2), making it difﬁcult to ascertain how much clinical improvement can be

P=0.01

SEPS alone SEPS +stripping

80 60

53% 41%

40

19%

20

12% 2%

0 0

1

14%

2

3

4

5

Years Limbs at risk 16 SEPS alone

12

8

5

1

1

SEPS + stripping 56

52

38

29

17

11

Figure 47.8 Ulcer recurrence based on the extent of venous surgery. Limbs undergoing subfascial endoscopic perforator surgery (SEPS) alone (n = 16) and limbs undergoing SEPS with saphenous vein stripping (n = 56). The 1, 3, and 5 year recurrence rates are indicated. SEPS alone vs SEPS with saphenous vein stripping (P < 0.05). (From Kalra et al.34)

The management of incompetent perforating veins with open and endoscopic surgery

Refill volume (mL/100 mL tissue)

0.8

*

Preoperative Postoperative

0.6

0.4 *

0.2

0.0 Operated limbs

Nonoperated limbs

(a) 15

* Refill rate (ml/100 ml tissue/min)

reduction in ambulatory venous pressure (AVP) after saphenous stripping in patients with recurrent venous ulcers, but the improvement in mean AVP did not reach signiﬁcance after further perforator interruption. In a classic study, however, using AVP measurements, Schanzer and Pierce39 documented signiﬁcant hemodynamic improvements after isolated perforator interruption in 22 patients. These results were conﬁrmed in a 1992 air plethysmographic study by Padberg and colleagues,40 using foot volumetry and duplex scanning. At a median follow-up of 66 months, in patients with no ulcer recurrence both expulsion fraction and half-reﬁlling time had improved signiﬁcantly. We used strain-gauge plethysmography to quantitate calf muscle pump function and venous incompetence before and after SEPS (Figs 47.9 and 47.10).37 We observed signiﬁcant improvement in both calf muscle pump function and venous incompetence in 31 limbs studied within 6 months after SEPS. Twentyfour of the 31 limbs underwent saphenous stripping in addition to SEPS. Although the seven limbs undergoing SEPS alone had signiﬁcant clinical beneﬁts, the hemodynamic improvements did not reach statistical signiﬁcance. Proebstle et al.41 reported that Ep patients demonstrate signiﬁcantly better hemodynamic improvement than Es limbs.41 Further research for the best preoperative test with which to determine the hemodynamic effects of incompetent perforators and to help select patients for perforator interruption is clearly justiﬁed. As less invasive techniques have evolved, often being performed in the ofﬁce setting under local anesthetic, we may now have the ability to better delineate the role of these incompetent perforating veins by treating the overall venous incompetence in the leg in a stepwise fashion. At present, the body of literature on these other treatments, percutaneous endovenous perforating vein ablation and ultrasoundguided sclerotherapy of perforating veins, is limited and results have focused on technical success rather than clinical and hemodynamic improvements. These topics are discussed in greater depth in other chapters. Masuda et al.9 reported their clinical results with UGS with sodium morrhuate in 80 limbs with predominantly perforator incompetence alone. After treatment there was a signiﬁcant improvement in Venous Clinical Severity Score and an 86.5% ulcer healing rate with a mean time to heal of 36 days. The ulcer recurrence rate was 32% at a mean of 20 months despite only a 15% compliance with compression hose. These results are very similar to those seen in the NASEPS registry (all patients, 28% recurrence at 2 years; SEPS only, 35% at 2 years).8 New and recurrent perforating veins were identiﬁed in 33% of limbs and ulcer recurrence was statistically associated with perforating vein recurrence as well as presence of post-thrombotic syndrome (Es). Based on available data it seems likely that the clinical outcome and hemodynamic beneﬁt of perforating vein ligation will be similar regardless of the method of ablation: open, endoscopic, or endovenous.

Preoperative Postoperative

10

* 5

0

Operated limbs

Nonoperated limbs

(b) Figure 47.9 (a) Calf muscle pump function (reﬁll volume) measured in 28 limbs before and after subfascial endoscopic perforator vein surgery and in 18 contralateral non-operated limbs. Asterisk, P < 0.01; dashed line, normal reﬁll volume ≥ 0.7 mL/100 mL tissue. (From Rhodes et al.37) (b) Venous incompetence as assessed by reﬁll rate after passive drainage both pre- and postoperatively in the operated (n = 30) and nonoperated contralateral limbs (n = 20). Asterisk P < 0.001; dashed line, normal reﬁll rate ≤ 5.0 mL/100 mL tissue per minute. (Adapted from Rhodes et al.37 with permission.)

25

Refill rate improvement (ml/100 ml tissue/min)

532

20 15 10 5 0 ⫺5 0

2

4 6 8 Clinical score improvement

10

12

Figure 47.10 Correlation between clinical and hemodynamic improvement measured by reﬁll rate after subfascial endoscopic perforator surgery with or without ablation of superﬁcial reﬂux (n = 29). The mean values ± SEM and the results of linear regression analysis are depicted with 95% conﬁdence intervals (r = 0.77, P < 0.01). (Adapted from Rhodes et al.37 with permission.)

References 533

Guidelines 4.20.0 of the American Venous Forum on the management of incompetent perforating veins with open and endoscopic surgery No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.20.1 For open surgical treatment we no longer recommend the modiﬁed open Linton procedure owing to associated morbidities

1

A

4.20.2 We suggest treatment of perforator incompetence in patients with advanced venous disease to improve venous hemodynamics and clinical outcomes

2

B

4.20.3 We suggest perforator interruption preferentially in patients with primary valvular incompetence and less so in those with post-thrombotic syndrome

2

B

CONCLUSIONS Treatment of perforating vein incompetence in patients with advanced chronic venous disease remains controversial. The debate has continued because of the lack of studies that address isolated treatment of perforating vein incompetence. Use of more radical open perforating vein ablative techniques is considered of historical interest only and is not advised. Treatment of superﬁcial axial reﬂux is clearly beneﬁcial in patients with advanced chronic venous insufﬁciency. The addition of perforating vein ablation by SEPS appears to add to the overall hemodynamic and clinical beneﬁt, although the exact degree of beneﬁt remains undetermined. Despite the increasing popularity of ofﬁce-based endovenous techniques of perforating vein ablation, they are still in their infancy and clinical efﬁcacy needs to be proven before they can be endorsed as alternatives to SEPS and widespread use recommended.

REFERENCES ★

= First formal publication of a management guideline 1. Gay J. Lettsonian Lectures 1867. Varicose Disease of the Lower Extremities. London: Churchill, 1868. 2. Linton RR. The operative treatment of varicose veins and ulcers, based upon a classiﬁcation of these lesions. Ann Surg 1938; 107: 582–93. 3. Cockett FB. The pathology and treatment of venous ulcers of the leg. Br J Surg 1956; 43: 260–78. 4. Dodd H. The diagnosis and ligation of incompetent perforating veins. Ann R Coll Surg Engl 1964; 34: 186–96. 5. Negus D, Friedgood A. The effective management of venous ulceration. Br J Surg. 1983; 70: 623–7.

6. Wilkinson GE Jr, Maclaren IF. Long term review of procedures for venous perforator insufﬁciency. Surg Gynecol Obstet 1986; 163: 117–20. 7. Hauer G. Endoscopic subfascial discussion of perforating veins: preliminary report (in German). Vasa 1985; 14: 59–61. ★8. Gloviczki P, Bergan JJ, Rhodes JM, et al. Mid-term results of endoscopic perforator vein interruption for chronic venous insufﬁciency: lessons learned from the North American subfascial endoscopic perforator surgery registry. The North American Study Group. J Vasc Surg 1999; 29: 489–502. 9. Masuda EM, Kessler DM, Lurie F, et al. The effect of ultrasound-guided sclerotherapy of incompetent perforator veins on venous clinical severity and disability scores. J Vasc Surg 2006; 43: 551–7. 10. Peden E, Lumsden A. Radiofrequency ablation of incompetent perforator veins. Perspect Vasc Surg Endovasc Ther 2007; 1: 73–7. 11. Proebstle TM, Herdemann S. Early results and feasibility of incompetent perforator vein ablation by endovenous laser treatment. Dermatol Surg 2007; 33: 162–8. ★12. Mozes G, Gloviczki P, Menawat SS, et al. Surgical anatomy for endoscopic subfascial division of perforating veins. J Vasc Surg 1996; 24: 800–8. 13. Beecher HK, Field ME, Krogh A. The effect of walking on the venous pressure at the ankle. Skand Arch F Physiol 1936; 73: 133–40. ★14. Labropoulos N, Delis K, Nicolaides AN, et al. The role of the distribution and anatomic extent of reﬂux in the development of signs and symptoms in chronic venous insufﬁciency. J Vasc Surg 1996; 23: 504–10. ★15. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised control trial. Lancet 2004; 363: 1854–9.

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★33.

★34.

★35.

★36.

★37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

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48. Pierik EGJM, Wittens CHA, van Urk H. Subfascial endoscopic ligation in the treatment of incompetent perforator veins. Eur J Vasc Endovasc Surg 1995; 5: 38–41. 49. Wolters U, Schmit-Rixen T, Erasmi H, Lynch J. Endoscopic dissection of incompetent perforating veins in the treatment of chronic venous leg ulcers. Vasc Surg 1996; 30: 481–7. 50. Pierik EG, van Urk H, Wittens CH. Efﬁcacy of subfascial endoscopy in eradicating perforating veins of the lower leg and its relation with venous ulcer healing. J Vasc Surg 1997; 26: 255–9.

51. Illig KA, Shortell CK, Ouriel K, et al. Photoplethysmography and calf muscle pump function after subfascial endoscopic perforator ligation. [see comments]. J Vasc Surg 1999; 30: 1067–76. ★52. Iafrati MD, Pare GJ, O’Donnell TF, Estes J. Is the nihilistic approach to surgical reduction of superﬁcial and perforator vein incompetence for venous ulcer justiﬁed? J Vasc Surg 2002; 36: 1167–74. 53. Baron HC, Wayne MG, Santiago CA, Grossi R. Endoscopic perforator vein surgery for patients with severe chronic venous insufﬁciency. Vasc Endovasc Surg 2004; 38: 439–42.

48 Percutaneous ablation of perforating veins STEVE ELIAS Introduction History Theoretic advantages Theoretic disadvantages

536 536 537 537

INTRODUCTION This chapter will introduce a new term for the minimally invasive management of incompetent perforating veins, PAPs or percutaneous ablation of perforators. The acronym is analogous to SEPS or subfascial endoscopic perforator surgery. All methods of PAPs have certain commonalities: (1) ultrasound-guided percutaneous intravenous access, (2) application of some energy source within the lumen leading to vein wall contraction and/or occlusion, (3) local anesthesia with possibly some form of sedation (oral or intravenous), (4) an outpatient ofﬁce location, and (5) simple retreatment, if needed. PAPs is a natural progression of endovenous ablative procedures utilized for great, small, and accessory saphenous venous incompetence. The term PAPs was initially introduced in April 2005.1

HISTORY Although the term PAPs may be relatively new, the concept is not. As early as 19742 liquid sclerosant has been used with fairly good clinical results.3,4 In previous sections of this book the indications, technique, and results of more traditional perforator management have been discussed. This chapter will not cover the indications or justiﬁcation for treating incompetent perforating veins (IPVs). The indications for PAPs are the same as other methods used to treat incompetent perforators. However, four assumptions are made: (1) perforator incompetence is a signiﬁcant source of venous hypertension, (2) it is important to treat IPVs, (3) other methods of perforator treatment have

Technique Results Summary References

537 540 542 543

some inherent limitations of technique, and (4) PAPs may circumvent these limitations. Assumptions 1 and 2 are addressed in other chapters and by many others.5–7 Assumptions 3 and 4 are encompassed within this chapter. Of course, PAPs has its own inherent issues and limitations which will be discussed later on. More traditional methods such as the Linton procedure and its modiﬁcations of open perforator ligation have a relatively high incidence of wound complications ranging from 20% to 40%.8,9 These older procedures require general or regional anesthesia and involve an in-hospital stay of 3–5 days. The use of local anesthesia has been reported.10 Postoperative pain is signiﬁcant and may require narcotics. The SEPS procedure overcomes some of Linton’s limitations but has some of its own. Wound infection rates are dramatically lower, ranging from 3% to 5%.11 This is because of incisions made remote from the affected skin at the perimalleolar area.12 The ability to access and ligate perforators located close to the malleolus can be limited by the angulation of the working instruments involving “sword ﬁghting” in the subfascial space, a large edematous extremity, and the inability of the operator to open and explore the deep posterior compartment. Attempts to modify these shortcomings have been addressed in the past, but some have not been commercially available or adopted on a widespread basis.13,14 Although SEPS is usually performed on an outpatient basis, it still requires regional or general anesthesia and can be associated with moderate pain and nerve injury.15 Subfascial endoscopic perforator surgery certainly is an advance in perforator treatment compared with open perforator ligation techniques.16,17 Yet despite the adoption and utilization of SEPS since the mid-1990s,

Technique 537

challenges have been encountered. The learning curve of SEPS may have hindered more global adaptation.

THEORETIC ADVANTAGES Conceptually, PAPs overcomes some of the issues discussed above. The theoretic advantages will be discussed ﬁrst and then the actual technique and realistic results and goals will be analyzed. Percutaneous ablation of perforators is performed in an ofﬁce or ambulatory center setting with local and/or oral intravenous sedation. Most PAPs are carried out with local anesthesia alone. This overcomes the necessity for general or regional anesthesia. Theoretically, a percutaneous approach should decrease wound or infection complications to near zero. Dissection of tissue is non-existent, thus not separating or stretching tissue (SEPS) or cutting and undermining tissue (open ligation). Postoperative pain is minimal and generally can be managed with nonsteroidal anti-inﬂammatory drugs (NSAIDs) or no pain medication whatsoever. If in the course of lifelong followup patients develop new or recurrent perforators, PAPs is easily repeatable with minimal morbidity. New or recurrent perforator disease is a well-described entity and these patients may require multiple interventions lifelong.18,19 One of the main technical issues of SEPS is access to distal (close to malleolus) perforators. The location of perforating veins does not matter with PAPs; as long as a perforating vein is visualized, it can be accessed and ablated. Even inframalleolar perforating veins can be treated. A ﬁnal theoretic advantage is better physician and patient acceptance of this minimally invasive procedure. However, no procedure is without real or theoretic disadvantages.

healing. Therefore, occluding every IPV with PAPs, although desirable, may not be necessary or practical. Yet, as of this writing, missed treatment of unidentiﬁed IPVs is a theoretic disadvantage of PAPs. Other theoretic disadvantages of PAPs include skin injury, nerve injury and deep vessel injury, as well as recanalization and recurrence of IPVs. This author’s experience and others21 has shown that using current technology and current technique skin, nerve, and deep vessel injury does not occur. Yet, this still remains a minimal but real theoretic disadvantage until long-term data become available. Of course, both open ligation and SEPS procedures also have deep vessel and nerve risk. Lastly, PAPs may share a theoretic disadvantage with SEPS – the learning curve. To access the relatively small IPVs (3–5 mm on average), one needs to be quite familiar with ultrasound-guided percutaneous access. Although they are two or three times larger than competent perforating veins, IPVs are still relatively small.22 With a shorter learning curve, ultrasound-guided access to IPVs, especially low, perimalleolar ones, is much easier with PAPs than with the SEPS technique even in experienced hands using SEPS. In summary, this author feels that most of the theoretical disadvantages of PAPs can be overcome: nerve injury, deep vessel injury, skin injury, and access failure. The issue of missed preoperative IPVs needs to be studied. This may or may not have an adverse clinical result. As of this writing, this issue remains unresolved. If PAPs can achieve as good ulcer healing and decreased ulcer recurrence rates as SEPS studies have14 in a less invasive manner, then it is a viable technique for the treatment of IPVs.

TECHNIQUE THEORETIC DISADVANTAGES The main theoretic disadvantage of PAPs is missed IPVs. One can ablate only those IPVs that are identiﬁed by ultrasound. It has been documented by this author and others that there is an average of two or three more IPVs seen during the time of visual SEPS than were identiﬁed preoperatively.13,14 No matter how diligent one is during the preoperative duplex examination, a certain number of IPVs will not be identiﬁed.20 Whether this affects the ultimate outcome of ulcer healing and maintenance of ulcer healing remains to be evaluated. The “hypertensive threshold” in venous disease is a concept that may have merit. The idea that lowering the ambulatory venous pressure below a certain level is a desirable goal for ulcer healing and decreased ulcer recurrence may be a valid one. The goal of “perfect” ambulatory venous pressure may not be necessary for good clinical results. The goal may be to attain an ambulatory venous pressure below a certain level (unknown at this time) to achieve and maintain ulcer

The basic method, no matter what energy source used, involves (1) ultrasound-guided intraluminal access, (2) instillation of some ablative energy source (chemical or thermal), (3) conﬁrmation of initial treatment success, and (4) follow-up of treatment success. Thus far, the energy used has been either chemical4,21 (sodium tetradecyl sulfate, aethoxysclerol, or sodium morrhuate) or thermal23,24 (radiofrequency or laser). Ultrasound-guided access can be made by needle, angiocatheter, or specialized catheter (Fig. 48.1). Incompetent perforating veins should be visualized by both ultrasound (Fig. 48.2) and duplex imaging (Fig. 48.3). The issue of conﬁrmation of access can be addressed in various ways. Of course, ultrasound intraluminal visualization and aspiration of blood is the sine qua non of access. The radiofrequency catheter (VNUS Medical Technologies, San Jose, CA, USA) also has the ability to measure impedance in ohms. This allows a conﬁrmation of visual, intraluminal placement. As of this writing, using laser or sclerosant only, visual and blood aspiration is the

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Figure 48.1 Catheter/needle at the fascia level.

Figure 48.2 Pretreatment of an incompetent perforating vein by duplex ultrasound.

Figure 48.4 Clips on incompetent perforating veins at fascia level during subfascial endoscopic perforator surgery.

method used to document intraluminal placement. This author performs PAPs with radiofrequency, laser, or chemical energy with equal access success. When access is obtained, it should be at or just below the fascia to minimize deep vessel and nerve injury. This is analogous to SEPS when clips are placed just below the fascia level to minimize nerve and deep vessel injury (Fig. 48.4).The patient is placed in the reverse Trendelenburg position to fully dilate the vein for access. For access, the radiofrequency (RF) catheter, a 16 gauge angiocatheter (for 600 μm laser ﬁber) or a 21 gauge micropuncture needle (for a 400μm laser ﬁber) can be used. For chemical ablation a no. 25 or no. 27 gauge needle is used. If the anatomy of the perforator allows it, a wire may be placed into the deep system for better control of access. After access the various modalities differ enough in the method of energy application. Therefore, each technique will be discussed separately so that key technical points can be elucidated.

Radiofrequency

Figure 48.3 Pretreatment of an incompetent perforating vein by color duplex ultrasound.

As already mentioned, the RF catheter is unique in that it also has the capability to measure impedance in the tissues (Fig. 48.5). It has been this and other authors’ experience that this is quite helpful. There are times when one appears to be intraluminal by duplex imaging with the catheter but impedance readings indicate an extraluminal location. An impedance value between 150 and 350 ohms is indicative of intravascular placement. If the probe is in soft tissue then higher values are registered. This feature is additive to ultrasound visualization. After attaining good placement and a good location level relative to the fascia and deep system, local anesthesia is inﬁltrated around the perforator with ultrasound guidance. The patient is placed in Trendelenburg position.

Technique 539

Figure 48.6 After percutaneous ablation of perforating veins with no ﬂow above the fascia.

Figure 48.5 Radiofrequency catheters.

Both maneuvers – tumescence and Trendelenburg – are done to exsanguinate the vein and improve catheter/vein wall contact. Energy is then applied using a target temperature of 85°C. The RF energy is applied to all four quadrants of the vein wall for 1 minute each. The catheter is then withdrawn 1–2 mm and a second level of vein is treated. If anatomy and access allows, the longer the segment of the vein treated, the better. After energy delivery, pressure is applied to compress the walls of the treated perforator with the ultrasound probe for 1 minute. Immediately after treatment, a duplex scan should show no ﬂow in the treated section of the perforator with normal ﬂow in the deep-paired veins and arteries (Fig. 48.6). Comparison of the pretreatment duplex scan (Fig. 48.3) with the post-PAP scan (Fig. 48.7) should be performed to document adequate energy delivery and success of PAPs. As with any of the other modalities, multiple perforators can be treated in this manner at the same sitting. The ﬂexible RF catheter available may be advantageous in unique circumstances such as a large thigh perforating vein exiting from the great saphenous vein (GSV). Under such conditions, the GSV can be accessed with ultrasound guidance and a wire can be placed into the perforating vein with the ﬂexible catheter following. However, the majority of perforating veins are being treated with the rigid stylettype probe.

Figure 48.7 After percutaneous ablation of perforating veins with no ﬂow in the incompetent perforating vein.

Laser As of this writing, there is no proprietary catheter or system available for treating perforating veins with laser. Prototypes have been proposed and, as with RF, access is key. There are many methods of laser access. This author utilizes two main types: 21 gauge micropuncture needle or a 16 gauge angiocatheter. A direct puncture is made utilizing ultrasound guidance with the patient in the reverse Trendelenburg position. Intraluminal placement is conﬁrmed by ultrasound and aspiration of blood, at or just below the fascial level similar to RF. If a micropuncture needle is used (21 gauge) a 400 μm ﬁber can be passed directly through the needle into the perforating vein with ultrasound visualization (Fig. 48.8). If a 600 μm ﬁber is

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each segment; three segments are usually treated. Proebstle and Herdemann24 also attempt to treat three locations within the perforator (just below fascia, at fascia level, and just above). Each treated segment receives between 60 and 100 joules. After energy delivery, pressure is applied for 1 minute over the perforator with the ultrasound probe, as with RF. When the extremity is wrapped, a pressure bandage is placed with direct pressure over each perforating vein with a cotton ball or something similar. Prior to wrapping, conﬁrmation of occlusion is documented with duplex imaging and patency of the deep vessels is also conﬁrmed. Results have been quite good. These will be discussed later.

Figure 48.8 Laser ﬁber in the incompetent perforating vein.

used, then a 16 gauge angiocatheter is utilized for access as the 600 μm ﬁber diameter is too large for the micropuncture. Once again local anesthesia may be inﬁltrated around the catheter and the patient is placed in the Trendelenburg position. Energy is then applied to the segment, with pressure being applied with the ultrasound probe to ensure ﬁber/vein wall contact. It is advisable to treat as long a segment as possible. Therefore, areas approximately 1–2 mm apart should be treated as the ﬁber is withdrawn with a total of two or three segments. After treatment, signiﬁcant vein wall thickening is seen by ultrasound (Fig. 48.9). There are various methods of energy application used. This author uses a pulsed technique. The generator is set for 15 watts with a 4 second pulse interval. Each segment of vein is treated twice, thus giving 120 joules to

Chemical This method also involves ultrasound-guided access and conﬁrmation with aspiration of blood. Many types of sclerosants have been used: sodium morrhuate, sodium tetradecyl sulfate, or aethoxysclerol. Some advocates use the sclerosant in a liquid state. More recently, foam sclerotherapy has been advocated as being more efﬁcacious. Most studies21,25 use sodium tetradecyl sulfate 3% in the liquid form, injecting 0.5–1 mL of sclerosant, or sodium morrhuate 5% in a similar manner with care being taken not to inject the accompanying artery. As well, the patient’s leg is elevated to avoid ﬂow into the deep system. After infusing the sclerosant, compression is applied with wraps or stockings with direct pressure over the treated perforator.

RESULTS

Figure 48.9 After laser percutaneous ablation of perforating veins, changes can be seen at the vein wall (arrow).

In general, results have been good. It must be remembered that PAPs utilizing thermal energy is quite new and longterm data are not available. Chemical ablation has been performed for longer and more data are available. It seems that the same principles that govern successful endovenous ablation of the great or small saphenous veins apply to PAPs as well. These are good techniques and require adequate energy delivery to the treated vessel. In short, you need to gain access and get the energy source to the tissue you wish to destroy (IPV). If these two principles are satisﬁed, occlusion rates are similar. Initial studies addressed these issues, and the techniques elucidated in the previous section are the results of the trial and error that attempted to set energy delivery parameters and technique. Initial energy delivery was low because of the concern for skin, nerve, and vessel injury. The energy was gradually increased until perforating vein occlusion was attained and skin, nerve, and vessel injury did not occur.

Results 541

Sclerotherapy Sclerotherapy for IPVs has been performed for many years. In 1963, Fegan26 described injection of varicosities adjacent to IPVs in the hope that the sclerosant, sodium tetradecyl sulfate (STD), would course into the IPV. The IPVs were isolated on a clinical basis alone without the use of ultrasound. Thibault and Lewis3 used ultrasoundguided sclerotherapy (UGS) to treat incompetent perforating veins with 3% STD liquid with amounts ranging from 0.5 to 1 mL per IPV. They used compression for 4 weeks. At 6 months, approximately 80–85% of IPVs remained closed. No cases of deep vein thrombosis or nerve injury were reported. The use of either STD 3% or polidocanol 3% for IPVs was reported by Guex28 in 2000. One to three treatment sessions were required to treat IPVs with a 90% success rate. Masuda et al.21 in 2006 reported the use of UGS and sodium morrhuate 5% for the treatment of IPVs. Eighty limbs were treated with an initial success rate of 98%. Follow-up with a mean of 20 months revealed 75% of limbs remained occluded. These patients had isolated IPVs without axial reﬂux at the time of treatment. Venous Clinical Severity Scores improved. Others have used sodium tetradecyl sulfate foam (1–1.5%) to treat IPVs (L. Kabnick, personal communication). Twenty-six perforating veins treated were occluded and reﬂux free at 4 months. The conclusions reached by Masuda et al.21 were that “UGS may lead to fewer skin and wound healing complications, perforating vein recurrence occurs particularly in those with ulcerations, and therefore, surveillance duplex scanning after UGS and repeat injections may be needed.” This statement succinctly describes two key issues of PAPs. In summary, sclerotherapy of IPVs is utilized by many physicians with fairly good results.29 All emphasize the need for continued surveillance to identify what Masuda et al.21 call recurrent or new perforating veins. This concept applies to all methods of PAPs. Complications are similar to other sclerotherapy techniques: hyperpigmentation, phlebitis, skin necrosis, and allergy.3,30 Further follow-up is needed, as with all PAPs, regarding occlusion rates long term, recurrence rates of IPVs, and ulcer recurrence rates. A consensus document by Perrin et al.31 emphasized that UGS of IPVs is a technique worth pursuing.

Radiofrequency As of this writing, there are few published data regarding RF ablation of perforators. Early data were presented as a poster at the Society for Clinical Vascular Surgery (SCVS) meeting in March 2005.32 Chang et al.32 evaluated four conﬁgurations of early RF ablation catheters. Access was obtained with a 12 gauge angiocatheter through which the various catheters were placed. Treatment was either

intravascular or extravascular. A temperature of 85°C was used and applied to the vein for 70 seconds on average without tumescent anesthesia. The procedural success rate was 100% for the 20 perforators treated in 14 limbs. At the week 3 examination, two perforating veins remained open, one with reﬂux and one without. Both of these perforating veins were treated extravascularly. No complications were noted. Chang et al. subsequently reported 6 and 12 month follow-up at the VEITH vascular meeting in November 2005.32 At 6 months, 38 perforating veins were studied. Eighty-seven percent were reﬂux free, but 37% were patent. At 1 year 91% were reﬂux free but 56% were patent. This illustrates a ﬁnding by others: that post-treatment patency does not always reveal post-treatment incompetency. Longer follow-up may ﬁnd that continued patency does correlate with increasing recurrent incompetence. Lumsden et al.23 presented data at the general meeting of the SCVS a year later, reporting on 97 IPVs in 55 limbs from four centers. Access was performed with the use of the 12 gauge RF catheter. Perforators were treated intra- or extravascularly. Intravascular treatment was performed in a manner similar to that described in Techniques. The intravascular occlusion rate was 91.2% (31/34) at 3 weeks. Extravascular treatment was stated as yielding “a signiﬁcantly lower occlusion rate.” Two asymptomatic deep (tibial) vein thromboses occurred which were successfully treated with anticoagulation. Six month follow-up studies were planned. There are unpublished series that also yield short-term occlusion rates with minimal morbidity. This author has treated 20 IPVs with RF for CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) classes 4–6 with a 1 month occlusion rate of 100% and a 4 month occlusion rate of 90%, and a 4 month ulcer-healing rate of 90%. It appears that presented and unpublished data yield good safety and good short-term efﬁcacy using radiofrequency for PAPs.

Laser As with RF, the use of laser energy for PAPs has been performed only very recently. In 2007 Proebstle published early results of PAPS using laser.24 Sixty-seven IPVs were treated in 60 limbs. The majority of patients were CEAP class 2 and only one CEAP class 6. The median diameters of perforating veins were 3.3 mm (range 1.1–8.0 mm). Two wavelengths of laser were used: 940 nm and 1320 nm. The initial pilot study delivered a lower amount of energy to each perforating vein with an average of 130 joules (27 IPVs). With this energy delivery, minimal shrinkage of perforating veins occurred. No morbidity was seen. Therefore, increased energy was applied to the next 40 IPVs with an average of 250–290 joules per IPV. This yielded a signiﬁcant reduction in perforating vein diameter without any increased morbidity. An eccentric

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compression bandage was applied for 24–48 hours; compression hose were then used for another week. An initial occlusion rate at day 1 was 100%. A 3 month follow-up in 16 IPVs revealed continued occlusion in those IPVs that received a total of 250 joules or more at the time of treatment. Again, initial success seems attainable but long-term follow-up needs to be addressed. Kabnick33 has presented data using a 980 nm wavelength. Twenty-ﬁve IPVs with an average size of 4.4 mm were treated. Seventy joules were delivered to each segment of vein treated attaining a 85% closure rate at 4 months. This author’s own experience34 treating 50 IPVs (CEAP classes 4–6) with laser energy (810 nm wavelength) for PAPs parallels Proebstle’s. The average perforating vein diameter prior to treatment was 3.5 mm (range 2.8– 7.0 mm) with an average energy delivery of 120 joules per segment of IPV treated (three segments = 360 joules in total). Access was performed with a 21 gauge micropuncture needle for a 400 μm ﬁber or a 16 gauge angiocatheter for a 600 μm ﬁber. Treatment was begun just below the fascial level and continued upward at one or two other levels. Similar post-treatment compression was employed. Follow-up at 1 month revealed a 90% occlusion rate. Long-term follow-up is under way. No nerve, skin, or vessel injury was encountered. In a study by Murphy35 comparing 100 IPVs treated by RF and 100 IPVs treated with laser, a 6 month 90% closure rate was obtained for RF and a 100% closure rate for laser. Complications were minimal but included six patients who developed redness, numbness, or blistering. It appears that PAPs with laser is as efﬁcacious as PAPs with RF. As has already been realized with laser or RF treatment of saphenous incompetence, enough energy must be delivered to the vein being treated.36 If this is satisﬁed, good early occlusion rates occur.

SUMMARY All published or presented series on PAPs have shown that it is a safe procedure. Complications have been minimal and are equal to or less than those reported for SEPS. It

also appears that given enough energy short-term success can be expected. The theoretical issues of skin injury, nerve damage, and vessel injury have been minimized. Access success with experience is nearly 100%. More importantly, once access experience is gained, distal perimalleolar perforators are more easily treated than with SEPS in this author’s and others’ experienced SEPS practitioners’ hands. The main issue that still needs to be addressed is recurrent or new incompetent perforating veins. A number of studies have addressed the “natural history” of recurrent or new perforating veins.37–39 Venous disease, even when treated appropriately and completely, has an accepted rate of new disease, e.g., the REVAS study into recurrent varices after surgery.31 Perforating veins are no different. Surgeons treating IPVs need to accept the reality that recurrent/new IPVs will develop in patients over time. This does not mean that treating IPVs is a futile pursuit. It is merely a fact that, despite our best efforts, present technique, technology, and knowledge cannot completely halt progression of all venous disease. With lifelong surveillance and treatment a reality, PAPs offers an easily repeatable, minimally invasive method of management for surgeon and patient. Recurrent and/or new disease treatment does not require general or regional anesthesia or incisions. While the ultimate goal should be permanent treatment without recurrence of venous disease, until methods or medications are developed to prevent recurrence or progression of disease, we will need to address these issues. PAPs is a way of dealing with these facts in a minimally morbid manner.40 Ultrasound techniques and technology will continue to improve. More perforating veins should be visualized initially so that a more complete treatment can be delivered. Continued surveillance is recommended and early intervention and retreatment is warranted. The position of PAPs in relation to SEPS for the treatment of IPVs is evolving. More data are certainly needed. If PAPs can attain ulcer healing rates and ulcer recurrence rates similar to or better than SEPS, it should supplant SEPS as the treatment of choice for IPVs. The advantages of PAPs over SEPS are: PAPs is performed without incisions, utilizes local anesthesia, and is easily repeatable if necessary. Older patients with

Guidelines 4.21.0 of the American Venous Forum on percutaneous ablation of perforators No.

Guideline

4.21.1 We suggest percutaneous ablation of perforators using ultrasoundguided sclerotherapy or thermal ablation as an outpatient procedure, performed under local anesthesia. It is repeatable with minimal morbidity

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

2

C

References 543

comorbidities can be treated with PAPs. Those patients with technically challenging lower extremities for SEPS (edema, obesity, etc.) can also be more easily treated with PAPs. Having performed SEPS since 1996 and utilizing PAPs since 2005, this author ﬁnds the learning curve of PAPs to be shorter and the adaptation rate of PAPs to be greater among surgeons. There is a place for both techniques. As of now, all data and recommendations are level 2C and it is incumbent upon those physicians treating IPVs to devise studies that will yield evidence-based conclusions so that more deﬁnitive recommendations can be made. Percutaneous ablation of perforating veins is a percutaneous endovenous technique similar to saphenous ablation procedures that needs continued evaluation. Its status presently is a promising method to manage incompetent perforating veins and their clinical sequelae. In evaluating PAPs or any new technique, surgeons need to respect the elders, embrace the new, and encourage the impractical and improbable without bias.

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van Neer PAFA, Verant JCJM, Neumann HAM. Venae perforantes: a clinical review. Dermatol Surg 2003; 29: 931–42. Fegan WG. Continuous compression technique of injection varicose veins. Lancet 1963; 2: 109–12. Thibault PK, Lewis WA. Recurrent varicose veins. Part 2. Injection of incompetent perforating veins using ultrasound-guidance. J Dermatol Surg Oncol. 1992; 18: 895–900. Guex JJ. Ultrasound guides sclerotherapy (USGS) for perforating veins (PV). Hawaii Med J 2000; 59: 261–2. Bergan JJ. Perforating veins. In: Bergan JJ, Goldman MP, eds. Varicose Veins and Telangiectasias: Diagnosis and Treatment. St. Louis: Quality Medical Publishing, 1993. Biegeleisn K, Neilsen RD, O’Shaugnessy A. Inadvertent intraarterial injection complicating ordinary and ultrasound guided sclerotherapy. J Dermatol Surg Oncol 1993; 19: 953–8. Perrin MR, Guex JJ, Ruckley CV, et al. Recurrent varices after surgery (REVAS) a consensus document. Cardiovasc Surg 2000; 4: 233–45. Chang DW, Levy D, Hayashi RM, et al. Ultrasound-guided radiofrequency ablation (VNUS) can be used to treat perforator incompetence: 1-year results and how to do it. Vascular 2005; 13: 518. Kabnick L. Perforator vein treatment. In: Presented at the Vein Meeting, Uncasville CT, June 2006.

34. Elias S. PAPs: a minimally invasive treatment for incompetent perforating veins. In: Presented at the Society for Clinical Vascular Surgery Annual Meeting, Scientiﬁc Session, March 2007. 35. Murphy R. Comparison of radiofrequency and laser for perforator treatment. American College of Phlebology, Poster Session, November 2006. 36. Timperman PE, Sichlau M, Ryu Rk. Greater energy delivery improves treatment success of endovenous laser treatment of incompetent saphenous veins. J Vasc Interv Radiol 2004; 15: 1061–3. 37. van Rij AM, Hill G, Gray C, et al. A prospective study of the fate or venous leg perforators after varicose vein surgery. J Vasc Surg 2005; 42: 1156–62. 38. Labropoulus N, Tassiopoulos AK, Bhatti AF, Leon L. Development of reﬂux in the perforator veins in limbs with primary venous disease. J Vasc Surg 2006; 43: 558–62. 39. Sybrandy JEM, VanGent WB, Pierk EGSM, Wittens CHA. Endoscopic versus open subfascial division of incompetent perforating veins in the treatment of venous leg ulceration: a long term follow up. J Vasc Surg 2001; 33: 1028–32. 40. Proebstle TM. Early results and feasibility of incompetent performating vein ablation by endovenous laser. Dermatol Surg 2007; 33: 162–8.

49 A treatment algorithm for venous ulcer: current guidelines* RALPH G. DEPALMA Introduction Treatment

545 546

INTRODUCTION Experience is the oracle of truth … where its responses are unequivocal; they ought to be conclusive and sacred. James Madison, Federalist 18–20. Life is short, and art long; … experience fallacious and judgment difficult. Hippocrates, Aphorisms. Recommendations based on experience in contrast to those based upon “evidence-based” guidelines are at once challenging and controversial. On the surface, the two concepts appear contradictory. Evolving surgical and endovascular interventions for venous ulcers reﬂect similar contradictions. Yet truth resides in each statement. This chapter provides a general interventional algorithm for venous ulcer treatment with intent to heal. Venous ulcers have singular pathologic appearances but several underlying causes. Proposed intervention guidelines, therefore, become complex and ideally require a diagnosis of ulcer etiology using the CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) classiﬁcation.1 The optimal intervention for venous ulcers depends upon correction of the underlying abnormal anatomy and physiology. The reader should, at the outset, recognize that 1A recommendations, strong recommendation, high-quality, evidence-based on randomized controlled trial,2 are sparse for interventions intended to heal and maintain healing of venous ulcers. High-level recommendations are generally based on randomized controlled trials (RCTs) applicable

References

549

to patients receiving a uniform treatment alternative for a relatively singular disease entity medically treated with a single drug. Even in these cases, we now know that some of these trials stand on clay feet. Trophic and ulcerative changes of the skin at the ankle medially appear to be a relatively uniform entity. However, the underlying pathophysiology and anatomy giving rise to this condition vary, and can differ from limb to limb. Kistner3 emphasized the concept of deﬁnitive diagnosis in the treatment of advanced chronic venous disease, a concept that the author and others1,3,4 consider important in selecting targets for intervention strategies, particularly for deep venous system involvement. Varying patterns of anatomy and physiology tend to complicate singular algorithmic constructs, yet compression and medical therapy trials under the rubric of intention to cure venous ulcers exist; for example, the results of meta-analyses of nine trials using oral pentoxyphylline with calculated beneﬁt.5 Most medical and compression trials6–12 do not attempt classiﬁcation; however, some13 suggest that patterns of venous incompetence are not related to healing treated by compression and optimal medical treatment. This chapter conﬁnes itself to interventional surgical and endovascular treatment. A randomized comparison of intervention and compression and best medical treatment is suggested. Surgical and endovenous interventions for venous ulceration continue to evolve in a step-wise series of modiﬁcations. Ultimately, these procedures aim to interrupt or ameliorate abnormal hemodynamics: venous hypertension and reﬂux affecting the skin target the ankle. Outcomes of venous ulcer treatment appear as

*The opinions expressed are those of the author and not necessarily those of the United States Government or the Department of Veterans Affairs.

546

A treatment algorithm for venous ulcer: current guidelines

interventions that succeed in correcting axial and perforator reﬂux or in relieving venous hypertension. The algorithm in Fig. 49.1 provides a branched logic chain based upon literature review of the best available evidence. Separate proposals describe potential randomized trials to compare best medical and compressive treatment with surgical and interventional treatment for venous ulcers. These proposals are divided into those caused by superﬁcial venous involvement (most often primary) as contrasted to ulcer-related deep disease, either primary or more usually secondary. As interventional treatment requires accurate diagnostic classiﬁcation of abnormal anatomy and physiology, the use of CEAP classiﬁcation begins the sequence.

observational reports,14 a few crossover studies,15,16 and many case series with long-term follow-up.17–21 While Cochrane group evidence-based reports consistently favored medical treatment over surgical interventions up to 2003, a randomized trial comparing surgery combined with compression with compression alone (ESCHAR) appeared in 2004.22 The results favored surgery for “superﬁcial” venous interventions plus compression. In a subsequent prospective randomized trial of 200 ulcerated legs in 170 patients, with a follow-up of a mean of 29 months, surgery was clearly favored, particularly for ﬁrst time ulcers.23 This report is the ﬁrst approximation to the level 1A recommendation favoring surgery for venous ulceration in properly selected candidates. Interventional approaches to venous ulcers appear to have followed Popper’s24 scientiﬁc insights into problemsolving: a problem; attempted solutions; elimination of unsuccessful solutions; ﬁnally problem resolution using new solutions and techniques. Each step along the way imposes new options. Current venous interventions include compression, drug therapy, traditional surgery, novel methods of deep venous reconstruction and perforator interruption, endoluminal ablation of axial veins by laser and radiofrequency energy, and, lately, conventional or foam sclerotherapy for axial and perforating veins.25,26 A cautionary note is required as a stroke has been reported following treatment of varicose veins with foam sclerosants.27 This incident occurred during a clinical phase 2 trial of a commercial preparation of polidocanol microfoam. With this qualiﬁcation about one technique, overall outcomes provided by expert opinion and case series for axial and perforator ablation is 1C: strong recommendation with low-quality evidence. Beneﬁts outweigh risk burdens in skilled hands employing proactive

TREATMENT A. CEAP evaluation The CEAP classiﬁcation, as revised in 2004,1 is divided into three levels: level I, ofﬁce or clinic with history, physical examination which may include the use of a hand-held continuous wave Doppler; level II, non-invasive vascular laboratory testing including duplex color scanning and, possibly, a plethysmography method; and level III, complex imaging studies including ascending and descending phlebography, venous pressure measurements, computed tomography (CT) scanning or magnetic resonance imaging (MRI). Based on available information the most common testing levels in practice are levels I and II inasmuch as many ulcers relate to superﬁcial venous disease. Non-invasive testing offers no risk, appears intuitively obvious, and duplex examination is more

Fit patient with venous ulcer class 5/6* CEAP evaluation A Levels I and II Primary superficial B

Levels I, II and III

Plus deep C

Secondary No

D

Ileocaval occlusion

Yes

Axial/perforator ablation E Excision/skin graft ulcer Reconstruction when possible

F

Valve strategies Postoperative support G

Recur

Venography H

Valve repair I other procedures

Compression strategies K

Secondary procedures, J including axial and perforator ablation and local ulcer measures

Figure 49.1 General treatment algorithm. *Non-candidates include those with a BMI > 35–40 with global venous hypertension (48–50 mmHg); heart failure; arterial insufﬁciency; severe arthritis.

Treatment 547

accurate than hand-held continuous wave Doppler. Levels I and II are set at grade 1B strong recommendation, moderate quality evidence. For level III, including invasive techniques by adding a target needed for deep reconstruction, which is based mainly on observational studies and case series, grades would be set at 1C or 2A. Outcome evidence is weaker. As mentioned, most compression or medical trials28–31 have not employed this classiﬁcation, and with the exception of one trial of elastic versus non-elastic compression32 have depended upon randomization to balance treatment arms.

B–E. Primary superficial axial reflux and perforator ablation Experience with case series,14,17–22 a crossover trial with updated results,15,33 and venous registry data34 demonstrates favorable results with surgical intervention using subfascial endoscopic perforator surgery (SEPS), with beneﬁts exceeding risk, grading level 2A, and with much better results at mid-term for superﬁcial as opposed to deep disease.35 The ESCHAR trial22 can be cited along with the recent Dutch multicenter study23 to recommend an overall grading level of 1B. The optimal means of axial and perforator ablation including surgery vs radiofrequency or laser energy, subfascial and extrafascial perforating vein and foam sclerotherapy remain to be determined. The key to success is elimination of the transmission of venous hypertension to the skin target. Speciﬁc methods chosen will likely depend on size and distribution of axial veins, condition of the skin, ulcer location,36,37 operator experience, and speciﬁc skill sets.

C–E. Primary superficial and deep reflux combined Observational studies show that ablation of superﬁcial axial reﬂux and perforator incompetence often improves the hemodynamics of the deep system38,39 to promote ulcer healing; evidence level 1C. Logically then, deep valve reconstructive strategies can be added; here, the evidence is classiﬁed as 2B weak recommendation with moderate quality evidence, the beneﬁts are closely balanced with risks and burdens, owing to degrees of uncertainty in choice of technique and long-term beneﬁts. Kistner40 has summarized valve repair, transplantation, and vein transposition in case reports of Raju, Sottiuri, Perrin, and O’Donnell working this challenging area.

H and I. H and I indicate that valve strategies can be employed as secondary procedures with the same weak recommendations. Alternatives consist of local ulcer grafting and

enhanced compression using rigid as opposed to elastic supports.41,42

D–E. Secondary venous insufficiency, usually post-thrombotic Recurrence rates range over 23–24% using SEPS based on registry data.34,35 These have a grade 1C strong recommendation based on case series with low-quality evidence. The perforator strategies in this author’s hands have failed in the presence of uncorrected proximal iliac–caval occlusion, observational grade 2B.4,15 Overall, results of deep venous surgery as summarized by Perrin42 yields a 2C recommendation and emphasized a need for more trials.

F. Correction of vena cava or iliac occlusion by crossover bypass or stent This has a 2B weak recommendation, and beneﬁts may be closely balanced with risks and burdens. The best action may depend upon patient circumstances, symptoms, and societal values.43–45

G. Postoperative support Support is recommended for all cases of venous ulceration. The choice of dressings, bandaging when ulcers are open, and choice of rigid versus elastic support depend upon the presence of primary or secondary venous disease and the underlying physiology. After surgically treated superﬁcial disease with a healed ulcer, class 2 support may sufﬁce. With secondary deep disease, rigid support appears preferable based upon representative hemodynamic and ulcer outcome studies.22,28,32,33,41 Evidence 1B, strong recommendation: high-quality evidence; beneﬁts clearly outweighing risks particularly when combined with intervention. Previous trials compare differing types of medical and compressive therapy as primary rather than secondary ulcer treatment.

H–I. Valve repair and other deep venous infrainguinal procedures Improvement in deep reﬂux occurs after correction of superﬁcial axial reﬂux and associated perforating veins.38–40 This part of the sequence addresses the rationale for recurrence to include ascending and descending venography to quantify reﬂux and to examine valve stations and anatomy.4 Kistner40 summarized the results of a series of internal valve repair and addressed the issues of external versus open repair in terms of durability. “Good” results are reported in 62–75%. These procedures carry

548

A treatment algorithm for venous ulcer: current guidelines

Guidelines 4.22.0 of the American Venous Forum on a treatment algorithm for venous ulcer No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.22.1 We recommend ablation of superﬁcial axial reﬂux and treatment of perforator incompetence to improve venous hemodynamics and to promote ulcer healing

1

B

4.22.2 We recommend superﬁcial venous surgery to decrease ulcer recurrence in patients with superﬁcial venous incompetence

1

A

4.22.3 We suggest superﬁcial venous surgery with subfascial endoscopic perforator surgery for treatment of venous ulcers

2

C

ﬁnite risks of hematoma and postoperative pulmonary embolus. Four series of vein valve transplantation40 showed ulcer recurrence rates ranging from 18% to 54% cases in follow-ups ranging from 18 to 60 months; evidence level 1C based on sequential observations in series. The efﬁcacy of transposition procedures in 69 limbs from four series followed for 18–120 months were described as producing “good” results in 25–54% of these limbs; image testing was done to determine competence, which appeared to be about 50%. Level 2B, weak recommendations: moderate-quality evidence; beneﬁts closely balanced with risks and burdens.

J. Local secondary procedures With recurrences due to missed or recurrent perforators a logical step would be to deal with this problem ﬁrst by choosing an appropriate ablative procedure, e.g., axial vein ablation, extrafascial perforator interruption, or subfascial endoscopic perforator interruption and skin grafting; weak recommendation based on case series.14,18–20,33–36 These procedures are used for ulcers associated with perforator recurrence or missed perforators. An interesting report from an experienced group46 describes tangential excision of the ulcer base followed by mesh grafting in 62 patients with 100 leg ulcers with Kaplan–Meier results extending to 60 months. Long-term success, with no difference between large and small ulcers, was depicted at 60% at 5 years. Most recurrences were observed in the ﬁrst 2 months. CEAP classiﬁcation was not used. Evidence level is 2B where beneﬁts of local procedures in this case series outweighed risk burdens. Another recent strategy used hospitalization and local treatment with an applied wound vacuum device compared with conventional wound treatment. Median healing with the vacuum-assisted closure (VAC) treatment

was 29 days compared with 45 days for conventionally treated wounds. The need for hospitalization increases expense; most hospitalizations for interventional studies are short stay. There are, admittedly, some ulcers that never heal and VAC is useful.47 It is possible to estimate an approximate number of patients needed for a prospective randomized trial to test the hypothesis “that ulcers due to superﬁcial disease would be better treated surgically or with endovenous modalities along with compression, than best medical therapy plus compression”. A 5 year complete healing rate of 88–90% for intervention can be compared with a 60% healing rate for compression alone. Secondary end-points would use the number of recurrences and the time that the ulcer remained open, similar to the metrics in a prior crossover trial15 and case series.21 Using two-sided alpha testing one might estimate two arms of 40 patients each; one arm using axial and perforator interruption plus grafting of ulcers and the other using compression plus the best medical treatment, which might include pentoxyphylline. For secondary disease, most often post-thrombotic, patients with non-treatable ileocaval occlusion would require exclusion and separate analysis. Intervention strategies focusing on secondary infrainguinal and superﬁcial disease could require as many as 175 or more patients in each arm assuming 20–25% recurrence after optimally selected interventions compared with an estimated 40% for compression–medical treatment. Ideally, patients would be followed for 5 years for the primary and secondary end-points. Finally, the algorithm makes reference to morbid obesity (BMI > 35–40) resulting in global venous hypertension in the absence of speciﬁc correctable venous disease.48–50 Here, bariatric intervention can be used. Other indications for conservative care include heart failure, arterial insufﬁciency, and severe arthritis with muscle pump failure.

References 549

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Eklöf B, Rutherford RB, Bergan JJ, et al. The American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classiﬁcation. Revision of the CEAP classiﬁcation for chronic venous disorders: Consensus Statement. J Vasc Surg 2004; 40: 1248–52. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest 2006; 129: 174–81. Kistner RL. Deﬁnitive diagnosis and deﬁnitive treatment in chronic venous disease: a concept whose time has come. J Vasc Surg 1996; 24: 788–92. DePalma RG, Kowallek DL, Barcia TC, Cafferata HT. Target selection for surgical treatment of severe chronic venous insufﬁciency: comparison of duplex scanning and phlebography. J Vasc Surg 2000; 32: 913–20. Jull AB, Waters J, Arrol B. Pentoxyphylline for treating venous ulcers. Cochrane Database Syst Rev 2002; Issue 1. Art. No.: CD001733. Nelsen EA, Cullum N, Jones J. Venous leg ulcers: search date 2000. Clinical evidence. BMJ 2001; 5: 1365–75. Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen for treatment of chronic venous ulcer. Cochrane Database Syst Rev 2004; Issue 2. Art. No.: CD004123. Senet P, Bon FX, Benbunan M, et al. Randomized trial and local biological effects of autogenous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg 2003; 38: 1342–8. Flemming K, Cullum N. Electromagnetic therapy for the treatment of venous leg ulcers. Cochrane Database Syst Rev 2001; Issue 1. Art. No.: CD002933. Mani R, Vowden K, Nelson EA. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database Syst Rev 2001; Issue 4. Art. No.: CD001899. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev 2001; Issue 2. Art. No.: CD001737. Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2000; Issue 4. Art. No.: CD001180. Guest M, Smith JJ, Sira MS, et al. Venous ulcer healing by four-layer compression bandaging is not affected by the pattern of venous incompetence. Br J Surg 1999; 86: 1437–40. Bianchi C, Ballard JL, Abou-Zamzan AM, Teruya TH. Subfascial endoscopic perforator surgery combined with saphenous vein ablation: results and critical analysis. J Vasc Surg 2003; 38: 67–71. DePalma RG, Kowallek DL. Venous ulceration: a cross-over study from non-operative to operative treatment. J Vasc Surg 1996; 24: 788–810.

16. Bergan JJ, Pascarella L. Severe chronic venous insufﬁciency: primary treatment with sclerofoam. Semin Vasc Surg 2005; 18: 49–56. 17. Kalra M, Gloviczki P. Surgical treatment of venous ulcers: role of subfascial endoscopic perforator vein ligation. Surg Clin North Am 2003; 83: 671–705. ●18. DePalma RG. Surgical therapy for venous stasis; results of a modiﬁed Linton operation. Am J Surg 1979; 137: 810–13. 19. DePalma RG. Surgical treatment of chronic venous ulceration. In: Raymond-Martinbeau R, Prescott M, Summo M, eds. Phlebologie 92. Paris: John Libby Eurotext, 1992: 1235–37. 20. DePalma RG. Evolving surgical approaches to venous ulceration. In: Negus O, Jantet G, Coleridge Smith PD, eds. Phlebology. London: Springer Verlag, 1995: 980–2. 21. Obermayer A, Gostl K, Walli G, Benesch T. Chronic venous leg ulcers beneﬁt from surgery: results from 173 legs. J Vasc Surg 2006; 44: 572–9. 22. Barwell JR, Davies, Deacon J, et al. Comparison of surgery and compression alone in chronic venous ulceration (ESCHAR study). Lancet 2004; 363: 1854–9. 23. van Gent WB, Hop WC, van Praag MC, et al. Conservative versus surgical treatment of venous leg ulcers: a prospective randomized multicenter trial. J Vasc Surg 2006; 44: 563–71. ●24. Popper, K. All Life is Problem Solving: The Logic and Evolution of Scientiﬁc Theory. London: Routledge, 1999: 1–22. ●25. Redondo P, Cabrera J. Microfoam sclerotherapy. Semin Cutan Med Surg 2005; 24: 175–83. ●26. Pascarella L, Bergan JJ, Mekenas LV. Severe chronic venous insufﬁciency treated by foamed sclerosants. Ann Vasc Surg 2006; 20: 81–93. 27. Fourlee M, Grouden D, Moore D, Shanik G. Stroke after varicose vein foam injection sclerotherapy. J Vasc Surg 2006; 43: 162–4. 28. Nelson EA, Harper DR, Prescott RJ, et al. Prevention of recurrence of venous ulceration: randomized controlled trials of class 2 and class 3 elastic compression. J Vasc Surg 2006; 44: 803–8. ★29. O’Donnell TF Jr, Lau J. A systematic review of randomized controlled trials of wound dressing for chronic venous ulcer. J Vasc Surg 2006; 44: 1118–25. 30. Palfreyman SJ, Nelson EA, Locheiel B, Michaels JA. Dressings for healing venous ulcer. Cochrane Database Syst Rev 2006; Issue 3. Art. No.: CD0011103. 31. Iglesias C, Nelson EA, Cullum NA, et al. VenUS 1: a randomized controlled trial of two types of bandage for treating venous leg ulcers. Health Technol Assess 2004; 8: 1–105. 32. Blecken SR, Villavicencio JL, Kao TC. Comparison of elastic versus nonelastic compression in venous ulcers: a randomized trial. J Vasc Surg 2005; 42: 1150–5. ◆33. DePalma RG. Venous ulcer management: tried and true versus what’s new. In: Pearce WH, Matsumura JS, Yao JST, eds. Trends in Vascular Surgery. Chicago: Greenwood Academic, 2006: 79–88.

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Gloviczki P, Bergan JJ, Menawat SS, et al. Safety, feasibility and early efﬁcacy of subfascial endoscopic surgery: a preliminary study report from the North American Registry. J Vasc Surg 1997; 25: 94–105. Gloviczki P, Bergan JJ, Rhodes JM, et al. Midterm results of endoscopic perforator interruption for chronic venous insufﬁciency. Lessons learned from the North American subfascial endoscopic perforator surgery registry. The North American Study Group. J Vasc Surg 1999; 29: 489–502. DePalma RG. Case of perforator incompetence: making SEPS better. Hawaii Med J 2000; 59: 256–8. DePalma RG, Kowallek DL, Barcia TC. New approaches to an old and vexing problem. Improving the results of SEPS: an overview. Acta Chir Belg 2000; 100: 100–3. Ting AC, Cheng SW, Ho P, et al. Reduction in deep vein reﬂux after concomitant subfascial endoscopic perforating vein surgery and superﬁcial vein ablation in advanced primary venous insufﬁciency. J Vasc Surg 2006; 43: 546–50. Tawes RL, Barron ML, Coello AA, et al. Optimal therapy for advanced chronic venous insufﬁciency. J Vasc Surg 2003; 37: 545–51. Kistner RL. Three decades of progress in surgical repair of the venous valve. In: Pearce WH, Matsumura JS, Yao JST, eds. Trends in Vascular Surgery. Chicago: Greenwood Academic, 2006: 47–61. Partsch H, Menzinger G, Mostbeck A. Inelastic leg compression is more effective to reduce deep venous

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reﬂuxes than elastic bandages. Dermatol Surg 1999; 25: 695–700. Perrin M. Surgery for deep venous reﬂux in the lower limb. J Mal Vasc 2004; 29: 73–87. Raju S, Hollis K, Neglén P. Obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. J Vasc Surg 2006; 44: 820–7. Harris JP, Kidd J, Burnett A, et al. Patency of femorofemoral crossover grafts assessed by duplex scanning and phlebography. J Vasc Surg 1988; 8: 679–82. Neglén P, Hollis KC, Raju S. Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 2006; 44: 828–33. Burnand KG, Absisi S. Treatment of venous ulcers by excision and split-thickness grafting. Vascular 2006; 14: S108–109. Vuerstaek JDD, Vainas T, White J, et al. State-of the art treatment of chronic leg ulcers: a randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg 2006; 44: 1029–37. Sugarman HJ, Sugarman EL, Wolfe L, et al. Risks and beneﬁts of gastric bypass in morbidly obese patients with severe venous stasis disease. Ann Surg 2001; 234: 41–6. Padberg F Jr, Cerveira JJ, Lal BK, et al. Does venous insufﬁciency have a different etiology in the morbidly obese? Is it venous? J Vasc Surg 2003; 37: 79–85. Danielsson G, Eklöf B, Grandinetti A, Kistner RL. The inﬂuence of obesity on chronic venous disease. J Vasc Endovasc Surg 2002; 36: 271–6.

PART

5

SPECIAL VENOUS PROBLEMS Edited by Thomas W. Wakeﬁeld

50 Surgical and endovenous treatment of superior vena cava syndrome Manju Kalra, Haraldur Bjarnason and Peter Gloviczki 51 The management of extremity venous trauma David L. Gillespie and Reagan W. Quan 52 Primary and secondary tumors of the inferior vena cava and iliac veins Thomas C. Bower 53 Arteriovenous malformations: evaluation and treatment B.B. Lee, J. Laredo, D.H. Deaton and R.F. Neville 54 The management of venous malformations Heron E. Rodriguez and William H. Pearce 55 The management of venous aneurysms Heron E. Rodriguez and William H. Pearce 56 Management of pelvic venous congestion and perineal varicosities Graeme D. Richardson

553 568 574 583 594 604 617

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50 Surgical and endovenous treatment of superior vena cava syndrome MANJU KALRA, HARALDUR BJARNASON AND PETER GLOVICZKI Introduction Etiology Clinical presentation Diagnostic evaluation Conservative therapy Indications for treatment

553 553 553 554 554 557

INTRODUCTION Obstruction of the superior vena cava (SVC) or innominate veins occurs most frequently in patients with metastatic malignant disease. Non-malignant causes are, however, increasing because of the more frequent use of central venous lines and catheters and the widespread use of pacemakers. Signs and symptoms of venous congestion of the head, neck, and upper extremities are determined by the duration, progression, and extent of the venous occlusive disease, and by the amount of collateral venous circulation that develops. Mortality is high in patients with metastatic malignant disease, and usually occurs at 6–12 months after the onset of symptoms. In this chapter, we will review the etiology of SVC syndrome, and will discuss clinical presentation, preoperative evaluation, surgical and endovascular treatment of these patients.

ETIOLOGY Obstruction of the SVC caused by a syphilitic aortic aneurysm was ﬁrst described in 1757 by William Hunter.1 The most frequent etiology of SVC syndrome today is metastatic malignant disease. In a review of multiple large series in 1984, 85% of 1986 patients with SVC syndrome had metastatic pulmonary or mediastinal malignancy.2 The most frequent tumor was metastatic adenocarcinoma of the lung. Benign causes of SVC syndrome include ﬁbrosing mediastinitis or granulomatous fungal diseases

Endovenous treatment Surgical treatment Results Conclusions References

557 558 560 565 565

such as histoplasmosis. Previous radiation treatment to the mediastinum or retrosternal goiter are additional etiologies. Central venous lines and catheters used for hemodynamic monitoring, parenteral alimentation, or drug administration have become more frequent causes of SVC, innominate veins, or subclavian vein thrombosis.3 Over 5 million central venous catheters and 170 000 pacemakers are now implanted annually in the USA and are associated with upper extremity or central vein deep vein thrombosis (DVT) in 7–33% of patients.4,5 Superior vena cava syndrome reportedly occurs in 1–3% of patients with central venous catheters and 0.2–3.3% of patients with implanted pacemakers.6 In the past, mediastinal ﬁbrosis constituted up to 80% of cases of benign SVC syndrome,7 but recent data attribute up to 74% of new cases to indwelling catheters or wires.6,8 However, malignancy still remains the etiology in 60% of cases.6 Superior vena cava thrombosis can also be associated with thrombophilia, caused by deﬁciencies in circulating natural anticoagulants (antithrombin, protein S, protein C) or factor V Leiden mutation.

CLINICAL PRESENTATION The most frequent symptom of SVC syndrome is the feeling of fullness in the head and neck, which is more severe when the patient bends over or lies ﬂat in bed. These patients can sleep only by elevating the head on multiple pillows. Headache, dizziness, visual symptoms, or occasional blackout spells may result from cerebral venous

554

Surgical and endovenous treatment of superior vena cava syndrome

Table 50.1 Signs and symptoms of superior vena cava syndrome of benign etiology in 70 patients No. of patients

%

Symptoms Feeling of fullness in head or neck Dyspnea on exertion or orthopnea Headache Dizziness or syncope Visual problems Cough Nocturnal oxygen requirement Protein-losing enteropathy

61 39 27 25 11 10 3 1

87 56 39 36 25 22 16 2

Signs Head and neck swelling Large chest wall venous collaterals Facial cyanosis Arm swelling Pleural effusion

65 40 24 23 2

93 57 34 33 3

hypertension and can be incapacitating (Table 50.1). Additional symptoms may include mental confusion, dyspnea, orthopnea, or cough. Swelling of the face and

eyelids is evident and the patient notes the need for larger size shirts because of enlargement of the neck (Fig. 50.1). Ecchymosis and dilated jugular veins accompany cyanosis of the upper body. Extensive venous collaterals of the chest will frequently develop. Mild to moderate upper extremity swelling may occur, but the primary symptoms in these patients are localized to the head and neck.

DIAGNOSTIC EVALUATION A detailed clinical history with physical examination can usually establish the diagnosis of SVC syndrome. Routine laboratory tests, chest roentgenogram and computed tomography (CT) of the chest are performed in all patients to exclude underlying malignant disease. The CT imaging accurately depicts the location and extent of the obstruction and also distinguishes various types of benign and malignant mediastinal disease. The extent of venous collateral formation is also well demonstrated. These collateral pathways include the (1) azygos–hemiazygos pathway, (2) internal mammary pathway, (3) lateral thoracic–thoracoepigastric pathway, (4) vertebral pathway and small mediastinal veins. Less commonly, unusual shunts, including hepatic parenchymal as an intense focal enhancement in the medial segment of the left lobe of the

(b)

(a)

Figure 50.1 (a) Severe symptomatic superior vena cava (SVC) syndrome in a 69-year-old man. (b) Bilateral upper extremity venogram conﬁrms thrombosis of the SVC and both innominate veins following placements of pacemaker lines bilaterally.

Diagnostic evaluation

(d) (c)

Figure 50.1 (contd) (c) Right internal jugular vein–right atrial appendage spiral saphenous vein graft. Arrows indicate anastomoses. (d) Postoperative venogram conﬁrms graft patency. (e) The patient 5 days after spiral vein graft placement. The clinical result is excellent 8 years after the operation.

(e)

555

556

Surgical and endovenous treatment of superior vena cava syndrome

(a)

L. brachiocephalic vein

(b)

Accessory hemiazygos vein Azygos vein

Accessory hemiazygos vein Azygos vein

Type I Type II

Hemiazygos vein

(c)

Accessory hemiazygos vein

(d)

Right superior intercostal vein

Internal mammary veins

Chest wall collaterals

Type III

Type IV Hemiazygos vein Superior epigastric veins Inferior epigastric veins

Figure 50.2 Venographic classiﬁcation of superior vena cava (SVC) syndrome according to Stanford and Doty. (a) Type I. High-grade SVC stenosis with still normal direction of blood ﬂow through the SVC and azygos veins. Increased collateral circulation through hemiazygos and accessory hemiazygos veins. (b) Type II. Greater than 90% stenosis or occlusion of the SVC, but patent azygos vein with normal direction of blood ﬂow. (c) Type III. Occlusion of the SVC with retrograde ﬂow in both the azygos and hemiazygos veins. (d) Type IV. Extensive occlusion of the SVC and innominate and azygos veins with chest wall and epigastric venous collaterals. (From Alimi et al.9)

Endovenous treatment

liver, and pulmonary pathways are identiﬁed on CT scan. Magnetic resonance venography is also suitable to deﬁne anatomy, although patients with pacemakers are not candidates for this test. Patency of at least one internal jugular vein should be conﬁrmed with duplex scanning in those patients who are candidates for surgical reconstruction. Evaluation of patients considered for endovascular or open surgical treatment is continued with bilateral upper extremity venography. Based on the extent of venous occlusion, as deﬁned by bilateral upper extremity venography, Stanford and Doty classiﬁed patients with SVC syndrome into 4 types (Fig. 50.2a–d).9 Bronchoscopy, mediastinoscopy, thoracoscopy, thoracotomy, or median sternotomy may be necessary in some patients to provide tissue diagnosis or occasionally to attempt resection of a localized tumor causing SVC occlusion.

CONSERVATIVE THERAPY Conservative measures are used ﬁrst in every patient to relieve symptoms of venous congestion. These include elevation of the head during the night on pillows, modiﬁcations of daily activities by avoiding bending over, and avoidance of wearing constricting garments or tight collars. Patients frequently need diuretics to decrease venous edema, and anticoagulation with heparin and warfarin are used to protect the venous collateral circulation. Thrombolytic treatment should be considered in patients with acute or subacute SVC thrombosis causing SVC syndrome, although this may be contraindicated in patients in the end-stage of metastatic malignant disease. Since external compression by the tumor is the usual pathomechanism of caval occlusion in these patients, endovascular treatment, as discussed later, using stents is the best technique to alleviate symptoms. Symptoms of SVC syndrome associated with metastatic malignant disease frequently improve following irradiation or chemotherapy, and these constituted the mainstay of treatment in these patients before endovascular treatments became available. Chen et al.10 treated 42 patients with malignant SVC syndrome using external beam radiotherapy and/or chemotherapy. Symptoms of SVC syndrome resolved in 80% of the patients who underwent radiotherapy, with a mean interval of 4 weeks. A similar beneﬁt of radiation or chemotherapy has been noted by others as well.11

557

depending upon the etiology and anatomy of the SVC lesion. Traditionally, endovenous treatment has been the unequivocal ﬁrst choice for patients with malignant SVC obstruction because of the limited life expectancy. Patients with benign disease have been treated with surgical replacement/bypass of the occluded SVC because of their longer life expectancy and thereby need for a durable reconstruction. For more than two decades studies of endovascular treatment of non-malignant SVC syndrome were limited to case reports and small series with short follow-up,12–17 in spite of the fact that the ﬁrst reported endovenous treatment was for SVC occlusion of benign etiology.18 In recent years, however, much experience has been gained in this ﬁeld and today most patients with benign SVC syndrome would be considered for endovenous treatment ﬁrst.19 Indications for surgical treatment, however, are better deﬁned because experience dates back many years and long-term results are good. At present, surgical reconstruction is reserved for patients with extensive chronic venous thrombosis not anatomically suitable for endovascular treatment, and those with less extensive disease who have not beneﬁted from endovascular attempts. We have performed reconstruction of the SVC for obstruction caused by granulomatous and idiopathic mediastinal ﬁbrosis, central venous catheters, pacemaker electrodes, or ventriculoatrial shunt and in patients with antithrombin deﬁciency or idiopathic venous thrombosis.3,9,19–21 The indications for reconstruction of the SVC in patients with benign disease were similar in the reports by Doty et al.22 and Moore and Hollier.23 Surgical reconstruction of the SVC has also been performed in patients with different types and stages of malignant disease.23–27 However, endovascular techniques should clearly be the treatment of choice in these patients and surgical reconstruction should be contemplated almost exclusively only when the tumor is resectable. Patients with a malignant tumor should undergo reconstruction through a median sternotomy only if their life expectancy is greater than 1 year. This group of patients may include those with lymphoma, thymoma, or metastatic medullary carcinoma of the thyroid gland. Extra-anatomic subcutaneous bypass between the jugular vein and the femoral vein using a composite saphenous vein graft is an alternative if symptoms are severe and endovascular techniques fail or are not possible.28

ENDOVENOUS TREATMENT INDICATIONS FOR TREATMENT Patients with SVC syndrome can have severe, frequently incapacitating symptoms, which cannot be alleviated by conservative measures, including medical measures as well as chemoradiation in malignant cases. Further treatment options include endovenous or surgical intervention

The ﬁrst percutaneous treatment with angioplasty in an adult was performed in 1986 by Sherry18 for an SVC lesion caused by a pacemaker wire. There has been tremendous progress in the endovenous treatment of SVC syndrome since then with increasing technical and clinical success. This achievement served patients with malignant disease well with rapid symptomatic relief; however, long-term

558

Surgical and endovenous treatment of superior vena cava syndrome

results of stents placed in young patients for benign lesions are still not well known, and rethrombosis or intimal hyperplasia can be signiﬁcant. Treatment modalities include percutaneous transluminal balloon angioplasty (PTA), stenting, and thrombolysis performed alone or in combination. Following early interventions with angioplasty alone, it soon became evident that this resulted in early restenosis due to the elastic/ﬁbrotic nature of many SVC lesions with or without external compression from mediastinal masses. The earliest stents deployed were Gianturco Z stents as they were the only ones available in larger diameters. They are self-expanding stents with hooks for ﬁxation to prevent migration and have the advantages of ease of placement, rigidity, and lack of shortening. The large stent interstices, however, are worrisome for allowing tumor ingrowth. Palmaz (Cordis Corporation, Miami, FL, USA) balloonexpandable stents are ideally suited for short, focal ﬁbrotic/compressive lesions because of their precise deployment and good radial force (Fig. 50.3). Disadvantages include poor ﬂexibility and availability only in short lengths. In recent years, other self-expanding stents such as Wallstents (Boston Scientiﬁc Corp., Natick, MA, USA), Smart stents (Cordis Endovascular, Warren, NJ, USA), and Protégé stents (ev3, Plymouth, MN, USA) have been used more frequently for longer SVC stenoses because of ﬂexibility and availability in multiple sizes. Occasional reports of covered stents are also available for extravasation during the procedure and potentially to

(a)

(b)

control tumor ingrowth. Thrombolysis may be performed alone for acute SVC thrombosis related to indwelling catheters or prior to angioplasty/stenting to resolve the thrombosis and reveal the underlying stenotic lesion for deﬁnitive treatment. The technique of endovenous repair involves percutaneous venous access of the common femoral vein and placement of 6–10 Fr sheaths followed by crossing the stenotic/occlusive lesion with hydrophilic guide wires and catheters. If the lesion cannot be crossed from this approach, the right internal jugular vein can be accessed. Once wire access across the lesion is obtained, primary PTA using standard 10–16 mm angioplasty balloons is performed followed by stenting. Choice of stent is tailored to the etiology, degree, length, and tortuosity of the SVC stenosis. If thrombolysis is determined to be appropriate prior to PTA or stenting, a suitable length catheter with side holes is placed across the lesion for catheter-directed lytic therapy. For details of thrombolytic therapy refer to Chapter 20. The need for post-procedure anticoagulation is also individualized based on the cause of SVC syndrome. The majority of patients, especially those with malignancy and catheter-related thrombosis, receive oral anticoagulation at least for a few months until the stent is lined with pseudointima and the risk of rethrombosis decreases. Patients with mediastinal ﬁbrosis are often treated with antiplatelet therapy alone. Both rethrombosis following cessation of anticoagulation as well as excellent results without have been reported.29,30

Figure 50.3 (a) Venogram showing type II SVC obstruction due to mediastinal ﬁbrosis in a 31-year-old man. Successful placement of a Palmaz stent resulted in immediate resolution of symptoms. (b) The patient has since undergone balloon dilatation for in-stent stenosis 11 months later and remains asymptomatic.

Surgical treatment 559

SURGICAL TREATMENT Selection of graft For replacement of the SVC or the innominate vein in patients with benign disease, autogenous spiral saphenous vein graft is our ﬁrst choice. This graft was described in animal experiments by Chiu et al.31 in 1974, and Doty and Baker32 used it ﬁrst in patients. Our technique of preparing and implanting the spiral graft has been described previously in detail.3,19 The saphenous vein is harvested, it is opened longitudinally, valves are excised,

and the vein is wrapped around a 32 or 36 French polyethylene chest tube. The edges of the vein are then approximated with running 6-0 monoﬁlament polypropylene sutures (Fig. 50.4a–c). More recently, we have used non-penetrating vascular clips (US Surgical, Inc., Mansﬁeld, MA, USA) for this purpose, with good results Fig. 50.4d. The vein is continuously irrigated during the phase of preparation with heparinized papaverine solution to preserve the integrity of endothelial cells and to prevent desiccation. Spiral saphenous vein graft is a relatively nonthrombogenic autologous tissue. Disadvantages include the additional incision and the time (60–90 min) needed

Saphenous vein

(a)

(c)

(b)

(d)

Figure 50.4 (a) Technique for a spiral saphenous vein graft. The saphenous vein is opened longitudinally, valves are excised, the vein is wrapped around an argyle chest tube, and the vein edges are approximated with sutures. (b) A 15 cm long spiral saphenous vein graft ready for implantation. (c) Technique of left internal jugular–right atrial spiral vein graft implantation. (d) Spiral vein graft prepared using non-penetrating vascular clips. (From Gloviczki PG, Pairolero PC. Venous reconstruction for obstruction and valvular incompetence. In: Goldstone J, ed. Perspectives in Vascular Surgery. St. Louis: Quality Medical Publishing, 1988: 75–93.)

560

Surgical and endovenous treatment of superior vena cava syndrome

to prepare the graft. In addition, the length of the graft is limited by the availability of an adequate length segment of saphenous vein. The saphenous veins may also be used as a panel graft. The femoral vein, or the femoropopliteal vein, was one of the ﬁrst conduits used to reconstruct the SVC.33 It has been used with success because of its excellent suitability in terms of size and length.34,35 It is an excellent graft; however, if the patient has underlying thrombotic abnormalities, removal of a deep leg vein may result in at least moderate lower extremity post-thrombotic syndrome. For this reason, in young patients who undergo SVC reconstruction for benign disease, femoral vein has been only our second choice for graft following spiral saphenous vein graft. Of the available prosthetic materials, externally supported expanded polytetraﬂuoroethylene (ePTFE) is the one used for large vein reconstruction almost exclusively because of low thrombogenicity. Short, large-diameter (10–14 mm) grafts have excellent long-term patency because ﬂow through the innominate vein usually exceeds 1000 mL/min. If the peripheral anastomosis is performed with the subclavian vein, venous inﬂow is signiﬁcantly less and the addition of an arteriovenous ﬁstula is usually required in the arm to ensure graft patency. For an internal jugular–atrial appendage bypass a large-diameter (12 mm) PTFE graft is a suitable alternative if spiral saphenous vein is not possible. An arteriovenous ﬁstula with direct ﬂow into the graft has not been performed for jugular grafts. An externally supported prosthetic graft is a good choice in patients with a tight mediastinum and usually for all patients with malignancy, because recurrent tumor is more likely to compress and occlude a vein graft. Iliocaval allograft can be considered in those patients who receive immunosuppressive treatment for protection of a transplanted organ. Cryopreserved femoral vein grafts

(a)

are potential alternatives, as are grafts prepared from autogenous or bovine pericardium.

Surgical technique The operation is performed through a median sternotomy. If the internal jugular vein is used for inﬂow, the midline incision is extended obliquely into the neck along the anterior border of the sternocleidomastoid muscle on the appropriate side. The mediastinum is exposed, and biopsy of the mediastinal mass or resection of the tumor is performed before caval reconstruction. Once biopsy or tumor resection is done, the pericardial sac is opened to expose the right atrial appendage, which is used most frequently for the central anastomosis. A sidebiting Satinsky clamp is placed on the right atrial appendage, which is opened longitudinally. Some trabecular muscle is excised to improve inﬂow, and an end-to-side anastomosis with the vein graft is performed with running 5-0 monoﬁlament suture (Fig. 50.4). If not involved in the ﬁbrosing process, a patent SVC central to the occlusion can also be used for this purpose. The peripheral anastomosis of the graft is performed with the internal jugular or innominate vein in an end-to-side or, preferably, an end-to-end fashion. Although we have performed bifurcated spiral vein grafts or bifurcated prosthetic grafts in a few patients, a single straight graft from the internal jugular or innominate vein (Figs 50.5–50.7) is our current operative choice for SVC reconstruction. Because collateral circulation in the head and neck is almost always adequate, unilateral reconstruction is sufﬁcient to relieve symptoms in most patients. When only part of the circumference of the SVC is invaded by the tumor, resection and caval patch angioplasty using prosthetic patch, bovine pericardium, or

(b)

Figure 50.5 (a) Non-penetrating vascular clips used for preparation of a spiral vein graft. (b) Postoperative venogram demonstrating the patent left internal jugular–right atrial appendage bypass graft. The graft is patent and the patient is asymptomatic 3 years later.

Results 561

(a)

(a)

(b)

Figure 50.6 (a) Left innominate vein–right atrial appendage bypass graft using femoral vein. (b) Venogram 3 months after surgery conﬁrms the graft to be widely patent.

(b)

Figure 50.7 (a) Left internal jugular vein–atrial appendage externally supported expanded polytetraﬂuoroethylene (ePTFE) graft. (b) Widely patent graft at 13 months after the operation.

autogenous material, such as saphenous vein or pericardium, are also a viable option. Postoperative anticoagulation is started 24 hours later with heparin, and the patient is discharged on an oral anticoagulation regimen. Patients with spiral or femoral vein grafts who have no underlying coagulation abnormality are maintained on warfarin (Coumadin) for 3 months only. Those with underlying coagulation disorders and most patients with ePTFE grafts continue lifelong anticoagulation therapy.

RESULTS Results of endovenous treatment Initial attempts at treating SVC syndrome by endovascular means employed PTA alone, with early restenosis caused by elastic recoil or compression from surrounding ﬁbrosis. The earliest reports of SVC stenting in 1986/7 independently by Charnsangavej et al.13 and Rosch et al.29 were in patients with malignant SVC

Surgical and endovenous treatment of superior vena cava syndrome

years, following which there was maintained, durable graft patency (Fig. 50.9).19 Most studies have emphasized the need for customizing treatment with a combination of thrombolysis, angioplasty, and stenting to achieve an initial technical success rate of 90–100% and secondary patency rates up to 85% at 1 year in small numbers of patients.17 Barshes et al.44 recently reported 100% technical success and 96% symptomatic relief following stenting in 40 patients with malignant and 16 patients with benign SVC syndrome with primary patency of 64% and 76% at 1 year, respectively, and symptom-free survival ranging from 1 to 34 months. However, to this date, prospective, randomized data comparing stent types or treatment modalities do not exist. Oudkerk et al.45 reported on comparing Giantarco and Wallstents reported the latter to be more prone to reocclusion presumably because of a closer weave and greater surface area of metal. Dinkel et

85%

100

75% 68%

81%

75% 68%

80

Patency rate (%)

occlusion and resulted in prompt relief of symptoms that lasted till death at 3 weeks to 6 months. Early experience was with Gianturco Z stents which were subsequently modiﬁed by Rosch et al.14 to create a multibody design that minimized stent migration. In the early 1990s occasional cases of stent deployment for pacemaker wireinduced thrombosis were reported, but repeated interventions were required to maintain patency in the short term.13,14,30 Availability of the more ﬂexible Wallstents and Palmaz stents in larger sizes added to the versatility of endovascular treatment. Nicholson et al.36 reported the largest study of endovenous intervention of the SVC in 1997 in 75 patients with malignant SVC syndrome. Symptomatic relief was achieved in all patients within 48 hours and 90% remained symptom-free until death. The authors compared SVC stenting with palliative radiation for symptomatic SVC syndrome and concluded that radiation provided durable relief from symptoms in only 12% of patients. In a later study by Garcia Monaco et al.37 dramatic symptomatic improvement was seen in 91% of 40 patients following SVC stenting, and was maintained in 83% during the course of the disease. Greillier et al.38 reported that there was complete resolution of symptoms more frequently in stented than in unstented patients with lung cancer (75% vs 25%) as well as a lower relapse rate and longer time to relapse. Based on these and similar results reported in several smaller series endovenous treatment has become the unequivocal ﬁrst-line treatment for malignant SVC syndrome and also provides an opportunity for endovenous biopsy during the procedure.39–42 Kee et al.43 reported results of treatment in 16 patients with benign SVC syndrome with thrombolysis, PTA, and stents. Over a mean follow-up of 17 months in 13/16 patients primary patency was 77% and secondary patency 85%. Qanaldi et al.12 reported 12 patients treated with Wallstents; one symptomatic recurrence occurred at 2 months over a mean follow-up of 11 months. Sheikh et al.8 in a contemporary series treated 19 patients with benign SVC obstruction, with symptomatic relief in all, secondary interventions in three over a mean follow-up of 28 months, and one death from complications of anticoagulation. We recently reported our results of endovenous treatment of SVC syndrome of benign etiology in 28 patients: 19 with catheter-related thrombosis and nine with mediastinal ﬁbrosis.19 Six patients underwent PTA and 22 underwent stenting; ﬁve procedures (two PTA and three stents) were preceded by thrombolysis. Over a mean follow-up of 1.8 years (0–6.3 years) primary patency at 1 and 3 years was 70% and 44%, respectively, with assisted primary and secondary patency rates of 96% and 96% respectively (Fig. 50.8). These were not signiﬁcantly different from the patency of surgical reconstruction of the SVC at our institution. We did, however, notice that the need for reintervention persisted at least out to midterm, unlike in surgical graft patients in whom stenoses requiring intervention occurred mostly in the ﬁrst 1–2

58%

60

45%

45%

40 Primary Assisted primary Secondary

20

0 0

1

2

3

4

5

15 15 11

11 11 10

9 9 8

Years Number at Risk Secondary 42 Assisted Primary 42 Primary 42

23 22 16

16 16 12

(a) 96% 96%

96% 96%

100

70% 44%

80

Patency rate (%)

562

60

40 Primary Assisted primary Secondary

20

0 0

1

2

3

4

5

6 6 3

1 1

1 1

Years Number at Risk Secondary 28 Assisted Primary 28 Primary 28

15 15 10

9 9 5

(b) Figure 50.8 (a) Cumulative primary, assisted primary, and secondary patency rates at 1, 3 and 5 years of open surgical reconstruction (n = 42). Solid bars represent SEM < 10%. (b) Cumulative primary, assisted primary, and secondary patency rates at 1 and 3 years of endovascular repair (n = 28). Solid bars represent SEM < 10%. (From Rizvi et al.19)

Results 563

al.46 in a study of 84 patients with malignant SVC syndrome found bilateral Wallstent placement was technically feasible but was associated with a greater incidence of reocclusion. Occlusion of stents because of protrusion of tumor between stent struts in patients with malignancy as well as intimal hyperplasia, ﬁbrosis, and extrinsic compression from mediastinitis are real concerns following endovenous treatment. Restenosis is almost always associated with recurrence of symptoms and necessitates repeat interventions especially in patients with benign SVC syndrome. Other risks of endovenous treatment include access site complications, bleeding related to

thrombolysis/anticoagulation, stent migration, and cardiac tamponade from intrapericardial hemorrhage. The last occurs infrequently, has been reported after both PTA and stenting, and management entails urgent ultrasoundguided pericardiocentesis. We encountered this complication during repeat PTA in two patients.

Results of surgical treatment Reconstruction of the occluded SVC or innominate vein gives the most gratifying result of venous bypasses. Patency rate is very good, since the mean ﬂow through the graft

(a)

(b)

(c)

(d)

Figure 50.9 (a) Venogram showing type II superior vena cava obstruction (arrow) due to mediastinal ﬁbrosis in a 38-year-old man. Successful placement of a Palmaz stent resulted in immediate resolution of symptoms. (b) Venogram 14 months after stent placement shows high-grade stenosis of the left innominate vein proximal to the stent (arrow). This was successfully treated with balloon angioplasty. (c) Venogram 8 months later shows recurrence of stenosis (arrow). (d) Venogram following balloon angioplasty of stenosis left innominate vein and stent shows widely patent stent. Patient underwent two further balloon angioplasties over the next 10 months to maintain patency.

564

Surgical and endovenous treatment of superior vena cava syndrome

is usually high (mean 1440 mL/min, range 750– 2000 mL/min).47 Shorter grafts placed entirely within the mediastinum have a better chance of long-term patency than those with an anastomosis in the neck. Doty et al.22 reported on long-term results in nine patients who underwent spiral vein grafting for SVC syndrome, caused by benign disease. Seven of nine grafts remained patent during follow-up that extended from 1 to 15 years and all but one of the patients became asymptomatic. Their larger experience consisting of 16 spiral saphenous vein grafts for benign SVC syndrome reported in 1999 documented 88% long-term graft patency and excellent clinical results at a mean follow-up of 10.9 years.48 Similar results have been reported from our institution in the past with no operative mortality, 80% graft patency at 5 years (90% in vein grafts), and 79% symptom relief.21 We have recently reported our results with evolving treatment for benign SVC syndrome with endovascular means and compared them with surgical reconstruction, which has been the mainstay over the years.19 Forty-two patients underwent 22 spiral saphenous vein grafts, six reversed femoral vein, 13 ePTFE grafts, and one patient received an iliocaval allograft. The grafts originated from the internal jugular vein in 15 patients, subclavian vein in one, and innominate vein in 26; they were anastomosed centrally to the SVC in 12 patients and right atrial appendage in 30. No early deaths or pulmonary thromboembolism occurred. Six patients had early reoperation for graft thrombosis; thrombectomy of four ePTFE grafts, and thrombectomy and revision of side limbs of two bifurcated spiral saphenous vein grafts. All grafts, except one limb of a bifurcated graft, were patent at the time of discharge. Thirty day primary, assisted primary, and secondary patencies were 93%, 98%, and

(a)

100%, respectively. During a mean follow-up of 4.1 (0.1–17.5) years, primary and secondary patency rates of all the grafts at 5 years were 45% and 75%, respectively. Of the different graft types, spiral saphenous vein grafts performed well, with 86% secondary patency at 5 years, 19 of the 22 grafts patent at last follow-up, and good to excellent clinical results. Results with ePTFE grafts implanted into the mediastinum in some series have shown excellent patency. Dartevelle et al.25 observed continued patency in 20 of 22 ePTFE grafts, with a mean follow-up of 23 months. Moore and Hollier23 observed no graft occlusion at a mean follow-up of 30 months among 10 patients who underwent large central vein reconstruction. In eight of these 10 patients an additional arteriovenous ﬁstula at the arm was used to increase ﬂow and maintain patency. Magnan et al.24 reported on 10 patients who underwent reconstruction of the SVC using ePTFE grafts. Nine of the 10 patients had malignancy. Although early mortality was high with only two survivors during the follow-up period, no patient developed recurrent symptoms of SVC syndrome.24 Reviewing other series from the literature, however, we found that patency of ePTFE grafts at 2 years was approximately 70%. In our experience some thrombus formation occurs even in patent ePTFE grafts. Thrombosis occurs much more in patients in whom the distal anastomosis is performed with the internal jugular or the subclavian veins, and results appear much better in patients with innominate or SVC interposition grafts. Similar to our experience, Shintani et al.49 noted greater incidence of occlusion in bifurcated than in straight grafts. Although spiral vein graft continues to be our ﬁrst choice for SVC replacement, short, large-diameter ePTFE is an excellent alternative for SVC replacement.

(b)

Figure 50.10 (a) Venogram 10 months after placement of a left innominate vein–right atrial appendage spiral vein graft reveals severe stenosis at the proximal anastomosis (arrow). (b) Successful reconstruction with placement of a Wallstent. (From Alimi et al.9)

Conclusions 565

30 20 10 0

< 30 days

1–12 months

12–36 months

> 36 months

50

(a)

40 % patients

% patients

40

10 9 8 7 6 5 4 3 2 1 0

No. of interventions

50

# of secondary interventions % of patients

30 20 10 0

< 30 days

1–12 months

12–36 months

> 36 months

10 9 8 7 6 5 4 3 2 1 0

No. of interventions

# of secondary interventions % of patients

(b)

Figure 50.11 Treatment of benign superior vena cava syndrome. Secondary interventions required to maintain patency in (a) the open surgical group (n = 42) and (b) the endovascular group (n = 28). The bars represent the percentage of patients in each group and the line graphs represent total number of interventions. (From Rizvi et al.19)

+3

Symptom grade

Increasing success with femoral vein as an arterial conduit has resurrected this autologous graft for large vein reconstructions as well.35 Recent reports on good early results indicate that, when available, autologous femoropopliteal vein shows promise for replacement of large central veins. All six femoral vein grafts performed by us have remained patent. Still, the morbidity of harvesting a deep vein in patients with thrombotic potential and venous thrombosis elsewhere in the body is not well known. Two of our six patients who underwent SVC reconstruction using the femoral vein have mild but persistent swelling and venous claudication. Nonetheless, it is a good conduit in patients with unavailable or inadequate saphenous vein. Postoperative follow-up is important, but unfortunately duplex scans provide only indirect evidence of patency of an intrathoracic graft. Therefore, contrast or magnetic resonance venography are used, and they are performed before discharge and again at 3–6 months after surgery. In our experience, most graft stenoses presented within 1–2 years after implantation, and were invariably associated with recurrence of symptoms (Fig. 50.10). The need for reintervention occurred mostly during this time period with durable patency thereafter, unlike the continuing need for reintervention following endovascular treatment, especially in patients with benign disease (Fig. 50.11).19 Endovascular therapy, however, remains an invaluable adjunctive measure to treat graft stenoses and improve long-term graft patency.9,21 Relief from symptoms was equally good following endovascular and open surgical reconstruction (Fig. 50.12).

Open surgery

+2

Endovascular

+1

+3 – asymptomatic +2 – mild symptoms +1 – improvement 0 – no change

0 0

5

10 Years

15

20

Figure 50.12 Grading of symptom relief at last clinical followup in patients undergoing open surgical reconstruction (n = 42) or endovascular repair (n = 28). (From Rizvi et al.19)

CONCLUSIONS The incidence of SVC syndrome is increasing with the growing use of indwelling catheters and pacemakers. The techniques of endovascular treatment have been reﬁned and experience with their use has increased. Endovascular treatment is now an appropriate primary intervention in patients with SVC syndrome of both malignant and benign etiology. It is less invasive with lower morbidity than open surgical reconstruction with equal efﬁcacy and patency in the midterm, albeit at the cost of multiple secondary interventions. It does not adversely affect the feasibility or patency of subsequent open surgical reconstruction. Endovascular techniques are also helpful

566

Surgical and endovenous treatment of superior vena cava syndrome

Guidelines 5.1.0 of the American Venous Forum on surgical and endovenous treatment of superior vena cava syndrome No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.1.1 In patients with malignant superior vena cava obstruction we recommend stenting as the primary therapy

1

A

5.1.2 In patients with superior vena cava syndrome due to non-malignant etiology we recommend endovascular treatment as the initial therapy

1

B

5.1.3 We recommend surgical reconstruction of the superior vena cava with autogenous vein or expanded polytetraﬂuoroethylene bypass as an effective and durable alternative in patients who fail or who are unsuitable for endovascular intervention

1

B

adjuncts to prolong patency of grafts used for SVC replacement. Surgical treatment of SVC syndrome with spiral vein graft or prosthetic grafts is effective, provides long-term relief and remains an excellent option in patients not suitable for or who fail endovascular treatment.

REFERENCES ● ◆

= Key primary paper = Major review article 1. Hunter W. The history of an aneurysm of the aorta with some remarks on aneurysms in general. Med Obs Inq (Lond) 1757; 1: 323–57. 2. Ahmann F. A reassessment of the clinical implications of the superior vena cava syndrome. J Clin Oncol 1984; 2: 961–9. ●3. Gloviczki P, Pairolero PC, Toomey BJ, et al. Reconstruction of large veins for nonmalignant venous occlusive disease. J Vasc Surg 1992; 16: 750–61. 4. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics – 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69–171. 5. Korkeila P, Nyman K, Ylitalo A, et al. Venous obstruction after pacemaker implantation. Pacing Clin Electrophysiol 2007; 30: 199–206. 6. Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine (Baltimore) 2006; 85: 37–42. 7. Parish JM, Marschke RF Jr, Dines DE, Lee RE. Etiologic considerations in superior vena cava syndrome. Mayo Clin Proc 1981; 56: 407–13.

8. Sheikh MA, Fernandez BB Jr, Gray BH, et al. Endovascular stenting of nonmalignant superior vena cava syndrome. Catheter Cardiovasc Interv 2005; 65: 405–11. ●9. Alimi YS, Gloviczki P, Vrtiska TJ, et al. Reconstruction of the superior vena cava: beneﬁts of postoperative surveillance and secondary endovascular interventions. J Vasc Surg 1998; 27: 287–99. 10. Chen J, Bongard F, Klein SR. A contemporary perspective on superior vena cava syndrome. Am J Surg 1990; 160: 207–11. 11. Yellin A, Rosen A, Reichert N, Lieberman Y. Superior vena cava syndrome: the myth – the facts. Am Rev Respir Dis 1990; 141: 1114–18. 12. Qanadli SD, El Hajjam M, Mignon F, et al. Subacute and chronic benign superior vena cava obstructions: endovascular treatment with self-expanding metallic stents. Am J Roentgenol 1999; 173: 159–64. 13. Charnsangavej C, Carrasco CH, Wallace S, et al. Stenosis of the vena cava: preliminary assessment of treatment with expandable metallic stents. Radiology 1986; 161: 295–8. ●14. Rosch J, Uchida BT, Hall LD, et al. Gianturco–Rosch expandable Z-stents in the treatment of superior vena cava syndrome. Cardiovasc Intervent Radiol 1992; 15: 319–27. 15. Wisselink W, Money SR, Becker MO, et al. Comparison of operative reconstruction and percutaneous balloon dilatation for central venous obstruction. Am J Surg 1993; 166: 200–4. 16. Solomon N, Wholey MH, Jarmolowski CR. Intravascular stents in the management of superior vena cava syndrome. Cathet Cardiovasc Diagn 1991; 23: 245–52. ●17. Schindler N, Vogelzang RL. Superior vena cava syndrome. Experience with endovascular stents and surgical therapy. Surg Clin North Am 1999; 79: 683–94, xi. 18. Sherry CS, Diamond NG, Meyers TP, Martin RL. Successful treatment of superior vena cava syndrome by venous angioplasty. Am J Roentgenol 1986; 147: 834–5.

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Rizvi AZ, Kalra M, Bjarnason H, et al. Benign superior vena cava syndrome: stenting is now the ﬁrst line of treatment. J Vasc Surg 2008; 47(2): 372–80. Gloviczki P, Pairolero PC, Cherry KJ, Hallett JW Jr. Reconstruction of the vena cava and of its primary tributaries: a preliminary report. J Vasc Surg 1990; 11: 373–81. Kalra M, Gloviczki P, Andrews JC, et al. Open surgical and endovascular treatment of superior vena cava syndrome caused by nonmalignant disease. J Vasc Surg 2003; 38: 215–23. Doty DB, Doty JR, Jones KW. Bypass of superior vena cava. Fifteen years’ experience with spiral vein graft for obstruction of superior vena cava caused by benign disease. J Thorac Cardiovasc Surg 1990; 99: 889–95; discussion 895–6. Moore W, Hollier LH. Reconstruction of the superior vena cava and central veins. In: Bergan J, Yao JST, eds. Venous Disorders. Philadelphia: W.B. Saunders, 1991: 517–27. Magnan PE, Thomas P, Giudicelli R, et al. Surgical reconstruction of the superior vena cava. Cardiovasc Surg 1994; 2: 598–604. Dartevelle PG, Chapelier AR, Pastorino U, et al. Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal–pulmonary malignant tumors. J Thorac Cardiovasc Surg 1991; 102: 259–65. Herreros J, Glock Y, de la Fuente A, et al. Superior vena cava compression syndrome. Our experience apropos of 26 cases (in French). Ann Chir 1985; 39: 495–500. Ricci C, Benedetti Valentini F, Colini GF, et al. Reconstruction of the superior vena cava: 15 years’ experience using various types of prosthetic material (in French). Ann Chir 1985; 39: 492–5. Graham A, Anikin V, Curry R, McGuigan J. Subcutaneous jugulofemoral bypass: a simple surgical option for palliation of superior vena cava obstruction. J Cardiovasc Surg 1995; 36: 615–17. Rosch J, Bedell JE, Putnam J, et al. Gianturco expandable wire stents in the treatment of superior vena cava syndrome recurring after maximum-tolerance radiation. Cancer 1987; 60: 1243–6. Irving JD, Dondelinger RF, Reidy JF, et al. Gianturco selfexpanding stents: clinical experience in the vena cava and large veins. Cardiovasc Intervent Radiol 1992; 15: 328–33. Chiu CJ, Terzis J, MacRae ML. Replacement of superior vena cava with the spiral composite vein graft. A versatile technique. Ann Thorac Surg 1974; 17: 555–60. Doty DB, Baker WH. Bypass of superior vena cava with spiral vein graft. Ann Thorac Surg 1976; 22: 490–3. Klassen K, Andrews NC, Curtis GH. Diagnosis and treatment of superior vena cava obstruction. Arch Surg 1951; 63: 311–25. Gladstone DJ, Pillai R, Paneth M, Lincoln JC. Relief of superior vena caval syndrome with autologous femoral vein used as a bypass graft. J Thorac Cardiovasc Surg 1985; 89: 750–2.

35. Hagino RT, Bengtson TD, Fosdick DA, et al. Venous reconstructions using the superﬁcial femoral-popliteal vein. J Vasc Surg 1997; 26: 829–37. 36. Nicholson AA, Ettles DF, Arnold A, et al. Treatment of malignant superior vena cava obstruction: metal stents or radiation therapy. J Vasc Interv Radiol 1997; 8: 781–8. 37. Garcia Monaco R, Bertoni H, Pallota G, et al. Use of selfexpanding vascular endoprostheses in superior vena cava syndrome. Eur J Cardiothorac Surg 2003; 24: 208–11. 38. Greillier L, Barlesi F, Doddoli C, et al. Vascular stenting for palliation of superior vena cava obstruction in non-smallcell lung cancer patients: a future “standard” of procedure? Respiration 2004; 71: 178–83. ◆39. Urruticooechea A, Mesia R, Dominguez J, et al. Treatment of malignant superior vena cava syndrome by endovascular stent insertion. Experience on 52 cases with lung cancer. Lung Cancer 2004; 43: 209–14. 40. Bierdrager E, Lampmann LE, Loble PN, et al. Endovascular stenting in neoplastic superior vena cava syndrome prior to chemotherapy or radiotherapy. Neth J Med 2005; 63: 20–3. ◆41. Lee-Elliot CE, Abubacker MZ, Lopez AJ. Fast-track management of malignant superior vena cava syndrome. Cardiovasc Intervent Radiol 2004; 27: 470–3. 42. Chatziioannou A, Alexopoulos T, Mourikis D, et al. Stent therapy for malignant superior vena cava syndrome: should be ﬁrst line therapy or simple adjunct to radiotherapy. Eur J Radiol 2003; 47: 247–50. 43. Kee ST, Kinoshita I, Razavi MK, et al. Superior vena cava syndrome: treatment with catheter-directed thrombolysis and endovascular stent placement. Radiology 1998; 206: 187–93. 44. Barshes NR, Annambhotia S, El Sayed HF, et al. Percutaneous stenting of superior vena cava syndrome: treatment outcome in patients with benign and malignant etiology. Vascular 2007; 15: 314–21. 45. Oudkerk M, Kuijpers TJ, Schmitz PI, et al. Self-expanding metal stents for palliative treatment of superior vena cava syndrome. Cardiovasc Intervent Radiol 1996; 19: 146–51. 46. Dinkel HP, Mettke B, Schmid F, et al. Endovascular treatment of malignant superior vena cava syndrome: is bilateral wallstent placement superior to unilateral placement? J Endovasc Ther 2003; 10: 788–97. 47. Doty DB. Bypass of superior vena cava: six years’ experience with spiral vein graft for obstruction of superior vena cava due to benign and malignant disease. J Thorac Cardiovasc Surg 1982; 83: 326–38. ●48. Doty JR, Flores JH, Doty DB. Superior vena cava obstruction: bypass using spiral vein graft. Ann Thorac Surg 1999; 67: 1111–16. 49. Shintani Y, Ohta M, Minami M, et al. Long-term graft patency after replacement of the brachiocephalic veins combined with resection of mediastinal tumors. J Thorac Cardiovasc Surg 2005; 129: 809–12.

51 The management of extremity venous trauma* DAVID L. GILLESPIE AND REAGAN W. QUAN Introduction Etiology Distribution of injuries Diagnosis

568 568 568 569

Treatment Outcome Conclusions References

569 570 571 571

INTRODUCTION

ETIOLOGY

Trauma is the fourth leading cause of all civilian deaths in the USA, and the leading cause of death among young men.1 Injuries to young persons aged 25–44 years account for approximately 70% ($283 billion) of the total costs of injuries yearly.2 Similarly, in military trauma the average age of wounded soldiers is 22 years.3 Approximately 30% of all soldiers injured in the Global War on Terrorism (GWOT) had some form of vascular injury. The true incidence of venous injuries is under-reported in most series. In the GWOT Vascular Trauma Database only 85 patients were documented to have sustained 106 named venous injuries compared with over 200 arterial injuries over the same 5 year period.4 Most venous injuries occur in combination with arterial injuries. Isolated venous injuries occur much less commonly. Quan et al.4 reported only 25% of patients with extremity vascular trauma who had isolated venous injuries.4 This current report is similar to historical reports on the incidence of venous injuries occurring during wartime. Hughes and Cohen5 reported that venous injuries accounted for 39.4% of vascular injuries received during the Korean War. Rich et al.6,7 reported that 377/1000 arterial injuries were associated with concomitant venous injuries (38%) occurring over the same time frame. Despite dramatic differences in magnitude of injury, reports on civilian vascular trauma report that the majority (75%) of venous injuries also occur in association with arterial injuries.6,8–12

The majority of injuries occurring in the USA do so during motor vehicle accidents. Injuries resulting from the use of ﬁrearms are the second leading cause of injury death in the USA, but the leading cause of vascular injury. Penetrating injury from gunshot wound is also the leading cause of venous injury. Venous injuries from other causes occur much less frequently, including stab wounds (1–28%), blunt trauma (1–23%), and shotguns (1–17%). Historically, the majority of military vascular injuries result from penetrating trauma caused by projectiles that are generated by explosive devices.3,6,13,14 The type of explosive devices has changed over time from mortars and shells to the present-day improvised explosive devices (IEDs). Numerous reports on the conﬂicts in Iraq and Afghanistan have stated that up to 70% of patients are wounded by IEDs, 20% by high velocity riﬂes, and 10% by blunt traumatic injury.3,15

DISTRIBUTION OF INJURIES A review of the recent literature shows that nearly 90% of civilian venous trauma occurs in the extremities with a near equal distribution between upper and lower extremities.2 Gaspar and Trieman16 documented the incidence of civilian venous injuries as 17% femoral vein, 15% inferior vena cava, 15% internal jugular vein, 14% brachial vein, and 8% popliteal vein. In a report from

*The opinions contained herein do not necessarily reflect the opinions of the Uniformed Services University of the Health Sciences, Department of the Army, or Department of Defense.

Treatment 569

Louisiana State University, Smith et al.17 reported 25% of venous injuries involved the iliac veins, 45% femoral, 20% popliteal, and 10% basilic veins. Owing to the use of truncal body armor and ballistic helmets, extremity injuries predominate in military vascular trauma. A review of military injuries in the conﬂict reveals that injuries to the head and neck accounted for 31% of overall injuries, with the trunk accounting for 14%, lower extremities 26%, and upper extremities 30%. Injuries to the femoral vein accounted for the largest percentage of venous injuries (37%) during the Vietnam conﬂict. Injuries to the popliteal vein occurred in 29.3% and injuries to the common femoral vein (CFV) in 5%. Upper extremity venous injuries were less common, with brachial vein injuries accounting for 14% and axillary vein injuries 5%.

DIAGNOSIS Diagnosis of injuries to major extremity venous structures may not be obvious on initial presentation. The presence of an associated long-bone fracture or nerve injury should increase suspicion of a major venous injury. Patients may present with non-expanding hematomas or simply slow continuous hemorrhage from a missile track. More commonly, major extremity venous injuries are diagnosed during exploration for an associated arterial injury. Lacerations or transections of injured veins are easily recognized but often overlooked. These injuries may often be managed in the process of exposing and managing an arterial injury. Recognition of injured venous structures in patients with non-life- or non-limb-threatening trauma can be more of a challenge. Ultrasonography is the initial technique of choice for the detection and evaluation of venous thromboses associated with trauma. The loss of spontaneous venous ﬂow, respiratory variation, and compressibility conﬁrm venous thrombosis. Gagne et al.18 reported that color-ﬂow duplex ultrasonography (CFD) detected seven of eight (88%) venous injuries in 37 civilian patients with penetrating proximity extremity trauma. In military conﬂict we ﬁnd the use of ultrasonography extremely limited owing to the presence of large soft-tissue defects or external ﬁxtures. For this reason, either conventional venography or late-phase analysis of 64 slice computed tomography (CT) angiography is utilized for venous imaging. Both of these techniques, however, may be non-diagnostic because of artifacts created by retained missiles or fragments.

TREATMENT The most common method of managing venous injuries is ligation. This is true both for non-axial and major axial veins such as the common femoral, femoral, or popliteal

veins. Several reports exist on the results of venous ligation after civilian trauma.9,19–21 This method of management is the most expedient and appropriate for venous injuries associated with other multisystem life-threatening injuries. In more controlled circumstances, however, the ligation of venous injuries remains controversial. Controversy exists regarding the short- and long-term effects of ligating the main venous outﬂow to the extremity, namely the common femoral and popliteal veins. The immediate effects of venous ligation include not only venous hypertension and increased compartment pressures but also diminished arterial inﬂow. This was demonstrated in several animal studies by Barcia et al.,22 Hobson et al.23 and Wright and colleagues.24–28 Most reports agree that the immediate side-effects from venous ligation can be minimized by the liberal use of fasciotomy, appropriate ﬂuid resuscitation, and postoperative limb elevation. Long-term side-effects of common femoral or popliteal venous ligation have generally shown a higher incidence of edema and chronic venous insufﬁciency after ligation compared with venous repair;29–32 however, this is has not been found by all investigations.33,34 Ligation was the principal method of management of military venous injuries up to and through the Korean War. Not until Hughes,14,35 Hughes and Bower,36 and Spencer and Grewe37 began to explore the possibilities of arterial repair did they begin to attempt repair of military venous injuries. In the wars in Iraq and Afghanistan, ligation of venous injuries continues to be the most common method of managing the majority of axial and non-axial venous injuries. The physiologic effects of axillary, femoral, or popliteal vein ligation might be extrapolated from reports on the harvest of the axillary or femoropopliteal veins for vascular reconstruction. Raju et al.38,39 found only transient mild upper extremity swelling in less than 2% of patients undergoing axillary vein valve transfer for the treatment of popliteal vein reﬂux. The ligation and excision of the femoropopliteal vein for arterial reconstruction was ﬁrst reported by Clagett et al.40 This group reports ﬁnding less than one-third of patients had lower extremity edema, and no patient had major chronic venous changes or venous claudication.41 They found only fasciotomy was performed in 20.7% of limbs in response to the development of severe venous hypertension after complete deep vein harvest below the adductor hiatus. In contrast, the authors found that fasciotomies were not required in patients undergoing subtotal deep vein harvest, ending above the adductor hiatus. In addition, a fasciotomy was performed in 76.0% of limbs undergoing concurrent ipsilateral greater saphenous vein and deep vein harvest, compared with 11.7% of patients undergoing deep vein harvest alone.42 These observations show that elective harvest of the femoropopliteal vein conduit is possible and the associated morbidity acceptable. They may not, however, accurately reﬂect the physiologic situation of the acutely injured extremity with large soft-tissue injury and acute

570

The management of extremity venous trauma

interruption of extremity lymphatics in addition to compromised venous drainage. The use of temporary shunts has been advocated by several civilian trauma groups for the management of critically ill patients deemed too ill for prolonged surgery and vascular repair. These groups advocate for the use of intravenous as well as intra-arterial shunts.43–45 Basic science investigations have shown that shunts are effective and maintain patency without the use of systemic anticoagulation in the short term.46 Recently, military vascular surgeons have revisited the use of intravascular shunts for the management of venous and arterial injuries. Rasmussen et al.15,47–49 reported their series of 126 vascular injuries treated by intravascular shunting in Iraq. In this series, they report a high degree of short-term patency in a small subset of proximal venous injuries treated with silastic shunt interposition. In 1954, Hughes14 reported successful repair of 13 venous injuries occurring in patients with concomitant arterial injury. Stimulated by this experience Rich et al.3,6,35,36,50–56 investigated the utility of venous repair during the Vietnam War. Following these results, repair of traumatic venous injuries in civilian trauma has also been reported by several centers over the last 30 years.10,17,34,57–60 Simple lateral suture repair is the most common method of managing civilian venous trauma10,11,16,17,34,58 with 76–93% patency in short-term follow-up. Reports from the Korean and Vietnam War have shown that lateral venorrhaphy was used in 85% of venous repairs.5 Similarly, lateral venorrhaphy has been employed most often for the management of venous injuries during the wars in Iraq and Afghanistan.4 Venous repair should be considered when dealing with major outﬂow veins of the lower extremity such as the common femoral or popliteal veins. After debridement of the injured venous segment back to normal vein, the surgeon should then assess whether an end-to-end repair can be performed. This is usually achievable after mobilization of the proximal and distal venous segments. Reports from civilian institutions have shown that end-toend venous repairs of the femoral vein have been very successful with patencies up to 74% in the early postoperative period.10 Hughes14 reported the ﬁrst use of endto-end anastomosis for the management of military venous trauma in 1954. During the Vietnam War, it is reported that 15% of military venous injuries were managed using end-to-end anastomosis. In more recent conﬂicts, end-to-end repair of major venous injuries has been documented rarely in injured US service personnel.4 When there is a large segmental loss of the common femoral or popliteal vein, interposition grafting is the procedure of choice. The greater saphenous vein is an excellent conduit for the majority of interposition grafts and should be harvested from the uninjured or contralateral lower extremity. When performing interposition grafting in the venous system, the vein is used in a nonreversed fashion. In civilian trauma series, interposition

grafting accounts for 11–42% of venous repairs by several recent reports.10,11,16,17,34,58 Long-term patency of interposition grafts, however, have been somewhat disappointing with 30 day patencies reported in the range of 40–75%. The largest military experience with vein graft interposition for repair of venous injuries has been reported by Rich et al.3,6,35,36,50–56 During the Vietnam conﬂict, 4% of patients with venous injuries underwent surgery for major venous injuries. In recent military conﬂicts, documented use of this technique has rarely been reported. Prosthetic conduits have been used for traumatic vascular reconstruction when the greater saphenous vein is of inadequate size, poor quality, or needed for venous outﬂow in the multiply injured patient.61–63 Interposition grafting using expanded polytetraﬂuoroethylene (ePTFE) bypasses has led to diminished venous hypertension and the ability to evacuate the patient to a facility where reconstruction using autologous conduits can be performed. Reports of good short-term patency have been reported; however, the long-term patency of these conduits in the venous system has been disappointing. Review of the literature ﬁnds that roughly 100% of these grafts used for civilian venous injuries were thrombosed in postoperative follow-up.64 In recent conﬂicts, ePTFE interposition grafts have been used as temporary shunts in the venous system and have facilitated rapid evacuation of many patients back to the USA. Experience has shown that these prosthetic venous reconstructions have limited the effects of venous hypertension, thereby facilitating extremity wound management. Spiral and panel grafts are rarely used for the management of venous injuries.34,60,63–65 In 1997, surgeons from the University of Medicine and Dentistry of New Jersey published their experience with the use of complex venous repairs for the management of civilian venous trauma. These authors found that only 8% of patients received spiral vein grafts and 11% panel grafts in the iliac, common femoral, or popliteal veins. The patency of these complex repairs is signiﬁcantly lower than when simpler techniques are used. Nearly 50% of these repairs will be thrombosed in early postoperative period. The use of panel or spiral grafts for military injuries has not been reported.

OUTCOME Long-term follow-up of traumatic venous injuries ranging from 6 to 20 years after initial management has been reported. These studies have shown patency rates for simple repairs are in the range of 67–100% in long-term follow-up.64,66–68 In recent conﬂicts we have found that six of 39 (15%) vein repairs thrombosed in the postoperative period. Two patients developed phlegmasia, both as a result of a CFV ligation.

References 571

Guidelines 5.2.0 of the American Venous Forum on the management of extremity venous trauma No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.2.1 For patients with multisystem injury who are unstable, we recommend ligation of the injured veins including the common femoral or popliteal veins

1

B

5.2.2 For hemodynamically stable trauma patients with single-system injuries we recommend repair of major venous injuries. Speciﬁcally, the axillary, subclavian, common iliac, external iliac, common femoral, or popliteal veins should be repaired

1

B

5.2.3 For patients with massive extremity swelling following traumatic venous injuries or ligation of major veins, we recommend leg elevation and four compartment fasciotomies

1

B

Morbidity from complications of venous repairs such as pulmonary emboli or deep venous thrombosis has been cited as a reason to avoid these techniques when managing venous trauma. Numerous reports from both military and civilian trauma centers, however, have not found a high incidence of venous thromboembolic complications (0–1%) from patients managed by venous repair.10,36,37,56,60 Three patients had postoperative venous thrombosis after primary repair of major lower extremity veins and two patients after interposition graft. Three patients developed pulmonary embolism after saphenous or femoral vein repair with an interposition vein graft. Two patients developed pulmonary embolism (PE) after ligation of an injured vein, one patient from a brachial vein ligation and the other from an iliac vein ligation. In this study, we found no signiﬁcant difference with regard to pulmonary emboli when comparing ligation with venous repair (3.1% vs 2.5%, P = NS).

CONCLUSIONS The management of traumatic venous injuries should be performed with consideration for the overall physiologic status of the patient. In patients with multisystem injury who are unstable, ligation of the venous injury, even if common femoral or popliteal, seems prudent. In stable trauma patients with single-system injuries, however, major venous injuries should be repaired if possible. Speciﬁcally, the axillary, subclavian, common iliac, external iliac, common femoral, or popliteal veins should be repaired. Even short-term patency of these veins in the acute trauma patient will help to avoid massive swelling distal to these injuries in the extremities and the possibility of developing a compartment syndrome. To date, there is

no evidence that repair of venous injuries leads to a higher incidence of venous thromboembolic events. If repair of these injured veins is not safe or possible, ligation is the obvious alternative and should be accomplished. In these cases, the surgeon should expect massive extremity swelling in the acute setting and manage it accordingly. Fasciotomies should be performed on the involved extremity accompanied by elevation.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

1. Rice DP, MacKenzie EJ, et al. Cost of Injury in the United States: A Report to Congress. Baltimore: Institute for Health & Aging, University of California and Injury Prevention Center, The Johns Hopkins University, 1989. 2. Corso P, Finkelstein E, Miller T, et al. Incidence and lifetime costs of injuries in the United States. Inj Prev 2006; 12: 212–18. ●3. Fox CJ, Gillespie DL, O’Donnell SD, et al. Contemporary management of wartime vascular trauma. J Vasc Surg 2005; 41: 638–44. ●4. Quan RW, Adams ED, Cox MW, et al. The management of trauma venous injury: civilian and wartime experiences. Perspect Vasc Surg Endovasc Ther 2006; 18: 149–56. 5. Hughes CW, Cohen A. The repair of injured blood vessels. Surg Clin North Am 1958; 38: 1529–43. 6. Rich NM, Baugh JH, Hughes CW. Acute arterial injuries in Vietnam: 1,000 cases. J Trauma 1970; 10: 359–69. ★7. Rich NM, Hughes CW, Baugh JH. Management of venous injuries. Ann Surg 1970; 171: 724–30.

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The management of extremity venous trauma

8. Feliciano DV, Herskowitz K, O’Gorman RB, et al. Management of vascular injuries in the lower extremities. J Trauma 1988; 28: 319–28. 9. Hardin WD Jr., Adinolﬁ MF, O’Connell RC, Kerstein MD. Management of traumatic peripheral vein injuries. Primary repair or vein ligation. Am J Surg 1982; 144: 235–8. 10. Hobson RW, Yeager RA, Lynch TG, et al. Femoral venous trauma: techniques for surgical management and early results. Am J Surg 1983; 146: 220–4. 11. Menzoian JO, Doyle JE, LoGerfo FW, et al. Evaluation and management of vascular injuries of the extremities. Arch Surg 1983; 118: 93–5. 13. DeBakey ME, Simeone FA. Battle injuries of the arteries in World War II: an analysis of 2,471 cases. Ann Surg 1946; 123: 534–79. 14. Hughes CW. Acute vascular trauma in Korean War casualties: an analysis of 180 cases. Surg Gynecol Obstet 1954; 99: 91–100. 15. Clouse WD, Rasmussen TE, Peck MA, et al. In-theater management of vascular injury: 2 years of the Balad Vascular Registry. J Am Coll Surg 2007; 204: 625–32. 16. Gaspar MR, Treiman RL. The management of injuries to major veins. Am J Surg 1960; 100: 171–5. 17. Smith LM, Block EF, Buechter KJ, et al. The natural history of extremity venous repair performed for trauma. Am Surg 1999; 65: 116–20. 18. Gagne PJ, Cone JB, McFarland D, et al. Proximity penetrating extremity trauma: the role of duplex ultrasound in the detection of occult venous injuries. J Trauma 1995; 39: 1157–63. 19. Mullins RJ, Lucas CE, Ledgerwood AM. The natural history following venous ligation for civilian injuries. J Trauma 1980; 20: 737–43. 20. Pasch AR, Bishara RA, Schuler JJ, et al. Results of venous reconstruction after civilian vascular trauma. Arch Surg 1986; 121: 607–11. 21. Yelon JA, Scalea TM. Venous injuries of the lower extremities and pelvis: repair versus ligation. J Trauma 1992; 33: 532–6. ●22. Barcia PJ, Nelson TG, Whelan TJ Jr. Importance of venous occlusion in arterial repair failure: an experimental study. Ann Surg 1972; 175: 223–7. ●23. Hobson RW, Howard EW, Wright CB, et al. Hemodynamics of canine femoral venous ligation: signiﬁcance in combined arterial and venous injuries. Surgery 1973; 74: 824–9. ●24. Wright CB, Swan KG. Hemodynamics of venous repair in the canine hind limb. J Thorac Cardiovasc Surg 1973; 65: 195–9. 25. Wright CB, Swan KG. Hemodynamics of venous occlusion in the canine hindlimb. Surgery 1973; 73: 141–6. 26. Wright CB, Hobson RW. Hemodynamic effects of femoral venous occlusion in the subhuman primate. Surgery 1974; 75: 453–60. 27. Wright CB, Hobson RW, Swan KG, Rich NM. Extremity venous ligation: clinical and hemodynamic correlation. Am Surg 1975; 41: 203–8.

28. Wright CB, Hobson RW, Giordano JM, et al. Acute femoral venous occlusion. (Management by segmental venous replacement in the dog). J Cardiovasc Surg (Torino) 1977; 18: 523–9. ●29. Pappas PJ, Haser PB, Teehan EP, et al. Outcome of complex venous reconstructions in patients with trauma. J Vasc Surg 1997; 25: 398–404. 30. Rich NM. Principles and indications for primary venous repair. Surgery 1982; 91: 492–6. 31. Rich NM, Collins GJ Jr., Andersen CA, McDonald PT. Autogenous venous interposition grafts in repair of major venous injuries. J Trauma 1977; 17: 512–20. 32. Rich NM, Hobson RW, Collins GJ Jr., Andersen CA. The effect of acute popliteal venous interruption. Ann Surg 1976; 183: 365–8. ●33. Timberlake GA, O’Connell RC, Kerstein MD. Venous injury: to repair or ligate, the dilemma. J Vasc Surg 1986; 4: 553–8. 34. Timberlake GA, Kerstein MD. Venous injury: to repair or ligate, the dilemma revisited. Am Surg 1995; 61: 139–45. 35. Hughes CW. Acute vascular trauma in Korean War casualties: an analysis of 180 cases. In: Howard JM, Hughes CW, Crosby WH, et al., eds. Battle Casualties in Korea: Studies of the Surgical Research Team. Washington, DC: Army Medical Service Graduate School, 1955: 132–47. 36. Hughes CW, Bowers WF. Traumatic Lesions of Peripheral Vessels. Springﬁeld, IL: Charles C. Thomas, 1961. 37. Spencer FC, Grewe RV. Management of acute arterial injuries in battle casualties. Ann Surg 1955; 141: 304–13. 38. Raju S, Neglén P, Doolittle J, Meydrech EF. Axillary vein transfer in trabeculated postthrombotic veins. J Vasc Surg 1999; 29: 1050–62. 39. Raju S, Hardy JD. Technical options in venous valve reconstruction. Am J Surg 1997; 173: 301–7. 40. Clagett GP, Bowers BL, Lopez-Viego MA, et al. Creation of a neo-aortoiliac system from lower extremity deep and superﬁcial veins. Ann Surg 1993; 218: 239–48. ●41. Wells JK, Hagino RT, Bargmann KM, et al. Venous morbidity after superﬁcial femoral–popliteal vein harvest. J Vasc Surg 1999; 29: 282–9. ●42. Modrall JG, Sadjadi J, Ali AT, et al. Deep vein harvest: predicting need for fasciotomy. J Vasc Surg 2004; 39: 387–94. 43. Johansen K, Hedges G. Successful limb reperfusion by temporary arterial shunt during a 950-mile air transfer: case report. J Trauma 1989; 29: 1289–91. 44. Nalbandian MM, Maldonado TS, Cushman J, et al. Successful limb reperfusion using prolonged intravascular shunting in a case of an unstable trauma patient: a case report. Vasc Endovasc Surg 2004; 38: 375–9. 45. Rozycki GS, Tremblay LN, Feliciano DV, McClelland WB. Blunt vascular trauma in the extremity: diagnosis, management, and outcome. J Trauma 2003; 55: 814–24. 46. Dawson DL, Putnam AT, Light JT, et al. Temporary arterial shunts to maintain limb perfusion after arterial injury: an animal study. J Trauma 1999; 47: 64–71.

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47. Rasmussen TE, Clouse WD, Jenkins DH, et al. The use of temporary vascular shunts as a damage control adjunct in the management of wartime vascular injury. J Trauma 2006; 61: 8–12. 48. Clouse WD, Rasmussen TE, Perlstein J, et al. Upper extremity vascular injury: a current in-theater wartime report from Operation Iraqi Freedom. Ann Vasc Surg 2006; 20: 429–34. 49. Chambers LW, Green DJ, Sample K, et al. Tactical surgical intervention with temporary shunting of peripheral vascular trauma sustained during Operation Iraqi Freedom: one unit’s experience. J Trauma 2006; 61: 824–30. 51. Rich NM, Hobson RW. Venous trauma: emphasis for repair is indicated. J Cardiovasc Surg (Torino) 1973; Spec No: 571–5. 52. Rich NM, Hobson RW, Wright CB, Fedde CW. Repair of lower extremity venous trauma: a more aggressive approach required. J Trauma 1974; 14: 639–52. 53. Rich NM, Clagett GP, Salander JM, et al. Surgical treatment of arterial and venous injuries. Acta Chir Belg 1982; 82: 473–84. ◆54. Rich NM. Management of venous trauma. Surg Clin North Am 1988; 68: 809–21. 55. Rich NM, Rhee P. An historical tour of vascular injury management: from its inception to the new millennium. Surg Clin North Am 2001; 81: 1199–215. 56. Rich NM. Complications of vascular injury management. Surg Clin North Am 2002; 82: 143–74. 57. Menzoian JO, LoGerfo FW, Doyle JE, et al. Management of vascular injuries to the leg. Am J Surg 1982; 144: 231–4. 58. Meyer J, Walsh J, Schuler J, et al. The early fate of venous repair after civilian vascular trauma. A clinical, hemodynamic, and venographic assessment. Ann Surg 1987; 206: 458–64.

59. Ross SE, Ransom KJ, Shatney CH. The management of venous injuries in blunt extremity trauma. J Trauma 1985; 25: 150–3. 60. Parry NG, Feliciano DV, Burke RM, et al. Management and short-term patency of lower extremity venous injuries with various repairs. Am J Surg 2003; 186: 631–5. ●61. Feliciano DV, Mattox KL, Graham JM, Bitondo CG. Five-year experience with PTFE grafts in vascular wounds. J Trauma 1985; 25: 71–82. 62. Shah DM, Leather RP, Corson JD, Karmody AM. Polytetraﬂuoroethylene grafts in the rapid reconstruction of acute contaminated peripheral vascular injuries. Am J Surg 1984; 148: 229–33. 63. Bermudez KM, Knudson MM, Nelken NA, et al. Long-term results of lower-extremity venous injuries. Arch Surg 1997; 132: 963–7. 64. Borman KR, Jones GH, Snyder WH III. A decade of lower extremity venous trauma: patency and outcome. Am J Surg 1987; 154: 608–12. 65. Zamir G, Berlatzky Y, Rivkind A, et al. Results of reconstruction in major pelvic and extremity venous injuries. J Vasc Surg 1998; 28: 901–8. 66. Goff JM, Gillespie DL, Rich NM. Long-term follow-up of a superﬁcial femoral vein injury: a case report from the Vietnam Vascular Registry. J Trauma 1998; 44: 209–11. ●67. Nypaver TJ, Schuler JJ, McDonnell P, et al. Long-term results of venous reconstruction after vascular trauma in civilian practice. J Vasc Surg 1992; 16: 762–8. ●68. Phifer TJ, Gerlock AJ Jr., Rich NM, McDonald JC. Long-term patency of venous repairs demonstrated by venography. J Trauma 1985; 25: 342–6.

52 Primary and secondary tumors of the inferior vena cava and iliac veins THOMAS C. BOWER Introduction Tumor types Clinical presentation Evaluation

574 574 575 575

INTRODUCTION Tumors which involve the inferior vena cava (IVC) or iliac veins are rare and usually malignant.1,2 Most tumors manifest themselves after metastases have occurred and the patient is too debilitated to tolerate operation. Currently, surgical resection is the only hope for cure because chemotherapy and radiation afford little beneﬁt. The most common tumor involving the IVC is renal cell carcinoma (RCC) with intracaval tumor thrombus.1,2 With most renal cell cancers, tumor thrombus can be removed without IVC replacement.3–11 In the past, a secondary tumor invasion of the IVC was considered a contraindication to operation.1,12–18 Technical advances have allowed for successful tumor resection with graft replacement of the IVC in select patients.1,2,12–17,19,20 For reference, the IVC is divided into three segments. The infrarenal segment extends from the conﬂuence of the common iliac veins to the renal veins; the suprarenal segment from the renal veins to the hepatic veins; and the suprahepatic segment from the hepatic veins to the right atrium. The suprarenal IVC is further classiﬁed into infrahepatic and retrohepatic portions, based on the relationship to the caudate lobe veins.

TUMOR TYPES Inferior vena cava and iliac vein tumors originate from the smooth muscle cells of the vein (primary) or from endothelial or mesothelial cells of abdominal or retroperitoneal organs (secondary).2 Local growth may be

Treatment Outcomes and survival References

575 580 581

intraluminal, extraluminal, or by a combination of these mechanisms.18 Distant metastases occur via lymphatics or hematogenous routes, depending on tumor type. Renal cell or adrenal cortical carcinoma, pheochromocytoma, germ cell tumors, and sarcomas of uterine origin may exhibit intraluminal growth as tumor thrombus, which is encapsulated in most cases.1–11,21 The types of primary and secondary IVC tumors are listed in Box 52.1. Primary venous leiomyosarcomas (PVLs) are rare but more common than their arterial counterparts.22 Between 50% and 60% of PVLs involve the IVC, and the suprarenal segment is most commonly involved.13,23,24 These tumors are more prevalent in women, and occur over a wide age range.13,24 Over 80% of 144 patients with IVC leiomyosarcoma reviewed by Mingoli et al.24 were women and the mean age was 54.4 years. Pathologically, the tumors are polypoid or nodular, ﬁrmly attached to the vessel wall, but exhibit less intratumor hemorrhage and necrosis than other retroperitoneal sarcomas.18,22,24,25 The most common growth pattern is intraluminal, but PVLs can invade the caval wall and inﬁltrate adjacent organs or structures. When the latter growth pattern occurs, the tumors are difﬁcult to differentiate from retroperitoneal sarcomas of non-venous origin.2 Lung, liver, kidney, bone, pleura, or chest wall are the most common sites for metastases and are apparent in nearly one-half of patients by the time the diagnosis is made.13,22,25 Untreated, patients have a mean survival of only 3 months.26 Secondary malignancies of the IVC include cancers of the solid organs or viscera; cancers or germ cell tumors which metastasize to pericaval lymph nodes; retroperitoneal liposarcomas, leiomyosarcomas, or malignant ﬁbrous histocytomas; or malignancies with tumor

Evaluation 575

BOX 52.1 Tumors of the inferior vena cava Primary ●

Inferior vena cava leiomyosarcoma

Secondary ●

●

●

Retroperitoneal soft-tissue tumors – Liposarcoma – Leiomyosarcoma – Malignant ﬁbrous histiocytoma Hepatic tumors – Cholangiocarcinoma – Hepatocellular carcinoma – Metastatic (e.g., colorectal) Pancreaticoduodenal cancers

Secondary tumors which may have tumor thrombus ● ● ● ●

●

Renal cell carcinoma Pheochromocytoma Adrenocortical carcinoma Sarcomas of uterine origin – Leiomyomatosis – Endometrial stromal cell Germ cell tumors – Embryonal – Teratocarcinoma

thrombus.1,21 These tumors occur in patients between the ﬁfth and seventh decades of life.1,2,12,14–17 Cancers of the liver (primary or metastatic), pancreas, duodenum, kidney, or adrenal gland affect the suprarenal IVC. Retroperitoneal sarcomas may involve any segment of the vena cava, and are the most common cause of malignant obstruction of the infrarenal IVC.1 These sarcomas grow extrinsic to abdominal or pelvic vessels in two-thirds of cases.18,25 In the other one-third, they invade the IVC and exhibit both intraluminal and extraluminal growth, which makes them pathologically indistinguishable from PVL.1,2 Renal cell carcinoma is the most common malignancy to affect the IVC.1–11 Tumor thrombus occurs in 4–15% of patients, originates in the right kidney more often than the left, and is more frequent in cancers over 4.5 cm in diameter.1,9,11,26 In approximately 50–60% of patients, the thrombus is in the renal vein or at the IVC–renal vein conﬂuence; in 30–40% it is in the suprarenal segment; and in the remaining 5–10%, thrombus extends into the right atrium.1,3,11 Survival of patients with secondary cancers of the IVC is less than 1 year without treatment.1,16

CLINICAL PRESENTATION Patients with IVC malignancies present with symptoms and signs related to the primary tumor or to metastatic disease, but rarely from obstruction of the vena cava.1 Only 4/144 patients with PVLs reported by Mingoli et al.24 and associates were asymptomatic at the time of diagnosis while the others had multiple symptoms or signs. Abdominal pain occurred in 95 patients (66%), abdominal mass in 69 (47.9%), lower limb edema in 56 (38.9%), weight loss in 44 (30.6%), and Budd–Chiari syndrome in 32 (22.2%). Non-speciﬁc symptoms such as fever, anorexia, malaise, weakness, nocturnal sweating, vomiting, and dyspnea were noted in less than 15%. Rare presentations include consumption coagulopathy and red blood cell abnormalities.24 In a Mayo Clinic report of patients who underwent IVC replacement for primary and secondary tumors, the majority of patients were symptomatic with pain being most common (58.6%). Weight loss, fatigue, or nausea occurred in 24.1% of patients, lower extremity edema affected 10.3%, and one patient had a lower extremity deep vein thrombosis. Almost one-third of patients were asymptomatic but had a mass discovered on physical examination or by an imaging study. Inferior vena cava obstruction results in symptoms or signs when the occlusion occurs acutely so there is no time for venous collaterals to develop; or with outﬂow obstruction from the right heart, liver, or kidney.1,2 Tumor thrombus in the right heart may cause arrhythmias, syncope, pulmonary hypertension or embolism, or right heart failure. Hepatic vein outﬂow obstruction results in hepatomegaly, ascites, jaundice, but rarely liver failure (Budd–Chiari syndrome). Occlusion of the suprarenal IVC may cause back or right upper quadrant abdominal pain, biliary tract symptoms, nausea, vomiting, renal dysfunction, or lower extremity edema. Nephrotic syndrome or dialysis-dependent renal failure is a rare occurrence because of collateral drainage from the left kidney.1,2 Infrarenal IVC involvement usually causes back or abdominal pain, or presents with a palpable mass. If pelvic tumors invade the lumbosacral plexus, nerve roots, psoas muscle, or iliac veins, patients complain of lower extremity pain, dysesthesias, weakness, or lower extremity edema.1,2,27,28 Deep vein thrombosis is unusual with IVC malignancies but common in the rare patient with PVL of the iliac or peripheral veins.1,2,13,24,29

EVALUATION A multidisciplinary team for the evaluation and treatment of patients with IVC tumors works well.1,16 Medical oncologists, surgical oncologists, or subspecialists (vascular, hepatobiliary, urologic, cardiothoracic surgeons) are needed to direct the evaluation and determine treatment.

576

Primary and secondary tumors of the inferior vena cava and iliac veins

The goals of evaluation include identiﬁcation of the tumor type and local extent, a search for metastases, and assessment of the degree of venous obstruction.1,2,16 These are accomplished by computed tomography (CT), magnetic resonance imaging (MRI), venacavography, and ultrasonography, alone or in combination (Figs 52.1–52.3).1,2,26,30 Computed tomography and MRI are used more often in our practice, and venacavography is used only in the occasional patient in whom biopsy is needed to differentiate tumor thrombus from bland thrombus.1,2,16,17,30

Figure 52.2 Magnetic resonance imaging scan showing intracaval tumor thrombus extending into the right heart chambers (arrow) secondary to an endometrial stromal cell sarcoma.

(a)

(b) Figure 52.1 Computed tomographic scan (CT) of a patient with a large leiomyosarcoma (a) involving the right lobe of the liver, right kidney, and retroperitoneum (black arrow). The retrohepatic segment of the suprarenal inferior vena cava was invaded by the tumor (vertical arrow). The patient underwent tumor and liver resection with inferior vena cava (IVC) replacement. (b) CT scan of a patient with a retroperitoneal leiomyosarcoma surrounding the infrarenal IVC. The tumor is shown by the large arrow. This patient also required resection of the infrarenal aorta shown by the smaller arrow. (Fig. 52.1b is from Bower TC, Stanson AW. Evaluation and management of malignant tumors of the inferior vena cava. In: Rutherford R, ed. Vascular Surgery, 5th edn. Orlando: W. B. Saunders, 2000, with permission.)

If the tumor looks to be resectable for cure, the next step is patient medical risk assessment for operation. It is imperative that a thorough cardiopulmonary evaluation be carried out as most of the postoperative mortality and morbidity is related to problems in these organ systems.1–4,11,16 The patient’s preoperative physical condition (performance status) is an important predictor of postoperative quality of life.1,2 A performance score of zero indicates that the patient is fully active with no limitations in daily function, whereas a score of 4 indicates that the patient is bedridden and unable to perform selfcare. Patients with performance status scores of zero or 1 have the best chance of retaining functional capacity postoperatively in our experience, those with scores of 2 may have a prolonged recovery, and patients with scores of 3 or 4 are not offered operation.1,2,16

TREATMENT Patients with localized tumors, few medical comorbidities, and a good performance status should be considered for operation.1,2 Operative treatment and approach depends on the type and extent of the malignancy, the segment of IVC involved by the tumor, the degree of caval obstruction, and the status of collateral veins. Choice of incision is based on the patient’s body habitus, the segment of vena cava which requires reconstruction, the need for major liver resection, and whether cardiopulmonary bypass will be necessary.1,12,14–16 A midline abdominal incision is used for tumors of the infrarenal IVC and in patients with narrow costal margins

Treatment 577

➡

➡

(a)

Figure 52.3 Axial (a) and sagittal (b) view of a large pelvic sarcoma encasing the left iliac vessels (arrows). A portion of the tumor extended into the left psoas muscle and toward the foramina of L2–L5 (not shown).

who require resection and replacement of the infrahepatic IVC. A bilateral subcostal incision works well for those with wide costal margins who need liver resection and infrahepatic caval replacement. For those who require replacement of the retrohepatic IVC in conjunction with major liver resection, a right thoracoabdominal incision through the eighth or ninth intercostal space provides excellent exposure.16,17 If cardiopulmonary bypass is needed, median sternotomy is combined with either a midline or subcostal abdominal incision.1–4,9

Inferior vena cava resection without replacement The decision to replace the IVC during cancer resection is controversial.12,14–15,28 Inferior vena cava resection without replacement is well tolerated in patients with vena cava occlusion and well-developed venous collaterals.15–18,21–28,31 Of 24 patients who had IVC resection without replacement during operations for nonseminomatous germ cell tumors, Beck and colleagues28 reported acute renal failure in four patients and lower extremity edema in a further four patients, and chylous ascites in three. However, these authors could not predict late venous sequelae on the basis of a patient’s preoperative venous symptoms or imaging studies.28 Lower extremity edema or venous problems can be expected in over onethird of patients with acute IVC occlusion.1,27 Our preference has been to replace the suprarenal IVC because of the potential risk of renal dysfunction and lower extremity edema without a caval graft.17,31 Although venous blood ﬂow is re-routed through the perivertebral, lumbar, epigastric, adrenal, and gonadal pathways with

(b)

suprarenal IVC occlusion, the ability to predict which patients tolerate resection alone, without complications such as renal failure, is difﬁcult.1,15 Transient or permanent renal failure is more apt to occur in patients who require nephrectomy and ligation of the contralateral renal vein in order to remove the tumor.15,32 Huguet et al.15 recommend renal vein reconstruction if the suprarenal IVC requires resection and the patient develops anuria or a reduction in urine output while the renal vein is clamped, based on their experience with suprarenal IVC resection and replacement.

Renal cell carcinoma with inferior vena cava tumor thrombus The most common operation performed on the IVC is removal of intracaval tumor thrombus in patients with renal cell carcinoma.1–11 Patients with tumor thrombus at the IVC–renal vein conﬂuence or in the infrahepatic IVC tolerate removal of thrombus with little hemodynamic consequence by simple IVC cross-clamping. Caudate lobe veins may require division to gain additional room for proximal clamp placement. Patients whose thrombus extends into the retrohepatic IVC, or to the level of the hepatic veins, often need vascular isolation of the liver to remove the tumor to minimize blood loss.1 This requires exposure of the suprahepatic IVC and isolation of the portal triad structures for inﬂow occlusion. Once the thrombus is removed, the suprahepatic clamp is transferred to the infrahepatic IVC to complete the caval repair by either primary or patch closure. Care must be taken when the clamp is transferred to avoid air embolism. Inferior vena cava graft replacement for RCC may be

578

Primary and secondary tumors of the inferior vena cava and iliac veins

needed with recurrent intracaval tumor or at initial operation in some patients with large-diameter tumor thrombus which occasionally invades the caval wall. Tumor thrombus in the right heart requires removal with cardiopulmonary bypass, with or without hypothermic circulatory arrest.10 Deep hypothermia and circulatory arrest is advantageous in select cases, but carries a risk of coagulopathy and organ dysfunction.1–10 If the tumor thrombus extends to the cavoatrial junction on preoperative imaging, intraoperative transesophageal echocardiography helps determine whether there is room for a proximal caval clamp or whether cardiopulmonary bypass is needed.1,11 Ligation of the renal artery may allow the thrombus to contract so that a clamp can be placed on the suprahepatic IVC.1,11

Inferior vena cava replacement Replacement of the IVC should be considered at all levels for patients in whom the IVC is not obstructed but requires resection for tumor clearance, for individuals without well-developed venous collaterals, or for those in whom collateral veins require ligation or resection during tumor removal.16 Externally supported polytetraﬂuoroethylene (PTFE) grafts are used most often for these reconstructions.1,12–17,19,20,33 The grafts are readily available, their sizes match the diameter of the IVC (often

(a)

20 mm diameter) and they resist compression by the viscera. The graft is covered with omentum, but, if that is unavailable, bovine pericardium works well.16,17 We have little experience using spiral or pantaloon vein grafts in this position, but this conduit may be preferable in patients in whom tumor resection results in a contaminated ﬁeld.16 The need for an arteriovenous ﬁstula is controversial. We have used a ﬁstula at the femoral artery level for three patients with infrarenal IVC grafts who had compromise of inﬂow from the lower extremity veins. We have not used a ﬁstula with suprarenal IVC replacement because of the high blood ﬂow volume at this level.1,16 Arteriovenous ﬁstulas may enhance patency if the graft is less than 14 mm in diameter or if more than one caval segment requires replacement.16,33 Patients are given subcutaneous heparin and aspirin suppositories over the ﬁrst 2–3 postoperative days and are dismissed from the hospital on warfarin. Lower extremity pneumatic compression devices enhance venous ﬂow through the graft until the patients are ambulatory.16

Replacement of the suprarenal inferior vena cava in conjunction with major liver resection Resection of tumors involving the suprarenal IVC in conjunction with major liver resection has been reported from a number of centers, including our own.13,14,16,17,19,20,34,35 Careful patient selection, intraoperative ultrasonography to determine the proximity of the tumor to the major vascular structures, vascular isolation of the liver, and ligation of the appropriate afferent and efferent lobar vasculature prior to parenchymal division are the important operative principles.16,17 The technical steps of this operation are outlined in Fig. 52.4. Venovenous bypass may be needed if the systolic blood pressure cannot be maintained over

Figure 52.4 Key steps in performance of retrohepatic inferior vena cava (IVC) replacement and liver resection. (a) Early isolation of the suprahepatic and infrahepatic IVC. (b) Vascular isolation of the liver just prior to completion of tumor and IVC resection. (c) Upper caval anastomosis performed with vascular isolation of the liver. Some patients require venovenous bypass to maintain stable hemodynamics. (d) Blood ﬂow is re-established through the liver and the lower caval anastomosis is completed. (e) Completed graft reconstruction with reattachment of the ligaments of the liver to avoid torsion of the hepatic venous outﬂow. (Fig. 52.4a,c,d from Bower TC, Stanson AW. Evaluation and management of malignant tumors of the inferior vena cava. In: Rutherford R, ed. Vascular Surgery, 5th edn. Orlando: W. B. Saunders, 2000, with permission. Fig. 52.4b from Bower TC, Nagorney DM, Toomey BJ, et al. Vena cava replacement for malignant disease: is there a role? Ann Surg 1993; 7: 51–62, with permission.)

Treatment 579

(b)

(c)

(d)

(e)

580

Primary and secondary tumors of the inferior vena cava and iliac veins

100 mmHg during a test clamp of the suprahepatic IVC, and is required more often in patients with cardiopulmonary dysfunction or those over age 50 years.16 Sarmiento et al.17 reported a mortality rate of 5% among 19 patients (15 with major hepatectomy) with a variety of liver tumors involving the retrohepatic IVC, using in situ techniques for resection and IVC graft replacement. Mean total warm ischemia time to the liver was 18 minutes, which is well within the tolerable limits of liver ischemia reported by others.17,36 Ex situ or in situ perfusion techniques may be needed if concomitant hepatic or portal vein reconstruction is necessary, but have inherent problems of their own, including the need for salvage orthotopic liver transplant in the rare patient who undergoes ex situ reconstruction.34,35 Liver function tests remain elevated for the ﬁrst 2–3 days after operation but return to baseline within 7–10 days.16,17 If they do not, CT or ultrasound imaging is needed to evaluate hepatic and portal vein patency. Patients remain auto-anticoagulated for 24–48 hours, but are discharged home on warfarin. The remainder of the postoperative care is as outlined previously.

OUTCOMES AND SURVIVAL Patient outcome is dictated by the type, location, and extent of tumor, and the segment of vena cava that is resected and replaced. Kieffer et al.12 reported two deaths in 18 patients (11%) operated for caval tumors. Huguet et al.15 had one death among four patients who had suprarenal IVC graft replacement. In a series of 29 patients reported from the Mayo Clinic, the mortality rate was 6.9%, with major cardiopulmonary morbidity and bleeding requiring transfusion in 17% and 17%,

respectively. No patients developed renal failure or graft infection, and only three grafts occluded (10.3%) at a median follow-up of 2.9 years.16 The mortality rate for patients undergoing radical nephrectomy and IVC tumor thrombectomy ranges between 2.7% and 13%, including patients who need cardiopulmonary bypass or hypothermic circulatory arrest.1–11 Major morbidity has been reported in as many as 10–31% of patients, with cardiopulmonary problems most frequent.3,4,9,10 Pulmonary embolism may occur if the tumor thrombus is inadequately removed, or if there is bland thrombus remaining in the infrarenal IVC. In the latter case, we attempt to remove a bland thrombus from the infrarenal IVC if it is localized in order to preserve inﬂow from the iliac veins. If the infrarenal IVC has extensive bland thrombus, is scarred, or occluded, we use a vascular stapler to transect the pararenal IVC obliquely to avoid a cul-de-sac near the remnant renal vein.4 Survival after these operations is difﬁcult to determine because of the diverse etiology of the cancers and the limited experience at most centers. Patients with primary IVC leiomyosarcomas have an average survival of 3 months if not operated, 21 months with palliative resection, and 36.8 months with radical resection, based on a follow-up report by Mingoli et al.29 Almost 60% of patients in this series who had radical tumor resection developed local recurrent or distant disease at a mean of 32 months postoperatively. Size of tumor or growth pattern, segment of the IVC involved by the tumor, use of adjuvant therapy, or extent of caval resection or replacement did not affect long-term survival or disease recurrence by multivariable analysis among 120 patients reported in this registry.29 The majority of patients in the Mayo Clinic report had secondary IVC tumors.16 One year survival was 89.3%, 2

Guidelines 5.3.0 of the American Venous Forum on primary and secondary tumors of the inferior vena cava and iliac veins No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.3.1 For patients with invasion of the wall of the inferior vena cava by primary or secondary tumor we recommend caval replacement if the vein was patent before surgery, if the collateral circulation appears inadequate following caval resection and in those in whom important collateral veins had to be ligated or resected during tumor removal. Repair with externally supported polytetraﬂuoroethylene graft is safe, effective and durable

1

B

5.3.2 For inferior vena cava tumor thrombus, usually a renal cell carcinoma, that extends into the right heart we recommend removal with cardiopulmonary bypass, with or without hypothermic circulatory arrest

1

B

References 581

year survival was 80.3%, and 3 year survival was 75%. Survival was inﬂuenced by the type of tumor and the segment of IVC requiring resection, though patient numbers were too small to make statistical comparisons. Those who had the infrarenal segment replaced had a mean survival of 3.14 years versus 2.26 years in patients with suprarenal caval replacement and major liver resection. The longest survivor in that series lived 6.33 years after operation.16 Importantly, local control of the tumor was excellent with most deaths due to regional or distant metastases. Our experience now exceeds 70 patients (unpublished data). The best survival is noted in patients operated for RCC with IVC tumor thrombus and no metastatic disease. Five year survival rates of about 50% or more have been reported by several groups.3,10 The primary determinants of survival in patients with RCC are completeness of tumor resection and the presence of nodal or distant metastases.1,7,10 Tumor thrombus as an independent factor may not affect long-term survival if it is entirely removed, though patients with caval tumor thrombus (level I–IV) do worse than those with thrombus conﬁned to the renal vein (level 0).3 Quality of life after these operations is important but difﬁcult to predict. At least 80% of operated patients had a good or excellent performance status in the Mayo Clinic reports,16–18 although the preoperative performance scores were zero or 1 in all but two patients. Critical selection factors, better methods of early tumor detection, and neoadjuvant therapies should be the focus of future research.

REFERENCES ● ◆

= Key primary paper = Major review article ◆1.

◆2.

●3.

4.

5.

Bower TC. Diagnosis and management of tumors of the inferior vena cava. In: Rutherford RB (ed.). Vascular Surgery, vol. 2, 6th edn. Philadelphia: Elsevier, 2005: 2345–56. Bower, TC. Primary and secondary tumors of the inferior vena cava. In: Gloviczki P, Yao JST (eds). Handbook of Venous Disorders. London: Arnold, 2001: 430–8. Blute ML, Leibovich BC, Lohse CM, et al. The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumour thrombus. Urol Oncol 2004; 84: 33–41. Blute ML, Boorjian SA, Leibovich BC, et al. Results of inferior vena caval interruption by Greenﬁeld ﬁlter, ligation or resection during radical nephrectomy and tumor thrombectomy. J Urol 2007; 178: 440–5. Skinner DG, Pritchett TR, Lieskovsky G, et al. Vena caval involvement by renal cell carcinoma. Ann Surg 1989; 210: 387–94.

6. Shahain DM, Libertino JA, Zinman LN, et al. Resection of cavoatrial renal cell carcinoma employing total circulatory arrest. Arch Surg 1990; 125: 727–2. 7. Novick AC, Kaye MC, Cosgrove DM, et al. Experience with cardiopulmonary bypass and deep hypothermic circulatory arrest in the management of retroperitoneal tumors with large vena caval thrombi. Ann Surg 1990; 212: 472–7. 8. Montie JE, El Ammar R, Pontes JE, et al. Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 1991; 173: 107–15. 9. Stewart JA, Carey JA, McDougal WS, et al. Cavoatrial tumor thrombectomy using cardiopulmonary bypass without circulatory arrest. Ann Thorac Surg 1991; 51: 717–22. 10. Suggs WD, Smith RB, Dodson TF, et al. Renal cell carcinoma with inferior vena caval involvement. J Vasc Surg 1991; 14: 43–8. 11. Nesbitt JC, Soltero ER, Dinney CPN, et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Ann Thorac Surg 1997; 63: 1592–600. 12. Kieffer E, Bahnini A, Koskas F. Nonthrombotic disease of the inferior vena cava: surgical management of 24 patients. In: Bergan JJ, Yao JST, eds. Venous Disorders. Philadelphia: WB Saunders, 1991: 501. ●13. Dzsinich C, Gloviczki P, van Heerden JA, et al. Primary venous leiomyosarcoma: a rare but lethal disease. J Vasc Surg 1992; 15: 595–603. ●14. Bower TC, Nagorney DM, Toomey BJ, et al. Vena cava replacement for malignant disease: is there a role? Ann Vasc Surg 1993; 7: 51–62. 15. Huguet C, Ferri M, Gavelli A. Resection of the suprarenal inferior vena cava: the role of prosthetic replacement. Arch Surg 1995; 130: 793–7. ●16. Bower TC, Nagorney DM, Cherry KJ, et al. Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 2000; 31: 270–81. 17. Sarmiento JM, Bower TC, Cherry KJ, et al. Is combined partial hepatectomy with segmental resection of inferior vena cava justiﬁed for malignancy? Arch Surg 2003; 138: 624–31. 18. Hartman DS, Hayes WS, Choyke PL, Tibbetts GP. Leiomyosarcoma of the retroperitoneum and inferior vena cava: radiologic–pathologic correlation. Radiographics 1992; 12: 1203–20. 19. Kumada K, Shimahara Y, Fujui K, et al. Extended right hepatic lobectomy: combined resection of inferior vena cava and its reconstruction by ePTFE graft. Acta Chir Scand 1988; 154: 481–3. 20. Iwatsuki S, Todo S, Starzl TE. Right trisegmentectomy with a synthetic vena cava graft. Arch Surg 1988; 123: 1021–2. 21. Concepcion RS, Koch MO, McDougal WS, et al. Management of primary nonrenal parenchymal malignancies with vena caval thrombus. J Urol 1991; 145: 243–7. 22. Enzinger FM, Weiss SW. In: Gay SM, ed. Soft tissue tumors. 3rd edn. Missouri: Mosby-Year Book, 1995: 505–10.

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23. Kevorkian J, Cento DP. Leiomyosarcoma of large arteries and veins. Surgery 1973; 73: 390–400. ◆24. Mingoli A, Feldhaus RG, Cavallaro A, Stipa, S. Leiomyosarcoma of the inferior vena : analysis and search of world literature on 141 patients and report of three new cases. J Vasc Surg 1991; 14: 688–99. 25. Burke AP, Virmani R. Sarcomas of the great vessels. Cancer 1993; 71: 761–73. 26. Kallman DA, King BF, Hattery RR, et al. Renal vein and inferior vena cava tumor thrombus in renal cell carcinoma: CT, US, MRI and venacavography. J Comput Assist Tomogr 1992; 16: 240–7. 27. Donaldson MC, Wirthlen LS, Donaldson GA. Thirty-year experience with surgical interruption of the inferior vena cava for prevention of pulmonary embolism. Ann Surg 1980; 191: 367–72. 28. Beck SDW, Lalka SG, Donohue JP. Long-term results after inferior vena caval resection during retroperitoneal lymphadenectomy for metastatic germ cell cancer. J Vasc Surg 1998; 28: 808–14. 29. Mingoli A, Sapeinza P, Cavallaro, et al. The effect of extent of caval resection in the treatment of inferior vena cava leiomyosarcoma. Anticancer Res 1997; 17: 3877–82.

30. Stanson AW, Breen JF. Computed tomography and magnetic resonance imaging. In: Gloviczki P, Yao JST (eds). Handbook of Venous Disorders. London: Arnold, 2001: 190–232. 31. Duckett JW, Liﬂand JH, Peters PC. Resection of the inferior vena cava for adjacent malignant diseases. Surg Gynecol Obstet 1973; 136: 711–16. 32. McCullough DL, Gittes RF. Ligation of the renal vein in the solitary kidney: effects on renal function. J Urol 1975; 113: 295–8. ●33. Jost CJ, Gloviczki P, Cherry KJ, et al. Surgical reconstructions of iliofemoral veins and the inferior vena cava for non malignant occlusive disease. J Vasc Surg 2001; 33: 320–8. 34. Oldhafer KJ, Lang H, Schlitt HJ, et al. Long-term experience after ex situ liver surgery. Surgery 2000; 127: 520–7. 35. Lodge JPA, Ammori BJ, Prasad KR, Bellamy MC. Ex vivo and in situ resection of inferior vena cava with hepatectomy for colorectal metastases. Ann Surg 2000; 231: 471–9. 36. Huguet C, Gavelli A, Addario Chieco P, et al. Liver ischemia for hepatic resection: where is the limit? Surgery 1992; 111: 251–9.

53 Arteriovenous malformations: evaluation and treatment BYUNG-BOONG LEE, JAMES LAREDO, DAVID H. DEATON AND RICHARD F. NEVILLE Introduction Evaluation Treatment: strategy Treatment: modality

583 584 585 585

INTRODUCTION Arteriovenous malformation (AVM) is a congenital anomaly of the vascular system in which the anatomic defect results in shunting of arterial blood to the venous system in varying degrees.1–3 The vast majority of AVMs exist alone as independent lesions, but occasionally occur with other congenital vascular malformations (CVMs), making its diagnosis and management more difﬁcult. These mixed CVMs often become a clinician’s nightmare (e.g., Parkes–Weber syndrome) in which the management is quite confusing and the treatment results are often disappointing (e.g., microshunting AVM).4,5 Among all CVMs, classiﬁed by the Hamburg Classiﬁcation6,7 (Box 53.1), the AVM is a much more rare condition than the venous malformation (VM) or the lymphatic malformation (LM).8–11 The AVM is a much more hemodynamically complicated vascular lesion and potentially more life-threatening than the other CVMs.1,12 Its far-reaching hemodynamic impact involves the entire cardiovascular system – arterial, venous, and lymphatic systems – making it the most challenging and dangerous of all because of its hemodynamic complexity. The AVM has developed a notorious reputation among the CVMs owing to its wide range of clinical presentations, its unpredictable and erratic clinical course, its high rate of recurrence, and the high morbidity related to its treatment. Arteriovenous malformations are further classiﬁed into two subtypes, extratruncular and truncular, which are based on its embryological characteristics. The lesion classiﬁcation is dependent on when the developmental arrest has occurred during embryogenesis13–15 (Box 53.1).

Special strategy: ﬁstulous type Clinical experiences Conclusions References

587 589 589 590

BOX 53.1 Hamburg classification of congenital vascular malformations Primary classiﬁcation* 1 2 3 4 5

Predominantly arterial defects Predominantly venous defects Predominantly arteriovenous shunting defects Predominantly lymphatic defects Combined vascular defects

Embryological subclassiﬁcation† 1 Extratruncular forms ● Diffuse, inﬁltrating ● Limited, localized 2 Truncular forms ● Aplasia or obstruction – Hypoplasia, aplasia, hyperplasia – Stenosis, membrane, congenital spur ● Dilatation – Localized (aneurysm) – Diffuse (ectasia) *Modiﬁed based on the consensus on congenital vascular malformations through the international workshop in Hamburg, Germany, 1988. Capillary malformation was not included. †Developmental arrest at the different stages of embryonic life: earlier stage, extratruncular form; latter stage, truncular form. Both forms may exist together; may be combined with other various malformations (e.g., capillary, arterial, arteriovenous shunting, venous, hemolymphatic and/or lymphatic); and/or may exist with hemangioma.

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An extratruncular (ET) lesion is an embryonal tissue remnant that is the result of developmental arrest occurring during an “early stage” of embryogenesis. This lesion, therefore, retains the characteristics of mesenchymal cells along with the potential to proliferate, making its clinical behavior totally unpredictable. Stimulation of an ET lesion by various intrinsic (e.g., menarche, pregnancy) and extrinsic (e.g., trauma, surgery) mechanisms results in lesion recurrence or progression.13–15 The potential for further proliferation underscores the importance of a well-planned treatment regimen. Stimulation of a dormant ET lesion during treatment often leads to an erratic response with explosive growth, worsening the clinical picture.1 An inﬁltrating ET AVM lesion is far more complicated than a truncular lesion because of its embryologic characteristics. Furthermore, this lesion carries a higher risk of progression and has more destructive potential. On the other hand, the truncular (T) form of AVM, the other subtype of AVM classiﬁed by its embryologic background,6,7 no longer has the potential to proliferate. This potential to proliferate is lost during development. A truncular lesion is the result of developmental arrest occurring during a “late stage” of embryogenesis.13–15 In addition, this T form of AVM is hemodynamically more signiﬁcant than its ET counterpart, owing to its unique high-ﬂow “ﬁstulous” state.1 There is no nidus in the capillary beds that would allow some limitation on lesion blood ﬂow. Instead, this ﬁstulous lesion has a direct connection between the arterial and venous systems, resulting in central, peripheral, and local hemodynamic shunting often involving the entire cardiovascular system to varying degrees of severity. All AVMs should take priority over all other CVMs because of the potential for development of a life- and/or limb-threatening condition.1 Complete eradication of the AVM “nidus” (especially for ET lesions) is required for any potential cure. This is often difﬁcult, if not impossible, because of the high likelihood of recurrence following a conventional approach based on surgical treatment alone.16,17 A substantial improvement in outcomes in the management of AVMs has been achieved using a multidisciplinary approach utilizing various endovascular treatments in addition to traditional surgical treatment.18 Unfortunately, however, most of the currently available treatments still carry signiﬁcant risk of complication and morbidity. Careful planning, from diagnosis and treatment to long-term follow-up assessment, is critical for successful AVM management.19,20 Aggressive management should be considered only when the treatment beneﬁt outweighs the associated risk of complication and morbidity.21 The presence of an AVM does not mandate treatment, although AVMs are more serious than any other CVMs and have more dismal long-term outcome by their nature.1

EVALUATION Although most AVMs occur as single lesions, the evaluation of an AVM should be started as an evaluation of a CVM, followed by a more speciﬁc evaluation and conﬁrmation as AVM. The evaluation should follow basic differential diagnoses among the various CVMs. Arteriovenous malformations may also exist combined with other CVMs and classiﬁed as a hemolymphatic malformation (HLM), often known as an extended form of Klippel–Trenaunay syndrome called Parkes–Weber syndrome.22–24 Appropriate differential diagnosis, therefore, should be made initially with various combinations of non-invasive to less invasive tests.5,25–28 More speciﬁc diagnostic procedures then follow for precise and detailed assessment of the AVM as a whole and allows classiﬁcation into its embryological subtype (ET vs T form).1 The most common initial studies include: ● ● ● ●

●

duplex ultrasonography (arterial and venous)25 whole body blood pool scintigraphy (WBBPS)26 transarterial lung perfusion scintigraphy (TLPS)5 magnetic resonance imaging (MRI) of T1 and T2 images27 computed tomography (CT) angiography with contrast enhancement, and/or three-dimensional CT.28

Conﬁrmation of the ﬁnal diagnosis should be made with an invasive study to create a road map for the proper treatment.1 These studies include: ● ● ●

selective and superselective arteriography direct puncture arteriography standard direct puncture phlebography.

In addition to the assessment of the primary AVM lesion, assessment of its secondary impact on the nonvascular systems, especially on the musculoskeletal system, is also warranted. Early detection of vascular–bone syndrome with long-bone length discrepancy is essential for appropriate management.29–32 Among the many newly developed non-invasive to less invasive tests for the evaluation of CVMs, TLPS5 has a unique role in determining the degree of shunting through an extremity AVM lesion. Transarterial lung perfusion scintigraphy can detect and assess a micro-AV shunting lesion. These types of lesions are notoriously difﬁcult to detect with conventional arteriography alone. This microAVM lesion is often missed with conventional arteriography and frequently occurs in the combined form of CVM – the HLM (e.g., Parkes–Weber syndrome). Misdiagnosing this potentially limb-threatening lesion can be avoided with TLPS alone. Transarterial lung perfusion scintigraphy can also provide quantitative measurements of the shunting status during therapy; TLPS may replace the substantial role of traditional arteriography as a followup assessment tool for extremity AVMs.

Treatment: modality

585

TREATMENT: STRATEGY

TREATMENT: MODALITY

Following the appropriate diagnosis of the involved CVM(s), and classiﬁcation into its embryologic subtype, accurate assessment of the extent and severity of the lesion is mandatory for proper treatment. This often requires additional invasive studies (e.g., arteriography). After assessment of the extent and severity of the AVM has been performed, indications for treatment are determined. Indications for treatment include:1

Surgical excision still remains the most ideal treatment to produce a “cure.” However, surgical therapy alone often results in incomplete control of the lesion owing to the high morbidity associated with complete surgical resection. Total surgical removal of an AVM lesion often carries prohibitively high morbidity and complication rates (e.g., massive operative blood loss, functional loss). Unless the lesion is well localized, allowing minimum morbidity with total surgical excision, open surgery should be combined with an endovascular approach, utilizing embolic therapy and sclerotherapy. Over the last two decades, a new more contemporary concept of AVM management has gained acceptance as a treatment modality based on endovascular (embolotherapy and sclerotherapy) therapy as a component of the total care management. Complete integration with surgical therapy has been adopted on the basis of a multidisciplinary team approach.18,33–36 Embolo/sclerotherapy was introduced to the “surgically inaccessible” lesion initially with excellent results37–40 and was subsequently combined with conventional surgical therapy to “surgically accessible” lesion as well, resulting in much improved outcomes, compared with those treated by surgical therapy alone, especially among marginally accessible lesions.1,41 Embolo/sclerotherapy, therefore, should be considered as independent therapy in the non-surgical to poor surgical candidate, when the AVM lesion is surgically “inaccessible.” These extensive lesions extending beyond the deep fascia with involvement of muscle, tendon, and bone tend to be the diffuse inﬁltrating type of the extratruncular form of AVMs. Embolo/sclerotherapy should also be considered as adjunctive therapy in the surgically “accessible” lesion as well to supplement the surgical therapy. Preoperative embolo/sclerotherapy often improves the safety and effectiveness of subsequent surgical therapy, resulting in reduced morbidity and complications (e.g., intraoperative bleeding). Postoperative supplemental therapy can improve the overall efﬁcacy of the surgical therapy and should be implemented aggressively to residual lesions to reduce surgical morbidity. This new approach is now fully accepted as an alternative to traditional surgical resection in the majority of AVM lesions, especially of the diffusely inﬁltrating type. Although this approach cannot cure, local control of the lesion is often observed for a limited period of time.12 Despite the initial enthusiasm for endovascular therapy, many new associated problems have been reported which include both acute complications (e.g., tissue necrosis, vein thrombosis, pulmonary embolism, nerve damage, and cardiopulmonary arrest) and various chronic complications (e.g., muscle/tendon contraction) in addition to its related morbidity.12

● ● ● ●

●

● ● ● ●

●

hemorrhage high-output heart failure secondary arterial ischemic complications secondary complications of chronic venous hypertension lesions located at a life-threatening region (e.g., proximity to the airway), or located in an area threatening vital functions (e.g., seeing, eating, hearing, or breathing) disabling pain functional impairment cosmetically severe deformity vascular–bone syndrome – abnormal long-bone growth with leg length discrepancy19,20 lesions located in an area with potentially high risk of complication (e.g., hemarthrosis).

The role of careful assessment and diagnosis in the development of a treatment strategy that maximizes the risk–beneﬁt ratio is critical and cannot be overemphasized in which the ultimate goal of treatment must be clearly deﬁned with realistic expectations. Quite often, a docilelooking AVM lesion progresses dramatically into an explosive condition following an ill-planned therapeutic intervention. Early aggressive control of the nidus of the AVM lesion itself is generally warranted since the majority will eventually progress with an unavoidable long-term risk of progressive deterioration of the physiologic and hemodynamic status. Therefore, appropriate and frequent follow-up is required to detect and treat recurrence. However, the “controlled” aggressive approach should be exercised within the accepted boundary of the “palliative” concept only when the beneﬁt exceeds the associated morbidity of the proposed treatment. The temptation to initially intervene on an AVM radically must be tempered with a realistic assessment of the long-term goal of the treatment plan. To achieve this goal, the treatment strategy should be based on the consensus by the many different specialists involved in the patient’s care (e.g., vascular surgeon, orthopedic surgeon, plastic surgeon, head and neck surgeon, interventional radiologist, physiatrist). The ﬁnal decision for treatment, as well as selection of the treatment modalities, should be made by a multidisciplinary team approach, based on the various indications outlined above.4,18

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Arteriovenous malformations: evaluation and treatment

Every effort should be exercised during endovascular therapy to minimize collateral damage to the surrounding tissues – nerve, vessel, cartilage, skin and soft tissue – by the agent. Therefore, careful assessment of potential risk of collateral damage is critical in the selection of any embolic agent and sclerosing agent. In certain situations, collateral damage is unavoidable in order to control the critical lesion (e.g., ﬁstulous AVM). The preferred treatment modality should be selected based on a careful risk–beneﬁt analysis of the treatment in which the associated morbidity is justiﬁed, such as treatment of a life-threatening or limb-threatening condition (e.g., hemorrhage, high cardiac output failure). The old-fashioned approach to the AVM to shut off the feeding artery alone with ligation or embolization should be condemned. This approach leaves the nidus of the lesion intact and results in more aggressive neovascular recruitment by the primitive lesion, making the condition worse. Direct control of the nidus of the lesion itself is essential to prevent recurrence and further deterioration of the AVM lesion. Appropriate selection of embolic and sclerotherapy agents is essential in order to minimize the associated morbidity. Absolute ethanol, N-butylcyanoacrylate (NBCA), coils, and/or contour particles (e.g., Ivalon, Fabco, New London, CT, USA) can be utilized in various combinations,42–46 simultaneously or in multiple stages. The “staged” approach is especially useful for the pure “ﬁstulous” AVM lesion which belongs to an embryological subtype, i.e., the “truncular” AVM lesion in the Hamburg classiﬁcation.6,7 This ﬁstulous lesion has a unique condition with no sizable nidus between arterial and venous connection; it is, therefore, extremely dangerous with the conventional approach because of such high ﬂow. Further detailed discussion will be included in Special strategy: ﬁstulous type. Absolute ethanol46 still remains the sclerosing agent of choice for treatment of extratruncular AVM lesions, especially in situations where the lesion is surgically unresectable such as in the diffuse inﬁltrating type.12 NButylcyanoacrylate glue43–45 is an endovascular embolic agent primarily used preoperatively for treatment of surgically excisable lesions. The glue-ﬁlled lesion can be safely dissected with surgical removal with minimum collateral damage. Preoperative embolization of such AVM lesions has been shown to reduce morbidity associated with surgical resection. It has also been utilized with acceptable results as sole independent therapy in certain conditions (e.g., inoperable pelvic AVMs). But its long-term impact as a foreign body and also its permanent effect on the AVM lesion remain controversial when given as a sole independent therapy. Embolo/sclerotherapy should be planned to be performed in multiple sessions utilizing the minimal amount of agent during each session whenever possible in order to reduce the potential risk of acute and chronic morbidity and complication (e.g., ethanol).

Several valuable lessons have been learned to minimize the risk of complication of ethanol sclerotherapy, which remains the most effective sclerosing agent to manage AVM lesions. 1. General anesthesia should be used for all the patients to control the severe pain induced by ethanol injection. 2. Cardiopulmonary monitoring with a Swan–Ganz catheter is mandatory when the amount of ethanol is large and/or close to the maximum amount allowed (1.0 mg/kg of body weight). 3. Special precaution should be exercised to minimize the increased risk of skin necrosis when delivered via an arterial puncture. The minimally effective amount/ concentration of ethanol should be used, whenever possible, to reduce the subsequent complications; absolute ethanol may be diluted to 60% when used to treat a superﬁcial lesion, which carries a higher risk of skin necrosis, or to treat a lesion in close proximity to a nerve, in order to avoid injury. Smaller amounts in divided doses should be considered to help minimize the likelihood of complications. 4. Compression may be applied to the draining vein during the ethanol injection in order to prevent early and premature drainage of ethanol from the lesion, and to prolong the exposure time to the endothelium to maximize its effect. A great deal of caution should be exercised to avoid unnecessary collateral damage. 5. The residual ethanol within the lesion may be drained before the removal of needles especially when swelling/ reaction is severe; light compression may be applied for 5–10 minutes after the removal of needles following the completion of therapy. A combination of the three delivery routes should be utilized to reach the “nidus” of the AVM lesion: transarterial, transvenous, and direct puncture. These approaches should be utilized simultaneously in order to maximize the efﬁcacy of the treatment. The percutaneous direct puncture approach to the lesion, however, is generally preferred and carries minimal risk. The transarterial approach carries a higher risk of complications; therefore, its use should be limited to situations in which the direct puncture approach is not possible owing to small lesion size (e.g., facial AVM). In these situations, the transarterial delivery of glue would be a safer approach if indicated and would limit the high risk of skin necrosis. Alternatively, contour particle (polyvinyl alcohol; PVA) embolization, via the transarterial approach if feasible, is preferred for treatment of lesions requiring subsequent surgical excision. With the transvenous approach, coil embolization can be performed on the large, high-ﬂow draining vein ﬁrst, if present, before ethanol is injected; platinum spiral coils or tornado coils may be delivered to the venous side if available. Glue embolization42–45 is limited to the surgical candidates in our institutions, in which a 30–50%

Special strategy: ﬁstulous type

concentration of N-butylcyanoacrylate is often utilized to minimize foreign body reaction. Whenever possible, a puncture as close as possible to the AV–connection nidus should be made in order to deliver the agent and to make a glue cast from the nidus to proximal draining vein. Appropriate preparation for the anticipated morbidity and complication associated with the therapy is absolutely necessary before the procedure is performed. Close communication and consent for such anticipated morbidity/complication with the patient/family is absolutely necessary before any endovascular procedure is committed. Periodic follow-up evaluation and assessment of treatment results should be made based on duplex scan, WBBPS, TLPS, CT, and/or MRI in the majority of cases. This is especially important during therapy requiring multiple treatment sessions. For evaluation of the majority of AVMs, arteriography has been the gold standard for conﬁrmation of treatment results at its completion.12

SPECIAL STRATEGY: FISTULOUS TYPE Fistulous AVM is a unique “clinical” condition of AVM with extremely high ﬂow status; it generally belongs to a “truncular” lesion, which is one of the embryological subtypes of AVMs. The truncular lesion is an outcome of the developmental arrest in the late stage of embryogenesis so that it lacks a nidus of the lesion as its characteristics, as already explained in the Introduction. Owing to a lack of or minimal lesion nidus which allows free ﬂow through the lesion, its treatment carries higher risk with attendant high local/regional/systemic complications (e.g., pulmonary hypertension). Inﬁltrating ET lesions belonging to this type can be managed with relative safety based on the general strategy proposed above. However, the truncular AVM lesion needs additional precaution owing to its hemodynamically much more aggressive nature as a result of this “ﬁstulous” condition accompanying extremely fast blood ﬂow through the lesion. The high ﬂow status of the ﬁstulous type of AVM with no sizable nidus is extremely difﬁcult, if not impossible, to treat with a single embolo/sclerotherapy agent (e.g., ethanol, NBCA glue) owing to various factors inherent to this lesion: 1. decreased efﬁcacy owing to early wash-out of the agent by high ﬂow 2. increased local and/or systemic risk of deep vein thrombosis and pulmonary hypertension by the sclerosant (e.g., ethanol), and pulmonary embolism (e.g., NBCA glue) 3. less effective control of local circulatory arrest during the therapy (e.g., local compression, transarterial and/or transvenous balloon blockage)

587

Ethanol (absolute) often results in potentially fatal pulmonary hypertension due to the high-ﬂow shunting state of the ﬁstulous lesion. Therefore, ethanol (absolute) sclerotherapy is often contraindicated as independent therapy because of the high risk of spillage into the systemic circulation. N-Butylcyanoacrylate also carries an increased risk of pulmonary embolism as well as deep vein thrombosis because of the high-ﬂow shunting. NButylcyanoacrylate embolo/sclerotherapy is also relatively contraindicated owing to this increased risk of pulmonary embolism. A new endovascular approach to reduce the risk associated with the treatment of the ﬁstulous type of AVM has been developed where control of the high ﬂow is initially performed using various combinations of coil, glue, and/or contour particles, and ethanol embolo/ sclerotherapy in stages with and without surgical therapy. Preliminary preparation of the AVM lesion with coil embolization is essential to convert a high-ﬂow state to a reduced/low-ﬂow state and to make the lesion more amenable to subsequent permanent management with ethanol and/or NBCA glue embolo/sclerotherapy with a reduced risk of complication and morbidity.46,47 Conversion of the high-ﬂow state to a low-ﬂow state with coil embolotherapy, initially, makes the local condition more amenable to subsequent therapy; superﬁcial ﬁstulae become easily controllable with embolo/sclerotherapy, and more amenable to subsequent surgical excision. Deep ﬁstulae also become more easily controlled with this new approach and “occasionally” more amenable to a combined approach with perioperative embolo/sclerotherapy and surgical therapy. Coil embolotherapy is, therefore, the most effective method to convert a high-ﬂow state to a low-ﬂow state and to allow deﬁnitive and permanently effective treatment (e.g., ethanol). However, coil embolotherapy produces only a mechanical effect to block the ﬂow and induce thrombosis and does not have any direct effect on the endothelium. Sufﬁcient injury to the endothelium is required to prevent recanalization of the lesion nidus. Therefore, additional embolo/sclerotherapy with absolute ethanol and/or NBCA is required to control the nidus completely. The high-ﬂow “ﬁstulous” condition occurs in the truncular form of AVM lesions, which lack the ability to proliferate, unlike the extratruncular form. The importance of close monitoring of the cardiopulmonary–vascular system during each session of the ethanol therapy cannot be overemphasized. Increased pulmonary artery pressure is the earliest indication of the development of potentially fatal pulmonary hypertension. Pulmonary hypertension occurs when ethanol reaches the pulmonary circulation. Prompt recognition and immediate cessation of ethanol therapy in addition to the appropriate control with the various vasodilators is absolutely necessary to prevent pulmonary spasm and subsequent cardiopulmonary arrest.48

588

Arteriovenous malformations: evaluation and treatment

(a)

(b)

(c)

(e)

(h)

(d)

(f)

(g)

Figure 53.1 (a) Clinical appearance of arteriovenous malformation (AVM) lesion affecting the upper lip with painful swelling. (b) Whole body blood pool scintigraphy ﬁndings of AVM lesion localized to upper lip; this test can provide qualitative as well as quantitative measurement for the follow-up assessment. (c) T2-weighted magnetic resonance imaging ﬁnding of inﬁltrating extratruncular AVM lesion throughout the entire upper lip. (d) Duplex scan ﬁndings of hemodynamically very active AVM lesion affecting the entire upper lip. (e) Pretreatment arteriographic ﬁndings of the upper lip AVM lesion with a localized nidus and its extensive collaterals as well as its venous drainage. (f) Angiographic ﬁnding of initial ethanol sclerotherapy via direct puncture percutaneous approach; 4.0 mL of 75% of ethanol was used to control the nidus. (g) Arteriographic ﬁnding of completely controlled AVM lesion following two sessions of endovascular treatment. (h) Clinical appearance of upper lip with completely restored normal contour following successful ethanol sclerotherapy as independent treatment.

Conclusions 589

CLINICAL EXPERIENCES Among a total of 1556 patients with various CVMs, 177 patients [female (F), 105; male (M), 72; mean age 28.4 years; range 1.1–67 years] were diagnosed with AVM based on various combinations of non- to less-invasive tests. From these 177 patients, 115 (F, 68; M, 47; ET form, 99; T form, 16) were selected with various indications for endovascular treatment with/without surgical therapy combined; a total of 431 sessions of endovascular treatment were carried on mostly with ethanol-based sclerotherapy (408/431). Follow-up evaluation of the treatment has been made periodically in regular intervals of no longer than 6 months mainly with non- to less-invasive tests during and after the completion of multisession therapy. Surgically “inaccessible” ET lesions (N = 84) have shown excellent to good interim responses/results in the majority (N = 78) of patients following the completion of multisession embolo/sclerotherapies as independent treatment. There was no evidence of recurrence except four patients with incomplete therapy during the limited follow-up period of a mean of 18.4 months (Fig. 53.1). Patients with surgically “accessible” ET lesions (N = 15) completed multisession preoperative endovascular treatment for subsequent surgical excisions; all have shown excellent to good interim results except for one patient with no evidence of recurrence during the limited followup period (37.5 months) after the surgery (Fig. 53.2). Patients with surgically “inaccessible” T lesions (N = 12) completed multisessions of endovascular treatment as independent therapy and all achieved satisfactory control of the lesion, and maintained excellent interim treatment results during the follow-up period (mean 29.8 months) without evidence of recurrence and/or deterioration (Fig. 53.3). Four patients with surgically “accessible” T lesions completed preoperative multisessions of endovascular

treatment and underwent subsequent surgical excisions; all four achieved an excellent initial outcome. Two patients achieved successful results with a potential chance of cure, and interim results have shown no evidence of recurrence during the follow-up period (42.1 and 57.2 months). However, a further two patients developed major complications following initially successful management of AVM lesions: one patient developed recurrent massive bleeding from an incompletely controlled “intraosseous” AVM lesion in the same arm within a year of refusing treatment, and the other developed a massive soft-tissue infection along the hand within 6 months. Both ultimately required forearm amputations as life-saving measurements by the local team. The outcomes of the surgical treatment of AVM lesions remain excellent with no evidence of recurrence so far apart from the two forearm amputations.

CONCLUSIONS A multidisciplinary team approach is mandated to achieve effective control of AVM lesions with fully integrated endovascular therapy and surgical therapy. Endovascular therapy is preferred in the surgically “inaccessible” lesion, whereas surgical therapy combined with supplemental endovascular therapy is the best option for the surgically “accessible” lesion. An early aggressive approach to all AVM lesions is mandated in general in order to reduce the consequences of any hemodynamic impact. A calculated approach is warranted, however, based on a careful assessment of the risks and beneﬁts associated with the treatment, unless the treatment is indicated for a life-threatening or limbthreatening condition (e.g., hemorrhage, high cardiac output failure).

Guidelines 5.4.0 of the American Venous Forum on arteriovenous malformations: evaluation and treatment No.

Guideline

5.4.1 For symptomatic arteriovenous malformations we suggest endovascular treatment with embolization or sclerotherapy. We suggest it for both deﬁnitive treatment of surgically “inaccessible” lesions and for initial therapy of surgically “accessible” lesions

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

2

C

590

Arteriovenous malformations: evaluation and treatment

(a)

(d)

(b)

(e)

(c)

(f)

(g)

Figure 53.2 (a,b) T2-weighted magnetic resonance imaging (MRI) ﬁndings of a pelvic arteriovenous malformation (AVM) extensively affecting the uterus and para-adnexal soft tissues; this is a life-threatening lesion causing hemorrhagic shock and requiring emergency measures to control massive recurrent uterine bleeding. (c) Arteriographic ﬁndings of massively inﬁltrating extratruncular AVM lesions affecting the para-adnexal tissues and the uterus. (d) Angiographic ﬁnding of massively dilated pelvic veins as the venous drainage route for the extensive pelvic AVM lesions. (e) Angiographic ﬁndings of N-butylcyanoacrylate glue-ﬁlled pelvic AVM lesions; this preoperative embolotherapy reduces/eliminates the risk of massive intraoperative bleeding during the subsequent surgical excision of the lesions. (f) Surgical specimen ﬁndings of the uterus; (g) the inner lumen of the transected uterus also shows a glue-ﬁlled lesion inﬁltrating all along the endometrium as well as uterine muscle structures, compatible with its MRI ﬁndings.

ACKNOWLEDGMENT ●1.

The authors are deeply grateful to the individual team members of the CVM Clinic of Samsung Medical Center and SungKyunKwan University, Seoul, Korea, who were dedicated to the care of the majority of the patients included in this review during 1995–2004.

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

Lee BB, Do YS, Yakes W, et al. Management of arterialvenous shunting malformations (AVM) by surgery and embolosclerotherapy. A multidisciplinary approach. J Vasc Surg 2004; 39: 590–600. 2. Loose DA, Müller E. Problems in surgery of congenital vascular malformations with arteriovenous shunts. In: de Castro Silva M, eds. Atualizacao em Angiologia. Belo Horizonte, Brazil: Brazilian Society of Angiology, 1978: 121–41. 3. Mattassi R. Surgical treatment of congenital arteriovenous defects. Int Angiol 1990; 9: 196–202. ◆4. Lee BB. Critical issues on the management of congenital vascular malformation. Ann Vasc Surg 2004; 18: 380–92.

References 591

(c)

(a)

(b) (d)

(e)

(f)

Figure 53.3 (a) Clinical appearance of the left upper extremity affected by arteriovenous malformation (AVM) lesions along the elbow and forearm region as the cause of massive recurrent bleedings. (b) Arteriographic ﬁndings of extensive AVM lesions in the “ﬁstulous” condition; the feeding arteries are severely dilated and tortuous and its draining veins are also massively dilated. These ﬁndings suggest that the lesion accompanies extremely high ﬂow with a minimal to no nidus. (c) Angiographic ﬁnding of massively dilated vein with direct connection to the artery; this is the ﬁstulous AVM with no nidus, often belonging to the truncular type. This ﬁstulous lesion is extremely difﬁcult to manage with the conventional approach; it often requires a multistage approach to control the ﬂow with coils and/or glue ﬁrst before the ﬁnal treatment with ethanol. (d) Angiographic ﬁnding of the initial coil embolotherapy right at the junction of the arteriovenous connection to create an artiﬁcial dam/nidus to control the ﬂow. (e) Angiographic ﬁnding of subsequent Nbutylcyanoacrylate glue embolotherapy to stop the ﬂow before ﬁnal treatment with ethanol. (f) Angiographic ﬁnding of the ﬁnal stage of endovascular treatment on the “ﬁstulous” AVM with 17 mL of 100% ethanol.

5. Lee BB, Mattassi R, Kim BT, Park JM. Advanced management of arteriovenous shunting malformation with Transarterial Lung Perfusion Scintigraphy (TLPS) for follow up assessment. Int Angiol 2005; 24: 173–84. 6. Belov S. Anatomopathological classiﬁcation of congenital vascular defects. Semin Vasc Surg 1993; 6: 219–24.

★7.

Belov S. Classiﬁcation of congenital vascular defects. Int Angiol 1990; 9: 141–6. ●8. Lee BB, Kim DI, Huh S, et al. New experiences with absolute ethanol sclerotherapy in the management of a complex form of congenital venous malformation. J Vasc Surg 2001; 33: 764–72.

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21. ●22.

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25.

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Lee BB, Do YS, Byun HS, et al. Advanced management of venous malformation with ethanol sclerotherapy: midterm results. J Vasc Surg 2003; 37: 533–8. Lee BB, Seo JM, Hwang JH, et al. Current concepts in lymphatic malformation (LM). Vasc Endovasc Surg 2005; 39: 67–81. Lee BB. Lymphedema–angiodysplasia syndrome: a prodigal form of lymphatic malformation (LM). Phlebolymphology 2005; 47: 324–32. Lee BB. Statues of new approaches to the treatment of congenital vascular malformations (CVMs): single center experiences. Eur J Vasc Endovasc Surg 2005; 30: 184–97. Bastide G, Lefebvre D. Anatomy and organogenesis and vascular malformations. In: Belov St, Loose DA, Weber J, eds. Vascular Malformations. Reinbek: Einhorn-Presse Verlag GmbH, 1989: 20–2. Woolard HH. The development of the principal arterial stems in the forelimb of the pig. Contrib Embryol 1922; 14: 139–54. DeTakats G. Vascular anomalies of the extremities. Surg Gynecol Obstet 1932; 55: 227–37. Vollmar JF, Stalker CG. The surgical treatment of congenital arterio-venous ﬁstulas in the extremities. J Cardiovasc Surg 1976; 17: 340. Loose DA, Weber J. Indications and tactics for a combined treatment of congenital vascular malformations. In: Balas P, ed. Progress in Angiology. Torino: Minerva Medica, 1992: 373–8. Lee BB, Bergan JJ. Advanced management of congenital vascular malformations: a multidisciplinary approach. Cardiovasc Surg 2002; 10: 523–33. Lee BB, Kim HH, Mattassi R, et al. A new approach to the congenital vascular malformation with new concept: Seoul Consensus. Int J Angiol 2003; 12: 248–51. Lee BB, Mattassi R, Loose D, et al. Consensus on controversial issues in contemporary diagnosis and management of congenital vascular malformation: Seoul communication. Int J Angiol 2004; 13: 182–92. Lee BB. Advanced management of congenital vascular malformation (CVM). Int Angiol 2002; 21: 209–13. Jacob AG, Driscoll DJ, Shaughnessy WJ, et al. Klippel–Trenaunay syndrome: spectrum and management. Mayo Clin Proc 1998; 73: 28–36. Lee BB. Klippel–Trenaunay syndrome and pregnancy. Int J Angiol 2003; 22: 328. Gloviczki P, Stanson AW, Stickler GB, et al. Klippel–Trenaunay syndrome: the risks and beneﬁts of vascular interventions. Surgery 1991; 110: 469–79. Lee BB, Mattassi R, Choe YH, et al. Critical role of duplex ultrasonography for the advanced management of a venous malformation (VM). Phlebology 2005; 20: 28–37. Lee BB, Mattassi R, Kim BT, et al. Contemporary diagnosis and management of venous and AV shunting malformation by whole body blood pool scintigraphy (WBBPS). Int Angiol 2004; 23: 355–67. Lee BB, Choe YH, Ahn JM, et al. The new role of MRI (magnetic resonance imaging) in the contemporary

28.

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41. 42.

43.

44.

45.

diagnosis of venous malformation: can it replace angiography? J Am Coll Surg 2004; 198: 549–58. Sawhney R, LaBerge JM, Gordon RL. SCVIR Annual Meeting Film Panel Session: diagnosis and discussion of case 8. J Vasc Intervent Radiol 2000; 11: 661–7. Belov S. Hemodynamic pathogenesis of vascular-bone syndromes in congenital vascular defects. Int Angiol 1990; 9: 155–62. Kim YW, Do YS, Lee SH, Lee BB. Risk factors for leg length discrepancy in patients with congenital vascular malformation. J Vasc Surg 2006; 44: 545–53. Belov S. Correction of lower limbs length discrepancy in congenital vascular–bone disease by vascular surgery performed during childhood. Semin Vasc Surg 1993; 6: 245–51. Mattassi R. Differential diagnosis in congenital vascularbone syndromes. Semin Vasc Surg 1993; 6: 233–44. Belov S. Congenital agenesis of the deep veins of the lower extremities: surgical treatment. J Cardiovasc Surg (Torino) 1972; 13: 594–8. Kim JY, Kim DI, Do YS, et al. Surgical treatment for congenital arteriovenous malformation: 10 years’ experience. Eur J Vasc Endovasc Surg 2006; 32: 101–6. Loose DA. Combined treatment of congenital vascular defects: indications and tactics. Semin Vasc Surg 1993; 6: 279–96. White RI Jr, Pollak J, Persing J, et al. Long-term outcome of embolotherapy and surgery for high-ﬂow extremity arteriovenous malformations. J Vasc Intervent Radiol 2000; 11: 1285–95. Weber J. Technique and results of therapeutic catheter embolization of congenital vascular defects. Int Angiol 1990; 9: 214. Weber JH. Vaso-occlusive angiotherapy (VAT) in congenital vascular malformations. Semin Vasc Surg 1993; 6: 279–96. Yakes WF, Luethke JM, Merland JJ, et al. Ethanol embolization of arteriovenous ﬁstulas: a primary mode of therapy. J Vasc Intervent Radiol 1990; 1: 89–96. Yakes WF, Pevsner PH, Reed MD, et al. Serial embolizations of an extremity arteriovenous malformation with alcohol via direct percutaneous puncture. Am J Roentgenol 1986; 146: 1038–40. Lee BB. Current concept of venous malformation (VM). Phlebolymphology 2003; 43: 197–203. Berenstein A, Kricheff II. Catheter and material selection for transarterial embolization. Technical considerations: catheters. Radiology 1979; 132: 619. Zanetti PH. Cyanoacrylate/iophenylate mixtures: modiﬁcation and in vitro evaluation as embolic agents. J Intervent Radiol 1987; 2: 65–8. Novak D. Embolization materials. In: Dondelinger RF, Rossi P, Kurdziel JC, Wallace S, eds. Interventional Radiology. New York, NY: Thieme, 1990. Cromwell LD, Kerber CW. Modiﬁcation of cyano-acrylate for therapeutic embolization: preliminary experience. Am J Roentgenol 1979; 132: 799.

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46. Do YS, Yakes W, Shin SW, Lee BB. Ethanol embolization of arteriovenous malformations: interim results. Radiology 2005; 235: 674–82. 47. Jeon YH, Do YS, Shin SW, et al. Ethanol embolization of arteriovenous malformations: results and complications of 33 cases. J Kor Radiol Soc 2003; 49: 263–70.

48. Shin BS, Do YS, Lee BB, et al. Multistage ethanol sclerotherapy of soft-tissue arteriovenous malformations: effect on pulmonary arterial pressure. Radiology 2005; 235: 1072–7.

54 The management of venous malformations HERON E. RODRIGUEZ AND WILLIAM H. PEARCE Introduction Classiﬁcation Etiology Clinical presentation

594 594 595 595

Evaluation Diagnosis and management Summary References

596 597 601 602

INTRODUCTION

CLASSIFICATION

Congenital vascular malformations (CVMs) are rare. They develop as a result of abnormal vasculogenesis and angiogenesis. Most clinicians – including vascular surgeons – consider the management of congenital vascular malformations a difﬁcult task reserved for referral centers with specialized expertise in this area. The main reason why expertise on malformations is centralized to major centers is the low frequency at which they occur. The esotericism that surrounds this condition is at least in part due to the confusing nomenclature and the lack of a uniform classiﬁcation system. For example, some malformations were initially described according to their appearance (nevus ﬂammeus, port-wine stain, stork bite, etc.). Other descriptions relied on the pathology of the abnormality (angioma simplex, hemangioma cavernosum and racemosum, glomangioma). Many congenital vascular malformations are classiﬁed by eponyms given after the clinicians who ﬁrst described the abnormalities (Sturge–Weber, Klippel–Trenaunay, Adams, Oliver, Parkes–Weber, Maffucci, etc.). More recent classiﬁcations take into consideration the natural history and hemodynamic characteristics and set the grounds for comprehensive studies of these interesting disorders. The current chapter will deal with the diagnosis and management of “low-ﬂow” vascular malformations that are considered to be predominantly venous. The evaluation and treatment of “high-ﬂow” malformations with clinically signiﬁcant arteriovenous shunting is described in Chapter 53.

Various classiﬁcation systems have been developed based on anatomic, clinical, and embryologic criteria and no real consensus exists regarding nomenclature. Mulliken and Young1 and Mulliken and Glowacki2 made an enormous contribution to the study of vascular malformations when they grouped “vascular birthmarks” into two categories based on clinical features, histologic appearance, and biologic behavior. They distinguished hemangiomas from malformations.1,2 Hemangiomas are true neoplasms. Malformations can be categorized according to ﬂow characteristics, either high ﬂow or low ﬂow, with further subdivision into anatomic subgroups designated by the predominant element, i.e., arterial, venous, capillary, or lymphatic2 (see Chapter 53, Box 53.1). In this scheme, venous, lymphatic, and capillary malformations are all low-ﬂow lesions. Pure arterial malformations, including aneurysms and ectasia, arteriovenous malformations, and arteriovenous ﬁstulae are considered high-ﬂow lesions. The predominant element is identiﬁed ﬁrst by an A, then a V, C, or L for arterial, venous, capillary, or lymphatic malformations, respectively. This is followed with M for malformation. An arteriovenous malformation is a highﬂow lesion identiﬁed as an AVM (see Chapter 53) and a pure venous malformation is a low-ﬂow lesion identiﬁed simply as a VM. Vascular malformations usually occur alone, but they can also be found in association with other extravascular anomalies. Several syndromes in which vascular malformations are the predominant or an accompanying

Clinical presentation

feature have been described and are usually classiﬁed by eponyms. A detailed description of these syndromes is beyond the scope of this chapter, but the reader is referred to an excellent review by Garzon and colleagues.3

ETIOLOGY The etiology of vascular malformations is poorly understood. It is thought that they occur as a result of the abnormal development of the vascular system. Vessel development occurs in two different ways: vasculogenesis and angiogenesis. The exact mechanisms through which these processes occur remain largely unknown and have just recently begun to be unveiled.4 Vasculogenesis refers to the process by which endothelial cells are differentiated de novo from mesodermal precursors. It occurs only during embryonic development. In angiogenesis, new vessels are formed from pre-existing ones by budding (sprouting), splitting (intussusception), and fusion (intercalated growth). These new vessels formed by angiogenesis (so-called juvenile system) evolve into mature vessels by the processes of maturation and remodeling.5 These complex processes involve several receptor tyrosine kinases. Some of these receptors and their ligands have been identiﬁed [i.e., vascular endothelial growth factors (VEGFs) and Tie1 and Tie2]. Several speciﬁc genetic abnormalities affecting some of these receptors in families with malformations have been identiﬁed. The study of these mutations has not only helped the understanding of the molecular pathogenesis of vascular malformations but also the deﬁnition of each subtype into more speciﬁc clinical entities. For example, genetic analysis of families with autosomal dominantly inherited cutaneous venous malformations revealed mutations on the gene encoding for the kinase domain of the endothelial cell receptor Tie2 (also known as TEK) located at the VMCM1 locus on 9p2.6–9 This receptor has been associated to three ligands: angiopoietins 1, 2, and 4. It is theorized that mutations on this gene produce increased phosphorylation of the TEK and inhibition of apoptosis, resulting in abnormal remodeling with uncontrolled sprouting and branching of capillaries and small veins but not larger veins and arteries.10,11 Glomovenous malformations (GVMs), when familial, have an autosomal dominant mode of inheritance, with incomplete penetrance. Thirty mutations have been identiﬁed in 86 families affecting the glomulin gene on chromosome 1p21–22.6 Glomulin expression is limited to vascular smooth muscle cells and it is believed that, when lacking, abnormal differentiation towards the “glomus cell” phenotype occurs.12 Many other genetic abnormalities have been discovered in families affected by CVM. An excellent review of the genetic causes of vascular malformations has been published by Brouillard and Miikka.6

595

CLINICAL PRESENTATION Clinical presentation of venous malformations is variable. Some lesions remain quiescent for many years presenting only after some minor trauma, with pregnancy, or with the onset of menses. It seems likely that antecedent trauma can disturb a previously stable collateral system and unmask a VM. The relationship to hormones remains unclear. The reported incidence is less than 2% of the population and, unlike hemangiomas, there is no sex predilection for VM.13 Venous malformations are the most common form of vascular malformations with nearly two-thirds affecting the extremities.14 Patients most often seek medical attention for a cosmetic deformity such as cutaneous vascular stain, palpable mass, limb edema, varicosities, thrombophlebitis or other complications of venous hypertension (Table 54.1). An involved limb may be warmer than the uninvolved limb and patients complain of increased girth and heaviness from increased venous volume. Young adolescents may develop scoliosis and limb length discrepancies. The ﬁnding of lateral leg varicosities, vascular stains, unilateral limb hypertrophy, or other venous abnormalities in a young person should alert the examiner to the possibility of Klippel–Trenaunay syndrome (see below). Pelvic malformations are complex and can produce rectal pain, sexual dysfunction, massive uterine bleeding, and ureteral outlet obstruction with hydronephrosis. Central, high-ﬂow lesions in the pelvis and abdomen can produce high-output cardiac failure. Although physical examination alone is often sufﬁcient to make a diagnosis of a vascular malformation, it often will not deﬁne the extent of the lesion and further evaluation is indicated prior to any planned intervention.

Table 54.1 Incidence of physical changes in 82 affected extremities Changes Color changes Erythema Cyanosis Venous varices Edema Increased length Deformity Ulceration Pulse deﬁcit Bleeding From Szilagyi et al.20

No.

Percentage

57 (33) (24) 49 46 20 9 8 3 3

69.5

59.7 56.0 24.3 11.0 9.8 3.6 3.6

596

The management of venous malformations

EVALUATION The most important initial step in the management of a congenital vascular lesion is to differentiate CVMs from hemangiomas, as the clinical course and long-term consequences are distinctly different (Table 54.2). Congenital vascular malformations are present at birth and exhibit normal endothelial cell structure, function, and turnover. They grow proportionately with the child and do not regress over time. Hemangiomas are neoplasms that manifest during the ﬁrst several weeks of life, grow rapidly, with disproportionate growth relative to the child, then slowly involute over a period of years.1 The second step consists in deﬁning the anatomic extent and the ﬂow characteristics of the CVM. Plain radiographs, computed tomography, angiography, venography, duplex ultrasonography, and magnetic resonance imaging (MRI) are techniques currently used for this purpose. Plain ﬁlms can demonstrate soft-tissue and bony hypertrophy, limb length discrepancy, and phleboliths (Fig. 54.1). Contrast-enhanced computed tomography can identify the location of the venous malformation, bony involvement, vessel ectasia, and aneurysm formation. True extent of the lesion into soft tissue, however, is underestimated as only contrastenhanced vessels opacity. Direct puncture phlebography

may be necessary to fully demonstrate venous anomalies including venous lakes, ectasia, and venous aneurysm (Fig. 54.2). Duplex ultrasonography is a portable, non-invasive imaging technique that provides both functional and anatomic data in the evaluation of venous malformations.15 It is particularly helpful in deﬁning the ﬂow characteristics within the anomaly, thus aiding in differentiating among pure venous, arterial, and mixed malformations. Magnetic resonance angiography (MRA) is the diagnostic imaging modality of choice in patients with vascular malformations.16 It allows imaging in both axial and sagittal planes and more importantly can identify extension into soft tissue and bone (Figs 54.3 and 54.4). Using routine spin-echo technique, vascular channels appear as black holes or ﬂow voids. Exposure of tissue to a static magnetic ﬁeld causes proton alignment in the direction of the ﬁeld. In high-ﬂow lesions, that signal is lost as the blood leaves the imaging slice and the ﬂow void appears black. Time-of-ﬂight MRI uses pulsed waves to suppress soft-tissue signals and allows ﬂow-related enhancement of vessels supplying and draining the lesion. Finally, extravascular manifestations and possible inheritance patterns should be determined. For some disorders, accurate genetic diagnosis is now feasible.12,17

Table 54.2 Characteristics of vascular birthmarks

Clinical Clinical Clinical Cellular Cellular Cellular Cellular Hematologic Radiologic

Hemangioma

Malformation

Usually nothing seen at birth; 30% present as red macule Rapid postnatal proliferation and slow involution

All present at birth; may not be evident

Female-to-male ratio 3:1 Plump endothelium, increased turnover Increased mast cells Multilaminated basement membrane Capillary tubule formation in vitro Primary platelet trapping: thrombocytopenia (Kasabach–Merritt syndrome) Angiographic ﬁndings: well-circumscribed, intense lobular–parenchymal staining with equatorial vessels

Radiologic Radiologic Skeletal

Infrequent “mass effect” on adjacent bone; hypertrophy rare

Skeletal From Mulliken and

Commensurate growth; may expand as a result of trauma, sepsis, hormonal modulation Female-to-male ratio 1:1 Flat endothelium, slow turnover Normal mast cell count Normal thin basement membrane Poor endothelial growth in vitro Primary stasis (venous); localized consumptive coagulopathy Angiographic ﬁndings: diffuse, no parenchyma Low ﬂow: phleboliths, ectatic channels High ﬂow: enlarged, tortuous arteries with arteriovenous shunting Low ﬂow: distortion, hypertrophy or hypoplasia High ﬂow: destruction, distortion or hypertrophy

Young,1

p. 35, with permission.

Diagnosis and management 597

Truncal arteriovenous fistula

Venous malformation

b a d c Arteriovenous malformation

Lymphatic malformation

Figure 54.1 Early development of blood vessels in the anterior appendage bud of a 12 mm long pig embryo. (a) persistent axial artery (retiform); (b) cephalic vein; (c) basilic vein.

(a)

Figure 54.2 Direct puncture phlebography on a patient with a venous malformation of the leg.

Figure 54.4 (a,b) Magnetic resonance angiograms of a 26 year old woman with a venous malformation in the right forearm.

(b)

DIAGNOSIS AND MANAGEMENT Hemangiomas Figure 54.3 Magnetic resonance angiogram of a 24 year old woman with a painless, soft, compressible blue mass in the shoulder and chest. The study shows involvement limited to the subcutaneous tissues and muscle.

Hemangiomas, commonly called “strawberry marks,” are the most common benign tumor of infancy. They are wellcircumscribed lesions and are not usually present at birth. Although highly vascular during the early proliferative phase, hemangiomas are not considered true vascular

598

The management of venous malformations

malformations. More than half of these lesions are present on the head and neck, and approximately 20–25% are located on the extremities. Hemangiomas are more common in female infants. They are usually isolated lesions, but can have visceral, i.e., hepatic, cardiac, and pulmonary, involvement. Observation, patience, watchful waiting, and serial photography to document lesion regression are warranted along with parental education and reassurance. Most patients will have entered the involution phase by the second half of their ﬁrst year of life, with the great majority having complete resolution by school age.2 Craniofacial hemangiomas, especially lesions involving periorbital tissues and oropharyngeal lesions, deserve special consideration and a more aggressive approach is taken with these lesions. Untreated eyelid lesions can result in permanent refractive errors, strabismus, and the failure to develop normal binocular vision. Oropharyngeal lesions can result in an abnormal suck response, neonatal feeding problems, and even airway obstruction. Steroids and laser therapy are potentially useful during the proliferative phase for patients with complicated hemangiomas. Systemic steroids should be dosed at 2–3 mg/kg/day and then weaned over a period of 4–6 weeks.1 Systemic steroid therapy in the neonate should be approached with caution and if no clinical improvement is noted after the ﬁrst 7–10 days steroid therapy should be stopped. Limited surgical excision remains an option. Patients with hemangioma and visceral involvement have a high mortality secondary to congestive heart failure and should be treated with systemic steroids, and regression should be followed with serial computerized tomography scan. Cutaneous and mucosal hemangiomas may ulcerate and bleed during the proliferative phase. These complications may require surgical excision if they fail local wound care. Patients with hemangioma can develop thrombocytopenia and coagulopathy due to platelet trapping, known as Kasabach–Merritt syndrome.1 These patients develop petechiae, persistent bleeding, or a tense, rapidly enlarging hemangioma because of an intralesional bleed. Supportive care is indicated with transfusion of packed cells as necessary and occasionally systemic steroids. Platelet transfusion is generally not helpful owing to continued sequestration. Embolization with gel, coils, methacrylate glues, polyvinyl alcohol, and detachable balloons has been used alone and in combination with surgical excision for complicated lesions. Plasmapheresis and chemotherapeutic agents have also been used for life-threatening complications.

“nevus simplex,” and angel’s kiss.” Their presentation is protean. They can be single or multiple, be small or involve an entire limb, they can occur in the face, head, trunk, or extremities. Some disappear within the ﬁrst years of life and some persist into adulthood. They can occur isolated or as part of the following syndromes. STURGE–WEBER SYNDROME

This syndrome is characterized by the presence of CMs located in the distribution of the ﬁrst branch of the trigeminal nerve, ipsilateral leptomeningeal angiomatosis associated with seizures, and vascular malformation of the choroids of the eye associated with glaucoma. KLIPPEL–TRENAUNAY SYNDROME

This is a rare, sporadic syndrome characterized by the clinical triad of (1) capillary malformations, (2) soft-tissue and bone hypertrophy or, occasionally, hypotrophy of usually one lower limb, and (3) an atypical mostly lateral varicosity with or without deep venous anomalies (Fig. 54.5). It can also include lymphatic anomalies. It is important to differentiate Klippel–Trenaunay syndrome from Parkes–Weber syndrome on the basis that the latter has associated arteriovenous communications and Klippel–Trenaunay has none. The extensive experience at the Mayo Clinic managing these syndromes was recently published by Gloviczki and Driscoll.18 Many other syndromes include CM as one of their main components (cutis marmorata telangiectatica congenita, Adams–Oliver

Capillary malformations Capillary malformations (CMs) are low-ﬂow CVMs with involvement limited to the skin. They occur in approximately 3 in 1000 infants and are also known as a port-wine stain. They have also been called “stork bite,”

Figure 54.5 Lateral varicosity, limb hypertrophy, and capillary malformation in Klippel–Trenaunay syndrome. (From Gloviczki and Driscoll,18 with permission.)

Diagnosis and management 599

syndrome, Rubinstein–Taybi syndrome, Beckwith– Wiedemann syndrome, nova syndrome, etc.).3 Histologically, CMs present as ectatic blood vessels with abnormal features, and are present in increased numbers in the papillary and reticular dermis. As with all other CVMs, studies such as Doppler scans, bone radiographs, and MRI are performed to determine the ﬂow characteristics and the presence of associated anomalies. For many patients reassurance about the benign nature of the lesion is sufﬁcient. For cosmetic reasons, CMs can be lightened with the use of ﬂashlamp-pumped pulsed dye lasers.10

Venous malformations Venous malformations are low-ﬂow vascular malformations composed of abnormal ectatic venous-like vessels. Several misnomers have been applied to venous malformations, such as cavernous hemangioma and venous angioma. They typically present at birth but become more evident as the patient ages. Venous malformations are painless, soft masses with bluish discoloration that enlarge with dependency and compress with pressure. They may be limited to the subcutaneous tissues or involve deep structures such as muscles, bones, and joints. As with other CVMs they may or may not be part of complex syndromes and the goals of evaluation should be to characterize their ﬂow, to deﬁne their extent, and to determine the presence of associated anomalies. Several syndromes are associated with venous malformations. The blue rubber bleb nevus syndrome – also known as Bean’s syndrome – is characterized by a compressible blue subcutaneous nodule that can vary greatly in size and number and venous malformations in the gastrointestinal tract. These are the major source of morbidity in this syndrome and may be asymptomatic, causing chronic occult gastrointestinal bleeding or abdominal pain and hemorrhage. Other syndromes include Proteus syndrome and Maffucci’s syndrome.3 Venous malformation should be treated conservatively with external support where appropriate. It is particularly important that patients with VMs have accurate assessment of their deep system. Surgical resection of dilated superﬁcial varicosities in a patient with an absent or hypoplastic deep venous system is disastrous. The remaining venous collateral system is not adequate to drain the limb, and massive lower extremity swelling and ulceration develop. Patients with VM should be placed in compressive stockings and sleeves early on to offset longterm complications of venous stasis. Evaluation with a plan toward intervention, in patients with VM, is best done by a multidisciplinary team including vascular surgeons, interventional radiologists and plastic and orthopedic surgeons. Patients, their families, and the entire team must be committed to longterm treatment, multiple reintervention and control of the lesion rather than cure in the majority of cases. Indications

for treatment of vascular malformations using interventional techniques and/or surgical excision include congestive heart failure, ischemia, bleeding, and ulceration. Functional impairment and severe cosmetic deformity are also considerations. Treatment options include multiple, staged transcatheter embolizations and surgical excision. The vast majority of patients require lifelong compressive therapy. Deﬁnitive cure is possible in patients with limited, superﬁcial lesions that are amenable to complete surgical excision. In reviewing the literature, only 20–30% of patients with vascular malformations are candidates for complete excision.19 No single author has a signiﬁcant surgical experience. The largest surgical series were published in 1976, 1983, 1990, and 1992, comprising fewer than 100 patients.19–21 Szilagyi et al.20 reported on 18 patients with vascular malformations treated surgically. Fifty-ﬁve percent of patients reported improvement in their symptoms following excision, 11% were unchanged, and fully a third were worse after surgery than before.20 In 1992, Scott et al.19 reported the Northwestern experience in 15 patients with vascular malformations treated surgically. Five patients were lost to follow-up. Assuming those patients did well and did not seek further intervention, two-thirds of those undergoing excision improved. Thirteen percent were unchanged and 20% were worse after surgical excision. Ford et al.22 reported that more than 85% of patients were improved following embolic therapy for vascular malformation, although not cured, and that surgical excision was associated with a 50% complication rate. If complete excision of the malformation is not possible, some authors suggest isolation of the lesion as an alternative. Skeletonization of lesions by ligation of all vessels feeding and draining the lesion is conceptually appealing, but more difﬁcult in practice. Even minor collateral inﬂow can compensate over time and result in recurrence. Proximal ligation or embolization of major feeding vessels results in temporary improvement of symptoms. Recurrence of the lesion occurs as collaterals restore inﬂow to the vascular mass. Occlusion of the main feeding trunk surgically or through endovascular means precludes further interventional approaches and should be avoided. In contrast, superselective catheterization and embolization of secondary feeders and the nidus of the lesion are appropriate therapy either alone or in combination with surgical excision to decrease operative blood loss (Fig. 54.6). Materials used for embolic therapy should be permanent and include stainless-steel coils, alcohol foam (Ivalon; Fabco, New London, CT, USA), detachable balloons, and cyanoacrylate glues that polymerize at body temperature.23 Synthetic adhesives delivered at the nidus of the lesion form a cast of the malformation and decrease recurrence. Temporary agents such as gel foam are not used because recanalization of embolized vessels results in recurrence. These are

600

The management of venous malformations

(a)

(b) Figure 54.6 A 42 year old woman with a right internal iliac arteriovenous malformation (AVM). (a) Before and (b) after alcohol embolization of a large superior feeder. A small venous AVM is seen inferiorly following embolization (arrows).

complicated, long procedures requiring multiple injections that can be painful, and general anesthesia is appropriate. The results of embolization for treatment of vascular malformations compare favorably with surgical series.

Yakes et al.24 obtained follow-up studies in 19 out of 20 patients with AVMs treated with ethanol embolization. All patients showed persistent occlusion of the malformation radiographically at up to 24 months. Widlus et al.25 treated 11 patients with cyanoacrylate embolization. During a 40 month follow-up period, 82% reported complete resolution of their symptoms and the remaining patients’ improvement. No patients reported worsening of their symptoms with superselective embolization in these two series. Rosen et al.14 reported follow-up on 108 out of 120 patients with vascular malformations treated by interventional means.14 Fifty-ﬁve percent were asymptomatic at 3 years, 21% were symptomatic, but improved. Twenty percent had had no signiﬁcant change in symptoms after the procedure and 4% reported worsening of their symptoms following embolization. Sclerotherapy and embolotherapy with absolute alcohol, sodium tetradecyl sulfate, and polidocanol foam and coils have been used, alone or in combination, with success in several series in patients with low-ﬂow venous malformations. Excellent work on this topic has been published by Lee et al.,26,27 Villavicencio,28 and Burrows and Mason29 with emphasis on details of how to optimize results and avoid major complications. Burrows and Mason29 reported good to excellent results after serial sclerotherapy in 75–90% of patients with low-ﬂow venous malformations. Ethanol injections should be avoided close to major nerves or cutaneous lesions. There was a 12% complication rate per session and 28% complication rate per patient in this series, with at least some skin necrosis occurring in 10–15%. Lee et al.27 reported outstanding results with 95% initial success in 87 patients with venous malformations, with no recurrence in 71 patients at a mean follow-up of 24 months. Complications, consisting mostly of skin necrosis, developed in 28% of the patients. Only one patient in this series had permanent neurological deﬁcit. Unfortunately, some patients after alcohol sclerotherapy develop a chronic pain syndrome, which is difﬁcult and frustrating to treat. Complications of endovascular therapies occur in less than 6% of patients with vascular malformations.30 They include swelling, ischemia, distal tissue necrosis, contrast nephrotoxicity, allergic reactions, and, rarely, inadvertent embolization of particulate matter through large ﬁstulae and subsequent pulmonary emboli or stroke. Distal ischemia can range from superﬁcial sloughing of skin to compartment syndrome to limb ischemia requiring amputation. Nevertheless, Ford et al.22 and others from the Los Angeles Children’s Hospital concluded that superselective angiography and embolization should be primary therapy for symptomatic peripheral arteriovenous malformations in children, reserving surgery for complicated residual disease. When embolization is used as an adjunct to surgical excision, it should be performed as close to the time of surgery as possible to decrease the time available for collateral recruitment.

Summary 601

Glomovenous malformations Glomovenous malformation is a rare VM that was ﬁrst described by Masson in 1924. Although GVMs have been described in extracutaneous locations, they most commonly present as small, blue, cutaneous nodules/ papules, causing pain out of proportion to size, localized tenderness, and temperature sensitivity (Fig. 54.7). Although they are present at birth, they become more noticeable with aging. Clinically, they are frequently confused with VM with cutaneomucosal involvement. Boon et al.,30 after analyzing more than 1600 patients, described the main characteristics that help to distinguish GVMs from cutaneomucosal VMs. Glomovenous malformations are typically raised, with a cobblestone-like appearance, slightly hyperkeratotic, non-compressible by pressure, and tender upon palpation. Histologically, they are characterized by the presence of glomus cells in surrounding vascular channels. Genetically, familial cases have been mapped to a loss-of-function mutation in the glomulin gene on chromosome 1p221. The inherited form is characterized by autosomal dominance with incomplete penetrance and is associated with multiple lesions in one of three distributions: segmental (limited to trunk or one limb), disseminated, or congenital plaque-like. The sporadic form accounts for 90% of GVMs and more commonly presents as a solitary lesion.31 Historically, these lesions have been treated with surgical excision, but treatment modalities such as sclerotherapy32 and laser therapy33 can be considered.

SUMMARY Vascular malformations are a fascinating group of disorders. Signiﬁcant progress has been made in recent

(a)

(b) Figure 54.7 A 32-year-old woman who presented with clusters of multiple, painful, dark blue deep dermal papules on her face, left arm, left buttock area (a), right hand, and both legs (b). Histologic examination after surgical resection was compatible with a glomovenous malformation (glomangioma).

Guidelines 5.5.0 of the American Venous Forum on management of venous malformations No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.5.1 For symptomatic venous malformations, not responding to compression treatment, we suggest sclerotherapy with alcohol or foam

2

C

5.5.2 For surgically accessible and localized symptomatic venous malformations we suggest surgical excision as an alternative to sclerotherapy

2

C

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The management of venous malformations

years in their classiﬁcation and in the understanding of their molecular basis. They may occur alone or in association with extravascular anomalies in the form of complex syndromes. A systematic evaluation of venous malformation is based on the characteristics of the blood ﬂow, it delineates their anatomic extent of involvement and determines the presence of associated extravascular anomalies. For most asymptomatic venous malformations, observation alone is the best strategy. For others external compression alone is sufﬁcient treatment. Many venous malformations can be treated with success by a multidisciplinary team with the use of surgical and endovascular techniques that include a combination of alcohol or foam sclerotherapy and embolotherapy.

REFERENCES ● ◆

= Key primary paper = Major review article

1. Mulliken JB, Young AE, eds. Vascular Birthmarks: Hemangiomas and Malformations. Philadelphia: WB Saunders, 1988. ●2. Mulliken JB, Glowacki GA. Hemangiomas and vascular malformations in infants and children: a classiﬁcation based on endothelial characteristics. Plast Reconstr Surg 1982; 69: 412–22. ◆3. Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations. Part II. Associated syndromes. J Am Acad Dermatol 2007; 56: 541–64. 4. Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell 1996; 87: 1153–5. 5. Cohen MM Jr. Vascular updated: morphogenesis, tumors, malformations and molecular dimensions. Am J Med Genet 2006; 140A: 2013–38. ◆6. Brouillard P, Miikka V. Genetic causes of vascular malformation. Hum Mol Genet 2007; 16: 140–9. 7. Vikkula M, Boon LM, Carraway KL III, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181–90. 8. Calvert JT, Riney TJ, Kontos CD, et al. Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet 1999; 8: 1279–89. 9. Nobuhara Y, Onoda N, Fukai K, et al. TIE2 gain-of-function mutation in a patient with pancreatic lymphangioma associated with blue rubber-bleb nevus syndrome: report of a case. Surg Today 2006; 36; 283–6. ◆10. Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations, Part I. Associated syndromes. J Am Acad Dermatol 2007; 56: 353–70. 11. Fachinger G, Deutsch U, Risau W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene 1999; 18: 5948–53. ●12. Brouillard P, Boon LM, Enjolras JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous

13.

14.

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16.

17.

◆18.

19.

20.

21.

22.

23.

24.

25.

●26.

27.

28.

29.

malformations (“glomangiomas”). Am J Hum Genet 2002, 70: 866–74. Tasnadi G. Epidemiology and etiology of congenital vascular malformations. Semin Vasc Surg 1993; 6: 200–3. Rosen RJ, Riles TS, Berenstein A. Congenital vascular malformations. In: Rutherford RB, ed. Vascular Surgery, 4th edn. Philadelphia: W.B. Saunders, 1995: 1218–32. Rutherford RB. Noninvasive testing in the diagnosis and assessment of arteriovenous ﬁstula. In: Berenstein EF, ed. Noninvasive Diagnostic Techniques in Vascular Disease. St. Louis: CV Mosby, 1985: 666–79. Pearce WH, Rutherford RB, Whitehall TA, et al. Nuclear magnetic resonance imaging: its diagnostic value in patients with congenital vascular malformations. J Vasc Surg 1988; 8: 64–70. Boon LM, Mulliken JB, Vikkula M, et al. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 1994; 3: 1585–7. Gloviczki P, Driscoll DJ. Klippel–Trenaunay syndrome: current management. Phlebology 2007; 22: 291–8. Scott EE, Pearce WH, McCarthy WJ, et al. Arteriovenous malformation: long-term follow-up. In: Yao JST, Pearce WH, eds. Long-Term Results in Vascular Surgery. Norwalk: Appleton and Lange, 1993: 401–10. Szilagyi DE, Smith RF, Elliot JP, et al. Congenital arteriovenous anomalies of the limbs. Arch Surg 1976; 111: 423–9. Flye WW, Jordan BP, Schwartz MZ. Management of congenital arteriovenous malformations. Surgery 1983; 94: 740–7. Ford EG, Stanley P, Tolo V, et al. Peripheral arteriovenous ﬁstulae: observe, operate obturate? J Pediatr Surg 1992; 27: 714. Rosen RJ. Embolization in the treatment of arteriovenous malformations. In: Goldberg HI, Higgins CB, Ring EJ, eds. Contemporary Imaging. San Francisco: University of California Press, 1985: 153. Yakes WF, Luethke JM, Parker SH, et al. Ethanol embolizations of vascular malformations. Radiographics 1990; 10: 787–96. Widlus DM, Murray RR, White RI, et al. Congenital arteriovenous malformations: tailored embolotherapy. Radiology 1988; 2: 511–16. Lee BB, Kim I, Huh S, et al. New experiences with absolute ethanol sclerotherapy in the management of a complex form of congenital venous malformation. J Vasc Surg 2002; 33: 764–72. Lee BB, Do YS, Byun HS, et al. Advanced management of venous malformation with ethanol sclerotherapy: midterm results. J Vasc Surg 2003; 37: 533–8. Villavicencio JL. Primum non nocere: is it always true? The use of absolute ethanol in the management of congenital vascular malformations. J Vasc Surg 2001; 33: 904–6. Burrows PE, Mason KP. Percutaneous treatment of low ﬂow vascular malformations. J Vasc Interv Radiol 2004; 15: 431–45.

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30. Boon LM, Mulliken JB, Enjolras O, Vikkula M. Glomuvenous malformation (glomangioma) and venous malformation. Distinct clinicopathologic and genetic entities. Arch Dermatol 2004; 140: 971–6. 31. Goodman TF, Abele DC. Multiple glomus tumors. Arch Dermatol 1971; 103: 11–18.

32. Parsi K, Kossard S. Multiple hereditary glomangiomas: successful treatment with sclerotherapy. Aust J Dermatol 2002; 43: 43–7. 33. Antony FC, Clif S, Cowley N. Complete pain relief following treatment of a glomangiomyoma with the pulsed dye laser. Clin Exp Dermatol 2003; 28: 617–19.

55 The management of venous aneurysms HERON E. RODRIGUEZ AND WILLIAM H. PEARCE Introduction Etiology Popliteal aneurysms Other venous aneurysms of the extremities Cervical and facial venous aneurysms Thoracic aneurysms

604 604 605 606 607 607

INTRODUCTION Venous aneurysms are rare abnormalities. The ﬁrst description of a venous aneurysm was made by Sir William Osler in 1913.1 Since then, venous aneurysms have been reported to occur in virtually every major vein. Despite numerous case reports and small single-center series, our current knowledge about this uncommon vascular abnormality remains limited. Most of the recommendations regarding management of venous aneurysms are supported only by anecdotal and retrospective experience. The terminology used to describe vein dilatations is often used without precise deﬁnitions. Not infrequently, the terms phlebectasia, venous aneurysm and varix are used as synonyms. In this chapter, we will use the term aneurysm for any signiﬁcant venous dilatation, whether saccular or fusiform. The term phlebectasia is used to describe a fusiform, diffuse dilatation. The association of a dilatation with tortuosity is called a varix. Aneurysmal dilatation of veins is often observed in association with either high-ﬂow states or congenital venous malformations.2 Following the creation of an arteriovenous ﬁstula, venous dilation occurs to accommodate the high shear forces. Eventually, venous aneurysms form. Such aneurysms are associated with arteriovenous ﬁstula access for chronic hemodialysis and with trauma. Occasionally, venous aneurysms form proximal to a partial venous obstruction, presumably as a result of increased pressure.3 Multiple venous aneurysms are also found in association with vascular malformations that do not have arteriovenous shunting. Phlebectasia with venous aneurysms is associated with “genuine diffuse

Abdominal venous aneurysms Inferior vena cava aneurysms Conclusions Clinical practice guidelines References

609 610 610 611 611

phlebectasia” and the Klippel–Trenaunay syndrome. Genuine diffuse phlebectasia is a rare disease characterized by diffuse venous enlargement of any extremity (usually upper) that is present at birth and progresses with age.4 Pathologic specimens reveal smooth muscle atrophy and loss of elastin ﬁbers. A related disease, Klippel–Trenaunay syndrome, is characterized by abnormalities of the deep venous system including ectasia, hypoplasia, aberrant vessels (i.e., lateral vein), and venous aneurysms.5 As these venous malformations form during embryologic development, multiple abnormalities exist simultaneously, including multiple venous aneurysms (Fig. 55.1). Solitary venous aneurysms (those not associated with high-ﬂow states, trauma, inﬂammation, or congenital malformations) are uncommon and they are the focus of this paper. A systematic literature review was performed and all case reports obtained that describe venous aneurysms have been included in chronological order in the reference section. It appears that the most common site affected by venous aneurysms is the popliteal vein,6–11 followed by saphenous and superﬁcial extremity veins.12–15 Other venous aneurysms occur in the jugular vein,16–55 portal vein,56–112 azygos vein,113–135 superior vena cava (SVC),136–161 mediastinal veins,118,148,149,152,156,158,162–173 inferior vena cava (IVC),149,175–196 axillary vein,197 facial vein,198,199 and parotid vein.200

ETIOLOGY The pathogenesis of venous aneurysms is unknown. The histologic ﬁndings in reported cases vary from normal to marked medial disruption and inﬂammation. With

Popliteal aneurysms

605

between the artery and vein. Cystic hygromas occur when there is a failure of the lymph sacs to completely separate from the venous system. The failure of the jugular venolymphatic structures to completely mature may explain the high incidence of cervical and thoracic venous aneurysms with cystic hygromas.151 On occasion, a persistent jugular sac may be misinterpreted as a venous aneurysm.205 The etiology of a solitary peripheral venous aneurysm is the most difﬁcult to understand. The very localized nature of these lesions suggests a speciﬁc abnormality in the vein wall. Similar to arterial aneurysms, the media of the vein wall is thinned with loss of smooth muscle.8 The reason for the frequent occurrence of venous aneurysms in the popliteal vein is unknown, but may be related to the ﬁndings of Lev and Saphir.201,202

POPLITEAL ANEURYSMS

Figure 55.1 Lower extremity venogram of a patient with diffuse phlebectasia.

increased ﬂow, “arterialization” of the venous outﬂow occurs with early hypertrophy of the vein wall followed by dilation and sclerosis (calciﬁcation). Venous remodeling termed endophlebohypertrophy and endophlebosclerosis may be important factors in the development of venous aneurysms.210,202 In a study of the popliteal vein, Lev and Saphir201,202 found that endophlebohypertrophy begins at birth and is associated with areas of stress (entry of tributaries and adjacent to the artery). Endophlebosclerosis (thinning) increases with age and occurs immediately adjacent to the artery. Lev and Saphir believe that thinning of the vein wall occurs where the vein and artery are opposed. This ﬁnding suggests that an external force (rather than an intraluminal force) could alter venous histology. The pathogenesis of venous aneurysms found in association with major vascular malformations is somewhat easier to understand. During embryologic development the major vascular and lymphatic spaces coalesce and separate to form the arterial, venous, and lymphatic components of the circulatory system. Arteriovenous malformations are formed by abnormal communications

The popliteal vein is believed to be the most common site of venous aneurysms, with 147 cases reported in the literature.6 The true prevalence of popliteal venous aneurysms and the frequency with which they cause symptoms are impossible to estimate. In a recently published, comprehensive review of the world literature, Bergqvist et al.6 found that, in most of the reported cases, the popliteal aneurysms were discovered in patients with chest symptoms suggestive of pulmonary embolism (46/105) followed by patients complaining of local symptoms in the popliteal fossa (38/105). Four cases of fatal pulmonary embolism in patients have been published. Rupture has never been reported. Bilaterality can occur but is uncommon. Very often, associated symptoms of venous insufﬁciency are present. The diagnosis can be accurately made with duplex ultrasonography. Operative plans can be made with ultrasound (US) alone but most surgeons prefer the details of venography. Computed tomography (CT) venograms and magnetic resonance (MR) venograms have virtually replaced ascending phlebography in our (and most) practices. Given their frequent association with pulmonary embolism, popliteal venous aneurysms should undergo surgical treatment once the diagnosis is made. Anticoagulation alone was used in two patients with fatal outcomes.10,11 The size of the aneurysm does not appear to correlate with the risk of thromboembolism.9 The shortterm results of surgical treatment at our institution2,8 and those reported in the literature are excellent. Aneurysmectomy with lateral venorraphy or patch angioplasty repair, resection with end-to-end anastomosis, or bypass (using non-reversed great saphenous vein, internal jugular vein, saphenous panel composite, or spiral vein) appear to have similar results. The long-term patency rates of venous repairs remains poorly deﬁned. Reported rates in the literature vary from 40% to 90%11 but very few studies report patency rates after 12 months.

606

The management of venous aneurysms

Figure 55.2 Popliteal vein aneurysm exposed through a posterior approach. The sural nerve is observed lateral to the venous aneurysm and the popliteal artery has been encircled with vessel loops medially.

Some have suggested that even short-term patency may facilitate the development of collateral venous channels.173 Most aneurysms can be approached posteriorly (Fig. 55.2) and perioperative intravenous anticoagulation has been routinely used and frequently continued via the oral route for 1–3 months postoperatively.

OTHER VENOUS ANEURYSMS OF THE EXTREMITIES Venous aneurysms of the extremities can develop in the superﬁcial or in the deep venous system. Most superﬁcial venous aneurysms of the extremities present as a soft, blue, compressible mass with few symptoms. Aneurysms of the saphenous vein are often associated with varicosities (Fig. 55.3). It is not uncommon for those aneurysms located in the upper thigh to be misdiagnosed as reducible inguinal or femoral hernias. If the aneurysm is located in the superﬁcial venous system, engorgement causing expansion during inspiration (upper extremities) or expiration (lower extremities) is typical. The risk of pulmonary embolism due to aneurysms in the superﬁcial veins of the lower extremity is low and very likely null for those in the upper extremities. For these reasons, most superﬁcial venous aneurysms should be treated only if symptoms occur (cosmesis, pain, thrombosis). In the majority of cases, excision of the aneurysmal segment alone is the best management option. In cases when there is evidence of thrombosis or occlusion of the deep system, excision with reconstruction may be necessary.12,13

Figure 55.3 Lower extremity venogram showing a saphenous vein aneurysm in a patient with varicose veins.

Deep venous aneurysms of the extremities usually present as an asymptomatic soft mass or are discovered incidentally during imaging studies performed for other reasons. Surgical repair of venous aneurysms of the extremities is determined by location. Venous aneurysms of the brachial or axillary veins (Fig. 55.4) are not associated with pulmonary embolism and should be treated only if symptoms occur (cosmetic, thrombosis). Iliac aneurysms (Fig. 55.5), although rare, appear to be associated with thromboembolic events in the majority of the reported cases2,3,161 and, thus, should be treated surgically. The same applies to femoral vein aneurysms. As with popliteal aneurysms, tangential excision with lateral venorraphy or resection with reconstruction are viable options.

Thoracic aneurysms 607

Figure 55.4 Venogram showing a large left axillary vein aneurysm.

Figure 55.5 Large left external iliac vein aneurysm discovered incidentally in an asymptomatic patient undergoing a computed tomography scan of the pelvis.

CERVICAL AND FACIAL VENOUS ANEURYSMS Venous dilatations have been described in the facial vein,198,199 over the parotid gland200 and in the jugular system.16–55 Jugular aneurysms can be saccular or – more commonly – fusiform. The latter condition is more often seen in children and has been named jugular phlebectasia. It was recognized by Gruber16 in 1875 and by Harris17 in 1928. It has also been described as venoma, venous cyst, venous aneurysm, and congenital venous cyst.43 Most cases are deemed to be idiopathic, but various theories of pathogenesis related to venous wall defects29 and increased intrathoracic venous pressure46 have been proposed. In a review of the English literature

published in 2001, Paleri et al.46 found 31 cases of pediatric internal jugular phlebectasia. We found over 100 additional cases of jugular aneurysms in children and adults.18–20,22–25,27–31,33–44,46–55 Typically, a unilateral soft mass in the neck is discovered. It enlarges on straining, crying, coughing, and Valsalva maneuver. The mass is almost always asymptomatic, although some patients have described the feeling of constriction, sensation of choking and giddiness, bluish discoloration of the neck, discomfort during physical activity, coughing, swallowing, and cessation of voice during reading or speaking out loud.33 In a single instance, an aneurysm of the internal jugular vein was discovered when the patient was being ventilated with positive pressure following an operative procedure.31 Phlebectasia occurs more commonly on the right internal jugular vein and bilaterality is uncommon. Duplex US is the diagnostic method of choice and should be used to differentiate jugular phlebectasia from other neck masses in childhood, especially from the other two conditions that enlarge on Valsalva maneuver: superior mediastinal tumor or cyst and laryngocele. The management of jugular phlebectasia is controversial, especially in asymptomatic cases. Spontaneous rupture has never been described although massive bleeding during tonsillectomy occurred in one instance.40 The risk of thromboembolic complications appears to be very low. Spontaneous thrombosis has been reported in only six cases, all of them adults with external jugular vein aneurysms.37,38,41,42 No instances of pulmonary embolism associated with jugular phlebectasia have been described. For these reasons, most authors strongly recommend conservative treatment.13,34,43,46 Others follow a more aggressive approach with liberal surgical repair.55 The arguments for surgical repair are fear of enlargement, fear of future misdiagnosis or rupture, potential for thromboembolic complications, and cosmetic and psychologic considerations.52,55 If surgical management is entertained, a choice is made between simply ligating the ectatic jugular vein versus the use of reconstructive techniques to maintain patency. Jugular vein ligation can result in head and neck edema.52,55 Three out of 32 cases undergoing surgical repair for jugular phlebectasia in a single institution developed head and cerebral edema causing intracranial hypertension, craniofacial edema, and even a stroke in one instance.55 The group reporting these cases cautions about ligating the right jugular vein and suggests that temporary preoperative internal jugular vein occlusion facilitates the development of collateral circulation between the intracranial and the extracranial veins.52

THORACIC ANEURYSMS Thoracic aneurysms can arise from the SVC, the azygos vein system, or the innominate and subclavian veins.

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The management of venous aneurysms

Superior vena cava aneurysms We found 30 reports of SVC aneurysms.118,136–160 Most aneurysms were found incidentally in asymptomatic patients undergoing imaging studies for other reasons or in patients with mild symptoms such as cough, dyspnea, and chest discomfort. In ﬁve cases, the SVC aneurysm coexisted with subclavian,148 innominate118,152,156,158 and azygos118 venous aneurysms. An association of SVC aneurysms and neck hygroma has been described.151 Fifteen patients underwent surgical management: 10 with excision or aneurysmorrhaphy,137,143,145,147,150,152,154–157 one aneurysm was wrapped in cellophane,136 one case was aborted,148 and in three cases the operation was performed for diagnostic purposes.138,140,141 Among the patients that underwent surgery, one patient died of intraoperative pulmonary embolism while his aneurysm was being palpated.140 All other surgically managed patients apparently did well, although the reported follow-up period was almost always very short. On the other hand, half of the patients reported in the literature did not undergo surgical treatment. One patient died from pulmonary embolism while undergoing diagnostic superior vena cava venography160 and one patient experienced contained rupture but survived and did not require surgery.148 As with the surgically treated cohort, the follow-up period was often short or not reported, although some authors documented 4138 and 14144 years of follow-up. Based on the collective experience obtained from this review, some observations can be made. Surgical repair for fear of hemorrhage appears unjustiﬁed, since only two cases of aneurysm rupture exist and, in both, the rupture was contained. One was treated surgically and the other one did well with observation alone. No cases of free rupture with hemodynamic collapse have ever been reported. Although thrombus was observed within several aneurysms on imaging studies or in surgical specimens, no cases of documented spontaneous pulmonary embolism or, more importantly, spontaneous fatal pulmonary embolism have been reported. On the other hand, pulmonary embolism has occurred with catastrophic consequences during venography and during surgery as well. It seems that a prudent approach to SVC aneurysms is justiﬁed, with non-invasive imaging follow-up using magnetic resonance venography (MRV) and dynamic CT scans. In patients with progressive enlargement, severe symptoms, presence of thrombus, or evidence of pulmonary embolism, operative intervention should be considered. Pasic et al.156 recommends the use of cardiopulmonary bypass during excision of SVC aneurysms.

associated anatomic and hemodynamic abnormalities were found. These abnormalities include cirrhosis and portal hypertension,133 pulmonary sequestration,122 IVC obstruction,131,135 azygos continuation syndrome (congenital anomaly consistent with failure of the right supracardinal vein to anastomose with the hepatic vein, resulting in drainage of blood from the distal IVC through the azygos vein into the SVC),131,134 Ehlers–Danlos syndrome134 and lung cancer.124 There were three reported cases of false aneurysms occurring after chest trauma.118,121,123 In the remaining 20 cases, no evidence of increased ﬂow or obstruction was found and, thus, the aneurysms were considered to be idiopathic. Most aneurysms were discovered incidentally in asymptomatic patients or in patients complaining of mild chest discomfort, dyspnea, or cough. Chest radiographs showed mediastinal enlargement and non-speciﬁc ﬁndings. In cases published prior to the widespread use of dynamic CT and MR, diagnosis was often made at thoracotomy after imaging studies suggested the presence of a posterior mediastinal mass. In most recent reports, the diagnosis was made on the basis of imaging studies. Dynamic CT shows slight enhancement in the arterial phase and homogeneous enhancement in the late phase131,132,135 (Fig. 55.6). Respiratory and postural maneuvers induce changes in the size of the contrast-enhancing mass.125 Gadolinium injection during MR causes homogeneous enhancement of the aneurysm.129 Transesophageal echocardiogram shows an anechoic mediastinal mass.124 The aneurysm may compress the right main stem bronchus or the SVC. Thrombus has been documented in only two cases,130,132 although no instances of pulmonary embolism have been reported. Rupture has never been reported. Management strategies in the 38 reported cases varied from observation alone, aneurysm excision via a right

Azygos vein aneurysms Thirty-eight cases of azygos and hemiazygos vein aneurysms were found in the literature. In 15 cases,

Figure 55.6 Azygos vein aneurysm. (Courtesy of Dr. Francis J. Podbielski.)

Abdominal venous aneurysms 609

lateral thoracotomy to placement of a stent graft from the right hepatic vein to the azygos vein in a case of azygos continuation syndrome in a patient with Ehlers–Danlos syndrome.134 Given the very low incidence of thrombosis and the fact that no reported cases of pulmonary embolism or rupture exist, a conservative approach with imaging follow-up appears more reasonable for most patients with no symptoms. If obstruction of the right bronchus or SVC exists, if symptoms are present, or if follow-up studies show enlargement or thrombosis, surgical or interventional treatment may be indicated. Podbielski et al.126 and others127 suggest that azygos vein aneurysms are ideal for video-assisted thoracoscopic excision. Alternatively, the creation of azygo-systemic shunts as described by D’Souza and colleagues134 can be considered by experienced endovascular specialists after careful deﬁnition of suitable anatomy.

Other thoracic aneurysms Reports about a total of 19 aneurysms of the subclavian and innominate veins have been published.118,148,149,152,156,158,162–173 Coexisting venous aneurysms were found in the SVC (ﬁve cases), azygos vein (one case), and jugular vein (one case). In one report of right innominate vein aneurysm, cystic hygroma was present.167 The majority of these aneurysms are saccular, asymptomatic, and occur in females. No thromboembolic complications have been reported. In one case mentioned above,148 a 24 year old woman with an anomalous persistent left SVC experienced spontaneous, contained rupture. This patient was managed expectantly and the aneurysm thrombosed and eventually absorbed with a satisfactory outcome. These reports suggest that subclavian and innominate aneurysms should be managed conservatively unless symptoms or complications occur.

incidentally on abdominal ultrasounds, MR, or CT scan studies performed for other reasons. In one case, a portal aneurysm was discovered in utero.80 Small portal aneurysms are usually asymptomatic. Larger aneurysms can cause abdominal discomfort74 or compression of adjacent structures provoking jaundice (common bile duct), dyspepsia (duodenum), and even portal hypertension (as in one aneurysm of the superior mesenteric vein causing obstruction of the portal vein with no evidence of liver disease).64 Not infrequently, portal vein aneurysms are discovered during work-up for upper gastrointestinal bleeding in patients with portal hypertension. The natural history of these aneurysms has not been deﬁned. Most reports describe the imaging characteristics of the aneurysms at the time of diagnosis but only a few have followed up these aneurysms prospectively.60,88,96,104,107 Spontaneous thrombosis has been reported in at least a dozen cases99,102 and rupture in at least four.90,102 The more common occurrence of gastrointestinal bleeding is almost always caused by portal hypertension and is not a consequence of the aneurysm itself. From this review of the literature, it appears prudent to perform repeat imaging studies on asymptomatic patients with portal aneurysms.88,90,94,96 Aneurysm expansion appears to be rare in the absence of portal hypertension.96,107 In one case, the size of a splenic vein aneurysm changed along with the size of the spleen in a patient with leukemia, and regression occurred with resolution of splenomegaly.95 If gastrointestinal bleeding occurs, portosystemic shunts to alleviate portal hypertension should be considered. Patients presenting with thrombosis or symptoms related to compression of adjacent structures should be considered for aneurysm repair and those caused by portal hypertension for portal decompression.111 Successful thombectomy and aneurysmorrhaphy have been reported with 10 year follow-up.78 Others have

ABDOMINAL VENOUS ANEURYSMS Most reports of abdominal venous aneurysms are in the portal venous system (Fig. 55.7). We found 115 cases of portal system aneurysms.56–112 Although more than 25 cases were classiﬁed as idiopathic or congenital,112 the majority of portal aneurysms are associated with liver cirrhosis and portal hypertension. Pancreatitis has also been linked to the development of splenic and superior mesenteric aneurysms, presumably due to the severe local inﬂammation.63 Most aneurysms are found in the extrahepatic segment of the portal vein, but aneurysms have been reported in the intrahepatic portal segment (25 cases),60,69,90,94,96,102,106 the superior mesenteric vein (17 cases),34,59,63–65,67,68,75,79,86,88,104,108 and the splenic vein (10 cases).34,73,84,87,94–96,107,110 Given the widespread use of highdeﬁnition imaging modalities, the majority of portal aneurysms described in the recent past have been found

Figure 55.7 Large aneurysm of the portal vein discovered incidentally in an asymptomatic patient.

610

The management of venous aneurysms

obtained good results with resection alone.109 Alternatively, some authors have reported good outcomes with observation in cases of thrombosed aneurysms.102 Advocates of surgical repair argue that, although aneurysm thrombosis has been managed successfully without intervention, cavernous transformation of the porta hepatis, portal hypertension with potential variceal bleeding, and mesenteric venous infarction can be prevented by a more aggressive approach.111 This suggests that surgical intervention can be selectively applied to average and low-risk patients and that observation can be used in elderly, highrisk subjects.

makes their natural history unclear and, thus, management recommendations are difﬁcult to make. Since thrombosis, rupture, and embolism have been described, low-risk patients should be considered for operative repair. Simple resection, resection with primary repair, patch angioplasty repair, or caval replacement has been described. Patients who cannot undergo surgical treatment can be considered for ﬁlter placement in the suprarenal segment of the IVC for the prevention of pulmonary embolism.

CONCLUSIONS INFERIOR VENA CAVA ANEURYSMS We reviewed 25 cases of aneurysms of the IVC.149,175–196 In the majority of published cases, no symptoms were present and the aneurysm was discovered incidentally. Thrombosis was reported in eight cases,179–181,185,186,188,190 rupture in one180 and pulmonary embolism in two,180,190 one of which was fatal. One aneurysm was discovered during evaluation for penile bleeding.187 Modern imaging techniques usually allow for the diagnosis of these uncommon aneurysms. In cases of thrombosed IVC aneurysms, diagnosis may be difﬁcult and the aneurysm can be confused with retroperitoneal tumors, renal carcinoma, lymphadenopathy, and IVC tumors.188 In one report, an IVC aneurysm coexisted with a retroperitoneal ganglioneuroma.194 Some authors have classiﬁed IVC aneurysms depending on their anatomic location.185 As with other venous aneurysms, the limited number of cases

Venous aneurysms are uncommon. The presentation and management of these abnormalities depend on their location. Aneurysms of the deep veins in the lower extremities carry a signiﬁcant risk of thrombosis and embolism and repair should be carried out once the diagnosis is made. Aneurysms of the lower extremity superﬁcial system and those in the upper extremities – whether superﬁcial or deep – are rarely associated with thromboembolism and repair is only indicated for cosmetic reasons or if thrombosis occurs. Aneurysms of the neck and face often present as visible, soft masses that change in size with respiration and straining. In children, jugular phlebectasia should be included in the differential diagnosis of neck masses that enlarge during the Valsalva maneuver. The management of this condition remains controversial. Thoracic aneurysms are rarely associated with thromboembolism or hemorrhage and can be managed

Guidelines 5.6.0 of the American Venous Forum on the management of venous aneurysms No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.6.1 We recommend surgical repair of even asymptomatic lower extremity venous aneurysms because of the risk of thromboembolic complications

1

B

5.6.2 For aneurysms of superﬁcial veins of the arm or leg or of deep veins of the arm we suggest observation unless cosmetic reasons or complications warrant repair

2

C

5.6.3 For jugular vein aneurysms we suggest observation unless cosmetic reasons or psychological reasons warrant surgical repair

2

B

5.6.4 For abdominal venous aneurysms we suggest repair because of the risk of rupture and thromboembolism

2

B

5.6.5 Thoracic venous aneurysms are infrequently associated with rupture or thromboembolic complications and we suggest observation in most cases

2

B

References 611

conservatively. When enlargement or complications occur, traditional surgical repair, thoracoscopic excision, and endovascular techniques are viable alternatives. Venous aneurysms in the abdomen are most frequently discovered incidentally during imaging examinations. Management should be individualized with surgical treatment for low-risk patients and expectant management for asymptomatic patients who are poor candidates for surgery.

CLINICAL PRACTICE GUIDELINES ●

●

●

●

●

Venous aneurysms of the lower extremity deep system carry a signiﬁcant risk for thromboembolic complications and should be repaired (2 [1B], 6 [1B], 7 [1B], 9 [1B], 34 [1B], 161 [1C]). Venous aneurysms of the superﬁcial venous system in the upper and lower extremities and those in the deep system in the upper extremities are rarely associated with embolism or rupture and can be managed conservatively unless cosmetic reasons or complications occur (12 [2C], 13 [2C], 34 [2B]). Jugular phlebectasia carries a low risk for thromboembolism. Surgical management is indicated only for cosmetic and psychological reasons (13 [2C], 34 [2B], 43 [2B], 52 [2B]). Thoracic venous aneurysms are infrequently associated with rupture or thromboembolic complications and can be observed in most cases (113–173 [2B]). Abdominal venous aneurysms have been linked with complications such as rupture and embolism. Repair should be considered in patients ﬁt for surgery (56–112 [2B], 175–196 [2B]).

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105. Ertan N, Conkbayir I, Akkuzu E, Hekimoglu B. Aneurysm of the portal vein: report of two cases. Tani Girisim Radyol 2004; 10: 52–5. 106. Kaido T, Taii A, Nakajima T. A huge intrahepatic portal vein aneurysm. Abdom Imaging 2005; 30: 69–70 ●107. Heeren M, Op de Beeck B, Van den Brande P. Aneurysm of the splenic vein. Acta Chir Belg 2004; 104: 322–4. 108. DeGregorio MA, Gimeno MJ, Medrano J, et al. Ileocolic arteriovenous ﬁstula with superior mesenteric vein aneurysm: endovascular treatment. Cardiovasc Intervent Radiol 2004; 27: 556–9. 109. Jin B, Sun Y, Li YQ, et al. Extrahepatic portal vein aneurysm: two case reports of surgical intervention. World J Gastroenterol 2005; 11: 2206–9. 110. Kocakoc E, Kiris A, Bozgeyik Z, et al. Splenic vein aneurysm with calciﬁcation of splenic and portal veins J Clin Ultrasound 2005; 33: 251–3. ●111. Wolff M, Schaefer N, Schmidt J, Hirner A. Thrombosis of a large portal vein aneurysm: treatment by thrombectomy, aneurysmorrhaphy, and portocaval shunt. J Gastrointestinal Surg 2006; 10: 128–31. 112. Giavroglou C, Xinou E, Fotiadis N. Congenital extrahepatic portal vein aneurysm. Abdom Imaging 2006; 31: 241–4. 113. Siddorn JA, Worsornu L. Dilatation of the azygos vein simulating a mediastinal tumour. Thorax 1979; 34: 117–19. 114. Oibert F, Kobinia G, Neumann I. Angiographic demonstration of azygos aneurysm. Ann Radiol (Paris) 1980; 23: 363–8. 115. Barraine R, Gasquet C, Cabrol C, et al. Les aneurysms de la veine azygos. Arch Mal Coeur 1981; 6: 755–9. 116. Hayward I, Forrest JV, Sagel SS. Hemiazygos vein aneurysm: CT documentation. J Comput Assist Tomogr 1989; 13: 1072–4. 117. Seebauer L, Prauer HW, Gmeinwieser J, Sebening F. A mediastinal tumor simulated by a sacculated aneurysm of the azygos vein. Thorac Cardiovasc Surg 1989; 37: 112–14. 118. Rappaport DC, Ros PR, Moser RP Jr. Idiopathic dilatation of the thoracic venous system. Can Assoc Radiol J 1992; 43: 385–7. 119. Kurihara Y, Nakajima Y, Ishikawa T. Case report: saccular aneurysm of the azygos vein simulating a paratracheal tumor. Clin Radiol 1993; 48: 427–8. 120. Paramanathan A, Bapatla AS, Padmanabhan K, et al. An unusual cause of a right paratracheal mass. Chest 1994; 106: 1867–8. 121. Jain A, Blevea JS. Post-traumatic pseudoaneurysm of the azygos vein in a patient with azygos continuation. J Comput Assist Tomogr 1994; 18: 647–8. 122. Trigaux JP, Jamart J, Van Beers B, et al. Pulmonary sequestration. Visualization of the enlarged azygos system by CT. Acta Radiol 1995; 36: 265–9. 123. Anonymous. Image interpretation session: 1995. Case 3. Posttraumatic pseudoaneurysm of the azygos vein in a patient with azygos continuation of the IVC. Radiographics 1996; 16: 220–2.

124. Léna H, Desrues B, Heresbach D, et al. Azygos vein aneurysm: contribution of transesophageal echography. Ann Thorac Surg 1996: 61: 1253–5. 125. Mehta M, Towers M. Computed tomography appearance of idiopathic aneurysm of the azygos vein. Can Assoc Radiol J 1996; 47: 288–90. 126. Podbielski FJ, Sam AD II, Halldorsson AO, et al. Giant azygos vein varix. Ann Thorac Surg 1997; 63: 1167–9. 127. Watanabe A, Kusajima K, Aisaka N, et al. Idiopathic saccular azygos vein aneurysm. Ann Thorac Surg 1998; 65: 1459–61. 128. Gallego M, Mirapeix RM, Castañer Domingo CH, et al. Idiopathic azygos vein aneurysm: a rare cause of mediastinal mass. Thorax 1999; 54: 653–5. 129. Sakaguchi M, Hanazaki K, Nakamura T, et al. Idiopathic saccular aneurysm of the azygos vein. J Card Surg 1999; 14: 178–80. 130. Icard P, Fares E, Regnard JF, Levasseur P. Thrombosis of an idiopathic saccular azygos aneurysm. Eur J Cardiothorac Surg 1999; 15: 870–2. 131. Poll LW, Koch JA, Finken S, et al. Azygos continuation syndrome with aneurysm of the azygos vein: CT and MR appearances. J Comput Assist Tomogr 1999; 23: 19–22. 132. Gomez MA, Delhommais A, Presicci PF, et al. Partial thrombosis of an idiopathic azygos vein aneurysm. Br J Radiol 2004; 77: 342–3. 133. Lee SY, Kuo HT, Peng MJ, et al. Azygos vein varix mimicking mediastinal mass in a patient with liver cirrhosis. Chest 2005; 127: 661–4. ●134. D’Souza ES, William DV, Deeb GM, Cwikiel W. Resolution of large azygos vein aneurysm following stent-graft shunt placement in a patient with Ehlers–Danlos syndrome type IV. Cardiovasc Intervent Radiol 2006; 29: 915–19. 135. Chiu SS, Lau S, Kam CK. Azygos vein aneurysm. CT scan follow-up. J Thorac Imaging 2006; 21: 66–8. 136. Abbott OA. Congenital aneurysm of superior vena cava. Report of one case with operative correction. Ann Surg 1950; 131: 259–63. 137. Lawrence GH, Burford TH. Congenital aneurysm of the superior vena cava. J Thorac Surg 1956; 31: 327–8. 138. Gallucci V, Sanger PW, Robicsek F, Daugherty HK. Aneurysm of the superior caval vein. Vasc Surg 1967; 1: 158–61. 139. Bell MJ, Gutierrez JR, DuBois JJ. Aneurysm of the superior vena cava. Radiology 1970; 95: 317–18. 140. Ream CR, Giardina A. Congenital superior vena cava aneurysm with complications caused by infectious mononucleosis. Chest 1972; 62: 755–7. 141. Franken EA. Idiopathic dilatation of the superior vena cava (superior vena cava dilatation). Pediatrics 1972; 49: 297–9. 142. Gabriele AR, North L, Pircher FJ, Boushy SF. Aneurysmal dilatation of the superior vena cava. J Nucl Med 1972; 13: 227–9. 143. Madani MA, Loughran EH, Cooke JA Jr. Congenital venous aneurysm of superior mediastinum. N Y State J Med 1973; 73: 289–90.

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184. Hasan F, Gleeson F, Lock MR, et al. Diverticulum of the inferior vena cava: a case report. J Vasc Surg. 1992; 15: 578–80. 185. Gradman WS, Steinberg F. Aneurysm of the inferior vena cava: case report and review of the literature. Ann Vasc Surg 1993; 7: 347–53. 186. Levesque H, Cailleux N, Courtois H, et al. Idiopathic saccular aneurysm of the inferior vena cava: a new case. J Vasc Surg 1993; 18: 544–5. 187. Debing E, Vanhulle A, van Tussenbroek F, et al. Idiopathic aneurysm of the inferior vena cava as a cause of massive penile bleeding. Eur J Vasc Endovasc Surg 1988; 15: 365–8. 188. DeBree E, Klaase JM, Schultze Kool LJ, van Coevorden F. Case report. Aneurysm of the inferior vena cava complicated by thrombosis mimicking a retroperitoneal neoplasm. Eur J Vasc Endovasc Surg 2000; 20: 305–7. 189. Tatou E, Cognet F, Renaud-Bolard C, Brenot R. Aneurysm of the cardiohepatic segment of the inferior vena cava. Eur J Cardiothorac Surg 2001; 20: 849. 190. Lochbuehler H, Weber, H, Mehlig U, et al. Aneurysm of the inferior vena cava in a 5-year-old boy. J Pediatr Surg 2002; 37 (5): 10–12. 191. Sullivan VV, Voris TK, Borlaza GS, et al. Incidental discovery of an inferior vena cava aneurysm. Ann Vasc Surg 2002; 16: 513–15. 192. Jegananthan R, Reid JA, Hannon RJ. Aneurysm of the inferior vena cava. Surgeon. 2003; 1: 164–5. 193. Sheth R, Hanchate V, Rathod K, et al. Case report. Australasian Radiol 2003; 47: 94–6.

194. Nishinari K, Wolosker N, Yazbek G, et al. Idiopathic aneurysm of inferior vena cava associated with retroperitoneal ganglioneuroma: case report. J Vasc Surg 2003; 37: 895–8. 195. Yekeler E, Genchellac H, Emiroglu H, et al. MDCT appearance of idiopathic saccular aneurysm of the inferior vena cava. Am J Roentgenol 2004; 183: 863–4. 196. Tansel T, Harmandar B, Onursal E. Idiopathic aneurysm of the inferior vena cava. Cardiol Young 2005; 15: 322–3. 197. Owen WJ, McColl I. Venous aneurysm of the axilla simulating of a soft tissue tumour. Br J Surg 1980; 67: 577–8. 198. Shekib N, Hakami F. Venous aneurysm of the facial vein. Chest 1978; 73: 679–80. 199. Daily WW, Hertler CK. Aneurysm of the facial vein. Ear Nose Throat J 1989; 68: 548–52. 200. Jensen JL, Reingold IM. Venous aneurysm of the parotid gland. Arch Otolaryngol 1977; 103: 493–5. ●201. Lev M, Saphir O. Endophlebohypertrophy and phlebosclerosis. II. The external and common iliac veins. Arch J Pathol 1951; 51: 401–11. ●202. Lev M, Saphir O. Endophlebohypertrophy and phlebosclerosis. I. The popliteal vein. Arch J Pathol 1951; 51: 154–78. 203. Steinberg I, Watson RC. Lymphangiographic and angiographic diagnosis of persistent jugular lymph sac. N Engl J Med 1966; 275: 1471–4. 204. Rich NM, Honson RW, Wright CB, et al. Repair of lower venous trauma: a more aggressive approach required. J Trauma 1974; 14: 639–52.

56 Management of pelvic venous congestion and perineal varicosities GRAEME D. RICHARDSON Introduction Etiology Diagnosis Investigations Treatment

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INTRODUCTION Although the problem of pelvic varices with or without pelvic escape veins is not uncommon and is obviously not a new disease, it has been considered somewhat esoteric. In recent years with better imaging and endovascular techniques, diagnosis and treatment of the condition has gained acceptance, although there is still skepticism, interestingly often from obstetric and gynecological colleagues. Clinicians treating varicose veins have been aware of varicosities involving the vulva and upper medial thigh, the buttocks, and perianal areas, which often are a signiﬁcant component or even the only cause of leg varices. The patterns of leg varices clearly suggest that some originate in the pelvis. The connections from perineal and buttock varices to the pelvis are pelvic escape veins. They are tributaries of the anterior and posterior divisions of the internal iliac veins and the round ligament veins. Direct injection of external varices (varicography)1,2 shows the connections, as does per uterine3 venography or per osseus venography by injection of contrast into the ischium to demonstrate veins in the broad ligament. Such studies show anatomy but not pathophysiology. Historically, selective gonadal vein venography4,5 showed some very large veins ﬁlling broad ligament varices and this formed the basis of treatment for pelvic venous congestion, when it was assumed dilated ovarian veins were the source and thus could be sacriﬁced. If a catheter, however, is passed through the only valve at the upper end of a gonadal vein and, with the patient erect, contrast is injected it will travel caudally and suggest reﬂux.

Vulval veins in pregnancy Comparison of results of coil and surgical treatment of ovarian reﬂux Clinical practice guidelines References

624 624 625 625

With the advent of duplex ultrasound and the development of “windows” to avoid bowel gas and peristalsis6 it was possible to sample the upper gonadal vessels, non-invasively, and conﬁrm reﬂux. This allows selective ablation of the vein ﬁlling the pelvic varices whether by open surgery7,8 or by endovenous techniques of coils with or without sclerosant or glue.9–12 Not all venous disease is due to reﬂux. If obstruction leads to collateral ﬂow, ablation of the vein will exacerbate symptoms. Ablation of both ovarian veins if only the left is incompetent will thus cause obstruction on the right side. Typical symptoms of venous congestion such as aching and heaviness, as experienced in the leg, when present in the pelvis suggests the possibility of pelvic venous congestion. Recognizing those symptoms is the indication to proceed to pelvic ultrasound to conﬁrm dilated broad ligament veins. If there are pelvic escape veins, pelvic congestion will be dissipated to the vulva, buttocks, or legs. Some patients will have few or no pelvic symptoms despite their leg varices being ﬁlled entirely from ovarian vein reﬂux and large broad ligament veins connecting through to the legs. The reasons for lack of awareness of pelvic congestion syndrome (PCS) with or without perineal varicosities include the following. ●

There is increasing incidence with the number of pregnancies. This may explain the relative infrequency in USA after one or two pregnancies. In South America and elsewhere after 7–13 pregnancies the condition is extremely common.

618

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Failure to examine the patient standing with complete exposure. Gynecologists examine women lying down and may miss the diagnosis. When examining anyone with leg varices it is essential to look at the distribution of veins and speciﬁcally the pudendal, vulval, and buttock regions.

Male varicocele has been extensively described in the literature, and aching leads to treatment. The causes are the same as in females. Some attitudes in the medical profession may have prevented recognition of this problem and, therefore, appropriate treatment for many women. Most cases of PCS could be labeled as female varicocele. Pelvic congestion syndrome is characterized by chronic pelvic pain in the setting of pelvic venous varicosities. The syndrome, ﬁrst described as a vascular condition by Taylor and Wright in 1949,13 was more recently shown by Hobbs8 to be the result of venous engorgement of the pelvis due to gross dilatation and incompetence of one or both of the ovarian veins. In a series of 50 symptomatic patients with either pelvic or vulval varicose veins assessed by our ultrasound techniques in Wagga Wagga, the cause was found to be ovarian vein reﬂux in 71% of cases, more often the left than the right (24:9). Saphenofemoral tributaries were the only cause of vulval varicose veins in approximately 10% of cases, and the remainder were assumed to be caused by internal iliac reﬂux alone. The last probably accounts for at least 10% of the cases of PCS. In addition, it seems likely that segmental pelvic vein reﬂux accounts for a further 10% of cases. Many patients with recurrent leg varicose veins are found to have a signiﬁcant component of their problem from the pelvis. Seeking symptoms of PCS, a history of vulval varicose veins of pregnancy, and looking for a contribution from the pelvis in all patients presenting with leg varicosities will result in a greater awareness of a common yet poorly understood clinical problem.

when restudied in those patients with persisting vulval varices. Perhaps after pregnancy some ovarian veins do not return to normal size, and the limited one or two valves at the upper end of the ovarian veins may become incompetent. Possibly segmental reﬂux occurs in tributaries of the internal iliac veins such as the uterine veins and the round ligament veins, and can be responsible for persisting pelvic varicosities, even though we are unable to demonstrate ovarian vein or main trunk internal iliac vein reﬂux. We have often demonstrated this segmental reﬂux in our pelvic ultrasound assessment. Compression syndromes are a further cause of left ovarian vein reﬂux, particularly superior mesenteric artery compression of the left renal vein and retroaortic left renal vein with compression. Compression of the left common iliac vein by the right common iliac artery can produce internal iliac vein reﬂux. While hormonal and psychiatric factors have at times been implicated in the symptomatology, exacerbation of symptoms with menstruation, sexual activity, and ovulation suggests increased arterial ﬂow to the pelvis at these times results in pooling of venous blood in the pelvic varicosities. If large pelvic veins persist in the broad ligament, typical pelvic symptoms occur. Associated with these varicosities there may be pelvic escape through either the internal iliac tributaries, namely obturator or internal pudendal (Fig. 56.1), or the round ligament into the vulva and upper medial thigh (Fig. 56.2a), or posteriorly into the buttock and posterior thigh, sometimes including varices of the vein of the sciatic nerve resulting in sciatica-like symptoms. These veins usually feed into either the great or small saphenous system, and, if not treated at the same time as the great or small saphenous varicose veins, they cause recurrent varicose veins. A typical pattern is

ETIOLOGY Although rarely seen in nulliparous teenagers and young women, when one may assume the cause is identical to male varicocele, this condition largely follows pregnancy. Vulval varicose veins are said to occur in 2–7% of pregnancies.14,15 These become larger in subsequent pregnancies, although they often disappear in the postpartum period. Usually after three pregnancies some varicose veins remain in the vulva, upper medial thigh, perianal, or gluteal regions. Probably the majority of cases are related to massive enlargement of the ovarian veins draining the pregnant uterus, perhaps associated with internal iliac vein compression. These huge ovarian veins in pregnancy are easily seen using a posterior ultrasound window through the kidney.6 The ovarian veins are always competent during the pregnancy, yet became incompetent

Figure 56.1 Varicogram of vulval varices with obturator and internal pudendal pelvic escape veins.

Investigations 619

escape veins seems purely a question of chance as to which valves give way.

DIAGNOSIS

(a)

Clinical suspicion of PCS relies on typical symptoms, namely pelvic heaviness or deep pelvic pain, which is present before the period and on day 1 and sometimes day 2 of menstruation, midcycle and postcoital. The last is particularly noticeable on standing up immediately after having had morning intercourse. Aching may persist for several hours through the day and is particularly severe after long periods of standing. Many patients complain of dyspareunia and many are aware of vulval and leg varicosities which are worse at the time of their pelvic symptoms. Commonly, there are bladder symptoms related to perivesical varicosities causing frequency or a difﬁculty in starting the ﬂow of urine. Many patients have symptoms of irritable bowel syndrome. The diagnosis of PCS is often delayed until investigations looking for endometriosis, inﬂammatory bowel disease, urinary tract disease, or pelvic inﬂammatory disease have proved negative. It is common for patients to have suffered marital stress and dissatisfaction with their treating doctor’s lack of interest in their condition.

INVESTIGATIONS

(b) Figure 56.2 (a) Residual pudendal varices. (b) Vulval to posterior thigh to lateral calf varices.

Patients with symptoms consistent with PCS are examined to exclude other causes of pelvic pathology, and then undergo standard pelvic ultrasound and duplex ultrasound assessment of the pelvic, ovarian, and, when appropriate, groin and lower limb veins. Selective venography without any ultrasound is used in many centers for diagnosis as well as treatment. More recently, magnetic resonance imaging (MRI) and multislice computed tomography (CT) have been used to detect pelvic varices16 in the assessment of chronic pelvic pain. Dynamic MRI techniques are currently being developed in Madrid (F. Herraiz, personal communication) which can show ovarian vein reﬂux but will need to be compared with ultrasound techniques for cost and reliability.

Ultrasound assessment posterior vulval veins coursing posteriorly into the small saphenous via the intersaphenous vein (Fig. 56.2b). Crossover veins to the opposite side to the major source of reﬂux can cause confusion. Sometimes pelvic and vulval veins are more prominent on the right side even when the cause is the left ovarian vein. Although in most cases the root cause is the left ovarian vein, which ﬁlls large broad ligament varices, the course beyond there through pelvic

Pelvic congestion syndrome is conﬁrmed on transvaginal ultrasound by ﬁnding dilated varicose veins in the broad ligament which we would grade as mild (< 5 mm), moderate (5–7 mm), or marked (8–10 mm), and whether they distend when the patient is tilted head up by 60° on a motorized ultrasound examination table. Our ultrasound assessment begins with the patient presenting after 6 hours

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Management of pelvic venous congestion and perineal varicosities

of fasting, with a full bladder. Fasting reduces peristalsis. A full bladder enables standard gynecological pelvic ultrasound; however, it compresses pelvic varicosities, which become visible by transabdominal ultrasound after voiding. Transvaginal ultrasound then follows, and, having conﬁrmed PCS, we examine the ovarian veins, the internal iliac veins including anterior and posterior divisions, the round ligament veins and saphenofemoral tributaries. In Wagga Wagga, “windows” have been developed to assess ovarian vein incompetence using transabdominal duplex ultrasound and color ﬂow Doppler (3.5 or 5 MHz transducer)6 (Fig. 56.3a). We were able to locate ovarian veins and assess reﬂux in 93% of cases,17 which compares well with 92% visualization shown by Lechter7 using venography. The left ovarian vein is found by ﬁrst locating the left renal vein as it passes under the superior mesenteric artery. The ultrasound window is through the left lobe of the liver and the pancreas. The ovarian vein is located by following the left renal vein laterally and rotating the transducer through 90° (Fig. 56.3b). A retroaortic left renal vein, duplicated renal vein, or large ureteric veins are noted if present. It is important not to confuse accessory renal veins or the inferior mesenteric vein with the ovarian vein. The right ovarian vein is found using a window through the liver or gallbladder, by following the inferior vena cava upwards to where the right ovarian vein enters it anterolaterally at a very acute angle. Sampling by color and waveform is taken about 2 cm below the termination of the ovarian veins. The criterion for incompetence in the ovarian vein is reversed ﬂow when lying, sitting, or standing without augmentation. Treatment by surgery, or more recently endovascular methods, is based on the ultrasound ﬁndings.

(a)

(b)

Laparoscopy Laparoscopy is sometimes required to exclude other causes of pelvic pain, such as endometriosis or pelvic inﬂammatory disease in patients who have pelvic varices on ultrasound assessment. We do this with the patient’s gynecologist. Laparoscopy involves using an extra left iliac fossa port to retract the sigmoid colon. The patient, who initially is head down for gynecological laparoscopy, is then tilted head up and the ovarian and broad ligament veins distend rapidly if reﬂux is present.

Figure 56.3 (a) Ultrasound windows to left and right ovarian veins. (b) Ultrasound left ovarian vein (LOV) and left renal vein (LRV).

and assist in provision of informed consent should a patient be referred to an interventional radiologist for venography with a view to coils with or without sclerotherapy. Left renal venography is followed by selective ovarian venography (Figs 56.4 and 56.5). If indicated by ultrasound ﬁndings, we may carry out selective iliac venograms.

Venography TREATMENT Many centers rely on clinical ﬁndings, then proceed to selective venography for conﬁrmation, and then to endovascular treatment. Ultrasound conﬁrmation of excessive pelvic varicose veins by transvaginal ultrasound, even if ultrasound assessment for ovarian vein reﬂux is not possible, should prevent unnecessary invasive venography

Various methods have been used to treat the symptoms of pelvic congestion, including psychotherapy, ovarian suppression,18 intravenous dihydroergotamine,19 and bilateral oophorectomy with hysterectomy.20 Ovarian vein ligation has been performed to eliminate reﬂux since 1985,

Treatment 621

they signiﬁcantly contribute to the leg varicosities. In these cases, the pelvic veins are treated initially, and the response of symptoms is determined over a period of 2–3 months before treating the perineal or leg varicosities. In a few instances, the veins can reduce in size such that sclerotherapy of the residual perineal or leg veins might be appropriate, rather than surgical treatment.

Ovarian vein incompetence As most cases involve treatment of the left ovarian vein, the choice is between operation and endovascular ablation techniques. Laparoscopic treatment has been investigated, and, although it is possible to clip the upper end of the ovarian veins, it is currently not possible to remove a segment, nor easily deal with nearby tributaries. OPERATION Figure 56.4 Left renal venogram with reﬂux into a large left ovarian vein. Note the narrow upper end which helps prevent embolization of coils.

Figure 56.5 Selective left ovarian venogram ﬁlling large left broad ligament varices, with crossover to the right broad ligament.

as either a bilateral procedure (Lechter;7 Hobbs8) or a unilateral one based on ultrasound assessment (Richardson et al.17). Long-term success of such treatment has been poorly investigated. Assessment of treatment for venous conditions needs at least 5 year follow-up. In recent years, however, endovascular ablative techniques have been popularized, and again need to be adequately assessed. As many of these patients have associated perineal and leg varicosities, a treatment plan is required. The pelvic veins are treated only if there are pelvic symptoms, or if

Ovarian vein ligation has been performed on 120 patients since 1989 by the author. It involves a “sympathectomy” incision with a muscle-splitting extraperitoneal approach to the ureter and the adjacent ovarian vein, which is ligated carefully using non-absorbable material at the level of the pelvic brim. The ligature is then used for traction to enable further multiple ligations upwards to ﬁnish at approximately 2 cm from the left renal vein. A narrow Dever retractor helps expose this uppermost portion. There is signiﬁcant risk of major hemorrhage if the ovarian vein is not handled gently. Operation requires approximately 2 days’ hospitalization and causes a scar and about 2 weeks’ discomfort, which for a mother of young children is a considerable inconvenience compared with outpatient endovascular treatment. We assume surgical ligation is complete, and, provided all tributaries have been ligated, should produce long-term ablation of the ovarian vein. I would ligate an ovarian vein only if it was shown to reﬂux on ultrasound assessment. Other surgeons have routinely ligated both ovarian veins.7,8 It would seem unwise to ligate a draining vein that did not reﬂux. Some surgeons have advocated extensive dissection to include the ovarian pedicle.21 There is no evidence to suggest a more limited operation of treating only the ovarian vein shown on ultrasound to reﬂux, such as the Wagga Wagga technique, has inferior results. Surgical results Long-term results in a series of 72 patients treated until June 1995 in Wagga Wagga certainly encourage one to treat patients based on ultrasound ﬁndings of ovarian vein reﬂux.22 These patients were sent questionnaires and assessed independently by a surgical registrar for their quantitative response of symptoms to surgical treatment using visual analog scales.23 Sixty-seven of the 72 patients responded with a mean follow-up of 33 months (range 4–71) with a mean age of 35 years and mean pregnancies

622

Management of pelvic venous congestion and perineal varicosities

of 3.1. Pelvic heaviness was found to improve signiﬁcantly (> 50%) in 70% of patients, and, in 56% of patients, this was almost complete. Thirteen percent reported little or no improvement. When subsequently investigated, including further ultrasound and venography, no ovarian reﬂux could be found, and in all cases alternative diagnoses such as irritable bowel syndrome were present. Dyspareunia was present preoperatively in 82% of cases; 84% of these improved, with 50% of these patients reporting complete recovery. Post-intercourse pelvic aching was present in 75% of patients and improved in 70% of cases with 64% having complete recovery. Bladder symptoms of frequency and obstruction improved in 45% of patients, and some of the 20% of patients who preoperatively were aware of bowel spasm improved. Two patients had normal pregnancies subsequent to ovarian vein ligation with no development of vulval veins in the pregnancy and no recurrence of symptoms. OVARIAN ENDOVASCULAR ABLATION

There have been several reports of a single case, or a few cases, of successful treatment by ovarian vein embolization.9–12 Thus far, there has been no standardization of the techniques used by several centers but, in all instances, coils of various diameters and lengths have been used. In some centers, sclerotherapy has been used, but in the Dutch24 experience sclerotherapy was contraindicated because of a perceived risk of entering the portal system. A team in Vancouver, which has a very large experience of treatment of male varicocele using similar techniques, has utilized a combination of coils and glue (L. Machan, personal communication, 1996). Since January 1999 we have been using endovascular techniques. We prefer to use an inguinal approach; when cannulation of the ovarian vein is difﬁcult, we use a guiding catheter and still use the groin rather than a jugular or brachial approach. Our technique uses stainlesssteel coils with attached synthetic ﬁbers (Cook, Bloomington, IN, USA), choosing a diameter that is 2–3 mm larger than the ovarian vein diameter. In addition, sclerosant has been used with 2 mL of 3% Aethoxysklerol (Bioform, San Mateo, CA, USA) diluted with about 1– 2 mL of contrast so that the spread of sclerosant can be clearly seen on the screen to avoid spillover into the left renal vein. Air (1–2 mL) is added and the 5 mL syringe shaken to produce coarse bubbles (Fig. 56.6a). Our hope is that the sclerosant will help obliterate pelvic and broad ligament varices. By causing spasm we may help prevent migration of the coils. In no instances have we seen any contrast pass beyond the ovarian vein or broad ligament veins. While preparing the sclerosant as a foam would seem desirable, the contrast is further diluted and less visible than with coarse bubbles, and we are less sure of its spread. To reduce the cost to the patient we use the minimum number of coils to achieve the following

(a)

(b) Figure 56.6 (a) Large left ovarian vein with proximal tributary. Note coarse bubbles from sclerosant prior to proximal coils. (b) Two long coils and a short coil into a proximal tributary.

principles. The ﬁrst coil is deployed from the pelvic brim just above where it crosses the ureter. Depending on the anatomy of the ovarian vein, we aim to place a coil across junctions or selectively coil major tributaries. We try to have good cross-sectional coverage of the vein by varying the deployment, and we aim to have the highest point above all incompetent tributaries, and within 2–3 cm of

Treatment 623

the left renal vein. Usually, two long (20 cm) coils sufﬁce with occasional shorter coils in tributaries or at the upper end of the vein (Fig. 56.6b). We are aiming for the highest and longest possible ablation. Our approach has been via the right femoral vein. Having conﬁrmed ovarian vein reﬂux by a selective left renal venogram, a guide wire is passed down the ovarian vein to the pelvis, and a catheter advanced to the level of the pelvic brim. To contain sclerosant to the broad ligament varices, approximately half of the sclerosant is injected slowly, with the patient holding her breath with Valsalva as long as possible. In male patients with varicocele, this is combined with compression at the level of the external ring to prevent sclerosant passing into the scrotum. Further sclerosant is injected slowly with Valsalva, mid-ovarian vein, before deployment of further coils. Great care is required to avoid spillover of sclerosant or deployment of any coil in the left renal vein. Having the technical endovascular skills to use a snare to retrieve a coil should it be deployed into the renal vein is a prerequisite of performing this treatment. Risks of endovascular techniques include embolization, migration and perforation of coils, irritation of nerves such as the genitofemoral, and the possibility of late recanalization. There have been reports of recanalization resulting in recurrent symptoms requiring later surgical treatment.

In all cases coming to endovascular treatment, we have to be prepared for such anomalies and devise the best treatment strategy.

Other causes of pelvic congestion Some patients present with congestion symptoms or minor vulval varices, yet we are unable to demonstrate ovarian, ureteric, or internal iliac incompetence. As with most venous disease, symptoms vary with long periods of standing and the menstrual cycle. Repeat ultrasound studies show this and we try to perform studies when symptoms are maximal. There remain patients with signiﬁcant pelvic varices but no source of reﬂux. Some are due to venous obstruction associated with collateral venous pathways. We have observed patients with both ﬁxed and intermittent reﬂux of internal iliac veins associated with common iliac vein obstruction. Sometimes this is postural, when recumbent there is reversed ﬂow, and is associated with 1–2 mm anteroposterior diameter where the right common iliac artery crosses the left common iliac vein. Perhaps some of these patients would beneﬁt from a venous stent. A retroaortic left renal vein has frequently been associated with PCS and, rarely, left renal vein obstruction following surgical ligation. I avoid ablation of the ovarian vein in these patients with collateral drainage of the kidney.

Internal iliac veins Segmental pelvic vein reflux When patients are shown to have signiﬁcant internal iliac vein reﬂux as a cause for PCS, surgical treatment to ligate the main trunk or selectively the anterior division has been performed on a few patients in our series and by others.21 Surrounding structures, such as the ureter and iliac vessels, are at risk. There are also signiﬁcant risks to endovascular treatment of the internal iliac system. At its junction with the external iliac vein, the shape of the vein encourages embolization. In one case, we have deployed a coil into the anterior division together with sclerotherapy. When the patient has ovarian and internal iliac vein reﬂux on ultrasound assessment, we have treated only the ovarian vein. Thus far, we have not needed to treat the internal iliac vein because of a disappointing result.

Ureteric vein reflux Inevitably, unusual cases will appear associated with venous anomalies. We have treated several cases with large tortuous reﬂuxing ureteric veins which feed into the ovarian vein usually in the lower third of the abdomen. They are often difﬁcult to cannulate for coil treatment. Sometimes the ovarian vein joins a lower renal vein branch, or a large lumbar vein rather than the renal vein, and sometimes the ovarian or the renal vein is duplicated.

There remains a group of patients in whom we cannot demonstrate a deﬁnite cause. It appears quite feasible that some very large pelvic veins in pregnancy do not shrink and produce segmental reﬂux in uterine and broad ligament veins. In these patients and those whose symptoms fail to resolve after ovarian or iliac vein ablation, I would recommend hysterectomy.

Perineal varicosities Having treated the ovarian vein, these improve and can be treated by avulsion techniques by minor surgery, or at the time of dealing with the great or small saphenous varicosities. Large, round ligament veins can be ligated as they emerge from the external inguinal ring. Sclerotherapy of residual minor perineal varicosities is possible, and I have, on many occasions, used 2% Aethoxysklerol. To apply adequate compression after the sclerotherapy, I use cotton balls covered by tape and the patient wears a ﬁrm support, such as bicycle pants, in an attempt to provide as much compression as is practical. Side-effects from the sclerotherapy have been surprisingly few. Occasionally, I have seen women with very superﬁcial telangiectatic blebs on the labia which may bleed after

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Management of pelvic venous congestion and perineal varicosities

minimal trauma such as drying with a towel. Although difﬁcult and embarrassing, microsclerotherapy has been of signiﬁcant beneﬁt.

VULVAL VEINS IN PREGNANCY The incidence is said to be 2–7% of pregnancies, but they are more common after three pregnancies. They appear at 6–8 weeks, increasing in size until late pregnancy when they can be quite disabling. Several patients have been referred with an apparent inguinal hernia, with positive cough impulse and resolution when recumbent (Fig. 56.7). These are due to huge round ligament varices. There may also be large varices of the labia and near the clitoris due to the obturator vein, and more posteriorly in the vulva and perianal area from the internal pudendal vein. About 30 years ago, in trying to understand the natural history of vulval veins of pregnancy, I carefully followed a small series of patients. As the fetal head engaged in the pelvis the feeling of pressure in the vulval veins as well as their prominence subsided. It is therefore reasonable to reassure patients that the worst is over at about 36 weeks. External pressure with pads is not usually effective and women need to rest in the latter weeks to obtain relief. They are usually anxious about delivery, but the varices are displaced easily, and even with episiotomies bleeding is not troublesome and rupture of varices is rare. My suggestion would be that these veins should never be an indication to perform a cesarean section. We performed vulval varicography within a few days of delivery to try to determine the anatomy of the pelvic escape veins, hoping it would help in future management should the varices persist after pregnancy. To my surprise the largest varices presenting like inguinal hernias settled dramatically, and

Figure 56.7 Large round ligament (hernia like) and vulval varices in pregnancy.

were related to large round ligament veins. The vulval veins that persisted were more likely to be associated with obturator or internal pudendal pelvic escape veins. Despite huge varices, it is highly unlikely that there will be any indication to operate or inject these varices in pregnancy. By 6–8 weeks postpartum it is usually obvious which varices will be symptomatic and require early intervention. One can then predict how badly a subsequent pregnancy will affect the pelvic and vulval veins. In my experience, women usually decide three babies are enough and then we can plan deﬁnitive treatment.

COMPARISON OF RESULTS OF COIL AND SURGICAL TREATMENT OF OVARIAN REFLUX Patients treated by surgery from 1989 until 1998, and endovascular treatment from 1999 until June 2002, were studied using a questionnaire with visual analog scales. Statistical analysis of pelvic heaviness and overall satisfaction showed no difference between endovascular and surgical treatment.24 Both treatments resulted in statistically signiﬁcant improvement after treatment. A decision to treat in both groups was based on clinical ﬁndings and ultrasound assessment, and there was no statistical difference in the presenting features of patients in either the surgical or the endovascular series. Patients undergoing coil treatment were also subjected to follow-up ultrasound studies at 6 weeks to 6 months, and also abdominal radiographs. There was no evidence of coil migration in 34 patients. Early ultrasounds showed two clots in broad ligament veins, no signiﬁcant reduction in diameter at 6–10 weeks, but some evidence of reduction by 6 months. Long-term results of endovascular treatment have not yet been reported. Recanalization remains possible but should be amenable to further endovascular treatment. While the great majority of patients tolerate coil treatment with little discomfort, anxious patients are more difﬁcult to cannulate via the femoral vein, and spasm of the ovarian vein could lead to perforation. Patients have far less loin discomfort than after surgery, but if it seems excessive exercise should be restricted. A few patients have severe pain and this could be due to thrombosis of the ovarian vein or perforation. Patient satisfaction justiﬁes ablation of an ovarian vein shown by ultrasound to reﬂux. Provided endovascular ovarian vein ablation can be delivered safely and at reasonable cost, there are deﬁnite advantages over surgical treatment. Complications can occur from either method. The incidence of long-term recanalization is unknown. There is no evidence that endovascular treatment produces better results than surgery. Provided patients are prepared to accept the scar, pain, hospitalization and other potential complications of an operation, at this point one cannot say surgical treatment has been superseded.

References 625

Guidelines 5.7.0 of the American Venous Forum on the management of pelvic venous congestion and perineal varicosities No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.7.1 We recommend duplex scanning for initial evaluation of patients with suspected pelvic varicose veins. Ultrasound will conﬁrm pelvic varicose veins and usually determines their etiology

1

B

5.7.2 We recommend selective contrast pelvic venography to conﬁrm the diagnosis and exact etiology of pelvic and perineal varicose veins and delineate the anatomy for planning endovenous treatment

1

B

5.7.3 We recommend endovenous ablation of the ovarian vein reﬂux, but longterm results and degree of recanalization after coil embolization is not known

1

B

5.7.4 We suggest surgical ligation and excision of ovarian veins to treat reﬂux

2

B

CLINICAL PRACTICE GUIDELINES ●

●

●

●

●

●

Pelvic venous congestion should not be a diagnosis by exclusion, but suspected by typical symptoms and a past history of vulval veins of pregnancy. Visible perineal varices conﬁrm at least a component of the cause of leg varices to be pelvic varices. Ultrasound conﬁrms the presence, and in skilled hands can determine the cause, of pelvic varices (22 [1B]). Selective venography conﬁrms the cause and anatomical features, to then proceed to endovenous ablative treatment by coils with or without sclerotherapy. Both surgical and endovenous ablation of ovarian vein reﬂux are equally effective (24 [1B]). Coil treatment has greater patient acceptance, but longterm results, particularly possible recanalization, are unknown.

REFERENCES ● ◆

= Key primary paper = Major review article 1. Craig O, Hobbs JT. Vulval phlebography in the pelvic congestion syndrome Clin Radiol 1974; 24: 517–25. 2. Lea Thomas M, Hobbs JT. Vulval phlebography in the pelvic congestion syndrome. Clin Radiol 1974; 25: 517. 3. Chidakel N, Ediundh KO. Transuterine phlebography with particular reference to pelvic varicosities. Acta Radiol 1968; 7: 1–12. ●4. Ahlberg NE, Bartley O, Chidakel N. Retrograde contrast ﬁlling of the left gonadal vein. Acta Radiol 1965; 3: 385.

5. Chidakel N. Female pelvic veins demonstrated by selective renal phlebography with particular reference to pelvic varicosities. Acta Radiol 1968; 7: 193–209. ●6. Richardson GD, Beckwith TC, Sheldon M. Ultrasound windows to abdominal and pelvic veins. Phlebology 1991; 6: 111–25. ●7. Lechter A. Pelvic varices: treatment. J Cardiovasc Surg 1985; 26: 111. ◆8. Hobbs JT. The pelvic congestion syndrome. Br J Hosp Med 1990; 43: 200–6. 9. Edwards RD, Robertson IR, McLean AB, Hemingway AP. Case report: pelvic pain syndrome – successful treatment of a case by ovarian vein embolization. Clin Radiol 1993; 47: 429–31. 10. Sichlau MJ, Yao JST, Vagelzang RL. Transcatheter embolotherapy for the treatment of pelvic congestion syndrome. Obstet Gynecol 1994; 83: 892–6. 11. Boomsma J, Potocky V, Kievit C, et al. Phlebography and embolization in women with pelvic vein insufﬁciency. Medica Mundi 1998; 42: 22–9. 12. Cordts P, Eclavea A, Buckley P, et al. Pelvic congestion syndrome: early clinical results after transcatheter ovarian vein embolisation. Vasc Surg 1998; 5: 862–8. 13. Taylor HC, Wright H. Vascular congestion and hyperaemia. Am J Obstet Gynecol 1949; 57: 211–30. 14. Dodd H, Wright AP. Vulval varicose veins in pregnancy. BMJ 1959; 1: 831–2. 15. Dixon JA, Mitchell WA. Venographic and surgical observations in vulvar varicose veins. J Surg Gynaecol Obstet 1970; 131: 458–64. 16. Gupta A, McCarthy S. Pelvic varices as a cause of pelvic pain: MRI appearance. Magn Reson Imaging 1994; 12: 679–81.

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17. Richardson GD, Beckwith TC, Sheldon M. Ultrasound assessment in the treatment of pelvic varicose veins. Paper presented to The American Venous Forum 1991, Fort Lauderdale. 18. Farquhar CM, Rogers V, Franks S, et al. A randomized controlled trail of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion. Br J Obstet Gynaecol 1989; 96: 1153–62. 19. Reginald PW, Beard RW, Kooner JS, et al. Intravenous dihydroergotamine to relieve pelvic congestion with pain in young women. Lancet 1987; 2: 351–3. 20. Beard RW, Kennedy RG, Gangar KE, et al. Bilateral oophorectomy and hysterectomy in the treatment of

21.

◆22.

23. ●24.

intractable pelvic pain associated with pelvic congestion. Br J Obstet Gynaecol 1991; 98: 988–92. Gomez ER, Villavicencio JL, Conaway CW, et al. The management of pelvic varices by combined retroperitoneal ligation and sclerotherapy. In: Proceedings of the 1987 European American Venous Symposium, Washington DC. Richardson GD, Beckwith TC, Mykytowycz M, Lennox AF. Pelvic congestion syndrome: diagnosis and treatment. ANZ J Phlebol 1999; 3: 51–6. Scott J, Huskisson EC. Graphic representation of pain. Pain 1976; 2: 175–84. Richardson GD, Driver B. Ovarian vein ablation: coils or surgery? Phlebology 2006; 21: 16–23.

PART

6

LYMPHEDEMA Edited by Gregory L. Moneta

57 Lymphedema: pathophysiology, classification, and clinical evaluation Thom W. Rooke and Cindy Felty 58 Lymphoscintigraphy and lymphangiography Patrick J. Peller, Claire E. Bender and Peter Gloviczki 59 Lymphedema: medical and physical therapy Gail L. Gamble, Andrea Cheville and David Strick 60 Principles of surgical treatment of chronic lymphedema Peter Gloviczki 61 The management of chylous disorders Purandath Lall, Audra A. Duncan and Peter Gloviczki

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57 Lymphedema: pathophysiology, classification, and clinical evaluation THOM W. ROOKE AND CINDY FELTY Introduction Clinical presentation Etiology Anatomy

629 629 630 631

INTRODUCTION The CEAP (clinical, etiology, anatomy, pathophysiology) classiﬁcation has proven valuable for classifying venous disorders.1 A logical extension is to consider using it to classify lymphedema and lymphatic disorders.2 Indeed, given the similarities between the venous and lymphatic systems, it is somewhat surprising that this approach to classiﬁcation has not already been widely embraced. This chapter will therefore discuss the classiﬁcation of lymphedema in terms of CEAP categories (clinical, etiology, anatomy, pathophysiology).

CLINICAL PRESENTATION The purpose of the lymphatic system is to remove interstitial ﬂuid from the periphery and return it to the circulation.3 When this protein-rich interstitial ﬂuid is not removed because of lymphatic abnormalities the result is lymphedema.4 In the acute form, lymphedema resembles most other types of edema (such as that seen with congestive heart failure, venous disease, etc.). In the early stages of lymphedema, the swelling may be occult, although objective testing might reveal subclinical abnormalities involving the lymph vessels. As the condition becomes more overt, clinically signiﬁcant edema develops. At ﬁrst, the swelling is “reducible” with overnight rest, elastic compression, or topical pressure (pitting). Over time (often a year or more), the pressure of high-protein interstitial ﬂuid alters the cutaneous/subcutaneous tissues; this produces ﬁbrosis, cellular proliferation, inﬂammation,

Pathophysiology CEAP-L for lymphedema References

632 632 633

and other changes.5 The result is progressive hardening and induration of the skin which can be appreciated by inspection and palpation. These skin changes may include “peau d’orange” thickening and wrinkling. Lymphedema can often be appreciated by eliciting the “Stemmer sign,” which involves the inability to pinch the skin at the base of lymphedematous toes6 (Fig. 57.1). In chronic lymphedema, the skin gradually loses its ability to “pit” under pressure, and eventually the swelling becomes nonreducible even with prolonged limb elevation, wrapping, etc.7 Over time, the appearance of the limb may change further. Along with continued skin thickening there may be licheniﬁcation and the development of verrucous lesions.8 As these lesions proliferate and coalesce, the limb may acquire a cobblestone, irregular appearance. In its most extreme manifestations, this is referred to as “elephantiasis,” because the affected limb begins to resemble the leg of an elephant.9 Although commonly occurring in patients with chronic venous disease or other vasculocutaneous abnormalities, there is also an increased tendency for traumatic or erosive skin damage in patients with lymphedema, which can produce non-healing lesions.10 Patients may “weep” clear ﬂuid through the skin; sometimes, the trauma needed to produce this is so minimal that the weeping seems to be spontaneous.11 In the worst cases, copious ﬂuid production may soak patients’ stockings and/or ﬁll their shoes or boots. Limbs affected by lymphedema are susceptible to episodes of cellulitis or lymphangitis, usually caused by Gram-positive cocci such as Streptococcus.12 A crucial part of the clinical evaluation entails a search for occult

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Lymphedema: pathophysiology, classiﬁcation, and clinical evaluation

Figure 57.1 Positive Stemmer’s sign (a failure by the assessor to pick up or pinch a fold of skin at the base of the toe. (From Mortimer.4)

Figure 57.2 Myxedema can produce swelling and skin changes that resemble lymphedema. (From Bull et al.20)

infections or potential sites of infection. In some cases, a documented history of recurrent cellulitis will lead to intermittent or continuous prophylactic treatment with appropriate antibiotics.13 Lymphedema can produce a variety of other symptoms, and these should be sought and documented as part of the clinical evaluation.14 Although pain is relatively uncommon in patients with lymphedema, its presence can be debilitating.15 Many patients complain of heaviness due to their limb swelling and experience subsequent limitations in mobility; these impairments should be documented.16 Paresthesias and abnormal temperature sensations (typically “coldness”) are common and annoying.17 Some “symptoms” are striking; for example, the patient whose limb is so large that he or she cannot wear pants. This limitation obviously has signiﬁcant implications for employment, social interactions, etc.18 The combination of increased limb size, skin changes, weeping transudation, recurrent lymphangitis, and symptoms such as pain and limited mobility may cause disability in the most seriously affected individuals. It is essential that the clinician assesses and documents the degree of this disability, which may range from minimal to severe and debilitating.19 A ﬁnal note of caution: there are many disease entities that mimic lymphedema. For example, myxedema (associated with thyroid dysfunction) can produce swelling and skin changes that resemble classic lymphedema20 (Fig. 57.2). Another common “look-alike” is lipedema, which is caused by genetically determined

excessive subcutaneous fat deposits.21 Prolonged limb dependency, for example the dependency that follows traumatic spinal cord injury severe enough to conﬁne a patient to a wheelchair, may be erroneously assumed to be some type of post-traumatic lymphedema. Factitial edema, caused by the application of tourniquets or other methods, is rare but is occasionally seen22 (Fig. 57.3). Other conditions may also imitate lymphedema.

ETIOLOGY Lymphedema is traditionally divided into two mayor categories: primary and secondary.23 Even this simple classiﬁcation is not as straightforward as one might think. Primary lymphedema may be further subdivided into several categories. For example, congenital lymphedema typically develops within 2 years of birth.24 Some of the congenital forms are genetic and thought to be autosomal dominant (e.g., Noone–Milroy syndrome),25 while others follow non-dominant or more obscure genetic patterns. Still other types of congenital lymphedema may be associated with speciﬁc hereditary syndromes. These include chromosomal abnormalities such as Turner’s syndrome,26 Klinefelter’s syndrome, and trisomy 21, 13, or 18. Other congenital syndromes associated with lymphedema include Klippel–Trenaunay–Weber syndrome, Proteus syndrome, yellow nail syndrome,27 Maffucci’s syndrome,28 neuroﬁbromatosis, and many others.

Anatomy 631

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●

●

Figure 57.3 Factitial edema to right thigh from tourniquet.

Approximately 10% of all cases of primary lymphedema are “congenital.” However, when one considers the various entities associated with “congenital” lymphedema, it is sometimes difﬁcult to know whether the swelling is truly primary or secondary to occult pathology. For example, is primary lymphedema merely associated with Turner’s syndrome, or does Turner’s syndrome somehow cause secondary lymphedema in some patients? As more is learned about the underlying etiologies for primary lymphedema, it is possible that many forms of “primary lymphedema” will some day be explained as “secondary” to some other process. In addition to the congenital variety, there are two other forms of lymphedema that are thought to be “primary.” The ﬁrst and most common (accounting for roughly 80% of all forms of primary lymphedema) has been termed lymphedema praecox by Allen.24 This entity is deﬁned as lymphedema occurring spontaneously between the ages of 2 and 25 years, and, although it is called “spontaneous,” there are often minor events that trigger the onset, such as an insect bite, burn, etc. Although sporadic cases are most common, a few forms (i.e., Meige’s disease) are hereditary. Lymphedema tarda accounts for roughly 10% of all primary lymphedema.29 By arbitrary deﬁnition, it has its onset in those over 35 years of age. Secondary lymphedema is caused by inﬂammation or obstruction of the lymph vessels. Some of the most common causes include the following.

●

Cancer. In particular, (1) lymphoma, (2) cancer of the prostate, breast, or cervix, and (3) melanoma are frequent producers of lymphedema. However, any metastatic cancer may be responsible. Trauma. The most common type of trauma producing lymphedema is iatrogenic trauma. Radiation therapy, inadvertent disruption of lymphatics during surgical operations, lymph node resection, and other invasive therapies may damage lymphatics and produce lymphedema. Non-iatrogenic forms of trauma such as blunt or penetration injuries or burns can also damage lymphatics. Infection/inﬂammation. As noted earlier, cellulitis and lymphangitis are common in patients with preexisting lymphedema and may further damage lymph vessels. In some cases, an otherwise normal limb may develop lymphedema after a single initial episode of infection. Other inﬂammatory triggers include insect bites, rheumatoid or psoriatic arthritis,30 and a host of inﬂammatory conditions. Even diseases thought to be only minimally associated with inﬂammation, such as chronic venous disease or lipedema, may be complicated by the eventual appearance of true lymphedema. Filarial disease. By far the most common cause of lymphedema worldwide is ﬁlarial disease,31 caused by agents such as Wuchereria bancrofti or Brugia malayi and Brugia timori. The World Health Organization estimates that the number of people affected worldwide by this problem may approach one hundred million.

ANATOMY The anatomy of the lymphatic system is complex and underappreciated. An excellent review can be found in Browse et al.32 When discussing lymphatic anatomy, especially the anatomy of the limb lymph vessels, there are several ways to divide the proverbial pie. For example, lymphatics can be classiﬁed as superﬁcial or deep, with the superﬁcial system typically being more important than the deep. A distinction can also be made between distal lymph vessels (located below the inguinal region) as opposed to proximal or truncal vessels, which include the iliacs, lumbars, cisterna chyli, and thoracic duct. Similar, although more complicated, divisions exist for the lymphatics of the upper extremity. In addition, a systematic approach to lymphatic anatomy must address the various nodes through which the lymph vessels pass. An understanding of basic lymph node anatomy (e.g., recognizing that the efferent vessels leaving a node are normally larger and more tortuous than the afferent vessels entering one) is essential but beyond the scope of this short chapter. Additional information on lymphatic anatomy can be obtained elsewhere.32 Some authors have chosen to characterize lymphatics not just in terms of their location (superﬁcial versus deep,

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Lymphedema: pathophysiology, classiﬁcation, and clinical evaluation

proximal versus distal, etc.) but also in terms of their lymphangiographic appearance.29 For example, lymphatic abnormalities can be divided into four anatomical categories: aplasia, (no lymph vessels present), hypoplasia (less than a normal amount of lymph vessels present), numerical hyperplasia (more lymph vessels than normal), and hyperplasia (numerous lymph vessels, many of which are dilated and tortuous). Although this is strictly an anatomical classiﬁcation (since it is based entirely on the lymphangiographic appearance), it nonetheless has some pathophysiological and functional implications. In addition, some authorities33 question the signiﬁcance of these categories (e.g., is mild lymphatic hyperplasia a primary problem of lymph vessels or does it reﬂect a response to occult early proximal obstruction?).

actually have some occult obstruction of their lymphatics, it is reasonable to speculate that these high blood ﬂow states are accompanied by increased interstitial ﬂuid production, which subsequently leads to lymphedema.

CEAP-L FOR LYMPHEDEMA As noted earlier, it seems obvious to classify lymphedema using a similar system to that utilized for classifying venous disease. Indeed, Gasbarro and Cataldi2 have proposed modifying the existing CEAP system so that it is applicable to lymphatic diseases. Highlights of their work include: ●

Clinical classification

PATHOPHYSIOLOGY There are three major categories of lymphatic pathophysiological abnormalities, all of which can be further subdivided. These include obstruction, reﬂux, and overproduction of lymph ﬂuid. ●

●

●

Obstruction. This is the most common mechanism by which lymphedema is produced, accounting for nearly all cases of secondary lymphedema and most cases of primary lymphedema. With primary disease, the obstruction may be distal (hyperplasia or aplasia), proximal (upper limb or higher), or a combination of proximal and distal involvement. In cases of secondary obliteration by cancer, trauma, radiation therapy, ﬁlarial, etc., the obstruction may be located anywhere along the lymphatic pathway. Reﬂux. A signiﬁcant number of patients with primary lymphedema (perhaps as many as 10%) are thought to have chronic reﬂux.34 This includes patients with congenital lymphatic hyperplasia, which in its most extreme form is sometimes known as “megalymphatic” disease. Overproduction. A less common or obvious cause of lymphedema is overproduction of interstitial/lymphatic ﬂuid.35 Acutely, this can be seen with almost anything that increases capillary permeability and leads to an increase in interstitial ﬂuid production. Ambient heat, trauma, inﬂammation, and many other conditions are thought to produce lymphedema via this mechanism. Most of these underlying conditions resolve in time, and along with them so does lymphedema.

It is thought that some chronic states of lymph ﬂuid overproduction exist. While a chronically “leaky lymphatic” syndrome has been postulated, it is difﬁcult to prove its existence at this time. One exception is the lymphedematous changes seen in patients with chronic arteriovenous ﬁstula of the periphery. Although it is hard to rule out the possibility that some of these patients

This ranges from C0 to C4 (C0, normal; C1, reversible edema; C2, ﬁxed edema; C3, healed ulcer; C4, open ulcer). Perhaps in recognition that ulcers are somewhat atypical for lymphedema, the authors have created a clinical subcategory addressing the production of ﬂuid through the skin (S0, none; S1, minimal or “droplets”; S2, “wet”). It seems to this author that exudate status could be substituted for ulceration status. LYMPHANGITIS

The authors propose a subcategory describing the patient’s history of lymphangitis (L0, no episodes; L1, one to three episodes; L2, more than three episodes). SYMPTOMS

Patients can be classiﬁed as to whether they have no symptoms (asymptomatic) or speciﬁc symptoms such as pain, cramps, heavy or cold sensations, etc. (symptomatic). These patients may need to be reclassiﬁed after treatment if their symptoms are altered by effective therapy. DISABILITY

The clinical status of patients can be further categorized according to their disability (D0, none; D1, needs minimal help for activities of daily living; D2, needs regular daily help for activities of daily living; D3, needs continuous and complete help for activity of daily living). The patient’s need for support devices to control swelling could also be included as an “sd+” or “sd–” in the subscript. For example, D2sd+ or D2sd–. SKIN MORPHOLOGY

A ﬁnal clinical subcategory includes an assessment of skin morphology (S0, normal; S1, edema; S2, ﬁbrosis).

References 633

Guidelines 6.1.0 of the American Venous Forum on lymphedema: pathophysiology, classiﬁcation, and clinical evaluation No.

Guideline

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.1.1 Lymphedema is divided into two major categories: primary and secondary. Primary lymphedema may be further subdivided into three categories:

B

• Congenital lymphedema (10%) develops within 2 years of birth. Some of the congenital forms are hereditary • Lymphedema praecox (80%) occurs between the ages of 2 and 25 years. Although sporadic cases are most common, a few forms are hereditary • Lymphedema tarda (10%) has its onset in those over 35 years of age Secondary lymphedema is caused by inﬂammation or obstruction of the lymph vessels. Some of the most common causes include ﬁlariasis, cancer, trauma (mostly iatrogenic), infection/inﬂammation 6.1.2 Lymphatic abnormalities can be divided into four anatomical categories: aplasia, hypoplasia, numerical hyperplasia, and hyperplasia

B

6.1.3 There are three major categories of lymphatic pathophysiological abnormalities: obstruction, reﬂux, and overproduction of lymph ﬂuid

B

Other clinical classiﬁcation schemes also exist. Beninson36 suggests a strategy based on four elements: inspection, palpation, effect of leg elevation, and function. Beninson creates four categories ranging from grade 1 (normal inspection, normal skin with pitting edema on palpation, complete reduction of leg swelling with leg elevation, and normal function) to grade 4 (yellow, hyperpigmented, weeping keratotic, licheniﬁed, papulecovered skin on inspection; palpation revealing thick nonpitting skin; no reduction in edema with leg elevation; and serious functional loss with movement impairment). Numerous other clinical classiﬁcation schemes are possible. ●

Etiology

Gasbarro and Cataldi2 suggest dividing lymphedema into congenital (which includes the primary forms) and secondary forms. It seems logical to expand this to include separate categories for congenital, praecox, and tarda forms of primary lymphedema. ●

Anatomy

This is perhaps the most difﬁcult characteristic of lymphedema to classify. Strategies for dividing the lymphatic system into superﬁcial, deep, lateral, medial, or other components have been suggested, with complex

schemes that name the involved deep segments according to their nearby blood vessels or other structures. In addition, relatively complicated approaches for identifying the involved node groups have been outlined. Separate strategies for describing lower extremities versus upper extremities or trunk also exist. ●

Pathophysiology

A relatively simple way to describe the pathophysiology of lymphedema has been proposed (Pa, agenesis/hypoplasia; Po, obstruction; Ph, hyperplasia; Pr, reﬂux; Pov, overproduction).37 Additional reﬁnements to this scheme are possible. Finally, the authors have proposed a “gravity” score in which they assign points to various components of the CEAP score and derive an overall “severity” grade for the patient. For example, points might be assigned to the clinical grade, extent of disease, disability, and symptomatology; these can be totaled to give an overall severity score. The utility of this scoring system remains undetermined. In conclusion, a “CEAP” type approach to lymphedema could provide all the information necessary for accurate and complete classiﬁcation of the various lymphatic disorders. It would, therefore, appear that a universal “CEAP-L” system is ripe for development. At this time, proposals have been made to do this, but more input/consensus is needed in order to optimize the ﬁnal

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product. It is this author’s opinion that an international consensus committee approach, akin to that used to create the current CEAP system for venous disease,38 is needed to create a similar scheme for the classiﬁcation of lymphatic disorders.

◆18.

19. 20.

REFERENCES ◆21.

= Key primary paper ◆ = Major review article ●

●1.

●2.

3. 4. 5.

●6.

7. 8. 9. 10.

11.

◆12.

13.

14.

15.

16.

17.

Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: 635–45. Gasbarro V, Cataldi A. C.E.A.P. – L.: Proposal of a new classiﬁcation of lymphedema of the limbs. Eur J Lymphol 2004; 12: 41. Guyton AC. Human Pathophysiology and Mechanisms of Disease. Philadelphia: W.B. Saunders, 1982. Mortimer PS. The pathophysiology of lymphedema. Cancer 1998; 83: 2798–803. Witte CL, Wolfe JH. Lymphodynamics and the pathophysiology of lymphedema. In: Rutherford RB, ed. Vascular Surgery, 4th edn. Philadelphia: W.B. Saunders, 1995: 1889–98. Stemmer R. Ein klinisches Zeichen sur Früh – und Differential – Diagnose des Lymphöhdems. Vasa 1976; 5: 261–2. Watts GT. Lymphoedema (non-pitting) and simple (pitting) oedema are different. Lancet 1985; 2: 1414. Browse NL. The diagnosis and management of primary lymphedema. J Vasc Surg 1986; 3: 181–5. Schiff BL, Kern AB. Elephantiasis nostras. Cutis 1980; 25: 88. Doughty DB, Waldrop J, Ramundo J. Lower-extremity ulcers of vascular etiology. In: Bryant RA, ed. Acute and Chronic Wounds: Nursing Management. St. Louis: Mosby, 2000: 265–300. MacDonald JM. Wound healing and lymphedema: a new look at an old problem. Ostomy Wound Manage 2001; 47: 52–7. Schirger A. Lymphedema. Cardiovasc Clin 1983; 13: 293. Babb RR, Spittell JA, Martin WJ, et al. Prophylaxis of recurrent lymphangitis complicating lymphedema. JAMA 1966; 195: 871. Spittell JA, Schirger A. Edema, peripheral. In: Taylor RB, ed. Difﬁcult Diagnosis. Philadelphia: W.B. Saunders, 1985: 130–7. Woods M, Tobin M, Mortimer P. The psychological morbidity of breast cancer patients with lymphedema. Cancer Nurs 1995; 18: 467–71. Franks PJ, Moffatt CJ, Doherty DC, et al. Assessment of health-related quality of life in patients with lymphedema of the lower limb. Wound Repair Regen 2006; 14: 110–18. Kärki A, Simonen R, Mälkiä E, Selfe J. Impairments, activity limitations and participation restrictions 6 and 12 months

22.

◆23.

◆24.

●25.

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30. 31.

32.

33.

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35. 36. 37. 38.

after breast cancer operation. J Rehabil Med 2005; 37: 180–8. Smeltzer DM, Stickler GB, Schirger A. Primary lymphedema in children and adolescents: a follow-up study and review. Pediatrics 1985; 76: 206–18. Merli GL. Lymphedema. Clin Podiatry 1984; 1 (2). Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema. Lancet 1993; 341: 403–4. Wold LE, Hines EA, Allen EV. Lipoedema of the legs. Ann Intern Med 1949; 34: 1243–50. Brunning J, Gibson AG, Perry M. Factitious lymphoedema, Secretan’s syndrome. Acta Dermatol (Stockholm) 1983; 63: 271. Browse NL, Stewart G. Lymphedema: pathophysiology and classiﬁcation. J Cardiovasc Surg 1985; 26: 91–106. Allen EV. Lymphedema of the extremities. Arch Intern Med 1934; 54: 606. Milroy WF: Chronic hereditary edema: Milroy’s disease. JAMA 1928; 91: 1172. Benson PF, Gough MH, Polani PE. Lymphangiography and chromosome studies in females with lymphedema and possible ovarian dysgenesis. Arch Dis Child 1965; 40: 27. Siegelman SS, Heckman BH, Hasson J. Lymphedema, pleural effusions and yellow nails: associated immunologic deﬁciency. Dis Chest 1969; 56: 114. Carleton A, Elkington JStC, Greenﬁeld JG, Robb-Smith AH. Maffucci’s syndrome (dyschondroplasia with haemangiomata). Q J Med 1942; 11: 203–9. Kinmonth JB, Taylor GW, Tracy GD, Marsh JD. Primary lymphoedema: clinical and lymphangiographic studies of a series of 107 patients in which lower limbs were affected. Br J Surg 1957; 45: 1. Kyle VM, DeSilvia M, Hurst G. Rheumatoid lymphedema. Clin Rheumatol 1982; 1: 126. Dandapat MC, Mahapatro SK, Dash DM. Management of chronic manifestations of ﬁlariasis. J Indian Med Assoc 1986; 84: 219. Browse NL. Anatomy. In: Browse NL, Burnand KG, Mortimer PS, eds. Diseases of the Lymphatics. London: Arnold, 2003: 21–43. Browse NL. Aetiology and classiﬁcation of lymphoedema. In: Browse NL, Burnand KG, Mortimer PS, eds. Diseases of the Lymphatics. London: Arnold, 2003: 151–6. Wolfe JHN, Kinmonth JB. The prognosis of primary lymphedema of the lower limbs. Arch Surg 1981; 116: 1157. Wolfe JH. The prognosis and possible cause of sever primary lymphedema. Ann R Coll Surg Engl 1984; 66: 251–7. Beninson, J. Postmastectomy lymphedema. Lymphology 1985; 18: 54. Manson-Bahr PH, ed. Manson’s Tropical Disease, 16th edn. London: Cassell, 1966. Subcommittee on Reporting Standards in Venous Disease, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter, International Society for Cardiovascular Surgery. Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–81.

58 Lymphoscintigraphy and lymphangiography PATRICK J. PELLER, CLAIRE E. BENDER AND PETER GLOVICZKI Introduction Lymphoscintigraphy Lymphangiography

635 635 641

INTRODUCTION Imaging of the lymphatic system was revolutionized in the 1950s by the pioneering work of Kinmonth,1 who described a practical technique of direct cannulation of pedal lymphatic vessels and injection of radio-opaque contrast material to visualize pelvic and leg lymph vessels and lymph nodes. His systematic review and classiﬁcation of contrast lymphangiograms provided the basis of our understanding of lymphatic anatomy in patients with lymphedema.2 However, with the development of isotope lymphoscintigraphy, a less invasive imaging technique, the role of contrast lymphangiography has diminished in the evaluation of patients with lymphedema but there remain several situations in which contrast lymphography has distinct advantages, and, when required, the anatomic resolution of this technique is unparalleled. Later in this chapter we will discuss current indications for, and technique of, contrast lymphangiography.

LYMPHOSCINTIGRAPHY Lymphoscintigraphy, broadly described as an assessment of the lymphatic clearance of injected radioactive particles, was also developed in the 1950s. Because it is less invasive, easier to perform, and associated with fewer complications, lymphoscintigraphy has largely replaced contrast lymphangiography in the evaluation of lymphatic system. With newer imaging equipment and modern radiolabeled tracers, normal and pathologic lymphatic function can be accurately determined, and a great deal of anatomic information can also be obtained. Recently, lymphoscintigraphic techniques have been most commonly employed for the delineation of lymphatic drainage and potential nodal metastasis from a variety of neoplastic

Conclusions References

645 647

lesions. Magnetic resonance lymphangiography is a new, and also promising, imaging modality of the lymphatic system.

History of lymphoscintigraphy Sherman and Ter-Pogossian3 ﬁrst reported the transport of radioactive colloids by the lymphatic system in 1953. They utilized colloidal gold (198Au) in experiments, hoping to deliver tumoricidal doses of beta irradiation to regional lymph nodes as a treatment for metastatic cancer. Sherman and Ter-Pogossian performed autoradiographs of the regional lymph nodes, demonstrating the potential of this technique for lymphatic imaging. The same year, Jepson et al.4 demonstrated the feasibility of using plasma protein radiolabeled with 131I in the evaluation of lymphatic transport. They found slower clearance of interstitial protein via the lymphatic system than crystalloid 131I via the capillary network. In 1957, Taylor et al.5 showed delayed transport of radiolabeled protein from the subcutaneous injection site in patients with lymphedema compared with normal subjects. Although many lessons regarding the physical properties and rate of lymphatic transport of colloidal materials were gleaned from these early studies, it became evident that highenergy irradiation emitters are not appropriate for use in diagnostic imaging. The development of 99mTc-labeled radiocolloids and macromolecules, however, has made lymphoscintigraphy a safe and practical technique.

Technique of lymphoscintigraphy Selection of an appropriate radiolabeled macromolecule or colloidal material is key to high-quality imaging.

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Characteristics such as particle size and surface charge affect the biokinetic behavior of subcutaneously injected materials. Particles greater than 10 nm in diameter are transported by the lymphatics, whereas smaller particles are transported via the capillary network. Lymphatic transport time is directly related to particle size, and particles over 100 nm in size are transported very slowly. Optimal size for the delineation of lymphatic vessels and nodes in extremity lymphoscintigraphy is between 10 and 40 nm.6 The initial experience at the Mayo Clinic was with 99mTc–antimony trisulﬁde colloid, but for the past decade this compound has not been available in the USA. Currently, ﬁltered 99mTc–sulfur colloid (Tc-fSC) is the radiopharmaceutical most commonly used for lymphoscintigraphy in the USA. When Tc-fSC is passed through a 0.1 μm ﬁlter it yields a stable particle with a mean diameter of 38 nm, and 90% of the particles are less than 50 nm.7 Clinical and research studies have demonstrated that Tc-fSC produces similar results to earlier agents.8 Exercise is known to inﬂuence the rate of lymphatic transport, and therefore must be standardized during the performance of lymphoscintigraphy.9 Patients are comfortably positioned supine on the imaging table. For studies of the lower extremities, the feet are attached to a foot ergometer, and the patient is instructed in its use. For upper extremity studies, the patients are given a squeezable ball which is compressed during the study. For studies of a lymphedematous extremity, subcutaneous injection of the radiolabeled tracer utilizing a tuberculin syringe and 27 gauge needle is performed into the web space between the second and third digits of the hand or foot. A topical anesthetic is often applied to the skin 15–20 minutes prior to injection. The volume of the

injection is kept between 0.1 and 0.2 mL, which is associated with a brief period of discomfort at the injection site but is otherwise tolerated extremely well. We use 15–18 MBq (400–500 μCi) of Tc-fSC. Over 3 hours, 10–20% of the injected activity is transported from the injection site using these compounds. A gamma camera with a large ﬁeld of view is positioned immediately following injection of the tracer to include the groin region in the upper ﬁeld of view. An all-purpose collimator is used, and a 20% window is placed symmetrically around the 140 keV photopeak of the 99mTc isotope. Dynamic anterior images are obtained every 5 minutes during the ﬁrst hour (Fig. 58.1). Exercise using the foot ergometer or plastic ball is begun immediately following injection of the tracer compound. The patient is requested to exercise for 5 minutes initially and then for 1 minute out of every 5 for the remainder of the ﬁrst hour while dynamic images are obtained. Total body images over 20 minutes are obtained after 1 and 3 hours following the injection (Fig. 58.2). Patients are encouraged to ambulate between these images, although the degree of exercise is no longer standardized at this point in the study. In selected patients with delayed lymphatic transport, total body images may also be obtained at 6 and 24 hours to further delineate the degree of lymphatic obstruction.

Mapping of lymphatic drainage in neoplastic disease The primary focus of this chapter is on the evaluation of the extremity with lymphedema. However, injection of

Figure 58.1 Dynamic anterior images obtained every 5 minutes for 60 minutes following tracer injection in both feet. This 57 year old man with intermittent bilateral leg swelling had prompt, normal lymphatic transport, with activity appearing in the groin nodes within 15 minutes.

Lymphoscintigraphy 637

Tc-fSC to detect nodal drainage from the area of a tumor has become the primary clinical application of lymphoscintigraphic techniques. The potential for detection and treatment of lymph nodes draining a neoplasm was appreciated in the earliest days of lymphoscintigraphy, and later conﬁrmed in the 1970s.10,11 The clinical application of lymphoscintigraphy to identify and assist in sentinel node biopsy grew rapidly in the 1990s.12–15 Lymphatic mapping is commonly being utilized in a growing number of cancers, including those affecting the skin, breast, head and neck, vulva, and penis.15–19 The sentinel lymph node is the ﬁrst lymph node that ﬁlters lymph draining from the tumor site. Lymphatic drainage varies greatly in each individual. Lymphoscintigraphy maps the drainage pattern in each patient. The Tc-fSC particles injected adjacent to the tumor site are trapped in the sentinel node. Preoperative lymphoscintigraphy is valuable to identify lymphatic drainage and sentinel node location. A hand-held gamma probe is then used intraoperatively to identify the lymph nodes where radioactivity has accumulated. Tracer injections in the dermis, subcutaneous tissue, and peritumor locations have all been used with reasonable results. Most reports have agreed that a combination of radioactive tracer with a visible dye (isosulfan blue) has yielded the best results. Investigators have reported identiﬁcation of a sentinel node in well over 90% of patients. The utility and longterm impact of sentinel node mapping and examination in the management of melanoma and breast cancer is well established, but is beyond the scope of this chapter.20–23

Interpretation of lymphoscintigraphy Before any diagnostic information is derived from a lymphoscintigraphic study, the images can be used to insure proper injection technique. The liver should not be visualized over the ﬁrst 10–15 minutes of the study, and should only be faintly visible after 1 hour. Early visualization of the liver without activity in the regional or abdominal lymph nodes is suggestive of intravenous injection of the tracer compound, which may cloud interpretation of the study. Once proper technique is conﬁrmed, lymphatic function can be assessed quantitatively by the appearance of radioactivity in the regional lymph nodes during dynamic imaging, or qualitatively using the visual scintigraphic images. A

Figure 58.2 Anterior total body lymphoscintigram 1 hour after injection of tracer. This 54 year old woman was admitted with a 19 year history of bilateral lower extremity swelling. Lymph vessels, nodes, and transport kinetics appear normal. There are several collateral lymph channels at the right popliteal region. The activity in the left supraclavicular region is within the thoracic duct.

638

Lymphoscintigraphy and lymphangiography

combination of these techniques employs the visual images to derive a lymphatic transport index, a modiﬁcation of the scoring system initially described by Kleinhans et al.24 The transport index is a scoring system for the lymphoscintigraphic images that can range from near 0 in normal scans to a maximum of 45 in scans demonstrating the absence of lymphatic transport.24 The components of the score and criteria for scoring the studies are depicted in Fig. 58.3. By examining the images, information on the appearance tracer in the regional nodes, location and number of lymphatic channels and nodes, and distribution pattern of tracer can be scored and tabulated. This semiquantitative score is most useful for comparing serial scans in an individual patient, or comparison of lymphatic function between patients. A prospective evaluation of 386 extremities using the transport index demonstrated that asymptomatic extremities (n = 79) had an average transport index of 2.6, while lymphedematous extremities (n = 124) had a mean index of 23.8.25 In this series, a transport index of greater than 5 was highly suggestive of lymphedema (sensitivity, 80%; speciﬁcity, 94%). Unfortunately, the transport index was unable to distinguish those extremities with primary lymphedema from those with secondary lymphedema. This is not surprising since the lymphatic anatomy in the end stages of these disorders can be quite similar. However, lymphoscintigraphy allowed exclusion of lymphatic pathology as a cause for extremity swelling in one-third of patients. Several reports have noted the accuracy of lymphoscintigraphy using a variety of tracer compounds and interpretation methods. Stewart et al.26 reported very high

sensitivity and speciﬁcity rates using visual interpretation of lymphoscintigraphic images alone. These ﬁndings are supported by others.27,28 However, some authors have recommended the use of time–activity curves obtained with dynamic imaging over the regional lymph nodes for the analysis of lymphatic function.29–31 Weissleder and Weissleder9 reported an improvement in sensitivity of the examination when quantitative clearance data were used. Experience with quantitative analysis of regional lymph node tracer accumulation has demonstrated a great deal of variability in normal extremities, making interpretation of these data difﬁcult.32 Therefore, we have come to rely heavily on the visual interpretation of the lymphoscintigraphic images for a given study, and use the semiquantitative transport index as described above to compare serial examinations or studies in different patients.

Lymphoscintigraphic patterns in normal and swollen extremities In normal lymphoscintigrams the areas of highest tracer activity usually remain at the injection site. As mentioned previously, only 10–20% of the injected activity is normally transported from the injection site over the period of the study. In the case of the lower extremity, this intense area of activity overshadows any anatomic detail in the area of the foot. Gradual ascent of the tracer from the foot occurs, and, with normal transit, activity is detected in the inguinal lymph nodes on the dynamic images between 15 and 60 minutes from the time of injection. Appearance of signiﬁcant activity in the groin in less than 15 minutes

Patient’s initials Date

Clinic number LYMPHOSCINTIGRAPHY DATE EVALUATION Arms

Legs

Image

1 hour L R

3 hour L R

6 hour L R

24 hour L R

Lymph transport kinetics: 0⫽no delay, 1 ⫽ rapid, 3 ⫽ low-grade delay, 5 ⫽ extreme delay, 9⫽ no transport Distribution pattern: 0⫽ normal, 2 ⫽ focal abnormal tracer, 3 ⫽ partial dermal, 5 ⫽ diffuse dermal, 9 ⫽no transport Lymph node appearance time: Minutes Assessment of lymph nodes: 0 ⫽clearly seen, 3⫽faint, 5⫽ hardly seen, 9 ⫽no visualization Assessment of lymph vessels: 0 ⫽clearly seen, 3 ⫽ faint, 5⫽hardly seen, 9 ⫽ no visualization Abnormal sites of tracer accumulation (describe)

Figure 58.3 Evaluation form for calculation of lymphatic transport index.

Lymphoscintigraphy 639

Figure 58.4 Dynamic anterior images obtained every 5 minutes for 60 minutes following tracer injection in both feet. Normal lymphatic transport and image pattern of the inguinal nodes on the right, no visualization of the lymphatics of the left. This 26 year old woman had primary lymphedema of the left leg.

indicates rapid transport, and absence of activity after 1 hour is suggestive of delayed lymphatic transport (Fig. 58.4). On the total body images, several lymphatic channels may be seen in the area of the calf, but in the thigh the lymphatics run close together on the medial aspect. Separate activity in each of the channels is seldom seen. With normal transit times, the inguinal nodes should be clearly visualized 1 hour following injection, and faint visualization of the para-aortic nodes, liver, and bladder may be seen (Fig. 58.2). On the 3 hour image, the uptake in the pelvic and abdominal nodes and liver should be intense (Fig. 58.5), and occasionally the area of the distal thoracic duct in the left supraclavicular fossa will be visible. In lymphedematous extremities, several lymphoscintigraphic patterns may be observed either alone or in combination.33 These can be broadly classiﬁed as follows. 1. Delay or absence of lymphatic transport from the injection site. Little or no activity is detected in the regional lymph nodes by 1 hour following injection. In the extreme circumstance, no transport of activity from the foot can be detected. 2. Collateral channels or a cutaneous pattern consistent with dermal backﬂow may be seen in the extremity. These ﬁnding are suggestive of obstruction of lymphatic vessels in the extremity, with lymphatic ﬂow either ﬁnding new channels around the obstruction or backﬁlling the rich dermal lymphatic network (Fig. 58.6). 3. Reduced, faint, or no uptake in the lymph nodes of the groin, pelvis or para-aortic regions, indicating a localized area of lymphatic obstruction at the level of

the regional lymph nodes (Fig. 58.6). Although this pattern may be seen in primary lymphedema, it is more suggestive of secondary disease following lymph node dissection or radiation for neoplastic disease. 4. Abnormal tracer accumulation suggestive of extravasation, lymphocele, or lymphangiectasia (Fig. 58.7). These types of accumulation can be seen in a wide variety of lymphatic pathology ranging from direct trauma to the lymphatic vessels following surgery to extravasation of lymphatic ﬂuid into body cavities (chylous ascites or chylothorax) or reﬂux of chyle to the skin (lymphorrhea). Scintigraphic ﬁndings in these disorders rarely yield enough anatomic detail to pinpoint the site of lymphatic leak, however, and contrast lymphangiography may be helpful in this regard. Lymphoscintigraphy can be used to monitor the effects of therapeutic intervention or the progression of lymphedema over time. In one study, over 80% of extremities demonstrated an improvement in lymphoscintigraphic ﬁndings following a regimen of complex physical therapy and compression.34 Similarly, alterations in lymph ﬂow with the application of either hot or cold compresses can be measured with lymphoscintigraphy.35 The Mayo Clinic transport index (Fig. 58.3) has correlated well with the degree of symptoms on repeated examination in several patients. Lymphoscintigraphy has become quite useful in the evaluation of patients considered for direct lymphatic reconstruction. In the ideal patient (secondary lymphedema due to obstruction at the groin or axillary level) lymphoscintigraphy can identify dilated lymphatics

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in the involved extremity with sufﬁcient accuracy to proceed with surgical exploration on the basis of these ﬁndings.32 In addition, this study is suitable to follow the effectiveness of some lymphatic reconstructions. While patency of lymphovenous anastomoses cannot be directly demonstrated,36 the study can image patent suprapubic or axillary lymphatic grafts placed for unilateral lymphatic obstruction (Fig. 58.8).24 Lymphoscintigraphic ﬁndings in extremities with venous disease vary depending on the duration and extent of venous pathology. Early in the course of venous disease, before extensive edema formation or the development of lipodermatosclerosis, the lymphatic system is normal and the lymphoscintigraphic appearance will reﬂect this. An increase in lymphatic transport (rapid transit) develops as capillary ﬁltration and edema in the extremity increases. This was noted in early studies of lymphatic ﬂow with 131Ilabeled albumin37 and has been conﬁrmed in both animal models38 and humans.26 The increase in lymphatic transport occurs as a homeostatic mechanism where the lymphatic system attempts to reduce the increased tissue ﬂuid. Others have demonstrated a decrease in lymphatic transport associated with venous pathology.9,31,39 Lymphatic vessels are damaged in areas of extensive lipodermatosclerosis that accompanies advanced venous disease, leading to delayed lymphatic transport and exacerbation of edema in the extremity. In a prospective series in which 31 patients had evidence of deep venous insufﬁciency, four of these (13%) had rapid transport, nine (29%) had normal lymphatic transport, and 18 (58%) had delayed transport.25

Summary Lymphoscintigraphy has become the test of choice in patients with suspected lymphedema. Unlike contrast lymphangiography, it is non-invasive, well tolerated, and associated with very few complications. When necessary, it can be repeated serially to follow the clinical course of lymphatic function. Although initially developed as a functional study, newer imaging techniques and equipment can yield a great deal of anatomic information, which in certain cases may be sufﬁcient for direct surgical intervention on the lymphatic system. While diagnostic accuracy utilizing several methods of interpretation has been reported, we have come to rely largely on visual interpretation of scintigraphic images. When necessary, a simple scoring system can be applied to derive a lymphatic

Figure 58.5 Anterior total body image 3 hours after injection in a 75 year old man with a 5 year history of left leg swelling (primary lymphedema). There is a localized area of dermal distribution in the left calf with a diminished number of lymph nodes in left inguinal region.

Lymphangiography 641

transport index, which can then be used to compare individual scintigraphic studies with one another. Most recently, lymphoscintigraphy is used frequently for the mapping of lymphatic drainage and sentinel node localization in a variety of neoplasms.

LYMPHANGIOGRAPHY In 1943, Servelle performed the ﬁrst contrast lymphangiogram. Nearly a decade later, Kinmonth1 described the basic technique of the subcutaneous injection of a vital dye for identiﬁcation of superﬁcial dorsal foot lymphatics for cannulation and direct injection of contrast material. Almost 50 years later, there have been modiﬁcations only in the injected contrast agents and the radiographic ﬁlming of the examination. The continued development and reﬁnement of crosssectional imaging techniques (computed tomography, magnetic resonance imaging, and ultrasonography) and isotope lymphoscintigraphy have seen a reduced need for diagnostic lymphangiography. Although lymphangiography is a time-consuming and technically challenging radiologic procedure, it provides a highly detailed examination of both the lymphatic vessels and nodes.

Technique of lymphangiography Lymphangiography is an outpatient procedure. The patient is instructed not to eat or drink 8 hours prior to the examination. Medications and clear liquids are permitted. Conscious sedation may be given if the patient is anxious or unable to remain quiet for 30–60 minutes. The patient is placed supine on a padded radiographic ﬂuoroscopic table. The lymphatic channels must ﬁrst be visualized so that they can then be cannulated during lymphaniography. A variety of blue dyes have been used for opaciﬁcation of lymphatic channels, including methylene blue, patent blue violet, and isosulfan blue (Lymphazurin 1%; Hirsch Industries, Cherry Hill, NJ, USA). Lymph vessels are identiﬁed as thin walled in contrast to the thicker walls of nearby veins. Ninety percent of isosulfan blue is excreted via the biliary tract and the remaining 10% is excreted in the urine. The urine can be discolored for a few days. In patients with allergy to blue dyes, ﬂuorescein can be used to localize the lymph vessels, but is less intense than the traditional blue dyes.

Figure 58.6 Anterior total body image 6 hours after injection in a 25 year old woman with congenital primary lymphedema of both lower extremities and intestinal lymphangiectasias. Note the absence of lymph vessels and minimal lymph node activity at 6 hours, with only mild dermal backﬂow visible in the distal calves.

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Lymphoscintigraphy and lymphangiography

(b)

(a)

Figure 58.7 (a) Lymphoscintigram of an 18 year old man with lymphangiectasia, protein-losing enteropathy, and chylous ascites. Note large leg lymphatics and reﬂux of colloid into the mesenteric lymph vessels, ﬁlling almost the entire abdominal cavity. (b) Lymphangiogram of the same patient reveals reﬂux of dye into the dilated mesenteric lymphatics. (c) Note extremely dilated and tortuous but patent thoracic duct. (From Gloviczki and Wahner.33)

(c)

Lymphangiography 643

In this initial phase, the skin between each toe is cleaned with alcohol and 0.5 mL of lidocaine is injected intracutaneously in each web.40 This is followed with injection of 0.5 mL of isosulfan blue (Lymphazurin 1%). Some authors have mixed the solutions for a single injection in each web. The patient is then instructed to actively ﬂex and extend the toes and ankles until optimal visualization has occurred. The hair on the dorsum of the foot is shaved if necessary. The site for blue dye injection to visualize deep lymphatics of the leg is the sole of the foot, close to the abductor hallicus muscle. For lymphangiography of the arm, the dorsum of the hand, between the ﬁngers, is injected, and for cervical lymphangiography the site of injection is behind the ears. Striking blue streaks through the skin are visualized lymphatic channels. They may be difﬁcult to identify in dark-skinned patients. Sterile drapes are placed around both feet providing a large working surface for the examiners. A large lymphatic channel on the dorsum of the foot that is oriented in a direction which will accept easy cannulation and subsequent tubing ﬁxation is selected for cannulation. This channel is often located on the mid-dorsum of the foot, but, occasionally, a more proximal channel near the ankle is optimal. Using a cut-down technique, lidocaine 1% without epinephrine is generously injected into the subcutaneous tissues surrounding the blue lymphatic channel. The purpose of this liberal local anesthetic injection is to obtain a pain-free environment as well as to facilitate the delicate procedure of removal of perilymphatic adipose and other tissue. Lidocaine may also have an antispasmodic effect on the small lymphatic channel. A 2 cm vertical or transverse incision is made over the lymph vessel and blunt dissection is performed until the channel is located. A thin 3 × 1 cm malleable metallic wedge is then slipped under the vessel, which is further cleaned of any adjacent fat or ﬁbrous tissue. At both the proximal and distal ends of the exposed vessel, a 5-0 silk tie is gently positioned for further use. Next the proximal tie (toward the ankle) is taped with a Steri-strip. This tie is put under slight tension in order to distend the lymph vessel. The more distal tie can be used as a repair for leaks, but the needle must pass through the tie. We use either a 27 or 30 gauge lymphangiography needle based on the diameter of the visualized lymphatic vessel. The needle tip is held nearly parallel to the lymphatic channel for cannulation. The needle can be gently test injected with sterile saline to check position.

Figure 58.8 A 52 year old man with secondary lymphedema of the left lower extremity who underwent suprapubic lymphatic grafting 5 years previously. The arrow indicates a patent lymphatic graft. Note that injection of the colloid was made into the left foot and that the suprapubic graft ﬁlls the right inguinal lymph nodes.

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Once in position, a Steri-strip is used to secure the needle or the dorsum of the foot. The proximal tie is then released to allow ﬂow; it can be moved just proximal to the bevel of the needle and tightened for a better seal. The tubing of the needle can be draped between the appropriate toes and then taped to the skin. A Harvard infusion pump apparatus (Bard Medsystems, North Reading, MA, USA) is used to inject the heated contrast material at 0.10–0.15 mL per minute for a total of 5–7 mL per leg without leakage. The iodinated contrast material used for lymphangiography is Ethiodol (iodinated ethyl esters of fatty acids of poppyseed oil; Savage Laboratories, Missouri City, TX, USA). Almost 90% of the contrast material is retained by the lymph nodes and the remainder ﬂows into the thoracic duct entering the pulmonary bed. In patients with diminished pulmonary function, this may lead to further pulmonary compromise. If unsuccessful on one side, overﬁlling of the infused side using 10–12 mL can cross-ﬁll at the bilateral paraaortic lymph node level. After 1–2 mL of injection, brief ﬂuoroscopy or a radiograph is taken to conﬁrm lymphatic ﬁlling. Patients can experience leg cramping as contrast material ascends in the lower leg. After the injection, both incisions are washed with sterile saline. Single or double vertical mattress polypropylene sutures are used to close the incision. Antimicrobial ointment and a small dressing are applied. Sutures should be removed in 10 days. The standard series of radiographs obtained immediately after the procedure (for vessel evaluation) and at 24 hours (for node architecture and location) include: ● ●

●

(a)

pelvic: anteroposterior, lateral, both obliques lumbosacral spine: anteroposterior, lateral, both obliques chest: posteroanterior, lateral.

Radiographic spot ﬁlms are useful to identify sites of extravasation in the trunk, chest, or limbs. Early, frequent ﬂuoroscopic observation can assist in localization of leaks. Extremity ﬁlms are taken in addition if the test is being performed for lymphedema.

Interpretation of lymphangiography Complete evaluation of a lymphangiogram includes interpretation of the channel (immediate) and nodal (24 hours) phases of the study as well as any spot ﬁlms taken (Fig. 58.9). The lymphatic channels are evaluated for size, number, obstruction, or metastatic involvement. The lymph nodes are individually evaluated for size, number, contour, and internal architecture. Ethiodol usually clears from the lymphatic vessels within 3–4 hours. Delayed emptying occurs in proximal obstruction. Extravasation into the perilymphatic tissues

(b) Figure 58.9 (a,b) Normal lymphatic anatomy demonstrated by bipedal contrast lymphangiography.

Conclusions 645

can occur in lymphatic obstruction or too rapid infusion rates. The appearance of the lymph nodes depends on (1) the degree of opaciﬁcation and (2) histology. Contrast material is located within the sinuses. A normal lymph node appears as a sharply deﬁned round or oval density with a ﬁne, homogeneous, and granular appearance. From the hilus of the node, efferent lymphatic channels emanate centrally.

in those patients who are candidates for microvascular lymphatic reconstruction. It is very helpful in the evaluation of patients with lymphangiectasia and reﬂux of chyle. The details of extent and location of the dilated ducts are much better delineated with contrast lymphangiography than with lymphoscintigraphy (Fig. 58.7). Obstruction of the thoracic duct and localization of pelvic, abdominal, or thoracic lymphatic ﬁstulae is best studied by lymphangiography.

Complications of lymphangiography

Contraindications for lymphangiography

Lymphangiography is relatively safe as long as patients are carefully selected and standard precautions are taken.41 Complications are classiﬁed as follows:

Careful selection of patients and routine precautions are the keys to the success of this invasive procedure. Patients with prior history of signiﬁcant contrast reactions, pulmonary disease, or intracardiac or intrapulmonary shunts should be excluded. Lymphangiography should not be performed in patients undergoing pulmonary radiation therapy. It should not be performed in patients with possible extensive lymphatic obstruction (e.g., bulky pelvic or retroperitoneal adenopathy). Recently, magnetic resonance lymphangiography has been introduced as a non-invasive technique to better evaluate the thoracic duct and superﬁcial and deep lymphatic channels in patients with focal or diffuse vascular diseases or swelling of extremities. Using a heavily T2-weighted fast spin-echo sequence and a maximumintensity projection algorithm, this modality can obtain further information about various vascular anomalies which may be useful in current and future therapeutic applications. Both axial and off-axial evaluation of lymphatic channels in conjunction with magnetic resonance venography can help differentiate lymphatics from veins.48

● ● ● ● ● ● ●

idiosyncratic reactions to blue dyes and Ethiodol pulmonary complications central nervous system embolization of oily contrast local wound complications accidental intravenous injection of Ethiodol post-lymphography pyrexia progression of lymphedema.

Mild or anaphylactic reactions to either the blue dyes or Ethiodol are rare (less than 1%). Life support measures, however, must be available in the procedure room. Delayed reactions within a few hours can also occur. Weg and Harkleroad42 have detected modest decreases in total lung diffusion and capillary volume after lymphangiography in patients without pre-existing lung disease. The severity of pulmonary complications is related to preexisting pulmonary disease and larger volumes (> 20 mL) of Ethiodol. Extremely rare cases of hemoptysis, pulmonary infarction, and respiratory distress syndrome have been reported.43,44 Pulmonary embolization of Ethiodol has been reported by Bron et al.45 in 55% of patients. However, clinically signiﬁcant pulmonary complications were observed by Hessel et al.46 in only 0.4% of patients. If lymphangiography must be performed in patients with pulmonary disease, a single-extremity study using 4–5 mL of Ethiodol can be offered. The overall mortality rate reported by Hessel et al.46 is 0.01%. Clouse et al.47 have described mild to moderate fevers in 5% of patients in their series of 108 procedures. Worsening of the chronic obstructive lymphedema after contrast lymphangiography has also been reported.33

Indications for lymphangiography The current uses of lymphangiography are small in number. Lymphoscintigraphy is our examination of choice for routine evaluation of lymphedema. Contrast lymphangiography is rarely and selectively used for the diagnosis of lymphedema (Fig. 58.10a,b).33 It can be useful

CONCLUSIONS Lymphoscintigraphy has become the test of choice in patients with suspected lymphedema. Since lymphoscintigraphy is non-invasive and well tolerated, it can be repeated serially to follow the clinical course of patients with lymphatic dysfunction. Newer lymphoscintigraphy imaging techniques and equipment can provide sufﬁcient anatomic information for direct surgical intervention on the lymphatic system, especially for directing sentinel node biopsy. The authors rely largely on qualitative interpretation of scintigraphic images. A simple scoring system to derive a lymphatic transport index can be employed to compare scintigraphic studies with document response to treatment. Contrast lymphangiography should be used very selectively in patients with lymphedema. It provides useful information, however, in the evaluation of patients with lymphangiectasia, with abdominal or thoracic lymphatic ﬁstulae, or in patients with anomalies of the thoracic duct.

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Lymphoscintigraphy and lymphangiography

(b)

(a)

Figure 58.10 (a) Lymphoscintigram of a 43 year old woman with left lower extremity lymphedema following hysterectomy and bilateral iliac node dissection for cervical cancer. Dermal pattern is seen on the left with no visualization of the inguinal nodes. Transport was mildly delayed in the clinically asymptomatic right limb. Note the lack of visualization of iliac nodes bilaterally. (b) Contrast lymphangiography in the same patient conﬁrms the lymphoscintigraphic ﬁndings. Few small lymph vessels and two small nodes are seen only in the thigh. (From Gloviczki and Wahner.33)

References 647

Guidelines 6.2.0 of the American Venous Forum on lymphoscintigraphy and lymphangiography No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.2.1 We recommend lymphoscintigraphy for the initial evaluation of patients with lymphedema

1

B

6.2.2 We suggest lymphoscintigraphy, using visual interpretation of the images with a semiquantitative scoring index, to document response to treatment of lymphedema

2

B

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline

●11.

● ◆

●1.

2.

3.

4.

●5.

6.

7.

◆8.

●9.

10.

Kinmonth JB. Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci 1952; 11: 13–20. Kinmonth JB, Taylor GW, Tracy GD, Marsh JD. Primary lymphedema. Clinical and lymphangiographic studies of a series of 107 patients in which the lower limbs were affected. Br J Surg 1957; 45: 1–10. Sherman AI, Ter-Pogossian M. Lymph node concentration of radioactive colloidal gold following interstitial injection. Cancer 1953; 6: 1238–40. Jepson RP, Simeone FA, Dobyns BM. Removal from skin of plasma protein labelled with radioactive plasma protein. Am J Physiol 1953; 175: 443–8. Taylor GW, Kinmonth JB, Rollinson E, et al. Lymphatic circulation studied with radioactive plasma protein. BMJ 1957; 1: 133–7. Bergqvist L, Strand SE, Persson BRR. Particle sizing and biokinetics of interstitial lymphoscintigraphic agents. Semin Nucl Med 1983; 13: 9–19. Hung JC, Wiseman GA, Wahner HW, et al. Filtered technetium-99m-sulfur colloid evaluated for lymphoscintigraphy. J Nucl Med. 1995; 36: 1895. Szuba A, Shin WS, Strauss HW, Rockson S. The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. J Nucl Med 2003; 44: 43. Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients. Radiology 1988; 167: 729–35. Fee HJ, Robinson DS, Sample WF, et al. The determination of lymph shed by colloidal gold scanning in patients with malignant melanoma: a preliminary study. Surgery 1978; 84: 626–32.

12.

★13.

●14.

15.

16.

17.

18.

19.

◆20.

Meyer CM, Lecklitner ML, Logic JR, et al. Technetium-99m sulfur colloid cutaneous lymphoscintigraphy in the management of truncal melanoma. Radiology 1979; 131: 205–9. Morton DL, Wen DR, Cochran AJ. Management of earlystage melanoma by intraoperative lymphatic mapping and selective lymphadenectomy: an alternative to routine elective lymphadenectomy or “watch and wait”. Surg Oncol Clin North Am 1992; 1: 247–59. Cox CE, Pendas S, Cox JM, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998; 227: 645–53. Krag D, Weaver D, Ashikaga T, et al. The sentinel mode in breast cancer: a multicenter validation study. N Engl J Med 1998; 339: 941–6. Burak WE, Walker MJ, Yee LD, et al. Routine preoperative lymphoscintigraphy is not necessary prior to sentinel node biopsy for breast cancer. Am J Surg 1999; 177: 445–9. Kelemen PR, Essner R, Foshag LJ, Morton DL. Lymphatic mapping and sentinel lymphadenectomy after wide local excision of primary melanoma. J Am Coll Surg 1999; 189: 247–52. Vigili MG, Tartaglione G, Rahimi S, et al. Lymphoscintigraphy and radioguided sentinel node biopsy in oral cavity squamous cell carcinoma: same day protocol. Eur Arch Otorhinolaryngol 2007; 264: 163–7. Martinez-Palones JM, Perez-Benavente MA, Gil-Moreno A, et al. Comparison of recurrence after vulvectomy and lymphadenectomy with and without sentinel node biopsy in early stage vulvar cancer. Gynecol Oncol 2006; 103: 865–70. Kroon BK, Horenblas S, Meinhardt W, et al. Dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience. Eur Urol 2005; 47: 601–6. Uren RF, Thompson JF, Howman-Giles R, Chung DK. The role of lymphoscintigraphy in the detection of lymph node drainage in melanoma. Surg Oncol Clin North Am 2006; 15: 285–300.

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21. Uren RF, Howman-Giles R, Chung DK, et al. The reproducibility in routine clinical practice of sentinel lymph node identiﬁcation by pre-operative lymphoscintigraphy in patients with cutaneous melanoma. Ann Surg Oncol 2007; 14: 899–905. 22. Estourgie SH, Nieweg OE, Olmos RA, et al. Lymphatic drainage patterns from the breast. Ann Surg 2004; 239: 232–7. 23. Gentilini O, Triﬁro G, Soteldo J, et al. Sentinel lymph node biopsy in multicentric breast cancer. The experience of the European Institute of Oncology. Eur J Surg Oncol 2006; 32: 507–10. 24. Kleinhans E, Baumeister RGH, Hahn D, et al. Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 1985; 10: 349–52. ●25. Cambria RA, Gloviczki P, Naessens JM, Wahner HW. Noninvasive evaluation of the swollen extremity with lymphoscintigraphy: a prospective semiquantitative analysis in 386 extremities. J Vasc Surg 1993; 18: 773–82. ●26. Stewart G, Gaunt JI, Croft DN, Browse NL. Isotope lymphography: a new method of investigating the role of the lymphatics in chronic limb oedema. Br J Surg 1985; 72: 906–9. 27. Golueke PJ, Montgomery RA, Petronis JD, et al. Lymphoscintigraphy to conﬁrm the clinical diagnosis of lymphedema. J Vasc Surg 1989; 10: 306–12. 28. Richards TB, McBiles M, Collins PS. An easy method for the diagnosis of lymphedema. Ann Vasc Surg 1990; 4: 255–9. 29. Ohtake E, Matsui K. Lymphoscintigraphy in patients with lymphedema. Clin Nucl Med 1986; 11: 474–8. 30. Carena M, Campini R, Zelaschi G, et al. Quantitative lymphoscintigraphy. Eur J Nucl Med 1988; 14: 88–92. 31. Rijke AM, Croft BY, Johnson RA, et al. Lymphoscintigraphy and lymphedema of the lower extremities. J Nucl Med 1990; 31: 990–8. ●32. Vaqueiro M, Gloviczki P, Fisher J, et al. Lymphoscintigraphy in lymphedema: an aid to microsurgery J Nucl Med 1986; 27: 1125–30. 33. Gloviczki P, Wahner HW. Clinical diagnosis and evaluation of lymphedema. In: Rutherford RB, ed. Vascular Surgery. Philadelphia: W.B. Saunders, 1995: 1899–920.

34. Hwang JH, Kwon JY, Lee KW, et al. Changes in lymphatic function after complex physical therapy. Lymphology 1999; 32: 15–21. 35. Meeusen R, van der Veen P, Joos E, et al. The inﬂuence of cold and compression on lymph ﬂow at the ankle. Clin J Sport Med 1998; 8: 266–71. ●36. Gloviczki P, Fisher J, Hollier LH, et al. Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 1988; 7: 647–52. 37. Hollander W, Reilley P, Burrows BA. Lymphatic ﬂow in human subjects as indicated by the disappearance of I131labelled albumin from the subcutaneous tissue. J Clin Invest 1961; 40: 222–33. 38. Szabo G, Magyar Z, Papp M. Correlation between capillary ﬁltration and lymph ﬂow in venous congestion. Acta Med Hung 1963; 19: 185–9. 39. Larcos G, Wahner HW. Lymphoscintigraphic abnormalities in venous thrombosis. J Nucl Med 1991; 32: 2144–8. 40. Kadir S. The lymphatic system. In: Kadir S, ed. Diagnostic Angiography. Philadelphia: W.B. Saunders, 1986: 617–41. 41. Lossef SV. Complication of lymphangiography. Semin Intervent Radiol 1994; 11: 107–12. 42. Weg JG, Harkleroad LE. Aberrations in pulmonary function due to lymphangiography. Dis Chest 1986; 53: 534–40. 43. Koehler PR. Complications of lymphography. Lymphology 1986; 1: 116–20. 44. Silvestri RC, Huseby JS, Rughani I, et al. Respiratory distress syndrome from lymphangiography contrast medium. Am Rev Respir Dis 1980; 122: 543–9. 45. Bron KM, Baum S, Abrams HL. Oil embolism in lymphangiography: incidence, manifestations, and mechanisms. Radiology 1963; 80: 194–202. 46. Hessel SJ, Adams DF, Abrams HL. Complications of angiography. Radiology 1981; 138: 273–81. 47. Clouse ME, Hallgrimsson J, Wenlund DE. Complications following lymphography with particular reference to pulmonary oil embolization. Am J Roentgenol Rad Ther Nucl Med 1966; 96: 972–8. 48. Lear T, Hoffer FA, Burrous PE, Kozakewich HP. MR lymphangiography in infants, children and young adults. Am J Radiol 1998; 17: 1111–17.

59 Lymphedema: medical and physical therapy GAIL L. GAMBLE, ANDREA CHEVILLE AND DAVID STRICK Introduction Deﬁnitions of lymphedema Lymphedema risk factors and risk reduction measures Management strategies

649 649 650 651

INTRODUCTION The clinical assessment, diagnosis, and ultimately management of the condition of lymphedema remain perplexing for many clinicians. The two preceding chapters have addressed the pathophysiology and patient evaluation for this relatively rare but often functionally limiting afﬂiction. Although there has been much interest in recent years regarding the physiology of the lymphatic system at the molecular and genetic level, to date no curative therapy has been developed. For decades this condition has been thought by many clinicians to be noncurative and also largely untreatable. There now exist data supporting many types of successful treatment interventions, as will be discussed below. Patients with the physical and secondary functional and emotional effects of lymphedema now have options for treatment, often in the local community. The non-operative treatment of lymphedema can be divided into several different areas. Minimization of risk factors and preventative measures are being discussed in the literature with increasing frequency. Pharmacologic measures can be considered but are not the foundation of a chronic lymphedema management program. Physical therapeutic measures occurring in the setting of a speciﬁc lymphedema therapy program by specially trained lymphedema therapists have become the mainstay of successful lymphedema management in North and South America and European countries.

DEFINITIONS OF LYMPHEDEMA The causes of lymphedema are characterized into primary and secondary etiologies. Primary lymphedema occurs

Lymphedema comorbidities Summary References

655 656 656

when a developmental abnormality exists such as lymphatic vessel aplasia or hypoplasia, precluding appropriate lymph absorption and transport. Primary lymphedema occurs in the absence of other inciting factors and can present at birth or later during adolescent development.1 Primary lymphedema also can present later in life (lymphedema tarda). Other than inheritance, risk factors for these conditions are not known; however, through advances of molecular and genetic research, it is now possible to advise affected patients and families of potential risk for familial types of lymphedema.2 Secondary lymphedema occurs as the result of obstruction or injury to a normally functioning lymphatic system. The presentation of secondary lymphedema is more common. In the Western world and in moderate and more northern climates, lymphedema occurs most often as a sequela of tumor and subsequent treatments including lymphadenectomy, radiation, or direct tumor obstruction. In tropical climates the most common cause of lymphedema is lymph vessel destruction created by infection and the associated inﬂammation.3 Regardless of etiology, lymphedema is clinically staged by the extent of visible tissue degradation (Table 59.1).

Table 59.1 Stages of lymphedema Latency Stage I Stage II Stage III

Risk for lymphedema present. No clinical change evident Pitting, reduces overnight with simple measures (elevation). No ﬁbrosis No longer pitting, no full reduction with elevation, evident ﬁbrosis Non-reversible, hardened ﬁbrosis and sclerosis of cutaneous and subcutaneous tissues

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Grading the extent of lymphedema with associated tissue changes may be important to consider when treatment options and outcomes are discussed, but unfortunately are not always well characterized in comparative studies.

LYMPHEDEMA RISK FACTORS AND RISK REDUCTION MEASURES Primary lymphedema carries few known risk factors other than genetic predisposition. In families where risk has been documented, risk reduction measures addressed below may be appropriate. The list of secondary postsurgical risk factors for the development of lymphatic stasis/failure is shown in Box 59.1. Of these factors, weight gain since surgery and one or more infections in the limb were found to be the only two of signiﬁcance in a 20 year follow-up study of patients with breast cancer.6 Other studies have described signiﬁcant variables which are associated with increased risk for lymphedema development.5–8

Chronic venous insufficiency and obesity Lymphedema may develop after sustained, chronic overload of the lymphatic system in the absence of iatrogenic or other sources of injury. This may occur in morbid obesity or chronic venous insufﬁciency (CVI), which are increasingly recognized causes of secondary lymphedema.10 In both cases, lymph production exceeds the capacity of lymph transport vessels leading to eventual system failure. The pathophysiologic steps which lead to frank lymphedema remain poorly understood. When feasible, reversal of primary causes, particularly obesity, is critical for optimal treatment outcomes.

Infection In much of the world, the most common secondary cause of lymphedema is infection, including parasitic invasion of

BOX 59.1 Documented risk factors for development of secondary lymphedema ● ● ● ● ● ● ● ●

Extent/location of surgery4 Radiation location5 Tumor obstruction Infection5 Weight gain6,7 Age8 Trauma9 Chronic venous disease10

Wuchereria bancrofti with resulting ﬁlariasis in tropical countries.3 Public health measures to decrease transmission in at-risk populations are being reported.11 It is also thought that even chronic mild infection, such as chronic tinea pedis, may create enough inﬂammation and secondary sclerosis of the distal lymphatics to allow the development of lymphedema over time.12 Clinically, posttraumatic infection may also damage lymphatics with presentation of actual lymphedema occurring at that time or presenting much later after another minor insult. Minimizing risk factors may be helpful in reducing the incidence of lymphedema, although there are few prospective studies deﬁnitively describing this. A practical resource includes the National Lymphedema Network guidelines.13

Skin care Attention to skin care is imperative to avoid skin scaling and cracking, thus minimizing risk for bacterial or fungal invasion. After washing thoroughly with soap and water, the skin, while still moist, should be treated with an alcohol-free emollient cream in order to trap remaining moisture, and keep strong the protective skin barrier. Extremes of temperature for the skin should be avoided, especially the development of sunburn, which can cause an inﬂammatory response increasing ﬂuid in the interstitium. Sunscreens should be used routinely in a limb at risk.

Infection avoidance Meticulous skin hygiene, as mentioned above, is critical for minimizing the risk of limb infection. Unfortunately, for those very patients at risk with medically complicated obesity, poor resources, and lack of assistance with their care, skin hygiene is often neglected especially in hard-toreach areas of the distal lower extremity. Careful review of feet including intertriginous spaces and the development of a skin protective program including the use of antifungal cream as needed is indicated. There are no deﬁnitive studies addressing prophylaxis for patients at risk for lymphedema, but evidence has shown the relationship between chronic fungal infection and the development of cellulitis, which is known to increase potential for lymphatic failure. Prompt treatment of any cellulitis which does develop in a limb at risk may minimize potential lymphatic vessel damage by minimizing inﬂammation.12,14

Exercise A moderate exercise regimen has been shown to promote limb volume reduction.15,16 Exercise can take several different forms, and these affect ﬂuid ﬂow through the

Management strategies 651

interstitium and into the lymphatics and the veins somewhat variably. Stretching exercises are important as part of a risk minimization program to reduce potential for local ﬁbrosis, thereby enhancing normalcy of the interstitial environment and maintaining adequate lymph ﬂow. Aerobic conditioning exercises can create increased sympathetic tone, which then increases the rate of smooth muscle contraction within the lymph vessels. A negative pressure is then created through proximal greater than distal pumping, enhancing lymph absorption.17,18 Resistive exercises increase the functional capacity of individual muscles, thus increasing the threshold for overuse or fatigue.19 Recently, several studies have revealed from a practical standpoint that a normal resistive exercise regimen for breast cancer survivors has not been shown to increase the incidence of lymphedema development.20 Prophylactic exercise programs should be undertaken gradually to allow for progressive increase of muscle and local environmental capacity, so as not to overwhelm lymphatic vessels at risk.

effect of this change is suggested for those at risk for development of lymphedema.22

Healthy nutrition/weight management

MANAGEMENT STRATEGIES

Multiple studies have now shown that increased body mass index (BMI) is a statistically signiﬁcant predisposing factor for patients at risk for lymphedema and venous disease as well.5–7,21 Thus, a diet which maintains weight, or even promotes weight reduction, is encouraged to minimize development of edema. A well-balanced diet, which includes appropriate ﬂuid intake, not restriction, should be encouraged. There is no current evidence that restriction of certain dietary elements such as dairy products decreases lymphedema incidence.

Differential diagnosis

Healthy venous management The literature clearly relates advanced venous disease with secondary inﬂammation, skin breakdown, and possible infection to the secondary development of lymphatic compromise as well.10 Phlebolymphedema may develop more readily in a limb already at risk for secondary lymphedema. Meticulous attention to medical management of venous disease in the form of exercise, elevation, and compression may be helpful in deterring not only venous failure but subsequent lymphatic damage as well.

Prophylactic compression (air travel, exercise) Long plane ﬂights have been shown to precipitate development of lymphedema in limbs at risk, although this is not widely substantiated.22 This is presumed secondary to the difference in the moderately decreased pressure within the plane cabin versus the atmospheric pressure. Wearing a compression sleeve to minimize the

Avoid “extremes” (temperature, constriction, exercise, etc.) A practical approach in advising a patient at risk for development of secondary lymphedema is to avoid “extremes.” Temperature extremes, whether hot or cold, can create vascular challenge, changing the environment and increasing the lymphatic load.13 Tight constriction is also thought to create irritation to the local vascular environment, which may increase lymphatic compromise. Exercise overuse, alluded to earlier, may increase lymph load, which cannot be drained by an impaired outﬂow system. While many activities presented in moderation are not problematic, it appears that abrupt or large challenges to the lymphatic system can be associated with the development of secondary lymphedema.

The treatment of lymphedema ﬁrst depends on assurity of diagnosis. This has been discussed in Chapter 58, but other causes of edema must continue to be in the forefront of the clinician’s thoughts in order not to neglect potentially dangerous and reversible causes. Deep venous thrombosis, recurrent malignancy, and active infection must be considered and ruled out as potential causes prior to initiating treatment. Cardiopulmonary, renal, or hepatic dysfunction must also be considered. The role of lymphoscintigraphy has also been discussed as a tool in clarifying the extent and nature of lymphatic failure.

MANUAL THERAPIES Manual therapies in multiple forms remain the most widely used interventions for the therapeutic management of lymphedema, regardless of etiology. Treatments have evolved, and new technologies are continually being developed especially in the area of maintenance compression options. MANUAL LYMPH DRAINAGE

Manual lymph drainage (MLD) is a highly specialized form of massage, which employs very light and gentle cutaneous distension to enhance lymph transport. The technique is a very superﬁcial massage compared with a deeper decongestive massage. Physiologically, MLD is thought to stimulate and increase the intrinsic contractility of lymph-collecting vessels and encourage increased

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protein molecule sequestration and subsequent transport.23 Decreased protein molecule concentration in the interstitium assists in reducing lymph congestion. Stagnant lymph is thus removed via superﬁcial lymphatic transport from an obstructed drainage area to one with greater drainage capability. Speciﬁc massage duration, orientation of the massage toward working nodal basins, and sequence of massage strokes require signiﬁcant anatomic knowledge, skill, and training. Rarely is MLD utilized as a complete treatment modality. It is most often combined with other manual therapies including compression bandaging, exercise regimens, skin care techniques, pressure gradient garments, and pneumatic pump mechanisms. There are, however, several areas of the body where compression modalities are difﬁcult to maintain, such as the neck, face, genitalia, and proximal shoulder girdle, and manual lymph drainage techniques become increasingly important as a critical reduction therapy in these areas.

USA,25–31 and has become the standard of care for lymphedema management.27,30 Dramatic reduction is often readily apparent to visual inspection (Fig. 59.1a,b). The elements utilized, in addition to MLD, are described below. It should be noted that there are now multiple independent training programs in the USA and elsewhere, and consequently specialized lymphedema treatment programs are increasingly available in smaller community therapy departments. In the USA, a voluntary certiﬁcation program exists, requiring documentation of training, treatment hours of experience, and a certifying examination.32

COMPLEX DECONGESTIVE THERAPY

Combining some form of manual massage, compression wrapping, elevation, and eventual maintenance compression has been advocated for decades.16 Complex decongestive therapy (CDT) is a combined approach to lymphedema therapy that has been recently agreed upon by multiple international lymphatic treatment and specialized training programs.24 In the USA and Canada, similar schools have developed. The treatment regimen comprises two distinct treatment components with two phases: reduction of edema and maintenance of reduction (Box 59.2). The usual program includes initial manual lymph drainage techniques, followed by a program of complex multilayered low-stretch wrapping, and including components of meticulous skin care education and training and speciﬁc exercises. The success in lymphedema reduction with this regimen has been documented in literature worldwide, including the

(a)

BOX 59.2 Complex decongestive therapy ●

●

Intensive reduction therapy (phase I) – Manual lymphatic drainage massage – Multilayered low-stretch wrapping techniques – Speciﬁc exercise regimen – Skin care education and techniques Maintenance therapy (phase II) – Daily wear of pressure sleeve – Continued nightly multilayered wrapping – Self-manual lymph drainage massage – Exercise – Continued meticulous skin management

(b) Figure 59.1 Patient with phlebolymphedema before (a) and after (b) a 2 week course of complete decongestive therapy.

Management strategies 653

Compression techniques

NON-ELASTIC COMPRESSION DEVICES

Compression wrapping in various forms has been a standard of management for both venous and lymphatic edema. Lymphatic wrapping techniques are complex and utilize low-stretch bandages instead of the more traditional high-stretch elastic bandages. High-stretch wrapping provides high pressures with a limb at rest but yield when the limb muscles contract with movement.31,33,34 This decreases the ability of the wrap to raise the tissue pressure during exercise, reducing the hydrostatic pressure gradient and decreasing the desired stimulation of lymphatic ﬂow. Low-stretch wrapping (Fig. 59.2a–d), by providing resistance during muscle pump action, increases the pressure gradient and stimulates increased ﬂuid ﬂow. Variations in pressure, added by inserting different strength foam pads, can enhance pressure in needed areas. During intensive reduction periods, the wraps are worn constantly except for bathing. During the maintenance phase of lymphedema management, the wrap is still worn at night.

For patients who are unable to manage the complex wrapping program after intensive reduction, many newer static gradient compression devices are now available. Patients with signiﬁcant obesity, pain problems, or advanced disease may not be able to comply with the complexities of wrapping. Time constraints, physical impairments, obese habitus, poor manual dexterity, and discomfort are frequently cited reasons for poor adherence.35 A variety of “alternative” nocturnal compression devices that putatively offer greater donning ease and comfort have been developed. Examples include the Reid Compression Sleeve, Peninsula Medical Inc., P.O. Box 66149, Scotts Valley, CA 95067-6149; CircAid, CircAid Medical Products Inc., 9323 Chesapeake Drive, Suite B2, San Diego, CA 92123; Leg/Arm-Assist, Compression Design, 140 W. Washington Ave., Suite 200, Zeeland, MI 49464; Solaris Tribute sleeve, Solaris Inc., 6737 West Washington St., West Allis, Wisconsin 53214; CompreFit, Compression Design, 140 W. Washington Ave., Suite 200, Zeeland, MI 49464; and JoVi-Pak sleeves, JoViPak®, 19625 62nd Ave., S. Bldg. B., Suite 101, Kent,

(a)

(b)

(c)

(d)

COMPRESSION WRAPPING

Figure 59.2 (a–d) Sequential images of multilayer, short-stretch compression bandaging applied over foam to enhance patient tolerance and tissue remodeling.

654

Lymphedema: medical and physical therapy

WA 98032. These have not been rigorously studied to determine whether they improve outcomes or patient adherence. Clinically, patients and therapists ﬁnd these alternatives to wrapping very helpful in some patients with compliance problems, but follow-up studies for both compliance and efﬁcacy are badly needed.17 PUMPS

For decades, prior to the introduction of CDT, compression pumps were the mainstay of lymphedema therapy. Since the mid-1990s, when CDT became more widely available, the role of pumps has been a source of controversy. Current usage parameters, particularly pump pressures, are now quite different than in the past and less likely to cause harm. However, patients with compromise of the entire superﬁcial lymph node beds should be administered pumps with great caution given the associated risk of truncal and genital lymphedema. There are theoretical concerns that pump use may actually accelerate lymphedema progression to more advanced stages although these lack empirical support. Several reports suggest that pumps may be a useful adjunct to CDT in both the reductive and maintenance phases.36,37 Although underpowered and methodologically limited, these studies raise an important point: that for some patients compression pumps may help reduce the onerous burden of lymphedema maintenance tasks or accelerate volume loss. Investigation into which patients and CDT phases beneﬁt from pump supplementation is needed. Compression pumping, like many treatments, has a host of parameters that can be manipulated. Aside from the fact that sequential, multichamber pumps afford slightly greater volume reduction,38 scant data inform the selection of frequency, duration, peak pressure, pressure gradient, and chamber density. Although most pneumatic compression pumps classically exhibit sequential pumping from distal to proximal limb, there is a new class of sequential compression devices available which encompass the theory of manual lymphatic drainage in that the compression chambers include the proximal trunk lymphatic beds, and proximal to distal pumping occurs initially, followed by the traditional distal to proximal ﬂow. A pilot study has shown positive short-term results. Further studies are needed.36 COMPRESSION GARMENTS

The use of elastic compression garments is the mainstay of the maintenance portion of any lymphedema management program. Rigid adherence to daily garment wear is the key to maintenance of limb size and volume.39 Compression garments have many functions, including assisting with both lymphatic and venous ﬂow and preserving skin integrity and protection from skin trauma.17 Prescription compression garments are usually

graduated in compression. Over-the-counter “support stockings” are usually minimal 7–15 mmHg and may not be graduated in pressure. Antithromboembolism stockings [e.g., thromboembolic deterrent (TED) hose] provide 15–20 mmHg graduated pressure with most pressure occurring at the ankle and less proximally. Compression stockings for the management of mild to moderate venous insufﬁciency are usually prescribed in the strength of 20–30 mmHg, while the pressures to control recalcitrant lower extremity lymphatic stasis usually start at 30–40 mmHg and can require pressures of 50–60 mmHg. Upper extremity lymphedema sleeves are prefabricated at a pressure of 20–30 mmHg, and this pressure usually is adequate. Currently, there are numerous manufacturers with varied fabrics, pressure strengths, and color options for patients. Most patients now have excellent options among prefabricated garments, and the custom garment is reserved for the hard-to-ﬁt patient with severe lymphedema, requiring extra ﬁrm fabric offered by several companies. Patient comorbidity including obesity, degenerative joint disease, and occlusive arterial disease should affect decision-making regarding pressure strength and sometimes length of garment. Ability to independently don the garment is critical and should be considered. Knee-high lower extremity garments combined with a commercially available spandex/Lycra sports leotard for proximal pressure may be a “best” option for a patient with physical limitations.

Pharmacologic measures To date, there are no curative pharmacologic interventions for lymphedema. Several different classes of drugs may assist in management.

DIURETIC MANAGEMENT

Diuretic therapy was formerly included in treatment program regimens,40 but not in more recent literature.41 Removal of ﬂuid acutely, when massive edema has accumulated, may be indicated when the cause is multifactorial (lymphostasis, cardiopulmonary, renal). Long-term use of diuretics is not indicated, however, because the transport of large protein molecules is not affected by the ﬂuid reduction, and increased interstitial protein concentration could actually increase further lymph accumulation.42 Many patients are started on diuretics by well-meaning physicians and come to the treatment setting frustrated at the inconvenience of diuretic use, without signiﬁcant long-term edema reduction results. Weaning the diuretic is appropriate after assuring that the diuretic is not being prescribed for another concurrent medical condition (hypertension, chronic renal failure, chronic heart failure, etc.).

Lymphedema comorbidities

BENZOPYRONES

Benzopyrones are medications thought to reduce lymphedema by increasing protein degradation in the interstitium and increasing the hydraulic resistance of capillary membranes. A meta-analysis of double-blinded clinical trials with the use of benzopyrones revealed a mean reduction in lymphedema of 37%.43 Although available in other parts of the world, a placebo-controlled, randomized crossover study comparing the benzopyrone coumarin found no signiﬁcant reduction in limb volumes, and reported increased liver function abnormalities in 6% of patients.44 The drug has not been approved for use in the USA. Flavenoids have also been reported to be effective in reducing lymphedema, although they are not widely utilized clinically.45 Horse chestnut root extract has been studied within the venous literature and found to have some positive effects

within the management of chronic venous insufﬁciency.46,47 Horse chestnut may beneﬁt patients whose lymphedema is associated with chronic venous insufﬁciency although there is no empiric basis for therapy.

LYMPHEDEMA COMORBIDITIES The condition of lymphedema is associated with several important comorbidities. Patients with breast cancer with lymphedema report statistically signiﬁcant differences in symptoms and quality of life relative to survivors without lymphedema.48 Symptoms often include alteration of limb sensation, fatigue, altered body image, sexual dysfunction, and decrease in psychological well-being.48,49 Discussion of these issues should be included in any lymphedema assessment and appropriate interventions to address problems should be implemented in an ongoing surveillance program.

Guidelines 6.3.0. of the American Venous Forum on lymphedema: medical and physical therapy No.

655

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.3.1 To reduce lymphedema we recommend multimodal complex decongestive therapy that includes manual lymphatic drainage; multilayer short-stretch bandaging; remedial exercise; skin care; and instruction in long-term management

1

B

6.3.2 To reduce lymphedema, we recommend short-stretch bandages that remain in place for longer than 22 hours per day

1

B

6.3.3 To reduce lymphedema we recommend treatment daily, a minimum of 5 days per week, and continue until normal anatomy or a volumetric plateau is established

1

B

6.3.4 To reduce lymphedema we suggest compression pumps in some patients

2

C

6.3.5 For maintenance of lymphedema we recommend an appropriately ﬁtting compression garment

1

A

6.3.6 For maintenance of lymphedema in patients with advanced (stages II or III) disease we recommend using short-stretch bandages during the night. Alternatively, compression devices may substitute for short-stretch bandages

1

B

6.3.7 For remedial exercises we recommend wearing compression garments or bandages

1

C

6.3.8 For cellulitis or lymphangitis we recommend antibiotics with superior coverage 1 of Gram-positive cocci, particularly streptococci. Examples include cephalexin, penicillin, clindamycin, cefadroxil

A

6.3.9 For prophylaxis of cellulitis in patients with more than three episodes of infection we recommend antibiotics with superior coverage of Gram-positive cocci , particularly streptococci, at full strength for 1 week per month, Examples include cephalexin, penicillin, clindamycin, cefadroxil

C

1

656

Lymphedema: medical and physical therapy

Chronic recurrent infection (cellulitis) of the lymphedematous limb can be a major comorbidity.50,51 Patients with lymphedema appear to be at increased risk of infection owing to impaired immune function in the local environment associated with decreased lymph transport. Acute cellulitis is often treated with a second-generation cephalosporin or penicillin successfully. Historically, the management of recurrent cellulitis has been with a prophylactic dose of antibiotics either by monthly injection of benzathine penicillin or by daily low-dose oral suppression with penicillin, although this has been reported not effective in patients with lymphedema and streptococcal cellulitis.52 To date there are no comparative studies for the long-term management of chronic recurrent cellulitis associated with lymphedema, and management remains largely empiric. Patient-initiated prompt treatment of early symptoms has been found to be beneﬁcial. Patients with recurring episodes multiple times in a year should be on a regimen of prophylaxis. Further studies to clarify best practices for long-term prophylaxis remain to be carried out.

SUMMARY Lymphedema remains a difﬁcult condition for patients and practitioners alike with only modest data available for classiﬁcation and management strategies. Many interesting clinical questions remain to be studied but there is an emerging literature showing increasing success with early identiﬁcation and intervention with a variety of manual therapies.

REFERENCES 1. Szuba A, Rockson SG. Lymphedema: classiﬁcation, diagnosis and therapy. Vasc Med 1998; 3: 145–56. 2. Northup KA, Witte MH, Witte CL. Syndromic classiﬁcation of hereditary lymphedema. Lymphology 2003; 36: 162–89. 3. Hoerauf A. Control of ﬁlarial infections: not the beginning of the end, but more research is needed. Curr Opin Infect Dis 2003; 16: 403–10. 4. Herd-Smith A, Russo A, Muraca MG, et al. Prognostic factors for lymphedema after primary treatment of breast carcinoma. Cancer 2001; 92: 1783–7. 5. Segerstrom K, Bjerle P, Graffman S, Nystrom A. Factors that inﬂuence the incidence of brachial oedema after treatment of breast cancer. Scand J Plast Reconstr Surg Hand Surg 1992; 26: 223–7. 6. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 2001; 92: 1368–77. 7. Werner RS, McCormick B, Petrek J, et al. Arm edema in conservatively managed breast cancer: obesity is a major predictive factor. Radiology 1991; 180: 177–84.

8. Kocak Z, Overgaard J. Risk factors for arm lymphedema in breast cancer patients. Acta Oncol 2000; 39: 389–92. 9. Pavlotsky F, Amrani S, Trau H. Recurrent erysipelas: risk factors. J Dtsch Dermatol Ges 2004; 2: 89–95. 10. Mortimer PS. Implications of the lymphatic system in CVIassociated edema. Angiology 2000; 51: 3–7. 11. Vaqas B, Ryan T. Lymphoedema: pathophysiology and management in resource-poor settings – relevance for lymphatic ﬁlariasis control programmes. Filaria J 2003; 2: 4. 12. Semel JD, Goldin H. Association of athlete’s foot with cellulitis of the lower extremities: diagnostic value of bacterial cultures of ipsilateral interdigital space samples. Clin Infect Dis 1996; 23: 1162–4. 13. Committee NLNMA. Lymphedema risk reduction practices. Available from: http://www.lymphnet.org/pdfDocs/ nlnriskreduction.pdf. Accessed August 2008. 14. Baddour LM. Cellulitis syndromes: an update. Int J Antimicrob Agents 2000; 14: 113–16. 15. LeDuc O, PA, Bomgeois P. Bandages: Scintigraphic Demonstration of its Efﬁcacy on Colloidal Protein Reabsorption During Muscular Activity. Cirugía Vascular. Rutherford R (ed). Amsterdam; 1990. Elsevier Saunders. 16. Stillwell GK, Redford JW. Physical treatment of postmastectomy lymphedema. Mayo Clin Proc 1958; 33: 1–8. 17. Cheville AL, McGarvey CL, Petrek JA, et al. Lymphedema management. Semin Radiat Oncol 2003; 13: 290–301. 18. McKenzie DC, Kalda AL. Effect of upper extremity exercise on secondary lymphedema in breast cancer patients: a pilot study. J Clin Oncol 2003; 21: 463–6. 19. DeLateur B. Therapeutic Exercise. Philadelphia: W.B. Saunders, 1996. 20. Ahmed RL, Thomas W, Yee D, Schmitz KH. Randomized controlled trial of weight training and lymphedema in breast cancer survivors. J Clin Oncol 2006; 24: 2765–72. 21. Laurikka JO, Sisto T, Tarkka MR, et al. Risk indicators for varicose veins in forty- to sixty-year-olds in the Tampere varicose vein study. World J Surg 2002; 26: 648–51. 22. Casley-Smith JR, Casley-Smith JR. Lymphedema initiated by aircraft ﬂights. Aviat Space Environ Med 1996; 67: 52–6. 23. Smith C. The Pathophysiology of Lymphedema. Tel Aviv: Immunology Research Foundation Inc., 1983. 24. American Cancer Society Workshop. Lymphedema: Results from a workshop on breast cancer treatment-related lymphedema. Cancer. 1998; 83(12 Suppl): 2775–890. 25. Boris M, Weindorf S, Lasinski B, Boris G. Lymphedema reduction by noninvasive complex lymphedema therapy. Oncology (Huntington) 1994; 8 (9): 95–106; discussion 109–10. 27. Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment of lymphedema of the extremities. Arch Surg 1998; 133: 452–8. 28. Daane S, Poltoratszy P, Rockwell WB. Postmastectomy lymphedema management: evolution of the complex decongestive therapy technique. Ann Plast Surg 1998; 40: 128–34.

References 657

29. Murthy G, Ballard RE, Breit GA, et al. Intramuscular pressures beneath elastic and inelastic leggings. Ann Vasc Surg 1994; 8: 543–8. 30. Witte MH, Witte CL, Bernas M. ISL Consensus Document revisited: suggested modiﬁcations (summarized from discussions at the 16th ICL, Madrid, Spain, September 1997, and the Interim ISL Executive Committee meeting). Lymphology 1998; 31: 138–40. 31. Szuba A, Cooke JP, Yousuf S, Rockson S. Decongestive lymphatic therapy for patients with cancer-related or primary lymphedema. Am J Med 2000; 109: 296–300. 32. Lymphology Association of North America (LANA). Certiﬁed Lymphedema Therapist. Lymphology Association of North American (LANA) 2003 [Candidate Information Brochure]. 33. Stemmer R, Marescaux J, Furderer C. Compression therapy of the lower extremities particularly with compression stockings (in German). Hautarzt 1980; 31: 355–65. 34. Partsch H. Verbesserte Forderleistung der Wadenmuskelpumpe Unter Kompressionstrumpfen bei Varizen und Venoser Insufﬁzienz. Phlebol Proktol 1978; 7: 58. 35. Cheville A. Current and future trends in lymphedema management: implications for women’s health. J Surg Oncol 2007; 95 (5): 409–418. 36. Wilburn O, Wilburn P, Rockson SG. A pilot, prospective evaluation of a novel alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412]. BMC Cancer 2006; 6: 84. 37. Szuba A, Achalu R, Rockson SG. Decongestive lymphatic therapy for patients with breast carcinoma-associated lymphedema. A randomized, prospective study of a role for adjunctive intermittent pneumatic compression. Cancer 2002; 95: 2260–7. 38. Bergan JJ, Sparks S, Angle N. Lymphedema: a comparison of compression pumps in the treatment of lymphedema. Vasc Surg 1998; 32: 455–62. 39. Casley-Smith JR, Casley-Smith JR. Modern treatment of lymphoedema. I. Complex physical therapy: the ﬁrst 200 Australian limbs. Australas J Dermatol 1992; 33: 61–8. 40. Schirger A. Lymphedema. Cardiovascular Clin 1983; 13: 293–305.

41. Földi M, Földi E, Kubik S. Textbook of Lymphology for Physicians and Lymphedema Therapists. San Francisco: Urban & Fischer, 2003. 42. Schuchhardt C. There is no drug therapy for lymphedema. Interview by Elisabeth B. Moosmann (in German). Fortschr Med 1997; 115 (22–23): 37–8. 43. Casley-Smith JR. Benzo-pyrones in the treatment of lymphoedema. Int Angiol 1999; 18: 31–41. 44. Loprinzi CL, Kugler JW, Sloan JA, et al. Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 1999; 340: 346–50. 45. Vettorello G, Cerreta G, Derwish A, et al. Contribution of a combination of alpha and beta benzopyrones, ﬂavonoids and natural terpenes in the treatment of lymphedema of the lower limbs at the 2nd stage of the surgical classiﬁcation. Minerva Cardioangiol 1996; 44: 447–55. 46. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufﬁciency. Cochrane Database Syst Rev. 2006; Issue 1. Art No.: CD003230. 47. Suter A, Bommer S, Rechner J. Treatment of patients with venous insufﬁciency with fresh plant horse chestnut seed extract: a review of 5 clinical studies. Adv Ther 2006; 23: 179–90. 48. Ridner SH. Quality of life and a symptom cluster associated with breast cancer treatment-related lymphedema. Support Care Cancer 2005; 13: 904–11. 49. Tobin MB, Lacey HJ, Meyer L, Mortimer PS. The psychological morbidity of breast cancer-related arm swelling. Psychological morbidity of lymphoedema. Cancer 1993; 72: 3248–52. 50. Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg (cellulitis): case–control study. BMJ 1999; 318: 1591–4. 51. Baddour LM, Bisno AL. Non-group A beta-hemolytic streptococcal cellulitis. Association with venous and lymphatic compromise. Am J Med 1985; 79: 155–9. 52. Wang JH, Liu YC, Cheng DL, et al. Role of benzathine penicillin G in prophylaxis for recurrent streptococcal cellulitis of the lower legs. Clin Infect Dis 1997; 25: 685–9.

60 Principles of surgical treatment of chronic lymphedema PETER GLOVICZKI Introduction Preoperative diagnostic evaluation

658 658

INTRODUCTION Congenital or acquired obstructions of lymph vessels or lymph-conducting elements of lymph nodes results in impaired lymphatic transport. Primary or secondary valvular incompetence also decreases normal lymphatic transport capacity. Protein-rich extracellular ﬂuid accumulates and chronic lymphedema develops when the collateral lymphatic circulation becomes insufﬁcient and when all compensatory mechanisms, including the tissue macrophage activity and drainage through spontaneous lymphovenous anastomoses, have been exhausted. When the transport of excess tissue ﬂuid containing lymphocytes, different plasma proteins, immunoglobulins, and cytokines is impaired chronic inﬂammatory changes in the subcutaneous tissue and skin also occurs. Physical therapy, compression garments, and intermittent pneumatic compression pumps are currently the ﬁrst line of treatment in patients with chronic lymphedema. A variety of surgical techniques have also been attempted to treat patients with this disabling condition. The large number of individual techniques of physiologic and excisional operations that are practiced today worldwide is testimony to the difﬁculty of this problem. Excisional operations remove the excess tissue to decrease the volume of the extremity.1–3 The basic principles of excisional operations are used during debulking excess subcutaneous tissue with the minimally invasive technique of liposuction.4,5 Physiologic operations (Fig. 60.1) have been aimed at restoring lymphatic transport capacity with lymphovenous anastomoses, lymphatic grafting, enteromesenteric bridge operation, or free transfer of normal lymphatic tissue.6–22 Lymphatic

Surgical treatment References

659 663

valvular incompetence has been treated by ligation and excision of retroperitoneal lymphatics, with or without lymphovenous anastomoses.23

PREOPERATIVE DIAGNOSTIC EVALUATION Imaging studies are used selectively, depending on the age of the patient, the presentation of the disease, and whether surgical treatment is planned or not. Computed tomography is important to exclude underlying malignancy and magnetic resonance imaging is used in patients with suspected vascular malformations or softtissue tumors. Magnetic resonance imaging is also helpful to conﬁrm the presence of lymphedematous tissue in the subcutaneous space. Duplex scanning of leg veins excludes venous occlusion or valvular incompetence. Lymphoscintigraphy is used now most frequently as the main diagnostic tool to evaluate the lymphatic system. The study involves interstitial injections of small amounts of radiolabeled antimony trisulﬁde colloid (technetium 99mlabeled Sb2S3 colloid) or human serum albumin into the interdigital space and subsequently imaging the extremity with a dual-headed gamma counter. The semiquantitative transport index of Kleinhans and Baumeister18 is used at our institution to document the severity of the edema. The sensitivity of the semiquantitative interpretation is excellent (92%) with a speciﬁcity of close to 100% for the diagnosis of lymphedema. It remains the test of choice in differentiating lymphedema from edema of other origins. Contrast lymphangiography, because of the potential to increase chronic lymphedema, is reserved for patients with chylous reﬂux or abdominal or thoracic chylous ﬁstulas, and for evaluation of the thoracic duct. We have used

Surgical treatment 659

(a)

(b)

(c)

(d)

Figure 60.1 Reconstruction for lymphatic obstruction in secondary lymphedema. (a) End-to-end and end-to-side lymph node–vein anastomosis. (b) End-to-end and end-to-side lymph vessel–vein anastomosis. (c) Cross-femoral lymph vessel transposition for secondary lymphedema of the left lower extremity. (d) Treatment of postmastectomy lymphedema with transplantation of two lymph channels from the lower to the upper extremity.

contrast lymphangiogram only occasionally for preoperative assessment of chronic lymphedema before lymphatic microsurgery.

willing to proceed even with experimental operations). Operations for lymphedema are divided into two major groups: excisional and lymphatic reconstruction.

SURGICAL TREATMENT

Excisional operations

Potential indications for surgical intervention are (1) impaired function and movement of the involved extremity owing to its large size and weight in patients unresponsive to medical management, (2) recurrent episodes of cellulitis and lymphangitis, (3) intractable pain, (4) lymphangiosarcoma, and (5) cosmesis (patient unwilling to undergo more conservative treatment and

Excisional procedures usually involve staged removal of the lymphedematous subcutaneous tissue of the leg. If the skin itself is diseased, and has to be resected, coverage with skin grafting is necessary. The most radical excisional operation, the Charles procedure, includes total skin and subcutaneous tissue excision of the lower extremity from the tibial tuberosity to the malleoli. The skin grafts are

660

Principles of surgical treatment of chronic lymphedema

unfortunately difﬁcult to manage with frequent localized sloughing (especially in areas of recurrent cellulitis), excessive scarring, hyperkeratosis, and dermatitis. The modiﬁed Homans operations (Servelle’s excisional operation, Miller’s staged subcutaneous excision, Pﬂug’s staged excisional operations) involve localized excision of the ﬁbrosed edematous subcutaneous tissue.1,2 Moderately thick ﬂaps (1–1.5 cm) are elevated anteriorly and posteriorly to the midsagittal plane in the calf and/or thigh. The redundant skin is excised and the wound is closed usually in one layer only. Since not all edematous tissue is excised, most of these are palliative procedures and the results are directly related to the amount of subcutaneous tissue excised. The patients are susceptible to recurrences and should continue to wear elastic compression stockings. The results of most of these procedures are good as far as volume reduction is concerned. However, prolonged hospitalization, poor wound healing, long surgical scars, sensory nerve loss, and residual edema of the foot and ankle can be problems. These frequent complications preclude such procedures short of disabling lymphedema, not responding to medical measures. Results reported by the group at the University of California, Los Angeles, have been most satisfactory.1 Segmental excision of lymphedematous tissue must be performed with attention to preserve adequate blood supply to the skin to minimize healing complications. Salgado et al.3 reported good results in 15 patients treated with debulking surgery combined with microsurgical preservation of perforating skin vessels from the posterior tibial and peroneal arteries. The average overall lymphedema reduction at a mean of 13 months was 52%. There were no cases of wound breakdown or skin ﬂap necrosis. Complications consisted of cellulitis in three patients and seroma and hematoma in one patient.3 A minimally invasive form of excisional operations is liposuction. The rationale of this procedure is that chronic lymphedematous tissue transforms with time into adipose tissue, which cannot be reduced with physiologic lymphovenous operations nor by massage or compression treatment. Brorson and colleagues4,5 have advocated this technique and reported excellent results.5 Liposuction completely removed the excess adipose tissue, which formed 81% of the subcutaneous tissue of the patients. Complete reduction of the lymphedema was achieved in 11 patients by 6 months.5

Lymphatic reconstructions Developments in microvascular techniques have allowed surgical attempts at direct lymphatic reconstructions, performance of lymphovenous anastomoses, or lymphatic grafting.6–22 Such reconstructions are usually indicated in only a small subset of patients who have proximal obstruction with preserved lymphatics distally.

Unfortunately, patients with primary lymphedema usually have diffuse lymphatic obstruction and are not candidates for reconstruction. Efforts to increase lymph transport by implanting a piece of omentum or a segment of ileum (mesenteric bridge operations) to the affected areas in order to promote neolympholymphatic communication have had reported success in small groups of patients. Very few surgeons, however, have personal experience with such procedures. LYMPHOVENOUS ANASTOMOSES

The rationale for the operation is based on the observation that, in patients with chronic lymphedema, spontaneous lymphovenous anastomoses could be demonstrated by lymphangiography. Direct reconstructions on the lymphatic system must be initiated early in the course of the lymphedema, prior to development of subcutaneous ﬁbrosis and lymphatic vessel sclerosis. Venous hypertension is a contraindication. An ideal candidate is a patient with a proximal pelvic lymphatic obstruction with dilated infrainguinal lymph vessels. Microsurgical end-toend anastomoses in the leg are performed usually between lymph vessels of the superﬁcial medial lymphatic bundle and tributaries of the saphenous or deep femoral vein (Fig. 60.2a). These can also be carried out with an invagination of lymph vessels into the saphenous or femoral vein. Anastomoses between groin lymph nodes and adjacent veins can also be performed in an end-to-end fashion with the transected saphenous vein or an end-to-side fashion with the femoral or saphenous vein (Fig. 60.2b). In addition to ligation of the dilated incompetent lymph vessels, we have used lymphovenous anastomoses in patients with chylous reﬂux to divert chyle into the venous system. Thoracic duct–azygos vein or thoracic duct–internal jugular vein anastomosis can also be successful in patients with thoracic duct occlusion to treat chylous effusions or lymphedema. Technically, lymphovenous anastomosis can be performed after signiﬁcant practice, using good microsurgical technique and high-power magniﬁcation. In experiments, the author had objective evidence of late patency. Anastomoses using normal femoral lymph vessels and a tributary of the femoral vein in dogs yielded a patency rate of 50% at 3–8 months after surgery by cinelymphangiography.19 The effectiveness of this operation is more difﬁcult to prove in humans. In 14 patients who underwent lymphovenous anastomoses at the Mayo Clinic, only ﬁve limbs maintained the initial improvement at an average of 46 months after surgery.10 Improvement occurred in four of the seven patients with secondary lymphedema and in only one of seven patients with primary lymphedema. Lymphoscintigraphy can provide only indirect evidence of improved lymph transport and cannot document patency of the anastomosis. Postoperative lymphangiography would be the only way to conﬁrm anastomosis patency. This is not

Surgical treatment 661

(a)

(a) Figure 60.2 Microsurgical lymphovenous anastomosis performed at the right groin. (a) Two dissected lymph vessels and a tributary of the saphenous vein with a side branch prepared for anastomosis. (b) Patent end-to-end lymphovenous anastomoses.

practical as the procedure is invasive and progression of lymphedema after such studies has been reported. Experience in large numbers of operated patients operated in Australia, Asia, and Europe suggests clinical improvement can be achieved with lymphatic drainage procedures.7–9,11–16 In the series reported by O’Brien et al.6 in Australia, 73% of the patients had subjective improvement and 42% experienced long-term improvement. In ﬁlariasis, lymphatics are frequently enlarged and lymph ﬂow is high. Lymphovenous reconstructions appear effective in patients with ﬁlariasis. Jamal8 reported success in India in 90% of patients who underwent lymph node venous shunts constructed in the inguinal area. Campisi and colleagues11–13 in Italy have the largest experience with lymphatic microsurgery. His team reported results in 665 patients with obstructive lymphedema using microsurgical lymphovenous anastomoses,

with subjective improvement in 87% of the patients.11,12 Four hundred and forty-six patients were available for long-term follow-up and volume reduction was observed in 69% with discontinuation of conservative measures in 85%. The authors concluded that microsurgical reconstruction early in the course of lymphedema is more effective, since intrinsic contractility of the lymphatics is still maintained. Chances of normalization of the lymph circulation are better before signiﬁcant chronic inﬂammatory changes in the subcutaneous tissue develop. Campisi et al.13 reported updated experience with over 1500 patients treated with a variety of microsurgical techniques. Many of these operations were performed with a variety of microsurgical techniques (Fig. 60.3) Volume changes showed signiﬁcant improvement in over 83% of the patients at a mean follow-up of over 10 years. There was an 87% reduction in the incidence of cellulitis after microsurgery.13 Signiﬁcant improvement at a mean of 3.3 years after lymphovenous anastomosis was also conﬁrmed in eight out of 13 operated patients by Koshima et al.15 from Japan. Another group from Japan suggested that lymphovenous anastomosis can prevent the development of lymphedema in patients who undergo pelvic lymphadenectomy for cancer.16 However, Vignes et al.17 failed to conﬁrm the therapeutic beneﬁt of lymphovenous anastomoses in a group of 13 patients, 10 with primary and three with secondary lymphedema. Global assessment of clinical outcome was very good or good in ﬁve patients and intermediate in another ﬁve; however, the operation failed to improve the volume of lower limbs and did not reduce the frequency of erysipelas. LYMPHATIC GRAFTING

The concept of lymphatic grafting is attractive in that the problems inherent to lymphovenous anastomoses (such as venous hypertension causing reversal of ﬂow into the lymphatic circuit) can be avoided. Also, patency of lymph–lymphatic anastomoses should in theory be better than patency of a blood-ﬁlled system. This technique, pioneered by Baumeister and colleagues,18,20,21 has been offered to patients with unilateral secondary lymphedema of the lower extremities or to patients with postmastectomy lymphedema of the arm. It is important to document normal lymphatics in the donor leg with lymphoscintigraphy before considering surgery. In post-mastectomy lymphedema, autotransplantation of two or three lymph vessels from the major lymphatic bundle from the medial aspect of the thigh to the arm is performed. The distal anastomosis is performed on the proximal arm with epifascial and subfascial lymph vessels in an end-to-end fashion. The proximal anastomosis is best performed in the neck to one of the larger cervical descending lymphatic vessels. The procedure for lower extremity reconstruction is a transposition of two or three normal lymphatic trunks in

662

Principles of surgical treatment of chronic lymphedema

(a)

(b)

(c) Figure 60.3 Techniques of lymphatic reconstructions according to Campisi et al.13 with (a) interposition vein graft or (b) lymphovenous anastomosis. (c) Technique of invagination of multiple lymphatics into interposition vein graft (lymphatic–venous–lymphatic anastomoses). (By permission of the Mayo Foundation.)

the thigh to the diseased limb with a lympholymphatic anastomosis in the groin (cross-femoral grafting). In a report of 55 patients undergoing such procedures, 80% were noted by Baumeister and Siuda21 to have improvement (volume reduction) after a mean follow-up of 3 years. Objective documentation of ﬂow through the lymphatic graft can be obtained with lymphoscintigraphy (Fig. 60.4). In a recent study from this group, eight patients with primary or secondary lymphedema of the lower limb were investigated before and for 8 years after autologous lymph vessel transplantation. In all eight

patients, lymphatic function, measured by semiquantitative lymphoscintigraphy, signiﬁcantly (P ≤ 0.01) improved after microsurgical treatment.22 Lymphatic grafting is a promising operation but it requires true microsurgical expertise and commitment to treat this frequently frustrating and difﬁcult disease. Longterm patency rates associated with documented clinical improvement need to be reported in a larger numbers of patients, operated on in more than one center, before this operation can be recommended for routine treatment or as an alternative to conservative measures.

References 663

Guidelines 6.4.0 of the American Venous Forum on principles of surgical treatment of chronic lymphedema No.

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.4.1 All interventions for chronic lymphedema should be preceded by at least 6 months of non-operative compression treatment

1

C

6.4.2 We suggest excisional operations or liposuction only to patients with late stage non-pitting lymphedema, who fail conservative measures

2

C

6.4.3 We suggest microsurgical lymphatic reconstructions in centers of excellence for selected patients with secondary lymphedema, if performed early in the course of the disease

2

C

Figure 60.4 Lymphoscintigraphy 3 months after cross-femoral lymphatic transposition. Note visualization of the left inguinal nodes following injection of isotope into the right edematous foot. There was no uptake prior to operation.

REFERENCES ● ◆

= Key primary paper = Major review article ●1.

Miller TA, Wyatt LE, Rudkin GH. Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. Plast Reconstr Surg 1998; 102: 1486. 2. Puckett CL, Silver D. Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results (Discussion). Plast Reconstr Surg 1998; 102: 1499.

3. Salgado CJ, Mardini S, Spanio S, et al. Radical reduction of lymphedema with preservation of perforators. Ann Plast Surg 2007; 59: 173–9. ●4. Brorson H, Svensson H. Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone. Plast Reconstr Surg 1998; 102: 1058. 5. Brorson H, Ohlin K, Olsson G, Nilsson M. Adipose tissue dominates chronic arm lymphedema following breast cancer: an analysis using volume rendered CT images. Lymph Res Biol 2006; 4: 199–210. 6. O’Brien BMcC, Shaﬁroff BB. Microlymphaticovenous and resectional surgery in obstructive lymphedema. World J Surg 1979; 3: 3–15. 7. Huang GK, Ru-Qi H, Zong-Zhao L, et al. Microlymphaticovenous anastomosis for treating lymphedema of the extremities and external genitalia. J Microsurg 1981; 3: 32–9. 8. Jamal S. Lymphovenous anastomosis in ﬁlarial lymphedema. Lymphology 1981: 14: 64–8. 9. Gong-Kang H, Ru-Ai H, Zong-Zhao L, et al. Microlymphaticovenous anastomosis in the treatment of lower limb obstructive lymphedema: analysis of 91 cases. Plast Reconstr Surg 1985; 76: 671–85. ◆10. Gloviczki P, Fisher J, Hollier LH, et al. Microsurgical lymphovenous anastomosis for treatment of lymphedema: a critical review. J Vasc Surg 1988; 7: 647–52. ●11. Campisi C, Boccardo F, Zilli A, et al. Long-term results after lymphatic–venous anastomoses for the treatment of obstructive lymphedema. Microsurgery 2001; 21: 135–9. 12. Campisi C, Boccardo F. Lymphedema and microsurgery. Microsurgery 2002; 22: 74–80. ●13. Campisi C, Eretta C, Pertile D, et al. Microsurgery for treatment of peripheral lymphedema: long-term outcome and future perspectives. Microsurgery 2007; 27: 333–8.

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O’Brien BMcC, Mellow CG, Khazanchi RK, et al. Long-term results after microlymphatico-venous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 1990; 85: 562–72. Koshima I, Nanba Y, Tsutsui T, et al. Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconst Microsurg 2003; 19: 209–15. Takeishi M, Kojima M, Mori K, et al. Primary intrapelvic lymphaticovenular anastomosis following lymph node dissection. Ann Plast Surg 2006; 57: 300–4. Vignes S, Boursier V, Priollet P, et al. Quantitative evaluation and qualitative results of surgical lymphovenous anastomosis in lower limb lymphedema. J Malad Vasc 2003; 28: 30–5. Kleinhaus E, Baumeister RGH, Hahn D, et al. Evaluation of transport kinetics in lymphoscintigraphy: follow-up study in patients with transplanted lymphatic vessels. Eur J Nucl Med 1985; 10: 349–62. Gloviczki P, Hollier LH, Nora FE, Kaye MP. The natural

20.

●21.

22.

●23.

history of microsurgical lymphovenous anastomoses: an experimental study. J Vasc Surg 1986; 4: 148–56. Baumeister RG, Siuda S, Bohmert H, Moser E. A microsurgical method for reconstruction of interrupted lymphatic pathways: autologous lymph–vessel transplantation for treatment of lymphedemas. Scand J Plast Reconstr Surg 1986; 20: 141–6. Baumeister RG, Siuda S. Treatment of lymphedemas by microsurgical lymphatic grafting: what is proved? Plast Reconstr Surg 1990; 85: 64–74. Weiss M, Baumeister RG, Hahn K. Dynamic lymph ﬂow imaging in patients with oedema of the lower limb for evaluation of the functional outcome after autologous lymph vessel transplantation: an 8-year follow-up study. Eur J Nucl Med Mol Imaging 2003; 30: 202–6. Noel AA, Gloviczki P, Bender CE, et al. Treatment of symptomatic primary chylous disorders. J Vasc Surg 2001; 34: 785–91.

61 The management of chylous disorders PURANDATH LALL, AUDRA A. DUNCAN AND PETER GLOVICZKI Introduction Etiology and presentation Evaluation Non-surgical management

665 665 666 666

INTRODUCTION Chylous disorders develop because of abnormal circulation of chyle, the lipid- and protein-rich lymph ﬂuid collected by the mesenteric lymphatic system. Primary developmental abnormalities of the lymph vessels (lymphangiectasia, obstruction)1,2 or secondary causes (tumor, trauma)3,4 lead to accumulation of the chyle in abnormal areas of the body, and disruption of the lymphatics causes chylous ﬁstulae or effusions such as chylothorax, chylous ascites, or chylopericardium. Chylous reﬂux is the term used to describe retrograde ﬂow in the incompetent lymphatic system secondary to lymphangiectasia and loss of lymphatic valve function. In this chapter we will focus on the most frequent primary chylous disorder, lymphangiectasia, associated with reﬂux of chyle to the limbs and genitalia and discuss the management of chylous ascites and chylothorax. Most of the principles used for the treatment of primary chylous disorders can also be applied to those patients who develop chylous effusions due to iatrogenic or penetrating trauma or due to malignant tumors, most frequently lymphoma. Since these conditions occur rarely, the literature is sparse and consists of case reports and small observational series.

ETIOLOGY AND PRESENTATION Primary chylous disorders are fortunately rare and they are usually caused by congenital lymphangiectasia.1–3,5 The pathogenesis of these disorders is poorly understood. New molecular studies suggest members of the vascular endothelial growth factor and angiopoietin families collaborate during lymphatic development and that the absence of angiopoietin 2 may result in chylous disorders.6

Surgical treatment Clinical practice guidelines References

667 670 671

Lymphatic dilatation (megalymphatics) may develop without proximal occlusion, although associated agenesis or obstruction of the thoracic duct has also been documented.7,8 Patients may present with lymphedema of one or both lower limbs or with swelling of the scrotum or the labia. The typical sign of lymphangiectasia and chylous reﬂux is, however, leakage of milky ﬂuid due to disruption of the dilated lymphatics. Rupture of the distended lymph vessels or lymphatic cysts may manifest in protein-losing enteropathy (malabsorption associated with chyle leaking into the lumen of the bowel),5,7 chylous ascites,9 chylothorax,3,10 chyloptysis (chyle in the sputum, due to reﬂux into the lungs and tracheobronchial tree),11 chyluria, chylometrorrhagia or chylocutaneous ﬁstula, with or without lymphedema of the limbs or genitalia.1,2,12,13 Symptoms develop at a young age, since the underlying abnormality is congenital. Most patients are in their early teens at the onset of severe symptoms, although occasionally older patients may also present with chylous effusions without underlying malignancy or a history of trauma. The mean age of 35 patients, 15 males and 20 females, treated surgically for primary chylous disorders at the Mayo Clinic was 29 years and ranged from 1 day to 81 years.14 The patients presented with lower limb edema (54%), dyspnea (49%), scrotal or labial edema (43%), and abdominal distension (37%). The etiology was primary lymphangiectasia in 66%, yellow nail syndrome in 11%, lymphangioleiomyomatosis in 9%, and other etiologies in 18%. Loss of chyle results in malnourishment due to depletion in lipids, protein, calcium, and cholesterol. Signiﬁcant loss of lymphocytes and immunoglobulins will cause severe compromise of the immune system and these patients are susceptible to infections.

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EVALUATION History and physical examination are most important and will frequently reveal the diagnosis. A chest radiograph may show an effusion. Paracentesis or thoracentesis reveals milky ﬂuid, rich in albumin and lipids. Diagnostic criteria include a milky appearance, separation into a creamy layer on standing, odorless, speciﬁc gravity > 1.012 and triglyceride levels > 110 mg/dL.15,16 The presence of chylomicrons and lymphocytes at levels that are higher than the corresponding plasma values will also distinguish chyle from “pseudochylous collections” due to cellular degeneration from bacterial infection or neoplasms.17 Computed tomography (CT) is performed to conﬁrm effusion and exclude malignancy. The dilated lymphatics (megalymphatics, lymphangioleiomyomatosis) are better

seen with magnetic resonance imaging (MRI). The beneﬁts of lymphoscintigraphy are discussed in detail in Chapter 58. The radioactive colloid will reﬂux to the affected limb from the pelvis (Fig. 61.1a) Although lymphoscintigraphy is our initial diagnostic test, pedal lymphangiography performed with lipid-soluble contrast will conﬁrm the diagnosis, localize the dilated retroperitoneal lymphatics, and frequently conﬁrm the sites of the lymphatic leak.

NON-SURGICAL MANAGEMENT Patients with lymphedema of the limbs are treated with external compression, using elastic or non-elastic bandaging, elastic stockings or garments. Patients with

Figure 61.1 (a) Right lower extremity lymphoscintigraphy in a 16 year old girl with lymphangiectasia and severe reﬂux into the genitalia and left lower extremity. Injection of the isotope into the right foot reveals reﬂux into the pelvis at 3 hours and into the left lower extremity at 4 hours. (b) Intraoperative photograph reveals dilated incompetent retroperitoneal lymphatics in the left iliac fossa containing chyle. (c) Radical excision and ligation of the lymph vessels were performed. In addition, two lymphovenous anastomoses were also performed between two dilated lymphatics and two lumbar veins. (d) Postoperative lymphoscintigram performed in a similar fashion reveals no evidence of reﬂux at 4 hours. The patient has no signiﬁcant reﬂux 4 years after surgery. (From Gloviczki et al.13)

Surgical treatment 667

advanced lymphedema beneﬁt from the use of intermittent pneumatic compression pumps or manual lymphatic drainage. Since lymphatic occlusion is rare, leg elevation with conservative measures is usually more effective than in patients with congenital lymphedema caused by lymphatic hypoplasia or obstruction. Return of the swelling with the erect position, however, is more instantaneous and the amount of chylous leak from ruptured cutaneous blisters is directly dependent on the lipid content of the ingested food. Meticulous skin care in the areas of chylous leak is important as the open blisters are potential sites for infection. Chyle production should be decreased by avoidance of food ingestion and institution of parenteral nutrition. A medium-chain triglyceride (triglycerides with fewer than 12 carbon atoms) diet can be used in selected patients as these triglycerides are directly absorbed into the portal circulation, bypassing the lymphatic tree. Somatostatin and its analogs have been used with beneﬁcial effects as a result of improvements in electrolyte abnormalities, often reducing ﬂuid and electrolyte support; the mechanism of action has been attributed to an increase in splanchnic arteriolar resistance with a resultant reduction in blood and lymphatic ﬂow.18 Diuretics are frequently needed to decrease chyle production, and furosemide and aldactone are used in high doses in severe cases.9 Etilefrine, a sympathomimetic drug that causes smooth muscle contraction of the thoracic duct, has helped in the management of postoperative chylous disorders but has not been used for primary chylous effusions.19 Nutritional management is used in conjunction with medical therapy and paracentesis or thoracentesis in order to control symptomatic ascites or pleural effusions. Although these are only palliative measures, many patients may be controlled adequately. If not, surgical intervention is considered to provide long-term improvement.

tetracycline solution, 500–1000 mg diluted in 20 mL of normal saline, directly into the dilated retroperitoneal lymph vessels to provoke obstructive lymphangitis. Percutaneous CT- or MRI-guided cannulation of the dilated lymphatics is also possible and sclerotherapy to decrease reﬂux can be performed repeatedly, if necessary.20 Lymphovenous anastomoses can also be done, although reﬂux of blood into the incompetent lymphatics may be a problem. This procedure is technically demanding and requires microscope enhancement to complete the anastomosis. Although reﬂux of blood into the dilated and incompetent lymphatics can occur, a competent valve on the venous side will completely avoid reﬂux and increase the chance of successful lymphatic drainage.14 Servelle12 published excellent and durable results from ligation and excision of the dilated reﬂuxing lymphatics in 55 patients. In a series of 19 patients who underwent ligation of the retroperitoneal lymphatics for chylous reﬂux to the limbs and genitalia (antireﬂux procedure) by Kinmonth,2 permanent cure was achieved in ﬁve patients and alleviation of symptoms, frequently after several operations, in 12 patients. No improvement or failure was noted in only two cases. We recently reviewed the results of 35 patients with primary chylous disorders treated over a 24 year period.13 Twenty-one (60%) patients underwent 27 surgical procedures. Nineteen procedures were performed for chylous ascites or reﬂux; 10 of these patients (53%) underwent resection of retroperitoneal lymphatics with or without sclerotherapy of lymphatics, four (21%) had lymphovenous anastomosis or saphenous vein interposition grafts (Fig. 61.2), four (21%) had peritoneovenous shunts, and one (5%) patient had a hysterectomy for periuterine lymphangiectasia. All patients improved initially, but 29% had recurrence of symptoms at a mean of 25 months

SURGICAL TREATMENT Chylous reflux In patients with lymphedema and reﬂux of chyle to the genitalia and the limbs, excision, ligation and sclerotherapy of the incompetent retroperitoneal lymph vessels is performed, with or without lymphatic reconstruction with lymphovenous anastomosis or lymphatic bypass grafting.8 The patients are fed 60 g of butter melted in milk or cream 4 hours before the procedure. The lymphatics are approached retroperitoneally through a ﬂank incision. The fatty meal allows ready visualization of the retroperitoneal lymphatics during exploration. Careful ligation of the lymph vessels should be done in order to avoid further lymphatic avulsion and leaking (Fig. 61.1a–d). Adjunctive sclerotherapy of the dilated lymphatics is carried out to increase the efﬁcacy of the operation. We inject

Figure 61.2 Lymphovenous anastomosis using a saphenous vein graft between a large retroperitoneal lymph vessel (end to end) and the right common iliac vein (end to side). The competent valve in the vein prevents reﬂux of blood into the dilated and incompetent lymph vessel.

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The management of chylous disorders

(range 1–43). Three patients with leg swelling had postoperative lymphoscintigraphy conﬁrming improved lymphatic transport and diminished reﬂux.

Chylous ascites Browse et al.21 identiﬁed three possible mechanisms of ascites formation. First, congenital lymphangiectasia, caused by congenital valvular incompetence and dilatation of the mesenteric or retroperitoneal lymphatics, or both; second, congenital obstruction or agenesis of the thoracic duct; and, ﬁnally, obstruction localized to mesenteric lymph nodes and vessels. Preoperative evaluation of patients with chylous ascites includes CT or MRI to exclude abdominal malignancy, followed by lymphoscintigraphy and lymphangiography (see also Chapter 58). Paracentesis is both diagnostic and therapeutic. If conservative measures, including nutritional regulation and serial paracentesis fail, surgical intervention should be considered.

Preparation of the patient for surgery is the same as used for retroperitoneal lymphatic ligation. Four hours after a fatty meal is ingested, abdominal exploration will conﬁrm dilated and ruptured lymphatics, which can be oversewn, ligated or clipped (Fig. 61.3a–d). Chylous cysts, when found, should be excised. The most involved segments of the short bowel can be resected in patients who have severe protein-losing enteropathy. Success of the exploration is improved if a well-deﬁned abdominal ﬁstula is identiﬁed. However, if the mesenteric lymphatic trunks are ﬁbrosed, aplastic, or hypoplastic, and exudation of the chyle is the main source of the ascites, the prognosis is poor, and recurrence is frequent. In these patients, ascites may be controlled with a peritoneovenous shunt. Browse et al.9 reported on a series of 45 patients with chylous ascites. The age at presentation ranged from 1 to 80 (median 12) years; 23 patients were aged 15 years or younger. Thirty-ﬁve patients had an abnormality of the lymphatics (primary chylous ascites); in the remaining 10, the ascites was secondary to other conditions, principally non-Hodgkin’s lymphoma (six patients). Other associated

A

C Figure 61.3 (a) An 18 year old woman with lymphangiectasia and recurrent chylous ascites. (b) During the operation, 12 liters of chyle was aspirated from the abdomen. (c) The chylous ascites was caused by ruptured lymphatics and leaking large mesenteric lymphatic cysts (arrow). (d) The dilated retroperitoneal lymphatics containing chyle were ligated and excised. The patient had an excellent clinical result 8 months after the operation. (From Gloviczki and Noel.7)

Surgical treatment 669

lymphatic abnormalities were present in 36 patients, lymphedema of the leg being the commonest (26 patients). All patients were initially treated conservatively with dietary manipulation with best results in patients with leaking small bowel lymphatics. Surgery (ﬁstula closure, bowel resection, or insertion of a peritoneovenous shunt) was performed in 30 patients. Closure of a retroperitoneal or mesenteric ﬁstula, when present, was the most successful operation, curing seven of the 12 patients treated by Browse and colleagues.9 In those patients who develop chylous ascites due to iatrogenic trauma, frequently after aortic reconstructions, a short period of conservative management is justiﬁed. If chylous ascites reaccumulates, reoperation with ligation of the ﬁstula is the most effective treatment.4 In a retrospective single-center study, Campisi et al.22 reported on the surgical results of primary chylous ascites in 12 patients with a mean follow-up of 5 years (range 3–7). They demonstrated that laparoscopy is advantageous for conﬁrming the diagnosis, draining the ascites, and evaluating the extension of dysplasia. Carbon dioxide laser was also used as an adjunct for “welding” lymphatic vessels with a low degree of dilatation in 75% of the patients. Eight patients had no relapse of ascites, three had mild recurrence, one of which was treated effectively with a peritoneovenous shunt, one patient died 1 year after surgery from an unrelated cause.

Carotid a

Vagus n

Left subclavian a

Results with peritoneovenous shunts have been mixed, patency is usually judged by recurrence of ascites. In the study by Browse et al.,3 the nine peritoneovenous shunt placements all occluded within 3–6 months after insertion. We have use the LeVeen (BD, Franklin Lakes, NJ, USA) shunt with good results, although one of four patients developed symptomatic superior vena cava syndrome due to thrombosis around the shunt.14

Chylothorax Chylothorax may result from lymphangiectasia with or without thoracic duct obstruction (Fig. 61.4), or from chylous ascites passing through the diaphragm. In the latter group of patients, the chylothorax improves when the chylous ascites is controlled. Preoperative lymphangiography may localize the site of the chylous ﬁstula or document occlusion of the thoracic duct. Thoracentesis is diagnostic but rarely therapeutic, as chyle from the thoracic duct or large intercostal, mediastinal, or diaphragmatic collaterals will reaccumulate. Although percutaneous or tube pleurodesis may be effective in other forms of non-malignant chylothorax, it is less effective for primary chylothorax. Surgical pleurodesis, either with video-assisted thoracoscopy (VATS) or with open thoracotomy, with excision of the parietal pleura is the

Vertebral v Thoracic duct termination

Left subclavian v Thoracic duct Cisterna chyli

Figure 61.4 Cervical and thoracoabdominal anatomy of the thoracic duct. (From Gloviczki and Noel.7)

670

The management of chylous disorders

optimal treatment.9,10 After a fatty meal, thoracotomy or VATS is performed and the lymphatics oversewn or clipped. This is followed by pleurodesis. In the Mayo Clinic series, eight procedures for chylothorax included thoracotomy with decortication and pleurodesis (four patients), ligation of thoracic duct (three patients), and resection of a thoracic duct cyst (one patient), with excellent early results in all patients.14 In two patients, reported earlier, thoracic duct azygos vein anastomosis was performed, with good results.8 A recent prospective study from Cope et al.23 described 11 patients with primary and secondary chylothorax treated with percutaneous catheterization and embolization of the thoracic duct with a 45% technical success rate, suggesting a role for percutaneous intervention. Silk et al.,24 and more recently Engum and colleagues,25 reported on using pleuroperitoneal shunts in children with good results. If the upper thoracic duct is occluded, resulting in reﬂux of chyle into the pleural or peritoneal cavity, thoracic duct–azygos vein anastomosis can be attempted to reconstruct the duct and improve lymphatic transport. Preoperative imaging of the duct with contrast pedal lymphangiography in these patients is important because if occlusion of the entire duct is present it precludes anastomosis. Through a right posterolateral thoracotomy, an anastomosis between the lower thoracic duct and the azygos vein is performed in an end-to-end fashion, with 8-0 or 10-0 non-absorbable interrupted sutures and magniﬁcation using loupes or the operating microscope (Fig. 61.5a–c). Kinmonth,2 who performed this operation in several patients, suggested that the anastomosis alone is not effective for decompressing the thoracic duct; ligation of the abnormal mediastinal lymphatics and oversewing of the sites of the lymphatic leak are also necessary. Browse et al.9 reported on three patients who underwent thoracic duct–azygos vein anastomosis, but all shunts occluded by 1 year after intervention. In the series of Browse, a total of 20 patients were treated for primary or secondary chylothorax. They suggest initial conservative treatment, but it should be abandoned if the ﬂuid loss exceeds 1.5 liters per day for more than 5–7 days in an adult or more than 100 mL per day in a child. Open pleurectomy was the most successful treatment in preventing reaccumulation of the effusion. Twelve of 20 patients were alive and free from an effusion 3–22 years after treatment.

(a)

(b)

CLINICAL PRACTICE GUIDELINES ●

●

Chylous disorders are fortunately rare. The underlying abnormality of primary chylous disorders is congenital lymphangiectasia, with or without occlusion or atresia of the thoracic duct or obstruction localized to mesenteric lymph nodes and vessels (15, 19 [2C]). CT scanning of the chest, abdomen, and pelvis must be performed to exclude secondary chylous effusions,

(c) Figure 61.5 (a,b) Thoracic duct–azygos vein anastomosis performed through a right posterolateral thoracotomy in an endto-end fashion with interrupted 8-0 prolene sutures. (c) Chest radiograph 2 years later conﬁrms absence of chylothorax. (From Gloviczki and Noel.7)

References 671

Guidelines 6.5.0 of the American Venous Forum on the management of chylous disorders No.

●

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.5.1 For primary treatment of chylous effusions and ﬁstulas due to reﬂux we recommend ﬁrst a low-fat or medium-chain triglyceride diet, followed by drug therapy that may include somatostatin and its analogs, diuretics, and sympathomimetic drugs to enhance thoracic duct contractions. This is followed by percutaneous aspirations of chylous ﬂuid by thoracentesis or paracentesis

1

B

6.5.2 In patients with primary lymphangiectasia and chylous ﬁstulas or lymphedema who fail conservative treatment, we suggest the selective use of ligation of lymphatic ﬁstulas, excision of dilated lymphatics, sclerotherapy, lymphatic reconstruction, or placement of a peritoneovenous shunt

2

C

most frequently lymphoma or iatrogenic or penetrating trauma. Although medical management with diet, parenteral nutrition, somatostatin, and paracentesis or thoracentesis may control symptoms temporarily, surgical treatment is frequently the only permanent solution. Ligation of the incompetent retroperitoneal lymphatics and oversewing the sites of rupture can produce long-term improvement in many patients with lymphangiectasia and lymphatic reﬂux. Chylous ascites can effectively be treated with ligation of the mesenteric or retroperitoneal lymphatic ﬁstula, if it can be identiﬁed. Laparoscopy may be used for conﬁrming the diagnosis, draining the ascites and evaluating the extension of dysplasia (7, 12, 14, 15, 16, 20 [2C]). The role of peritoneovenous shunts remains controversial. Chylothorax needs surgical intervention in most patients and pleurodesis and ligation of the leaking lymphatics or the thoracic duct is frequently effective. In selected patients with chylothorax a thoracic duct–azygos vein anastomosis or pleuroperitoneal shunt may be considered as surgical options (3, 14, 23 [2C]).

◆3.

4.

●5.

6.

◆7.

8.

●9.

REFERENCES ★10.

= Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

1. Servelle M, Nogues, C. The chyliferous vessels. Paris: Expansion Scientiﬁque Francaise, 1981: 40–59. ◆2. Kinmonth JB. Chylous diseases and syndromes, including references to tropical elephantiasis. In: Kinmonth JB, ed.

11.

◆12.

The Lymphatics: Surgery, Lymphography and Diseases of the Chyle and Lymph Systems, 2nd edn. London: Edward Arnold, 1982: 221–68. Browse NL, Allen DR, Wilson NM. Management of chylothorax. Br J Surg 1997; 84: 1711–16. Gloviczki P, Lowell RC. Lymphatic complications of vascular surgery. In: Rutherford RB, ed. Rutherford’s Vascular Surgery, 6th edn. Philadelphia: Elsevier, 2005: 922–30. Servelle M. Congenital malformation of the lymphatics of the small intestine. J Cardiovasc Surg 1991; 32: 159–65. Gale NW, Thurston G, Hackett SF, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell 2002; 3: 411–23. Kinmonth JB, Cox SJ. Protein-losing enteropathy in lymphoedema. Surgical investigation and treatment. J Cardiovasc Surg 1975; 16: 111–14. Gloviczki P, Noel AA. Surgical treatment of chronic lymphedema and primary chylous disorders. In: Rutherford RB, ed. Rutherford’s Vascular Surgery, 6th edn. Philadelphia: Elsevier, 2005: 2428–45. Browse NL, Wilson NM, Russo F, et al. Aetiology and treatment of chylous ascites. Br J Surg 1992; 79: 1145–50. Peillon C, D’Hont C, Melki J, et al. Usefulness of video thoracoscopy in the management of spontaneous and postoperation chylothorax. Surg Endosc 1999; 13: 1106–9. Sanders JS, Rosenow EC, Piehler JM, et al. Chyloptysis (chylous sputum) due to thoracic lymphangiectasis with successful surgical correction. Arch Intern Med 1988; 148: 1465–6. Servelle M. Surgical treatment of lymphedema: a report on 652 cases. Surgery 1987; 101: 485–95.

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13. Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 1989; 9: 683–9. ◆14. Noel AA, Gloviczki P, Bender CE, et al. Treatment of symptomatic primary chylous disorders. J Vasc Surg 2001; 34: 785–91. 15. Staats BA, Ellefson RD, Budahn LL, et al. The lipoprotein proﬁle of chylous and nonchylous pleural effusions. Mayo Clin Pro 1980; 55: 700–4. ●16. Jahsman WE. Chylothorax: a brief review of the literature. Ann Intern Med 1944; 21: 669–78. ◆17. Aalami OO, Allen DB, Organ CH Jr. Chylous ascites: a collective review. Surgery 2000; 128: 761–78. ★18. Stajich GV, Ashworth L. Octreotide. Neonatal Network 2006; 25: 365–9. ★19. Guillem P, Papachristos J, Christophe P, et al. Etilefrine use in the management of postoperative chyle leaks in thoracic surgery. Interactive Cardiovasc Thorac Surg 2004; 3: 156–60.

20. Molitch HI, Unger EC, Witte CL, et al. Percutaneous sclerotherapy of lymphangiomas. Radiology 1995; 194: 343–7. 21. Browse NL, Burnand KG, Mortimer PS. Diseases of the Lymphatics. London: Arnold, 2003: 259–92. ◆22. Campisi C, Bellini C, Eretta C, et al. Diagnosis and management of primary chylous ascites. J Vasc Surg 2006; 43: 1244–8. ★23. Cope C, Salem R, Kaiser LR. Management of chylothorax by percutaneous catheterization and embolization of the thoracic duct: prospective trial. J Vasc Intervent Radiol 1999; 10: 1248–54. 24. Silk YN, Goumas WM, Douglass HO Jr, et al. Chylous ascites and lymphocyst management by peritoneovenous shunt. Surgery 1991; 110: 561–5. 25. 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.

PART

7

ISSUES IN VENOUS DISEASE Edited by Gregory L. Moneta

62 Outcome assessment in acute venous disease Patrick Carpentier and Peter Gloviczki 63 Outcome assessment in chronic venous disease Robert B. Rutherford, Gregory L. Moneta, Frank T. Padberg Jr and Mark H. Meissner 64 Mapping the future: organizational, clinical, and research priorities in venous disease Mark H. Meissner, Bo Eklöf, Peter Gloviczki, Joann M. Lohr, Fedor Lurie, Robert Kistner, Gregory L. Moneta and Thomas W. Wakeﬁeld 65 Summary of Guidelines of the American Venous Forum Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Gregory L. Moneta, Thomas W. Wakeﬁeld, Joann M. Lohr, Monika L. Gloviczki and Mark H. Meissner

675 684 694

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62 Outcome assessment in acute venous disease PATRICK CARPENTIER AND PETER GLOVICZKI Introduction Key points in the outcome assessment of acute venous disease Mortality

675 675 675

INTRODUCTION It was 50 years ago in 1957 when Barritt and Jordan1 ﬁrst performed a controlled trial using heparin and a vitamin K antagonist (VKA) for the treatment of patients with pulmonary embolism; results of their trial were published 3 years later. The study was halted after enrollment of only 35 patients because of high mortality in the control group of untreated patients. Although this pioneer study was criticized because of poor methodology,2,3 it was clear that the trial opened the way not only for anticoagulation therapy of venous thromboembolism (VTE) but also for objective assessment of treatment in acute venous disease. Since then, hundreds of clinical trials have been performed in acute VTE,4 dealing with prophylactic and therapeutic use of antithrombotic agents, with diagnostic evaluation of deep vein thrombosis (DVT) and pulmonary embolism (PE), with interventional treatments for iliofemoral DVT, and with indications and results of vena cava ﬁlters. The common issues of outcome assessment in these studies will be brieﬂy reviewed in this chapter.

Non-fatal venous thromboembolic events Bleeding Post-thrombotic syndrome References

676 676 676 682

1. The severity and the relatively high rate of hemorrhagic complications of the antithrombotic treatments (1.3– 3.8% of major bleedings per year for VKAs5) make the safety outcome criteria as important as the efﬁcacy criteria. 2. The acute onset of the most important complications makes event-related criteria more relevant than quality of life evaluation scales in most instances. 3. Time-course speciﬁcity is not limited to the acuteness of episodes and recurrences: a the preventive effect of antithrombotic drugs on recurrence is mainly restricted to the treatment duration; many recurrences are delayed rather than avoided and follow-up should include the post-therapy time period;6 b long-term complications can occur that can be disabling (post-thrombotic syndrome) or even life-threatening (pulmonary hypertension) and have to be taken into account.

MORTALITY KEY POINTS IN THE OUTCOME ASSESSMENT OF ACUTE VENOUS DISEASE As in any disease, the goal of the medical management in acute venous disease (i.e., venous thromboembolism) is to improve survival and the quality of life endangered or hampered by the disease; in addition, treatment should decrease complications and recurrence of disease, have as few side-effects as possible, and achieve all this at the lowest cost possible. In acute venous disease the following criteria of successful outcome are particularly important.

Pulmonary embolism is responsible for as many as 45 000 deaths each year in the USA,7 and reduction of mortality is one of the main goals in the prevention and treatment of venous thromboembolic disease. Reduction of PE-related mortality is the main efﬁcacy criterion for thrombolytic therapy in massive PE or PE with right ventricular dysfunction,8 and also for vena cava ﬁlter implantation9 and for prevention of VTE trials in high-risk patients.10 Death can also occur as a result of bleeding complications of antithrombotic therapy, and is obviously the most signiﬁcant tolerance criterion for these treatments. In addition, death is not uncommon in the months following

676

Outcome assessment in acute venous disease

an episode of PE or DVT, mostly because of the complications of associated conditions such as cancer and an increased occurrence of cardiovascular events.11,12 Therefore, not only PE-related death but also death from any cause is a meaningful outcome in VTE because it calls into question the beneﬁt of treatment and also because antithrombotic drugs may inﬂuence the natural history of some of these associated conditions, such as cancer,13 and the occurrence of cardiovascular events.14

NON-FATAL VENOUS THROMBOEMBOLIC EVENTS It is common to detect thrombi in the deep veins of the lower limbs of asymptomatic patients who are at high risk for VTE.15 Similarly, in patients with proximal DVT but no respiratory symptoms, ventilation perfusion lung scans or helical computed tomography scans will show asymptomatic PE in up to 40% of patients.16 These silent DVTs or PEs are often used as surrogate end-points in phase II prophylactic or therapeutic trials in patients with, or at risk of, VTE, not only because they are conceptually and statistically highly related to clinical outcomes but also because they are more sensitive; they, therefore, allow the sample size needed for proof of the hypothesis of the study to be decreased (Box 62.1). However, silent DVTs or PEs do not have the same signiﬁcance as the clinical occurrence or recurrence of DVT and PE conﬁrmed by objective diagnostic tests, which are the only valid endpoint for phase III prophylactic or therapeutic trials or for evaluation of diagnostic strategies. In such trials, the combination of occurrence or recurrence of clinical PE/DVT is most often chosen as a combined end-point of efﬁcacy (Box 62.2).

BLEEDING Bleeding is a serious side-effect of antithrombotic drugs. Systemic thrombolytic therapy for PE can lead to severe bleeding complications in up to 14% of the patients,8 and antivitamin K anticoagulants also have a high rate of bleeding complications.5 Heparin, even in prophylactic

BOX 62.2 Objective confirmation for deep vein thrombosis or pulmonary embolism ● ● ● ●

Non compressible venous segment on ultrasound scan Venography ﬁlling defect High probability ventilation perfusion lung scan Filling defect on spiral computed tomography scan or pulmonary angiogram

dosage, causes a signiﬁcant bleeding hazard,10 and, on the whole, a bleeding complication is considered more serious than a recurrent thromboembolic event.6 Bleeding complications can include minor bleeding from the site of a venipunture to massive cerebral hemorrhage and death. Evaluation of the risk of bleeding has improved considerably because of introducing standardized criteria. The criteria produced by the European Agency for the Evaluation of Medicinal Products (EMEA)17 for major bleeding (Box 62.3) and the criteria for major and minor bleeding of the Thrombolysis In Myocardial Infarction (TIMI) studies18 (Table 62.1) are the most widely used. More recently, a new bleeding score was proposed, which takes into account bleeding of any severity in a single evaluation tool to increase the power of bleeding evaluation in clinical trials; although conceptually interesting, this new score has not yet been validated19 (Table 62.2).

POST-THROMBOTIC SYNDROME Post-thrombotic syndrome (PTS) is a frequent and serious outcome for patients with venous thromboembolism. It is seldom taken into account in clinical trials, mainly because its evaluation requires long-term follow-up that exceeds the study time-course of most trials regarding anticoagulant therapy in venous thromboembolism. However, the prevalence of PTS 10 years after a ﬁrst episode of DVT is

BOX 62.3 European Agency for the Evaluation of Medicinal Products criteria for major bleeding17 BOX 62.1 Surrogate criteria for deep vein thrombosis or pulmonary embolism

● ●

● ● ● ● ●

Positive radiolabeled ﬁbrinogen scan Venography ﬁlling defect Non-compressible venous segment on ultrasound scan High probability on ventilation perfusion lung scan Filling defect on spiral computed tomography scan

●

● ●

Fatal bleeding Clinically overt bleeding with a fall in hemoglobin level of 20 g/L or more Clinically overt bleeding leading to transfusion of two or more units of packed cells or whole blood Retroperitoneal or intracranial bleeding Bleeding warranting treatment cessation

Post-thrombotic syndrome

677

Table 62.1 Thrombolysis In Myocardial Infarction bleeding criteria18 Major bleeding Hemoglobin drop > 5 g/dL (with or without an identiﬁed site); or intracranial hemorrhage; or cardiac tamponade

Minor bleeding

“Loss, no site”

Hemoglobin drop > 3 g/dL but ≤5 g/dL, with bleeding from a known site or spontaneous gross hematuria, hemoptysis, or hematemesis

Hemoglobin drop > 4 g/dL but ≤5 g/dL without an identiﬁed bleeding site

Table 62.2 Bleed score classiﬁcation19 Superﬁcial Internal Alarming

Easy bruising, bleeding from small cuts, petechia, ecchymosis Hematoma; epistaxis; blood loss from mouth, vagina, eye; melena; hematuria; hematemesis Transfusion needed, intracranial, life-threatening

higher than 30%,20–22 and it is increased in patients with obesity,23–25 underlying thrombophilia,26 ipsilateral recurrence of DVT, and inadequate anticoagulation.25 The prevalence of PTS was not affected by placement of a vena cava ﬁlter,27 but it decreased as a result of compression therapy28,29 and early clot removal using surgical thrombectomy,30 thrombolysis,31 or combined pharmacomechanical therapy.32 Post-thrombotic syndrome is most often associated with deep vein reﬂux,33 which appears early and is sometimes used as a diagnostic criterion for PTS.34 In some studies deep vein reﬂux was used as a surrogate endpoint for PTS, although clearly it does not always have clinical manifestations. Leg ulcers are the most disabling late complications of venous thrombosis; approximately 40% of all leg ulcers are related to previous DVT.35 However, earlier clinical manifestations of PTS also alter quality of life and they should be taken into consideration. Incidence and severity of PTS are meaningful outcome issues in patients with venous thromboembolic disease. Although their deﬁnition is conceptually straightforward, their operational determination requires the use of validated clinical tools. For the purpose of incidence evaluation, two speciﬁc diagnostic tools were developed. The Ginsberg measure36 (Box 62.4) is based on the persistence or the new onset of leg symptoms 6 months after a DVT. The Villalta scale is composed of 10 fourpoint scales scoring symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, induration of the skin, hyperpigmentation, new venous ectasia, redness and pain during calf compression)37,38 (Table 62.3); a Villalta score higher than 5 represents mild and a score of 15 or more represents severe PTS. A comparison of these two systems showed that the Ginsberg measure identiﬁes more severe cases than the Villalta scale; however, none was statistically associated with popliteal reﬂux.34

1 point 3 points 6 points

BOX 62.4 Ginsberg measure for the diagnosis of post-thrombotic syndrome36 ● ●

● ●

Presence of daily leg pain and swelling for 1 month Occurring 6 months or more after deep vein thrombosis Made worse by standing/walking Relieved by rest/leg elevation

Table 62.3 Villalta standardized scale for the assessment of post-thrombotic syndrome37 Subjective symptoms Heaviness Pain Cramps Pruritus Paresthesia

Objective signs Pretibial edema Induration of the skin Hyperpigmentation New venous ectasia Redness Pain during calf compression

Scores for each sign and symptom: 0 (absent) to 3 (severe). Deﬁnition of post-thrombotic syndrome: Absent Score < 5 Mild to moderate Score 5–14 in two consecutive check-ups Severe Score ≥ 15 in two consecutive check-ups or ulceration in one occasion.

Although speciﬁcally developed for the PTS, these instruments do not show any substantial advantage over the Venous Clinical Severity Score (VCSS; Table 62.4), introduced by the American Venous Forum39 with the aim of measuring changes over time in patients with any kind of chronic venous disorder. This scoring system has shown

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Outcome assessment in acute venous disease

Table 62.4 Venous Clinical Severity Score39 Attribute

Absent = 0

Mild = 1

Moderate = 2

Severe = 3

Pain

None

Occasional, not restricting activity or requiring analgesic agents

Daily moderate activity limitation; occasional analgesic agents

Varicose veins (> 4 mm diameter)

None

Few, scattered; branch veins

Venous edema

None

Evening ankle edema only

Multiple; great saphenous veins, conﬁned to calf or thigh Afternoon edema, above ankle

Skin pigmentation

None or focal, low intensity (tan)

Diffuse, but limited in area and old (brown)

Daily, severe limiting activities or requiring regular use of analgesic agents Extensive; thigh and calf, or great and small saphenous distribution Morning edema above ankle and requiring activity change, elevation Wider distribution (above lower third) plus recent pigmentation

Inﬂammation

None

Mild cellulitis, limited to marginal area around ulcer

Induration

None

Number of active ulcers Active ulcer duration Active ulcer diameter (cm) Compression therapy

0 None None Not used or patient not compliant

Focal, circummalleolar (<5 cm) 1 <3 months <2 Intermittent use of stockings

good construct validity and satisfactory intra- and interobserver reproducibility.40 In a thrombophilic population, Ricci et al.41 showed a good correlation of the VCSS with the results of ultrasound (US) scans: only 2% of limbs with a VCSS of 0 had an abnormal US scan compared with 67% of those with a VCSS ≥ 3; these authors concluded that VCSS could be used for the screening of PTS. The health burden related to PTS should also be measured by a patient-reported outcome instrument. This kind of tool is observer independent and can evaluate either symptoms or quality of life. Post-thrombotic syndrome signiﬁcantly alters the quality of life, even when

Diffuse over most of gaiter distribution (lower third) or recent pigmentation (purple) Moderate cellulitis, involves most of gaiter area (lower third) Medial or lateral, less than lower third of leg 2 >3 months, <1 year 2–6 Wears elastic stockings most days

Severe cellulitis (lower third and above) or signiﬁcant venous eczema Entire lower third of leg or more >2 Not healed >1 year >6 Full compliance, stockings + elevation

measured with a non-speciﬁc instrument such as SF36.34 The CIVIQ2 quality of life questionnaire42 (Fig. 62.1) was speciﬁcally developed for chronic venous disease and was successfully validated in several groups of patients including those with severe PTS. Hudgens et al.43 developed a questionnaire for the evaluation of symptoms using Lickert scales (Table 62.5), which also showed promising abilities, but the VEINES QoL/sym questionnaire is certainly the most accomplished tool44 (Fig. 62.2). It includes 10 questions assessing symptom severity and 15 questions evaluating the venous disease-related quality of life impairment. Its acceptability, reliability, and validity of content have been thoroughly validated in a large

Table 62.5 Patient-reported leg symptoms index43 Five-point Likert scale (0 = no problem to 4 = very much a problem) Leg pain/discomfort Swelling Leg-related sleep problems

Five-point Likert scale “how true” the statement is for you (0 = not at all to 4 = very much) Skin discoloration Cosmetic appearance Activity limitation Emotional distress

Post-thrombotic syndrome

population of more than 1500 patients with chronic venous disease,44 and in a group of patients with PTS it was found to correlate well with the Villalta scale and the SF36.45 This brief review has shown how broad the spectrum of outcome assessment of acute venous disease really is. As

the early studies mainly focused on pulmonary embolism and the risk of death, a comprehensive approach to all aspects including late venous events was developed more recently, emphasizing the importance of the preservation of venous function as a valuable additional target that should not be overlooked.

Auto-questionnaire: Patients Many people in the country complain of heavy aching legs. We are trying to find the frequency of these leg problems, and how they can affect the everyday life of the people suffering from them. You will find hereafter a certain number of symptoms, sensations or discomforts that you may or may not feel, and that can make everyday life more or less difficult. For each symptom, sensation or discomfort listed, we ask you to answer the corresponding question: Please indicate whether you have really experienced what is discribed in the sentence, and, if so to what intensity. Five answers are provided, please circle the intensity most suited to your situation. 1

if you do not feel concerned by the symptom, sensation of discomfort described,

2, 3, 4 or 5

if you have felt it with more or less intensity.

1

In the past 4 weeks, if you have felt pain in the ankles or leg, what was the intensity of this pain?

(circle the number corresponding to the right answer)

No pain

Light pain

Moderate pain

Strong pain

1

2

3

4

2

Intense pain 5

During the past 4 weeks, to what extent did you feel bothered/limited in your work or your other daily acitivities because of your leg problem?

(circle the number corresponding to the right answer) Not bothered/limited

A little bothered/limited

Moderately bothered/limited

Very bothered/limited

Extremely bothered/limited

1

2

3

4

5

3

During the past 4 weeks, did you sleep badly because of your leg problems, and, if so, how often?

(circle the number corresponding to the right answer) Never

Seldom

Fairly often

Very often

1

2

3

4

Figure 62.1

679

Every night 5

CIVIQ2 quality of life questionnaire.42 (continues over page)

During the past 4 weeks, to what extent did your leg problems bother/limit you while doing the movements or activities listed below?

Leg problems can also have an effect on one’s morale. To what extent do the following sentences correspond to the way you have felt during the past 4 weeks? (for each of the sentences list in the left-hand column of the table below, circle the number that best corresponds to the right answer)

(for each of the sentences listed in the left-hand column of the table below, indicate to what extent you were bothered/limited by circling the corresponding number) Not Very A little Moderately bothered/ bothered/ bothered/ bothered/ Impossible to do limited at limited limited limited all 4

5

6

To stand for a long time

To climb stairs

To crouch, to kneel

1

1

1

7

To walk briskly

1

8

To travel by car, bus, plane

1

9

To do housework such as standing about in the kitchen, carrying a child in your arms, ironing, cleaning floors or furniture, doing handy work

1

2

2

2

3

3

3

4

4

4

5

2

3

4

5

To go to discos, weddings, parties, cocktails

1

2

3

4

5

11

To do a sport, to make physically strenuous efforts

1

2

3

4

5

(continued) CIVIQ2 quality of life questionnaire.42

Absolutely

I feel on edge

1

2

3

4

5

13

I become tired quickly

1

2

3

4

5

14

I feel I am a burden to people

1

2

3

4

5

15

I must always take precautions (such as to stretch my legs, to avoid standing for a long time...)

1

2

3

4

5

16

I am embarrassed to show my legs

1

2

3

4

5

17

I get irritated easily

1

2

3

4

5

18

I feel handicapped

1

2

3

4

5

19

I find it difficult to get going in the morning

1

2

3

4

5

20

I do not feel like going out

1

2

3

4

5

5

10

Figure 62.1

A lot

12

5

4

4

Moderately

5

3

3

A little

5

2

2

Not at all

1. During the past 4 weeks, how often have you had any of the following leg problems?

5. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of your leg problem?

Every day

Several times a week

About once a week

Less than once a week

Never

1. Heavy legs

1

2

3

4

2. Aching legs

1

2

3

3. Swelling

1

2

4. Night cramps

1

5. Heat or burning sensation 6. Restless legs

(check one box on each line)

Yes

No

a. Cut down the amount of time you spent on work or other activities

1

2

5

b. Accomplished less that you would like

1

2

4

5

c. Were limited in the kind or work or other activities

1

2

3

4

5

d. Had difficulty performing the work or other activities (e.g. it took extra effort)

1

2

2

3

4

5

1

2

3

4

5

1

2

3

4

5

7. Throbbing

1

2

3

4

5

1. Not at all

4. Quite a bit

8. Itching

1

2

3

4

5

2. Slightly

5. Extremely

9. Tingling sensation (e.g. pins and needles)

1

2

3

4

5

3. Moderately

(check one box on each line)

2. At what time of day is your leg problem most intense? (check one)

6. During the past 4 weeks, to what extent has your leg problem interfered with your normal social activities with family, friends, neighbors or groups? (check one)

7. How much leg pain have you had during the past 4 weeks? (check one)

1. On waking

4. During the night

1. None

4. Moderate

2. At midday

5. At any time of day

2. Very mild

5. Severe

3. At the end of the day

6. Never

3. Mild

6. Very severe

3. Compared with 1 year ago, how would you rate your leg problem in general now? (check one) 1. Much better now that 1 year ago.

4. Somewhat worse now than 1 year ago

2. Somewhat better now than 1 year ago

5. Much worse now that 1 year ago

3. About the same now as 1 year ago

6. I did not have any leg problem last year

8. These questions are about how you feel and how things have been with you during the past 4 weeks as a result of your leg problem. For each question, please give the one answer that comes closest to the way you have been feeling. How much of the time during the past 4 weeks: All of the time

Most of the time

A good bit of the time

Some of the time

A little of the time

None of the time

a. Have you felt concerned about the appearance of your legs?

1

2

3

4

5

6

b. Have you felt irritable?

1

2

3

4

5

6

c. Have you felt a burden to your family or friends?

1

2

3

4

5

6

d. Have you been worried about bumping into things?

1

2

3

4

5

6

e. Has the appearance of your leg(s) influenced your choice of clothing?

1

2

3

4

5

6

(check one box on each line) 4. The following items are about activities that you might do in a typical day, Does your leg problem now limit you in these activities? If so, how much? No, not Yes, Yes, I do not limited at limited a limited a (check one box on each line) work all little lot 1

2

3

b. Daily activities at home (e.g., housework, ironing, doing odd jobs/repairs around the house, gardening)

1

2

3

c. Social or leisure activities in which you are standing for long periods (e.g., parties, weddings, taking public transportation, shopping)

1

2

3

d. Social or leisure activities in which you are sitting for long periods (e.g., going to the cinema or the theater, travelling)

1

2

3

a. Daily activities at work

Figure 62.2

VEINES QoL/sym questionnaire.44

0

682

Outcome assessment in acute venous disease

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ●

16.

◆

17. ●1.

2. 3.

◆4.

◆5.

6.

◆7.

★8.

●9.

◆10.

11.

12.

●13.

●14.

15.

Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; 1: 1309–12. Cundiff DK. Anticoagulant for deep venous thrombosis. J R Soc Med 2003; 94; 608–9. Iles S, Dalen JE. Clot burden and comorbidity in natural history of untreated pulmonary thromboembolism. Autopsy data in the trial by Barritt and Jordan. Chest 2003; 124; 1178–9. Meissner MH, Wakeﬁeld TH, Ascher E, et al. Acute venous disease: venous thrombosis and venous trauma. J Vasc Surg 2007; 46: 25S–53S. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2004; 126: 287S–310S. Ost D, Tepper J, Mihara H, et al. Duration of anticoagulation following venous thromboembolism. A meta-analysis. JAMA 2005; 294: 706–15. Goldhaber SZ, Elliott CG. Acute pulmonary embolism. Part I. Epidemiology, pathophysiology, and diagnosis. Circulation 2003; 108: 2726–9. Task Force on Pulmonary Embolism, European Society of Cardiology. Guidelines on diagnosis and management of acute pulmonary embolism. Eur Heart J 2000; 21: 1301–36. Decousus H, Leizorovicz A, Parent F, et al. for the PREPIC Study Group. A clinical trial of vena caval ﬁlters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998; 338: 409–15. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004; 126: 338S–400S. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–8. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998; 158: 585–93. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123–9. Sørensen HT, Horvath-Puho E, Pedersen L, et al. Venous thromboembolism and subsequent hospitalization due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370: 1773–9. Schindler OS, Dalziel R. Post-thrombotic syndrome after total hip or knee arthroplasty: incidence in patients with

18.

19.

●20.

21.

22.

23.

24.

25.

26.

●27.

28.

●29.

asymptomatic deep venous thrombosis. J Orthop Surg 2005; 13: 113–19. Lopez-Beret P, Pinto JM, Romero A, et al. Systematic study of occult pulmonary thromboembolism in patients with deep venous thrombosis. J Vasc Surg 2001; 33: 515–21. The European Agency for the Evaluation of Medical Products. Clinical investigation of medicinal products for prophylaxis of intra- and post-operative thromboembolic risk. Available from: http: //www.emea.europa.eu/pdfs/ human/ewp/070798en.pdf. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991; 115: 256–65. Serebruany VL, Atar D. Assessment of bleeding events in clinical trials: proposal of a new classiﬁcation. Am J Cardiol 2007; 99: 288–90. Janssen MC, Haenen JH, van Asten WN, et al. Clinical and haemodynamic sequelae of deep venous thrombosis: retrospective evaluation after 7–13 years. Clin Sci (Colch) 1997; 93: 7–12. Franzeck UK, Schalch I, Bollinger A. On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis. Thromb Haemost 1997; 77: 1109–12. Saarinen J, Domonyi K, Zeitlin R, Salenius JP. Postthrombotic symptoms after an isolated calf deep venous thrombosis. J Cardiovasc Surg 2002; 43: 687–91. Ageno W, Piantanida E, Dentali F, et al. Body mass index is associated with the development of the post-thrombotic syndrome. Thromb Haemost 2003; 89: 305–9. Kahn SR, Kearon C, Julian JA, et al. Predictors of the postthrombotic syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost. 2005; 3: 718–23. van Dongen CJ, Prandoni P, Frulla M, et al. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 3: 939–42. Bradbury AW, MacKenzie RK, Burns P, Fegan C. Thrombophilia and chronic venous ulceration. Eur J Vasc Endovasc Surg 2002; 24: 97–104. The PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava ﬁlters in the prevention of pulmonary embolism. The PREPIC Randomized Study. Circulation 2005; 112: 416–22. Brandjes DPM, Buller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997, 349: 759–62. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56.

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Plate G, Akesson H, Einarsson E, et al. Long-term results of venous thrombectomy combined with a temporary arteriovenous ﬁstula. Eur J Vasc Surg 1990; 4: 483–9. Arnesen H, Hoiseth A, Ly B. Streptokinase of heparin in the treatment of deep vein thrombosis. Follow-up results of a prospective study. Acta Med Scand 1982; 211: 65–8. Comerota AJ, Paolini D. Treatment of acute iliofemoral deep venous thrombosis: a strategy of thrombus removal. Eur J Vasc Endovasc Surg 2007; 33: 351–60. Haenen JH, Janssen MCH, van Langen H, et al. The postthrombotic syndrome in relation to venous hemodynamics, as measured by means of duplex scanning and straingauge plethysmography. J Vasc Surg 1999; 29: 1071–6. Kahn SR, Desmarais S, Ducruet T, et al. Comparison of the Villalta and Ginsberg clinical scales to diagnose the postthrombotic syndrome: correlation with patient-reported disease burden and venous valvular reﬂux. J Thromb Haemost 2006; 4: 907–8. Cornwall JV, Doré CJ, Lewis JD. Leg ulcers: epidemiology and aetiology. Br J Surg 1986; 73: 693–6. Ginsberg JS, Gent M, Turkstra F, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med 2000; 160: 669–72. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the postthrombotic syndrome (abstract). Haemostasis 1994, 24: 158a.

38. Prandoni P, Villalta S, Polistena P, et al. Symptomatic deepvein thrombosis and the post-thrombotic syndrome. Haematologica 1995; 80 (Suppl 2): 42–8. ●39. Rutherford RB, Padberg FT Jr, Comerota AJ, et al. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. 40. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the venous clinical severity score. J Vasc Surg 2002; 36: 889–95. 41. Ricci MA, Emmerich J, Callas PW, et al. Evaluating chronic venous disease with a new venous severity scoring system. J Vasc Surg 2003; 38: 909–15. ●42. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufﬁciency (CIVIQ). Qual Life Res 1996; 5: 539–54. ●43. Hudgens SA, Cella D, Caprini CA, Caprini JA. Deep vein thrombosis: validation of a patient-reported leg symptom index. Health Qual Life Outcomes 2003; 1: 76. ●44. Lamping DL, Schroter S, Kurz X, et al. Evaluating outcomes in chronic venous disorders of the leg: development of a scientiﬁcally rigorous, patient-reported measure of symptoms and quality of life. J Vasc Surg 2003; 37: 410–19. 45. Kahn SR, Hirsch A, Shrier I. Effect of post-thrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med 2002; 162: 1144–8.

63 Outcome assessment in chronic venous disease ROBERT B. RUTHERFORD, GREGORY L. MONETA, FRANK T. PADBERG JR AND MARK H. MEISSNER Introduction Evolution of venous outcome assessment methods and current status

684 685

INTRODUCTION Assessing outcomes of any treatment should include appropriate controls. The treatment should be pitted against an appropriate competitive treatment using prospective randomization or utilizing concomitant control patients with equal disease severity. The endpoints of before and after treatment comparisons should include standardized objective criteria that accurately characterize patients’ symptoms, characteristic signs, and objective measures of functional and disease-speciﬁc quality of life measures. This task is complex and difﬁcult for patients with chronic venous disease (CVD). These difﬁculties, and current and proposed solutions, are the focus of this chapter.

The challenge posed by the complexity of the venous system The complexity of measuring outcomes in CVD may be best brought out by contrasting it with outcomes assessment in peripheral arterial disease (PAD). For PAD assessment, success of relieving peripheral arterial occlusive lesions can be monitored by simply measuring the arterial systolic pressure at locations distal to the intervention. In CVD the pathophysiologic processes are more complex. Interventional treatment of CVD may involve relieving luminal obstruction, reducing valve reﬂux, interrupting communicating veins, or ablating incompetent superﬁcial veins. Peripheral arterial disease has a chronic ischemia classiﬁcation scheme with discrete categories that are based on symptoms and signs reﬂecting progressive

References

692

severity of ischemia. These levels of severity are incorporated into the Rutherford classiﬁcation system. An additional advantage is that each level or clinical class is linked to functional criteria in the form of standardized non-invasive tests. Both clinical class and non-invasive test values are capable of changing with relief of the obstructing lesions and, taken together, provide a convenient basis for outcome assessment.1 In contrast, the classiﬁcation of CVD uses the CEAP system. This is an excellent way of characterizing CVD at any one point in time. It does not lend itself to assessing change associated with treatment. A number of the C components are relatively static and not sensitive to change following treatment. Furthermore, CVD does not have a single non-invasive test that correlates with disease severity and serves as a common index of change following intervention. The venous equivalent of the ankle arterial pressure is the ambulatory venous pressure (AVP). Because it is invasive, the AVP has been supplanted by non-invasive venous physiologic tests, primarily plethysmographic studies, which indirectly gauge various parameters of venous fraction. No single non-invasive test serves as a surrogate for AVP. Furthermore, the noninvasive venous tests that are currently used are not standardized well enough to provide objective criteria of change. In PAD, normal values for the ankle brachial index and what constitutes a signiﬁcant change (i.e., greater than explainable by observer variability) are well established. Normal ranges for most non-invasive venous tests are not well established. What constitutes “signiﬁcant change” may vary with disease severity. Signiﬁcant changes following therapy have not yet been established well enough to serve the purpose of scientiﬁc reporting. These problematic issues, and their current and proposed

Evolution of venous outcome assessment methods and current status 685

solutions, will be discussed in further detail later in this chapter.

EVOLUTION OF VENOUS OUTCOME ASSESSMENT METHODS AND CURRENT STATUS Early clinical venous papers most often characterized treatment groups in simple terms, such as the percentage with “stasis dermatitis” or with “stasis ulcers.” After a variable “mean follow-up period” after treatment, the percentage of ulcers healed, or staying healed, was commonly reported as evidence of improvement attributable to the treatment. Pain and swelling were occasionally graded to show symptomatic relief provided by the treatment. Individual components of the sequelae of chronic venous hypertension, i.e., cutaneous pigmentation, inﬂammation, induration, subcutaneous ﬁbrosis, were also graded in a few reports. However, the characteristics of CVD are not assessed in a universally accepted, standardized fashion. As the use of the life table and Kaplan–Meier methods grew, they also began to be used in reports on therapies for CVD. Thus, the “ulcer-free interval” might be projected against time after treatment by life table methods. Finally, in most earlier evaluations of surgical treatments of CVD, background differences in the use of compressive therapy or adjunctive procedures were usually ignored, even though most patients after venous operations spent an extended period with their legs elevated and wrapped in compressive dressings or subsequently wore elastic stockings. The ﬁrst version of the Society for Vascular Surgery/ International Society for Cardiovascular Surgery reporting standards in venous disease, published in 1988,2 did much to improve these reporting ﬂaws. A three-level classiﬁcation system for CVD was proposed, a scheme of describing the segmental anatomy and etiology of the venous disease was offered, and it was recommended that objective measures of venous function be recorded before and after treatment. It also recommended the use of a +3 to –3 scale for gauging change in status after treatment, much like that proposed for lower extremity arterial disease.1 This required a change in clinical class plus a signiﬁcant change in a physiologic test value to claim signiﬁcant improvement or worsening. Although not all ﬂawed reporting practices were addressed, these reporting standards were a major step in the right direction and clearly established appropriate principles for venous outcomes assessment. Subsequently, an ad hoc international committee of the American Venous Forum was held in 1994 and the CEAP system of classiﬁcation of venous disease was developed.3 CEAP (for full details, see Chapter 4) categorizes the basic elements of the CVD at a given point in time. It separately categorizes the clinical condition of the extremity (C), the

etiology of the disease (E), the anatomic location of the problem (A), and the underlying pathophysiology (P). CEAP allows patients or groups of patients with venous disease to be distinguished from each other, or grouped in common classes and compared in a standard manner. This system was recommended as the main feature of a revision in the venous reporting standards published in 1995,4 and has been promulgated in previous editions of this book.5 However, certain features of CEAP are static and unable to assess change in response to treatment. Most of the C components are not sensitive to change following treatment, and the alphabetical designations in the EAP parts are not quantiﬁable. Pain can be present at any or all levels, and varicose veins can be present with or without pain and with or without swelling, skin changes or ulceration. A patient with a venous ulcer, even though healed, cannot move above C5 regardless of the degree of improvement produced by a treatment. An ad hoc American Venous Forum Committee on Venous Outcomes was charged with developing a more ﬂexible method for assessing the results of treatment of CVD without undermining the CEAP system. Ultimately, a venous severity scoring system was recommended, including a Venous Clinical Severity Score (VCSS) based on the clinical components of CEAP. A Venous Segmental Disease Score (VSDS, also known as the Anatomic Score) allowed scoring of the major venous segments according to duplex ultrasound-determined reﬂux or obstruction. The existing venous disability score was modiﬁed by keying it to a background of performing usual daily activities rather than an 8 hour working day. These three adjuncts to outcomes assessment have been published6 and will be presented in detail below. They are major changes from the original CEAP, the full version of which included a severity score, identiﬁed 18 anatomic segments for reporting purposes, and proposed a disability score, all of which have now been replaced by these new methods of assessment. Subsequently, the CEAP classiﬁcation system itself was revised7 to standardize nomenclature and better accommodate differences within two of the clinical classes. This is described in more detail in Chapter 4.

Venous severity scoring PRINCIPLES AND ADVANTAGES

To provide a practical evaluation of the success or failure of a treatment, methods of outcomes assessment need to gauge change in status using objective measures. The endpoints must also be capable of promptly reﬂecting improvement or worsening. Ideally, end-points are quantiﬁable. Properly comparing the outcomes of two or more treatments in the same institution, or the reported results of the same treatment from different institutions,

686

Outcome assessment in chronic venous disease

or the results of the same treatment using different adjunctive measures, is not possible unless the relative severities of the underlying disease in the treatment groups are known.8 If severity of disease is uniformly quantiﬁed, and the score can change signiﬁcantly with treatment, a disease severity score can not only serve as a background against which to view other outcome criteria, and in comparing treatment groups, but can also reﬂect the degree of change in disease severity associated with treatment. A venous severity scoring system is therefore a valuable adjunct in venous outcomes assessment. RATIONALE AND STRATEGY

Although a “clinical score” was included in the original full CEAP document, it used a 0–2 grading of a number of symptoms and signs. These included pain and venous claudication, as well as the characteristic elements of the C3–C6 levels of CEAP, for a maximum score of 18. The assignment of scores was subjective. Scoring levels were not delineated by descriptive terms. This scoring scheme did not gain widespread use or acceptance, and is not included in the current version of venous reporting standards.4 Nevertheless, the approach was conceptually sound; it simply needed a better grading scheme and clearer descriptors to assure uniform scoring. The new Venous Clinical Severity Score (VCSS), to be described below, was modiﬁed to correct these ﬂaws. Developing a severity score based on the EAP of CEAP was more problematic. The “E”, representing etiology, is ﬁxed and could not be incorporated. It was left alone, with the recommendation that primary, secondary (postthrombotic), and congenital venous disease be segregated in assessing treatment outcomes. However, both the anatomic segments “A” and the pathophysiology “P” of CEAP represented objective, gradable data. Since each segment (A) is or is not involved in the essential pathophysiologic processes (P) of reﬂux and/or obstruction, they could be combined and adapted into a grading scheme capable of not only reﬂecting disease severity but in some situations even gauging change with treatment. Importantly, it was felt that such a scheme should be able to be scored using duplex scan ﬁndings. The scheme chosen became the Venous Segmental Disease Score (VSDS) described below.

The Venous Clinical Severity Score: based on the clinical class of CEAP DESIGN FEATURES

The following strategy evolved in developing the venous clinical severity score. (1) Use the basic clinical elements of CEAP where possible. (2) Give additional weight to the upper levels, C4–C6, by separately scoring certain attributes of these levels. (3) Avoid static elements; use

only those able to reﬂect change over a relatively short period of time. Subcutaneous ﬁbrosis, one of the hallmarks of C4–C6, was therefore not included. (4) Employ the 0–3 grading scheme for all clinical descriptors (0, absent; 1, mild; 2, moderate; 3, severe) to allow assessment of improvement at each level. (5) Deﬁne and describe each level and each grade in sufﬁcient detail to minimize overlap and arbitrariness in assigning scores. CLINICAL DESCRIPTORS CONSIDERED AND CHOSEN

All six clinical class levels (C1–C6) and separate characteristics of C4–C6 (pigmentation, inﬂammation, induration, ulcer size, number, multiplicity, duration) were considered as gradable clinical descriptors. C1 (telangiectasias and reticular veins) was eliminated because it was not considered a major pathologic characteristic of the patient with CVD. Neuropathy, venous eczema, and venous claudication were considered, but not included. They were not considered universal enough characteristics of CVD. Disability scoring was felt to be important in its own right and was retained as a separate score (the new Venous Disability Score is presented separately below). Ultimately, nine clinical descriptors were selected: pain, varicose veins, edema, pigmentation, induration, inﬂammation, total number of ulcers, duration of active ulceration, and size of largest current ulcer. Advanced skin changes without ulceration in a very compliant patient may well represent a greater severity of CVD than multiple active ulcers in a non-compliant patient, or one who had never been introduced to compressive therapy and elevation. It was ultimately decided to include compressive therapy, and compliance with it, as a 10th component, including 0–3 points for differences in background conservative therapy and rounding out the maximum score at 30. The Venous Clinical Severity Score in its ﬁnal form is presented in Table 63.1. It is accompanied by qualifying comments regarding its application. As a minimum, it is recommended that each of these nine clinical characteristics be scored, as separate items, from 0 to 3. Their total, along with the 10th item, the degree of use of compressive therapy, can then be combined to facilitate numeric comparison. The current version of the VCSS admittedly represents opinion and is not drawn from study data. However, soon after its publication, validation studies were performed.9,10 It has been successfully used in a major clinical study.11 French phlebologists12 concluded that while the VCSS might be excellent for advanced CVD it was weak in evaluating superﬁcial venous disease. However, this view was recently repudiated by Vasquez et al.,13 who found good correlation with other outcome measures in symptomatic patients undergoing superﬁcial vein ablation. A possible explanation for these differing assessments of the VCSS may lie in the fact that the latter

Evolution of venous outcome assessment methods and current status 687

Table 63.1 Venous Clinical Severity Score (from Rutherford et al.6) Attribute

Absent = 0

Mild = 1

Moderate = 2

Severe = 3

Pain

None

Varicose veins*

None

Daily, moderate activity limitation, occasional analgesics Multiple: single-segment great saphenous/small saphenous reﬂux

Daily, severely limits activities, regular use of analgesics Extensive: multisegment great saphenous/small saphenous reﬂux

Venous† edema

None

Occasional, not restricting activity or requiring analgesics Few, scattered: branch varicose veins with. competent great saphenous/small saphenous Evening ankle edema only

Afternoon edema above ankle

Skin pigmentation

None or focal, low intensity (tan)

Diffuse, but limited in area and old (brown)

Morning edema above ankle requiring activity change, elevation Wider distribution (above lower third) and recent pigmentation

Inﬂammation

None

Induration

None

Total no. ulcers‡ Active ulceration, duration Active ulcer, size Compressive therapy¶

0 None None Not used or not compliant

Diffuse over gaiter distribution (lower third) or recent pigmentation (purple) Mild cellulitis, limited or Moderate cellulitis, marginal area around ulcer involves most of gaiter area Focal, circummalleolar Medial or lateral, less (< 5 cm) than lower third 1 2–4 < 3 months > 3 months, < 1 year < 2 cm diameter 2–4 cm diameter Intermittent use of Wears elastic stockings stockings most days

Severe cellulitis (lower third or above) or venous eczema Entire lower third or more >4 Not healed > 1 year > 4 cm diameter Full compliance stockings + elevation

*To assure differentiation between C1 and C2, “varicose” veins must be > 4 mm diameter to qualify for C2. Occasional or mild edema and focal pigmentation over varicose veins does not qualify for C3 or C4. †Presumes venous origin by characteristics, e.g., brawny (not pitting or spongy) edema, with signiﬁcant effect of standing/limb elevation and/or other clinical evidence of venous etiology, i.e., varicose veins, history of deep vein thrombosis. Edema must be a regular ﬁnding, e.g., daily occurrence. ‡Total number equals active and healed. ¶Sliding scale to adjust for background differences in use of compressive therapy.

experience did not include cosmetic indications but was limited to patients with signiﬁcant symptoms.

The Venous Segmental Disease Score: a combination of the anatomic and pathophysiologic components of CEAP DESIGN CONSIDERATIONS AND RATIONALE

This score attempts to combine the pathophysiologic designations of reﬂux and obstruction for each major anatomic venous segment involved with either process. Points are separately assigned for reﬂux and/or obstruction. It is important to emphasize that the VSDS is solely derived from anatomic evidence of reﬂux and venous obstruction. It does not score the physiologic severity of the reﬂux or obstruction.

ANATOMIC SEGMENTS CHOSEN

Although 18 venous segments are designated for the anatomic localization of disease in the original CEAP classiﬁcation system, scoring all 18 would be unwieldy and unnecessarily complex. Some were easy to eliminate as playing relatively insigniﬁcant roles when incompetent or obstructed; however, the relative roles of the remainder, as contributors to overall reﬂux and obstruction, were not considered equal. For example, superﬁcial venous reﬂux is a common and signiﬁcant cause of CVD; however, obstruction (e.g., thrombotic occlusion) of superﬁcial veins is usually of minor physiologic consequence. More proximal veins (inferior vena cava, iliac or common femoral vein) are generally considered to play a greater role in symptomatic venous obstruction than distal veins. However, the virtual absence of valves in these veins makes “reﬂux” a normal physiologic event in these segments. The

688

Outcome assessment in chronic venous disease

Table 63.2 Venous Segmental Disease Score (based on venous segmental involvement with reﬂux or obstruction*) (from Rutherford et al.6) Reﬂux 1/2 1 1/2 1 2 2 1 1 1

Small saphenous Great saphenous Perforators, thigh Perforators, calf Calf veins, multiple (posterior tibial alone = 1) Popliteal vein Femoral vein Profunda femoris vein Common femoral vein and above†

10

Maximum reﬂux score‡

Obstruction (excised/ligated)

1

Great saphenous (only if from groin to below knee)

1 2 1 1 2 1 1 10

Calf veins, multiple Popliteal vein Femoral vein Profunda femoris vein Common femoral Iliac vein Inferior vena cava Maximum obstruction score‡

*As determined by appropriate venous imaging (phlebography or duplex scan). †Normally there are no valves above the common femoral vein. ‡Not all of the 11 segments can be involved in reﬂux or obstruction. Qualifying comments 1 Reﬂux means that all the valves in that segment are incompetent. Obstruction means there is total occlusion at some point in the segment or > 50% narrowing of at least half of the segment. 2 Most segments are assigned 1 point but some segments have been weighted more or less to ﬁt with their perceived signiﬁcance, e.g., increasing points for common femoral or popliteal obstruction and for popliteal and multiple calf vein reﬂux and decreasing points for small saphenous or thigh perforator reﬂux. 3 Points can be assigned for both obstruction and reﬂux in the same segment. This will be uncommon but can occur in some post-thrombotic states, potentially giving secondary venous insufﬁciency higher severity scores than primary disease.

popliteal vein has an enhanced signiﬁcance when involved in either reﬂux or obstruction, presumably from its unique position as the only outﬂow of the calf muscle pump. Pathologic tibial veins, as well as the popliteal vein, are more highly associated with venous insufﬁciency than the proximal veins.14,15 With these considerations in mind, 2 points were assigned for the venous segments considered to play a signiﬁcant role in obstruction or reﬂux and 1 point was assigned to most other major veins, with the point value being reduced for those of lesser signiﬁcance. In recognition of the higher morbidity associated with post-thrombotic venous insufﬁciency, it seemed reasonable to assign points for both obstruction and reﬂux scales to involved segments of such limbs. Recanalized post-thrombotic veins can be incompetent but are also signiﬁcantly narrowed. The ﬁnal version of the VSDS is presented in Table 63.2, which includes qualifying comments regarding its application. Although it is recognized that this VSDS is also arbitrary, it is recommended that further modiﬁcations be done after appropriate ﬁeld testing, using objective correlative data. To the authors’ knowledge, no comprehensive studies validating this scheme or its value in evaluating the treatment of CVD have been reported.

The Venous Disability Score: a modification of the original CEAP disability score The disability score originally developed with CEAP was featured in the previous edition of this book,3 but is not part of the revised venous reporting standards.4 Unfortunately, in this version, disability is related to working an 8 hour day and ability to work. It is felt that this should be modiﬁed in that many patients with CVD do not ordinarily work an 8 hour day (retirees, students, etc.). The previous disability score also referred to ability

Table 63.3 Venous Disability Score (from Rutherford et al.6) 0 1 2 3

Asymptomatic Symptomatic but able to carry out usual activities* without compressive therapy Can carry out usual activities* only with compression and/or limb elevation Unable to carry out usual activities* even with compression and/or limb elevation

*Usual activities means patient’s activities before onset of disability from venous disease.

Evolution of venous outcome assessment methods and current status 689

to work with or without a “support device.” To avoid misinterpretation, it was felt that “support device” should be identiﬁed as compression therapy with or without intermittent leg elevation. “Usual activities” is further qualiﬁed as normal activities for the patient, carried on before being disabled by venous disease. This modiﬁcation, presented in Table 63.3, is intended to widen the application of this aspect of CEAP to a broader population.

operative approach to CVD, and claiming beneﬁt from one particular procedure or combination of procedures while sometimes performing them concomitantly with other procedures. There is nothing wrong with practicing what one feels is the most appropriate combination of operations in a given patient, but it is wrong to expect one’s colleagues to accept this as scientiﬁc proof that one approach is superior to another, or that one of several procedures performed has measurable beneﬁt. One of two ways of isolating the effect of the primary operation under consideration are recommended.

Other reporting practices recommended to compensate for differences in adjunctive treatments while assessing a primary intervention

1. Do not apply the primary operation until all indicated lesser procedures have been carried out. For example, perform deep venous valvuloplasty or valved transplant only after superﬁcial and/or perforating vein incompetence has been corrected and the clinical status stabilized. 2. Compare the outcomes of patients having the primary procedure plus the adjunctive procedure(s) with those having the adjunctive procedure(s) alone, making sure that the studied patients have a similar distribution and severity of disease. The recommended approaches should sufﬁce for evaluating perforating vein interruptions or operations to combat deep venous valvular insufﬁciency.

As has been pointed out, background differences in conservative therapy are often ignored when evaluating interventional therapy. Compression may contribute to improved initial outcome, as in enhanced ulcer healing, and has been called “the placebo effect of venous surgery.” Its impact should be recognized but, as part of proper postoperative care, it cannot be controlled. This has been only partly addressed by points awarded in the VCSS. Therefore, as a governing rule for standardized reporting of CVD, the following recommendation is made: It is recommended that assessments of the outcome of venous interventional procedures use randomized or concomitant matched controls with conservative treatment alone, if the intent is to demonstrate a benefit from such intervention over and above conservative treatment. Alternatively, investigators should take adequate measures to assure that the background treatment of compressive therapy and limb elevation remains constant in the period before and beyond the perioperative period. An equally vexing reporting practice is failure to control for concomitant adjunctive procedures carried out at the time of the primary operation under assessment. A common example is carrying out ligation and stripping of superﬁcial veins and/or perforating vein interruption at the same time as deep venous surgery. Beneﬁt may be assigned to the deep procedure, but it is not appropriate to assign all improvement to this procedure as studies have shown signiﬁcant improvement from correcting superﬁcial and/or perforating vein insufﬁciency alone. The same can be said for assessing perforating vein interruption in the setting of saphenous vein stripping. The rationale is that it is unfair to patients not to fully treat their CVD at one operation. However, misleading reporting practices are also unfair to future patients if credit is given to one procedure without considering the beneﬁt of concomitant procedures. The time has come to stop reporting retrospective outcome analyses of one’s

Although these two examples are the most common offenders, there are other operations in which these principles would equally apply. The bottom line is that a study protocol must isolate the procedure in question and use appropriate controls to assess its beneﬁt.

Others needed measures in the assessment of venous outcomes in chronic venous disease A number of other unmet needs remain, which, if resolved, would greatly improve outcomes assessment. These include the following. 1. Establishing a universally acceptable instrument for patient-based assessment of the impact of venous disease and its treatment on quality of life (QoL), by either selecting the best of the current instruments or combining the best elements of existing QoLs in a new instrument. 2. Comparing current venous diagnostic tests in terms of their ability to assess venous dysfunction and then establish standardized limits/range of normal as well as the degree of change that constitutes “signiﬁcant” change (improvement/worsening) resulting from treatment. 3. Identify and grade those risk factors that signiﬁcantly affect outcome after deep vein thrombosis (DVT), as opposed to risk factors which predict the risk of developing DVT.

690

Outcome assessment in chronic venous disease

This last point does not directly relate to assessing the treatment of CVD but is mentioned here in that it would allow comparing methods of treating DVT as judged in terms of its late consequences, often referred to as secondary CVD. In addition, proper cost–beneﬁt studies are also needed in assessing the treatment of CVD. The ﬁrst three of these residual needs, and their possible solutions, will be discussed separately. PATIENT-BASED ASSESSMENTS OF THE IMPACT OF THE TREATMENT OF CHRONIC VENOUS DISEASE ON THE QUALITY OF LIFE

There is general agreement that proper patient-based QoL instruments could be of signiﬁcant value in evaluating the treatment of CVD. Because severity of symptoms and signs of CVD do not always closely correlate with each other, QoL instruments might be particularly helpful in clinical investigations of CVD and its treatment. There is also a pressing need to demonstrate the value of certain treatments to healthcare authorities for authorization for reimbursement. (Compressive therapy to manage chronic symptoms of CVD is an obvious example.) The key issues in assessing QoL for venous outcomes assessment can be presented as a series of questions. (1) Do general QoL instruments sufﬁce for this purpose or should they be used in conjunction with disease-speciﬁc (venous) questionnaires, and vice versa? (2) If so, which general or generic QoL instrument should be used? (3) Of the venous-speciﬁc questionnaires, is any one adequate for evaluating the treatment of CVD in its broadest context, or should separate, more speciﬁc questionnaires be used (e.g., one for patients with varicose veins, another for patients with venous ulcer)? (4) Depending on the answers to the above questions, should an additional venous QoL instrument be developed which is more suitable for all of CVD? Varicose vein surgery16 and long-term DVT outcome17,18 have been evaluated using the Medical Outcomes Study Short Form (SF-36) health assessment questionnaire alone. However, most now feel that outcome assessment would be better served if a generic instrument were augmented by venous-speciﬁc questionnaires. Currently, the SF-36 or the SF-12 seems preferred for use in conjunction with a disease-speciﬁc questionnaire. Several (n = 8) venous disease-speciﬁc instruments have been developed to date suggesting possible dissatisfaction with existing instruments. Some have been speciﬁcally designed for evaluating patients after the treatment of deep venous thrombosis and will not be considered here. Four have been developed for evaluating CVD and deserve mention. 1. CIVIQ. A French group has developed and validated a questionnaire for patients with venous disease.19 It is short, consisting of only 20 questions, and has been prepared in an English version. It emphasizes four

dimensions – psychological, pain, physical and social function. Internal consistency (alpha > 0.82) and stability (r > 0.82) are excellent. External validity with the SF-36 was not measured. CIVIQ does not sufﬁciently emphasize the speciﬁc anatomic and physiologic issues of severe CVD. It is limited to certain objective ﬁndings and subjective symptoms, some of which are vague. Edema, induration, skin temperature change, cyanosis/erythema were primary inclusion criteria and symptoms included heavy legs, leg pain, nocturnal cramps, paresthesias, or burning sensations. Validation was performed in a diffuse group of patients from three general practice settings who were thought to have CVD. However, the presence of lipodermatosclerosis or ulceration was not noted and objective venous testing was not performed routinely. 2. The Aberdeen Questionnaire.20 This is well validated and has been used with the SF-36.21 It includes 20 questions, seven of which separately detail the right and left leg. The severity of its components are weighted in a scoring system which attributes the greatest value to the anatomic distribution of varicose veins, as drawn by the patient; the second greatest value is attributed to ulceration; and the third to eczema (rash). Cosmetic considerations are juxtaposed with the severity of longstanding disease. Smith et al.22 ﬁrst applied it clinically to the evaluation of varicose vein surgery and further validated it against a 25-question “patient’s symptoms and concerns” scale. This instrument clearly targets varicose veins primarily. There are no questions directed speciﬁcally towards deep venous disease. 3. The Charing Cross Venous Ulcer Questionnaire. Smith and colleagues23 have also formulated a questionnaire speciﬁcally for venous ulceration. This questionnaire, which was reﬁned from 32 down to 20 items, and the SF-36 general health measure were given to a prospective consecutive cohort of 98 patients with proven venous ulcers diagnosed on clinical and color duplex examination. The ulcer-speciﬁc questionnaire showed good reliability in regard to internal consistency (Cronbach’s α = 0.93) and test–retest analysis (r = 0.84). Four important health factors were identiﬁed: social function, domestic activities, cosmesis, and emotional status. Validity was demonstrated by a high correlation with all eight domains of the SF-36 general health measure (r > 0.55, P < 0.001). Responsiveness was demonstrated by a signiﬁcant reduction in the score of the ulcer questionnaire as ulcers healed at 6 and 11 weeks (P < 0.05). 4. VEINES. This instrument has been developed from a pool of 1531 patients with CVD from institutions in Belgium, France, Italy, and Canada.24 To date at least 15 articles have been published using this instrument to evaluate patients with CVD, each with a different focus, e.g., correlation with CEAP classes, patients with postthrombotic syndrome, patients with a history of venous thromboembolism, patients with varicose veins.24–29

Evolution of venous outcome assessment methods and current status 691

The usual validation studies have been carried out with acceptable performance. The only difﬁculty is that nearly all the studies have been published by those who developed the instrument. It is conceivable that it ﬁlls the need for a comprehensive venous QOL instrument which can be applied to all levels of CVD from varicose veins, to post-thrombotic syndrome, to primary deep venous valvular insufﬁciency, but it needs independent appraisal in patients not included in the cohort used to develop it. It also needs to be independently compared with the other available instruments.

STANDARDIZATION OF NON-INVASIVE VENOUS TESTING TO PROVIDE OBJECTIVE CRITERIA FOR REPORTING PRACTICES

The venous status scale featured in the current venous reporting standards to gauge the “ﬁnal outcome after surgery” combines a categorical change in clinical status with a signiﬁcant change in an objective functional test, in a +3 to –3 scale.4 What constitutes “signiﬁcant change” and which tests and values are appropriate and equivalent for use as objective gauges of reﬂux, obstruction, or overall abnormal venous function deserves clariﬁcation and standardization. The test values separating normal from abnormal for some of the more commonly used noninvasive tests are generally better known than what constitutes “signiﬁcant change.” In addition, the test conditions such as body or limb position, duration and method of standardizing leg muscle pump activity, release of venous occlusion, etc. need standardization. In principle, normalization of a test is clear evidence for signiﬁcant improvement, and would qualify for a +3 rating on the above scale. For a +2, or, in the absence of clinical categorical improvement, a +1 designation, one basically needs to know and apply the least degree of change which is beyond reasonable limits of operator error. Although it might seem a simple task to determine the conﬁdence limits of test reproducibility, this is not easy to do in a universally accepted way, considering variations in disease and variable operator skills and test reproducibility in different vascular diagnostic laboratories. Such factors have contributed to standardization not being achieved. Exemplifying this is the generalizable observation that in CVD a small change can normalize a slightly abnormal test value. Conversely, when the test is very abnormal, a greater degree of change may be needed to make a signiﬁcant difference. For example, for the Venous Filling Index (VFI), using air plethysmography, an abnormal value is stated to be > 2.0 mL/s (E Arkans, personal communication). Below that value, in the normal range, a change of 0.3 mL/s is said to be signiﬁcant; from 2 to 10 mL/s a change of 1 mL/s is signiﬁcant; and, in the very abnormal range > 10 mL/s, a change of 2 mL/s is signiﬁcant.22 In other tests, speciﬁcally duplex evaluation of valve reﬂux and venous obstruction, only normalization is accepted as

signiﬁcant change and evidence of improvement with treatment. Finally, the tests themselves do not correlate evenly with changes in clinical classiﬁcation. It is not a simple matter. The need for test standardization would best be met by a multicenter study of the most widely used tests, performed together and repeatedly on the same subjects, with normal subjects and patients with different degrees of abnormality fully represented and CEAP staged. The ad hoc subcommittee on Venous Outcomes of the American Venous Forum has approved the need for such a study and pilot studies have been carried out. However, accumulating and analyzing such data, as the basis for solid recommendations, will take considerable time. Meanwhile, can interim guidelines be proposed? Sixteen recognized experts on venous testing were surveyed as to which tests are acceptable to use as objective criteria to gauge “abnormal venous function” and a “signiﬁcant change” in venous function, as well as their view of the reliability of each as either a “stand alone” or a conﬁrmatory test of clinical evidence of change, as in the +3 to –3 scale suggested in the venous reporting standards.30 The results of this survey were viewed in the light of the “Paris consensus” on such investigations. The following are offered as interim guidelines. Reflux ●

●

●

●

Ambulatory venous pressure. Abnormal value, > 30 mmHg; signiﬁcant change, > 10 mmHg. Photoplethysmography. Venous reﬁll time: abnormal value, < 20 s sitting; < 18 s standing; signiﬁcant change, > 5 s. Air plethysmography. Venous Filling Index: abnormal value, > 2 mL/s; signiﬁcant change in abnormal value = improvement by > 2 mL/s or normalization. Duplex scan. Valve closure time: abnormal value, > 0.5 s or > 1.0 s (depending on position and technique of release of backﬂow); signiﬁcant change, conversion to normal.

Obstruction ●

●

●

Air plethysmography. Outﬂow fraction: abnormal value, < 35% in 1 s; signiﬁcant change, > 10%. Venous pressure gradient. Resting, > 4 mmHg; induced hyperemia, > 6 mmHg; signiﬁcant change > 2 mmHg and conversion to normal. Venous occlusion plethysmography [maximum venous outﬂow (VO) vs venous capacitance (VC)]. Abnormal value, > 200 mL/s or VC/VO ratio below discriminate line; signiﬁcant change, conversion from abnormal to normal.

Note that the values offered for signiﬁcant change in some tests do not represent the conﬁdence limits of reproducibility because such intervals are not well established. It was also felt that the least change that could be accepted as objective evidence of change in association with signiﬁcant

692

Outcome assessment in chronic venous disease

(e.g., categorical) clinical improvement would better serve the intended purpose. IDENTIFYING AND GRADING RISK FACTORS THAT SIGNIFICANTLY AFFECT LIMB OUTCOME AFTER DEEP VEIN THROMBOSIS

Although the incidence of recurrent venous thromboembolism, speciﬁcally pulmonary embolism and recurrent DVT, have been the most common end-points in trials evaluating the anticoagulant treatment of acute DVT; the incidence and severity of post-thrombotic signs and symptoms are also important end-points of treatment. To properly compare different therapeutic regimens for acute DVT in this latter regard, one really needs to know the determinants of long-term limb outcome after DVT and be able to grade the treatment groups accordingly. Currently, there is no scheme for doing this, so it is possible that differences in late outcome following treatment could be due to differences in the treatment groups with regard to factors that signiﬁcantly affect outcome rather than differences in the treatments themselves. Factors affecting outcome of DVT need to be identiﬁed which, when scored, would not only correlate with outcome (e.g., using severity scoring) but be able to be assessed at the time of a patient’s presentation with an acute DVT. This would permit a precise description of populations included in clinical trials. It would also allow subgroups that derived the greatest beneﬁt from any treatment to be identiﬁed. In comparing therapeutic regimens, it would also assure comparable treatment groups. Although substantial evidence relating factors affecting long-term outcome after DVT is lacking, the following should be considered and included in reports comparing DVT therapies. The extent of thrombosis Some means of comparing the extent of thrombus among patients subjected to various therapies is necessary. Use of the reporting scheme proposed in the most recent revision of the reporting standards in venous disease4 is recommended. The anatomic distribution of thrombosis At the very least, it would seem appropriate to specify the relative number of limbs with isolated calf vein and proximal venous thrombosis included in any clinical trial. A scoring system based on segments involved might be utilized. Previous thrombotic events The clinical prognosis is clearly worse after symptomatic recurrent thrombotic events, ipsilateral recurrences being associated with a sixfold increased risk of the postthrombotic syndrome.31 It therefore seems logical that patients with a history of previous DVT in the same limb would have a worse outcome with a new episode. The

relative proportion of patients with previous lower extremity thrombosis should be either included in reports of therapeutic clinical trials or speciﬁcally excluded by protocol. Thrombotic risk factors Irreversible thrombotic risk factors should contribute to an increased risk of recurrent thrombosis, and thus an increased risk of post-thrombotic sequellae. No individual clinical risk factors have yet been clearly related to the severity of chronic venous disease. However, some assessment of overall thrombotic risk, such as the weighted scheme included in the updated venous reporting standards,4 should be included in describing patients subjected to treatment. Pursuant to this approach, one of two options seems appropriate: (1) carrying out prospective studies of patients with DVT in signiﬁcant numbers to identify the relative contribution of the above risk factors and other potential determinants of long-term outcome after DVT, then use those data as the basis for a grading scheme, or (2) propose an arbitrary scheme and ﬁeld test it prospectively, modifying it later on the basis of the data obtained. Either way, this effort will likely require studies with large numbers of patients. Trials of new therapeutic approaches should characterize treatment groups in regard to at least the above four risk factors.

ACKNOWLEDGEMENTS The Venous Severity Scoring System, including both the Venous Clinical Severity Score and the Venous Segmental Disease Severity Score, and the modiﬁed Venous Disability, has been published in the Journal of Vascular Surgery.6 The tables in this chapter have been drawn from that article. In addition, certain members of the ad hoc committee on Venous Outcomes of the American Venous Forum have taken the lead in this committee’s ongoing projects that are discussed in this chapter, namely the evaluation of Quality of Life instruments (Frank Padberg), the proposed assessment of factors affecting the outcome of DVT (Mark H. Meissner), and the standardization of non-invasive venous testing (Gregory L. Moneta and, more recently, Fedor Lurie).

REFERENCES = Key primary paper = Major review article ★ = First formal publication of a management guideline ● ◆

1. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997; 26: 517–38.

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Porter JP, Rutherford RB, Clagett GP, et al. Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–81. Nicolaides AN, and members of the executive committee. Classiﬁcation and grading of chronic venous disease in the lower limbs: a consensus statement. In: Gloviczki P, Yao JST, eds. Handbook of Venous Disorders. London: Arnold, 1996: 652–60. Porter JP, Moneta GM, and an International Consensus Committee on Chronic Venous Disease. Reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635–45. Porter JP, Moneta GM, and an International Consensus Committee on Chronic Venous Disease. Reporting standards in venous disease: an update. In: Gloviczki P, Yao JST, eds. Handbook of Venous Disorders. London: Arnold, 1996: 629–51. Rutherford RB, Padberg FT Jr, Comerota AC, et al. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31: 1307–12. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classiﬁcation for chronic venous disorders: consensus statement. J Vasc Surg. 2004; 40: 1248–52. Rutherford RB. Presidential Address: vascular surgery – comparing outcomes. J Vasc Surg 1996; 23: 5–17. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the venous clinical severity score. J Vasc Surg 2002; 36: 889–95. Kakkos SK, Rivers MA, Matsagas MI, et al. Validation of the new venous severity scoring system in varicose vein surgery. J Vasc Surg 2003; 38: 224–8. Ricci MA, Emmerich J, Callas PW, et al. Evaluating chronic venous disease with a new venous severity scoring system. J Vasc Surg 2003; 38: 909–15. Perrin M, Dedieu F, Jessent V, Blanc MP. Evaluation of the new severity scoring in chronic venous disease of the lower limbs: an observational survey conducted by French angiologists. Phlebologie 2003; 56: 127–39. Vasquez MA, Wang J, Mahathanaruk M, et al. The utility of venous clinical severity score in 682 limbs treated by radiofrequency saphenous vein ablation. J Vasc Surg 2007; 45: 1008–15. Rosfors S, Lamke LO, Nordstroem E, Bydegman S. Severity and location of venous valvular insufﬁciency: the importance of distal valve function. Acta Chir Scand 1990; 156: 689. Gooley NA, Sumner DS. Relationship of venous reﬂux to the site of venous valvular incompetence: implications for venous reconstructive surgery. J Vasc Surg 1988; 7: 50–9. Baker DM, Turnbull NB, Pearson JC, Makin GS. How successful is varicose vein surgery? A patient outcome study using SF-36 health assessment questionnaire. Eur J Vasc Surg 1995; 9: 299–304. Beyth RJ, Cohen AN, Landesfeld CS. Long term outcome of DVT. Arch Intern Med 1995: 155: 1031–7.

18. Prandoni P, Lensing AWA, Cogo A, et al. The long term clinical course of acute deep venous thrombosis. Ann Intern Med 1996: 125; 1–7. ●19. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufﬁciency. Qual Life Res 1996; 5: 539–54. 20. Garratt AM, MacDonald LM, Ruta DA, et al. Towards measurement of outcome for patients with varicose veins. Qual Health Care 1993; 3: 5–10. 21. Garratt AM, Ruta DA, Abdalla MI, Russell IT. Responsiveness of the SF-36 and a condition speciﬁc measure of health outcome for patients with varicose veins. Qual Life Res 1996; 5: 1–12. ●22. Smith JJ, Garratt AM, Guest M, et al. Evaluating and improving health related quality of life in patients with varicose veins. J Vasc Surg 1999; 30: 710–19. ●23. Smith JJ, Guest M, Greenhalgh RM, Davies AH. Measuring quality of life in patients with venous ulcer. J Vasc Surg 2000, 31: 642–9. ●24. Lamping DL, Schroter S, Kurz X, et al. Evaluation of outcomes in chronic venous disorders of the leg: development of a scientiﬁcally rigorous, patient-reported measure of symptoms and quality of life. J Vasc Surg 2003; 37: 410–19. 25. Kahn SR, M’Lan CE, Lamping DL, et al. and the VEINES Study Group. Relationship between clinical classiﬁcation of chronic venous disease and patient-reported quality of life: results from an international cohort study. J Vasc Surg. 2004; 39: 823–8. 26. Kahn SR, M’Lan CE, Lamping DL, et al. and the VEINES Study Group. The inﬂuence of venous thromboembolism on quality of life and severity of chronic venous disease. J Thromb Haemost 2004; 2: 2146–51. 27. Kurz X, Lamping DL, Kahn SR, et al. and the VEINES Study Group. Do varicose veins affect quality of life? Results of an international population-based study. J Vasc Surg 2001; 34: 641–8. 28. Kahn SR, Ducruet T, Lamping DL, et al. Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Arch Intern Med 2005; 165: 1173–8. 29. Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med 2002; 162: 1144–8. ★30. Nicolaides AN, for the consensus group (Cardiovascular Disease Educational and Research Trust; European Society of Vascular Surgery; The International Angiology Scientiﬁc Activity Congress Organization; International Union of Angiology; Union Internationale de Phlebologie). Investigation of chronic venous insufﬁciency: a consensus statement. Circulation 2000; 102: E126–63. 31. Prandoni P, Lensing A, Cogo A, et al. The long term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1–7.

64 Mapping the future: organizational, clinical, and research priorities in venous disease* MARK H. MEISSNER, BO EKLÖF, PETER GLOVICZKI, JOANN M. LOHR, FEDOR LURIE, ROBERT KISTNER, GREGORY L. MONETA AND THOMAS W. WAKEFIELD Introduction Advancing the art and science of treatment of venous disease Acute venous thromboembolism Venous diagnostics and hemodynamics

694 695 696 697

INTRODUCTION Perhaps more so than in other areas of medicine and surgery, the management of acute and chronic venous disease remains somewhat diffuse. A wide variety of medical and surgical specialties are responsible for the prevention, diagnosis, and treatment of acute deep vein thrombosis (DVT) and patients with chronic venous disease (CVD) may be managed by primary care physicians, dermatologists, interventional radiologists, phlebologists, general surgeons, vascular medicine specialists, and vascular surgeons. Each may have a different approach to venous disease depending on their practice demographics, experience, and training. Furthermore, although the standard of care for acute venous thromboembolism has been established by randomized clinical trials and evidence-based guidelines have been developed,2 outcomes such as the postthrombotic syndrome have received inadequate attention, potential adjuncts such as thrombolytic therapy have not been adequately evaluated, and there remain problems with widespread dissemination of the guidelines. In the case of chronic venous disease, many treatment approaches are based on observational data and have not been subjected to rigorous trials. Furthermore, the current approaches to some problems, such as post-thrombotic

Primary chronic venous disease Secondary chronic venous disease Compression hosiery Imua: the future of venous disease References

698 699 701 702 702

deep venous incompetence and the prevention of ulcer recurrence, remain inadequate. Under the auspices of the American Venous Forum (AVF), the Fifth Paciﬁc Vascular Symposium was envisioned as a process to address many of the problems existing in our understanding and management of acute and chronic venous disease. The goals of the meeting were to deﬁne the current state of knowledge in acute and chronic venous disease, and, using this information as a baseline, to identify areas of deﬁciency, establish priorities, and map the future of venous disease with respect to needed research, professional and patient education, organization of the ﬁeld, and management of acute and chronic venous disease. This was accomplished through a process of professionally facilitated appreciative inquiry3 involving collaboration among experts from epidemiology and clinical trials, dermatology, hematology, interventional radiology, phlebology, vascular medicine and surgery as well as representatives from industry and the National Institutes of Health (NIH). The assembled experts were organized into four groups addressing acute venous disease, the hemodynamic and diagnostic evaluation of venous disease, primary chronic venous disease, and secondary chronic venous disease. A ﬁnal break-out group, the International Compression Club, evaluated the current status and future needs of medical compression hosiery.

*Proceedings of the 5th Pacific Vascular Symposium: An International Summit, Mauna Lau, HI, USA, January 20–24, 2006. Reprinted with permission from Meissner et al.1

Advancing the art and science of treatment of venous disease

The current state of knowledge in each of these areas has been reviewed in the December 2007 supplement of the Journal of Vascular Surgery4–7 and provided the basis for developing future priorities for the ﬁeld. Several of the priorities crossed group designations and are discussed ﬁrst below. These are followed by the individual groups’ recommendations for advancing the future of venous disease, in terms of both overall priorities and speciﬁc initiatives that can be begun immediately.

ADVANCING THE ART AND SCIENCE OF TREATMENT OF VENOUS DISEASE Organizational initiatives The American Venous Forum (AVF), with a few exceptions, is largely composed of vascular surgeons. However, physicians from several specialties participate in the care of patients with acute and chronic venous disease and more cooperative efforts across key specialties are needed. Such efforts need to include vascular surgeons, dermatologists, hematologists, interventional radiologists, cardiologists and ﬁeld-speciﬁc scientiﬁc experts in areas such as basic science, epidemiology, and genetics. Unless the quality of scientiﬁc collaboration and functional infrastructure are comprehensively improved and promoted (designated “we” priorities), priorities referring to the delivery of medicine from the physician to the patient (“me” priorities) are unlikely to advance effectively. Consistent with these goals, there was consensus that the AVF should direct efforts towards becoming a more broadly inclusive organization. As part of its scientiﬁc mission, the forum should move to establish a clearinghouse for projects related to venous disease, allowing experts to collaborate on speciﬁc initiatives. Such measures could include development of a non-proﬁt foundation to consolidate funding from disparate sources. The focus should be on highest quality evidence and credibility; this could be best achieved by collaboration between healthcare organizations, government funding agencies, industry, and members of the AVF and associated groups. A more uniﬁed, broadly inclusive organization would build a culture of cooperation and common purpose among venous specialists. With the purpose of strengthening, consolidating, and coordinating the resources of existing organizations; raising awareness about venous disorders among physicians and the public; and fostering relationships among those with an interest in all aspects of venous disease; formation of a Joint Venous Council was recommended. Council members would include representatives from the major societies, industry, government, and the public. This group might be structured similar to the PAD coalition that has focused on issues relating to peripheral arterial disease. A steering committee has been

695

formed to implement this proposal and will develop an organizational framework, propose membership of the Joint Council, and plan an agenda for the ﬁrst meeting. A second universal theme was the need to develop a new training paradigm to properly train physicians in the diagnosis, treatment, and investigation of the entire spectrum of venous disorders. There is a clear need for an organized, evidence-based postgraduate venous curriculum. The development of an “angiology” specialty was suggested as a long-term goal to be discussed at future meetings. Creation of dedicated venous clinics with accreditation standards and a focus on education would be part of this project. Signiﬁcant resources should also be devoted to educating non-specialists (especially in the primary care and hospital settings) in the prevention of DVT and leg ulcers. A global information system to facilitate reporting of venous disease was also considered important in advancing communication among investigators. Such a system could be used to develop and implement longitudinal epidemiologic studies characterizing the demographic, environmental, anthropomorphic, and social factors that lead to development of chronic venous disease in an international population. It would be useful in standardizing clinical trials of venous thrombosis, as well as evaluating drugs and devices for the treatment of venous disorders. Such a system could also improve the education of practicing physicians, private and governmental health care agencies, and the public. Finally, all groups agreed to the need for increased governmental recognition of the importance of venous disease and innovative approaches to research funding incorporating both private commercial investment and governmental funding.

Clinical and research initiatives The therapy of venous disorders must become more organized and evidence-based and should include development of better drugs for acute and chronic venous disease, as well as reﬁnement of existing surgical procedures and development of new procedures and devices. Potential new devices for the treatment of venous disease include improved stenting systems, biodegradable ﬁlters, venous conduits, angiogenesis factors, artiﬁcial valves, and skin replacements. A better understanding of the interaction among devices and the coagulation and inﬂammatory systems will be required to properly assess any new device. Quality of life assessments must also be part of the evaluation of any new drug, device, or therapeutic approach to venous disorders and the associated psychosocial problems need to be more fully addressed. Finally, from a clinical perspective, the development of integrated, multidisciplinary teams is essential in the treatment of patients with more advanced manifestations of CVD.

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Mapping the future: organizational, clinical, and research priorities in venous disease

ACUTE VENOUS THROMBOEMBOLISM The acute venous disease study section was charged with developing global programs to promote the awareness and prophylaxis of venous thromboembolism (VTE) as well as developing speciﬁc scientiﬁc projects to improve present standards of care. Several sessions were devoted to the identiﬁcation of projects that would advance the treatment of venous disease through emerging technologies in clinical and basic science. From these discussions came three speciﬁc research endeavors that could be implemented in the next funding cycle. Many other potential initiatives were discussed, with the goal of using this meeting to launch future projects.

General priorities in acute venous thromboembolism Several areas of need were identiﬁed and discussed in enough detail to initiate corrective measures and scientiﬁc studies in the near future. The need for a cooperative, interdisciplinary approach to venous disease; the advantages of a multidisciplinary, multicenter approach to research; and the need for a partnership between governmental funding agencies and industry has been discussed above. From an organizational standpoint a network of physicians interested in clinical protocols and basic research is also needed. This network should be internetbased and must be responsive to government-sponsored requests for proposals and industrial opportunities. Increased involvement of the AVF research committee in coordinating a web article repository, serving as a clearinghouse for Paciﬁc Vascular (V) reports and organizing lifeline venous research presentations, is also needed. From a research perspective, the basic mechanisms of venous thrombosis initiation and resolution need to be further investigated with the goal of designing future clinical trials in a hypothesis-driven manner. Crucial to further efforts is the integration of acute DVT outcomes research with therapies to improve and standardize patient care.

Specific research initiatives in acute venous thromboembolism Three speciﬁc research projects were identiﬁed as warranting immediate attention and planning. STRATEGIES FOR EARLY THROMBUS REMOVAL

Despite encouraging results from large multicenter registries8 and small trials,9,10 there is a lack of randomized clinical trial data supporting the use of early thrombus removal techniques in the treatment of acute DVT, and such strategies are not routinely recommended by current

consensus guidelines.2 There is a clear need for generalizable, randomized clinical trials comparing standard anticoagulation with “open vein” strategies designed to remove thrombus early after presentation with mechanical or pharmacological catheter-based thrombolytic techniques. Such trials should be of an international, multicenter design with anatomic stratiﬁcation (iliofemoral versus femoropopliteal thrombosis) of patients. The design should include a 1 year run-in period to bring all centers online and perform early harm analysis. There was consensus in allowing some latitude with respect to the speciﬁc technique of thrombus removal (mechanical, pharmacological, or combination) to accommodate improvements in technology. Emphasis was placed on 5-year as well as 1-year outcomes with respect to quality of life, rate of recurrent VTE, and objective development of the post-thrombotic syndrome. It is notable that a similar initiative, comparing best medical therapy with best interventional strategy for thrombus removal, was designated the highest research priority at a multidisciplinary consensus panel arranged under the auspices of the Cooperative Alliance for Interventional Radiology Research (CAIRR) and the Society for Interventional Radiology (SIR).11 The participants at the Paciﬁc Vascular Symposium broadly supported such a trial and agreed to assist in the design and implementation of a deﬁnitive study as needed. DEFINING THE ROLE OF INFERIOR VENA CAVA FILTERS

The safety of permanent ﬁlters, as well as the development of retrievable ﬁlters, has led to their extended use for a number of perceived relative indications12,13 without substantial evidence to support such practices. Trials comparing the use of permanent and retrievable inferior vena cava (IVC) ﬁlters with prophylaxis and DVT surveillance strategies in high-risk patients (e.g., comorbid obesity, trauma, and intracerebral hemorrhage) are desperately needed. The development and implementation of such a trial would optimally involve the multidisciplinary participation of surgeons and intensive care specialists. Trial end-points should include survival, incidence of VTE, cost, length of intensive care unit and hospital stay, and device-speciﬁc complications such as IVC patency and ﬁlter migration. BIOMARKERS IN DEFINING PROGNOSIS AND DETERMINING DURATION OF ANTICOAGULATION AFTER ACUTE DEEP VEIN THROMBOSIS

Preliminary data suggest that the levels of ﬁbrinolytic inhibition and activated coagulation are related to the extent of recanalization.14 Furthermore, although the duration of anticoagulation is currently based on the risk of recurrent VTE, determined by randomized clinical trials,2 observational data suggest that incomplete recanalization documented by ultrasonography15,16 and

Venous diagnostics and hemodynamics

persistently elevated D-dimer levels17 after discontinuing oral anticoagulants are important risk factors for recurrence. There is a need for robust management trials of speciﬁc markers of coagulation (D-dimer, thrombin– antithrombin complex, microparticles, prothrombin fragment 1 + 2) and ﬁbrinolysis (tissue-type plasminogen activator and plasminogen activator inhibitor 1) in determining the type and duration of therapy for acute VTE. End-points would include thrombus extension, recanalization, and recurrent VTE. Biomarkers would be quantiﬁed at presentation, 1 week prior to discontinuation of therapy and 4 weeks following the completion of therapy. Patients would be followed for at least 2 years to document end-points.

Other research priorities in acute deep vein thrombosis Other studies proposed, but not developed in detail, included development of a test or panel of tests (a “thrombochip”) to stratify the risk of VTE and predict outcomes after acute DVT. Such knowledge would permit interventions and duration of therapy to be individualized based on genomic, proteomic, and serum biomarker proﬁles. Studies deﬁning the true natural history and appropriate management both of secondary upper extremity DVT and proximal saphenous thrombophlebitis are also needed. There is clearly no consensus regarding the treatment of superﬁcial venous thrombophlebitis and a registry may be more appropriate than a formal trial as an initial step. Projects including strategies to promote DVT awareness and improve compliance with established American College of Chest Physicians (ACCP) guidelines18 were also encouraged. Multicenter projects to generate support for young investigators and to assist with AVFsponsored submissions to the NIH were also proposed.

VENOUS DIAGNOSTICS AND HEMODYNAMICS This group focused on unresolved issues and future projects involving the diagnosis of acute and chronic venous disease. As venous diagnostic testing requires a thorough understanding of venous physiology and hemodynamics, this group was termed the Diagnostics/ Hemodynamics Group. After preliminary discussions in break-out groups, the Diagnostics/Hemodynamics Group developed plans and recommendations for research projects relevant to venous diagnosis.

General priorities in venous diagnostics and hemodynamics The initial discussions of the Diagnostics/Hemodynamics Group were broadly focused and several ideas were

697

advanced. Future research should focus on the identiﬁcation of molecular, serologic, and genetic markers that may be useful in detecting venous disease a priori, perhaps in conjunction with targeted thrombophilia testing and assessment of environmental risk factors. Such information might facilitate more individualized treatment of patients with acute venous thrombosis and chronic venous disease and aid in identifying the contribution of individual risk factors to the overall risk of venous thrombosis. Further work is needed to improve our understanding of venous physiology, pathophysiology, and natural history. This is fundamental to improving diagnostic tests and facilitating precise treatment of patients with venous disorders. The development of a quantitative test for venous obstruction and a global non-invasive surrogate measure of ambulatory venous pressure are particular priorities. In addition, there is a critical need to standardize existing venous tests with respect to indications, testing protocols, and normal ranges. A clear deﬁnition of what constitutes a signiﬁcant change in a testing parameter is particularly needed in patients with advanced CVD who may undergo interventions.

Specific research initiatives in venous diagnostics and hemodynamics Based on these preliminary deliberations, the following projects have been identiﬁed as priorities in advancing our understanding of venous hemodynamics and improving diagnostic modalities. INVESTIGATING VENOUS DISEASE EVALUATION AND STANDARDIZATION OF TESTING (INVEST)

The goals of the INVEST project are to standardize noninvasive testing for acute and chronic venous disease; identify standard quality of life and hemodynamic outcomes; and develop uniform testing protocols. As initially proposed, this project involves three phases. First, the diagnostic modalities currently being utilized in vascular laboratories must be determined. Potential sources of data include the Intersocietal Commission for Accreditation of Vascular Laboratories (ICVAL) database, which can be used to identify tests actually being performed as well as the indications, protocols, and examination and interpretation standards of various vascular laboratories. The Center for Medicare and Medicaid Services (CMS) can also be queried for International Classiﬁcation of Diseases (ICD)-9 and Current Procedural Terminology (CPT) codes to deﬁne the range of tests performed, the indications for testing, and the demographics of those ordering examinations. Members of the venous societies can also be surveyed for their testing practices in patients with acute and chronic venous disease. Secondly, a comprehensive literature

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Mapping the future: organizational, clinical, and research priorities in venous disease

review should be undertaken to examine the tests and standards used in current venous research. Finally, appropriate societal representatives should evaluate the above data and a consensus statement developed regarding protocols for non-invasive venous testing, normal ranges, the deﬁnition of signiﬁcant within-patient change, and recommended examinations based upon common clinical presentations. These suggestions would be added to the existing reporting standards for venous disease.19–21 MAGNETIC RESONANCE OUTFLOW OBSTRUCTION OF VENOUS DISEASE

Magnetic resonance venography (MRV) is among the most promising modalities in venous diagnostic testing. This project aims to explore the use of MRV in assessing venous obstruction. Potential methods of interest include cine-gated MRV to quantify outﬂow obstruction. Softtissue water content should also be evaluated as a potential diagnostic measure. Pre- and post-therapy testing will be performed along with blood tagging (e.g., with gadolinium) studies to evaluate venous inﬂow and outﬂow. ASSESSMENT OF REFLUX AND SYMPTOMATIC EVALUATION

This study proposes to evaluate the anatomic patterns of reﬂux and hemodynamic parameters that most accurately identify individual CEAP (C, clinical; E, etiology; A, anatomy; P, pathophysiology) categories, forecast disease progression to higher CEAP classes, and predict response to therapy (quality of life, ulcer healing). Reﬂux will be evaluated from the inguinal ligament to the ankle using duplex ultrasonography and standing cuff deﬂation methods.22 Diagnostic measurements will include duration of reﬂux, reﬂux velocity, reﬂux volume, reﬂux velocity index and perhaps other as yet unknown parameters. An incompetent valvular severity score will be developed to quantify the overall severity of reﬂux. A multicenter design is required to provide adequate numbers of patients and insure inclusion of patients with varying demographics. Subjects with lymphedema, recent trauma, body mass index > 40, and previous vein surgery would be excluded. DUPLEX ULTRASOUND IN A MULTICENTER STUDY OF ACUTE DEEP VEIN THROMBOSIS (DUMSAD)

Most validated strategies for the diagnosis of acute DVT have limited examination to compression of the proximal veins and have required either serial examinations23,24 or combined algorithms including D-dimer measurement and clinical risk stratiﬁcation.25–28 Despite encouraging preliminary data,29,30 the accuracy of a single, technically adequate duplex scan, including the calf veins, has not yet been sufﬁciently validated. The purposes of the DUMSAD study are to evaluate the accuracy of a single color ﬂow duplex examination,

including the calf veins, in excluding acute DVT; to improve guidelines for the diagnosis of acute DVT; and to deﬁne an adequate scan technique. Subjects should have no prior history of DVT and be clinically symptomatic. In addition to clinical and demographic information, collected data will include physical examination (including calf circumference), clinical probability scores, and Ddimer and C-reactive protein levels. Complete, bilateral color ﬂow duplex scans will be performed including measurement of thrombus location, length, volume, and echogenicity as well as venous diameter and wall thickness. Subjects with negative scans but a high clinical probability of DVT will undergo serial imaging. As comparison with venography would be difﬁcult, this will be a management trial with end-points including the results of clinical and ultrasound follow-up at 6 months. OUTCOME RELATION TO THROMBUS CHARACTERISTICS (OTC)

The purposes of the OTC study are to evaluate the natural history of DVT, including the development of reﬂux, in relation to ultrasound characteristics of the thrombus. Thrombus-speciﬁc measurements will include the extent and location of the thrombus, degree and length of time to recanalization, gray-scale characteristics of the thrombus, and the development of reﬂux and its timing. Analysis will include the effects of type of anticoagulation (lowmolecular-weight heparin versus unfractionated heparin), the use of other adjuvant therapies, and serum markers of coagulation, ﬁbrinolysis, and inﬂammation.

PRIMARY CHRONIC VENOUS DISEASE The working framework for the primary chronic venous disease group was subdivided into topics including prevention, pathophysiology, diagnostics, research, and treatment and intervention.

General priorities in primary chronic venous disease The combination of declining healthcare budgets and an increasing number of patients with CVD will soon render the issue of funding care for complications of primary CVD critical. Population screening for early disease will likely become indispensable in containing the socioeconomic repercussions of primary CVD by enabling timely intervention and prevention of disease progression. Control of associated risk factors; genetic interventions in CVD-related aberrations; selective, safe and long-lasting suppression of inﬂammatory processes; and national awareness of primary CVD are also essential in disease prevention. Optimal treatment of CVD is currently hindered by insufﬁcient knowledge of the pathophysiology, including

Secondary chronic venous disease 699

the sentinel events preceding CVD progression and the effects of inﬂammation, re-epithelialization, matrix deposition, and tissue remodeling. An improved understanding of these pathophysiologic mechanisms, through clinical and basic research, is critical to further advancements in disease prevention and management. Comprehensive, cost-effective, and minimally invasive diagnostics must be developed to facilitate both early identiﬁcation of CVD and quantiﬁcation of the associated pathophysiology. Three-dimensional, limb-speciﬁc imaging equipment providing accurate data on the anatomy, hemodynamics, and cytochemical interactions can be envisioned in the near future. Such progress would certainly promote the development of new therapies optimized for clinical efﬁcacy, invasiveness, adverse effects, and cost-effectiveness. Treatment assisted by robotics, innovative drugs, gene therapy, high-technology compression hosiery, and endo-valves would greatly improve currently available surgical techniques. Development of such therapies will require a thorough reorganization of existing practices and institutions. There is a clear need for evidence-based management protocols in CVD. Geographic centers of clinical excellence, collectively cooperative, and a central venous disease clearing house (e.g., National Institute for Venous Clinical Excellence) might facilitate clinical and academic progress while safeguarding professional cohesiveness and ethical integrity. Based upon these considerations, the following priorities (in declining order) were proposed by the primary chronic venous disease group: a the development of minimally or non-invasive techniques for restoring vein function b enhancing public and physician awareness of primary CVD c identiﬁcation of important, quantiﬁable determinants of outcome at the macro-/microcirculation and tissue levels d identiﬁcation of tissue markers and precursors of primary chronic venous disease development e identiﬁcation of genetic and environmental factors leading to primary venous disease f the development of pharmaco- and physical therapies for prevention and treatment of primary chronic venous disease.

Specific research initiatives in primary chronic venous disease

both clinical and basic science research. Samples and deidentiﬁed demographic data would be stored by the consortium and made available to participating institutions. Academic investigators, the pharmaceutical industry, and other institutions undertaking venous research or research linked to venous specimens (internal medicine, rheumatology cardiology, etc.) would have access to the tissue bank. Potential targets for investigation would include proteonomics, evaluation of upregulated or downregulated genes, and inﬂammatory markers as well as their correlation with pathophysiological and clinical data. An initial goal of collecting specimens from 200 subjects, with targeted investigation of several of these questions, was proposed. ENDOVENOUS VALVE REPAIR

Despite the reported success of primary venous valve repair,31–34 these procedures are not widely performed, at least partly because the procedures are perceived as complex with good results obtained in only a few centers having extensive experience. There is a clear need for a minimally or non-invasive venoscopic valve repair to restore vein function. Making use of advanced stapling and suturing technology, this method would enable minimally invasive valve reconstruction, obviating the need for complex open surgery or vein ablation. The participation of industry would be required for design expertise, funding, prototype development, feasibility assessment, and animal testing. WIRELESS, FUNCTIONAL VENOUS DIAGNOSTIC TESTS (ISRVDS)

Many currently available diagnostic tests (duplex ultrasonography, air plethysmography) require cumbersome diagnostic equipment that limits their application under truly physiological conditions. An innovative, screenless, real-time, venous duplex system (ISR-VDS) would be a signiﬁcant addition to the venous diagnostic armamentarium. Such a system would optimally use wireless, real-time, three-dimensional, color duplex technology, delivered to the examiner through virtual reality eyewear and allowing superimposition of images on the surgical or endovascular ﬁeld. Development of a system would likely require assistance from the military, computer, and ultrasound industries for funding, development of a prototype, and initial animal and human testing.

CORE LABORATORY CONSORTIUM AND GENETIC DATABASE

SECONDARY CHRONIC VENOUS DISEASE

A core laboratory consortium to collect samples of blood, vein, skin, and other pertinent tissues would foster working relationships among investigators and expedite

Occurrence of the post-thrombotic syndrome after an episode of acute DVT is related both to failure of recanalization, with persistent venous obstruction, and the

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development of valvular incompetence.35,36 Important priorities in improving the care of patients with secondary chronic venous disease include prevention, development of diagnostic tests to precisely identify sites of abnormal venous function, and the development of technology to rectify chronic obstruction and secondary valvular incompetence.

General priorities in secondary chronic venous disease Advances in the treatment of acute DVT are critical to the prevention of the post-thrombotic syndrome. Early, complete thrombus removal by mechanical, pharmacological, or surgical thrombectomy is likely an important adjunct in preventing chronic obstruction as well as vein wall and valvular damage. The need for multicenter, international randomized clinical trials comparing catheter-directed thrombolysis, endovenous mechanical thrombectomy and surgical thrombectomy with standard anticoagulation alone has been detailed above. The development of oral thrombolytics and anti-inﬂammatory drugs that inhibit vein wall/valve ﬁbrosis would be ideal. Finally, “thrombosis teams,” with signiﬁcant expertise in this ﬁeld, should be organized at major healthcare centers. It is known that previous deep venous thrombosis, heredity, and prolonged occupational standing contribute to the development of symptoms, but the pathophysiology and genetic determinants of CVD are largely unknown. Our current understanding of CVD suggests that it develops from the following sequence of events: initial pericapillary extravasation caused by inﬂammation is followed by formation of a ﬁbrotic perivascular cuff with vascular proliferation, ﬁbroblast recruitment, and ﬁbrosis mediated by matrix metalloproteinases (MMPs) and other proteinases.37–42 The capillary endothelium likely includes a mechanism that detects the hemodynamic changes produced by venous hypertension. Drugs such as pentoxyphylline and Daﬂon (Servier International, Paris, France) are believed to act by inhibiting leukocyte– endothelium interactions and reducing tissue edema.43 However, advances in pharmacotherapy and other approaches, such as stem cell treatment, will be possible only through an improved understanding of the pathophysiological mechanisms underlying the progression from C0 to C6 disease. This must include a better deﬁnition of the genetic basis of chronic venous insufﬁciency (CVI), including inherited alterations in vein wall morphology, susceptibility to venous hypertension, and the inﬂuence of environmental factors. The phenotypes and genetic material of patients with CVD would optimally be correlated with CEAP classiﬁcation and duplex ultrasound studies. The identiﬁcation of genes associated with venous disease will need to be performed in collaboration with epidemiological studies in centers for genetic research.

The most useful diagnostic tools currently available are duplex ultrasonography, plethysmography, contrast venography, MRV and computed tomography (CT). However, all have limitations and the severity of symptoms does not correlate with methods currently used to evaluate reﬂux and obstruction. The ideal imaging study should precisely localize and quantify reﬂux and obstruction within the deep, superﬁcial and perforator venous systems (global and segmental). Such a test should also be portable, cost effective, highly reproducible and predictive of long-term outcome. A wireless device that can be applied at rest and enable real-time study during activity (equivalent to exercise ankle brachial index in arterial disease) as well as treatment simulation (e.g., temporary superﬁcial venous occlusion to predict outcome of saphenous ablation) would be optimal. Duplex ultrasonography and magnetic resonance imaging (MRI) are currently the most likely candidates for further development, but these may be replaced by other imaging modalities in the future. The primary goal of surgical therapy is to improve venous insufﬁciency through the obliteration of major reﬂux pathways and relief from obstruction. Unfortunately, interventions aimed at restoring deep valve competence are less successful in secondary than in primary venous disease.44 Furthermore, open interventions, such as venous bypass and valve repair, are performed only in highly specialized centers by experienced surgeons. However, minimally invasive techniques, potentially accessible to a broader group of specialists, have emerged in the past several years and their further development should be encouraged.

Specific research initiatives in secondary chronic venous disease EXTERNAL COMPRESSION DEVICES

Compression stockings reduce edema, improve venous pump function, impede venous reﬂux, and may improve arterial inﬂow.45–48 However, compliance is often poor owing to too much or little compression, difﬁculty in applying the stockings, discomfort, and aesthetics. An improved understanding of the hemodynamic effects of compression would allow it to be targeted and optimized for the individual patient. This may also allow design of more comfortable, easier to apply stockings that achieve the desired hemodynamic effect. Another approach to treatment of severe CVI associated with valve dysfunction would be an “external” valve closure compression pump that senses reﬂux and generates intermittent pressure peaks synchronized with the calf pump and speciﬁc for the degree of reﬂux and size of the leg. Such a device must be portable, easy to use, respond to patient movement and position, and give feedback to the physician.

Compression hosiery

DEDICATED VENOUS STENTS

Iliocaval obstruction can be treated by percutaneous insertion of stents.49,50 However, currently available stents are not speciﬁcally designed for the venous system and the development of in-stent re-stenosis requires frequent reintervention. Development of dedicated venous stents, including modular systems for the iliocaval conﬂuence, is a priority in the treatment of secondary CVD. The characteristics of such a stent should include higher radial strength, greater length and diameter, ﬂexibility, low thrombogenicity, and minimal in-stent re-stenosis. The development of such a stent will require further investigation regarding stent–vein wall interactions, mechanisms of re-stenosis, and periprocedural pharmacotherapy.

IMPLANTABLE VENOUS VALVES

As discussed in the section on secondary CVD, there have been extensive efforts to develop a percutaneously implantable deep venous valve and there are preliminary data regarding the use of acellular valve xenografts in humans. However, late malfunction and thrombosis continue to be a problem with current designs. Further development of implantable venous valves is a critical priority and will require a prosthetic that is nonthrombogenic, non-immunogenic, ﬂexible, and adaptable to all venous segments. Development of artiﬁcial biosynthetic mechanical valves was also ranked as a high priority by the SIR multidisciplinary consensus panel.51

COMPRESSION HOSIERY The mission of the International Compression Club is to provide a forum in which medical experts interested in compression therapy and representatives from the manufacturers of compression devices can discuss controversial issues and propose solutions. Much of the discussion at the Paciﬁc Vascular Symposium focused on the need to standardize compression parameters and reporting.

General priorities in compression hosiery Compression is a medical treatment, requiring a precise knowledge of the dose (i.e., pressure, stiffness) necessary to achieve the desired effect. Manufacturers currently provide a pressure range (mmHg) based on in vitro measurements, as well as a designated compression class. Compression classes vary according to national regulations and are not comparable. The medical literature should abandon use of “compression classes,” reporting the range of pressure in mmHg and the method of

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measurement. Prescribing compression stockings on the basis of compression ranges, rather than classes, is also recommended. There is a need to further evaluate current methods of pressure measurement, both in vivo and in vitro, with respect to the variability and reproducibility of different techniques. Compression stockings from all manufacturers should be independently evaluated using the three most common methods (Hatra, ITF and Hosy).52 Stiffness, which is deﬁned as the pressure change generated by an increase in the transverse stretch of the stocking, is not regularly declared by manufacturers. Use of the same method for designation of pressure and stiffness would be desirable in the future. There is also a need to standardize the marketing of compression bandages. As a minimum requirement, complete information regarding the constituents (composition), stretchability (elasticity), adhesion (cohesive, adhesive, or non-adhesive), and dimensions should be provided on the packaging. With respect to elasticity, the following terminology is recommended: No stretch Short stretch Long stretch

0–10% < 100% > 100%

Inelastic Inelastic Elastic

Scientiﬁc reports utilizing compression bandaging should further deﬁne the application technique (e.g., spiral, ﬁgure-of-8, Putter, etc.), the degree of bandage overlap, the number of layers, the experience of the practitioner, and the pressure delivered. The pressure may be measured at various speciﬁed sites, but site B1 (gaiter area) is recommended as the standard for recording in vivo compression.53 Pressure levels should be reported as follows: Light Medium Strong Extra strong

20 mmHg 20–40 mmHg 40–60 mmHg > 60 mmHg

Future innovations in compression bandaging should be directed towards medicated bandages; sprays applied after application to modify ﬁxation, cohesion, and stiffness; new materials to improve comfort and compliance; pressure-monitoring devices incorporated into bandaging; the combination of compression bandaging with intermittent pneumatic compression (IPC); and air- and water-ﬁlled devices. The role of IPC in the treatment of deep venous thrombosis, edema, venous ulcers, combined arterial/ venous ulcers, and causalgia also needs further deﬁnition. More deﬁnitive studies on the role of IPC in thromboprophylaxis are also needed. Future studies should focus on important clinical end-points as well as the effect of IPC on markers of coagulation, ﬁbrinolysis, inﬂammation, and angiogenesis.

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Table 64.1 Organizational initiatives of the Fifth Paciﬁc Vascular Symposium Initiative Joint Venous Council

Goals To form a new organization with the goals of: Increasing awareness about venous disorders among physicians and the public ● Fostering relationships with industry, government and national/international societies ● Achieving inﬂuence through critical mass and clinical/scientiﬁc excellence ● Acting as a project/grant clearinghouse ● Creating evidence-based practice guidelines ●

Redeﬁnition of the American Venous Forum as a broad-based, inclusive organization

Table 64.2 Research initiatives of the Paciﬁc Vascular Symposium Initiative Evaluation of venous outﬂow obstruction Duplex ultrasound in the diagnosis and prognosis after DVT

Early thrombus removal (open vein strategies)

Biomarkers in diagnosis and prognosis of DVT Core laboratory consortium and genetic database Evaluation and standardization of venous testing

Assessment of reﬂux and its relation to CVD progression

Inferior vena cava ﬁlters in high-risk patients Endovenous valves and venoscopic valve repair Pathophysiology of CVD External compression devices

Dedicated venous stents

Functional venous testing

Goals To explore the use of magnetic resonance venography in evaluating and quantifying venous outﬂow obstruction To evaluate the utility of a single color ﬂow duplex examination, including the calf veins, in excluding DVT To deﬁne standard scanning protocols To produce guidelines for the diagnosis of DVT To evaluate the natural history of DVT in relation to thrombus characteristics To evaluate the role of early thrombus removal in the management of acute DVT ● Multicenter, international randomized clinical trial ● Mechanical, pharmacological, and surgical thrombectomy arms ● Stratiﬁed for thrombus location (iliofemoral vs femoropopliteal) ● Objective clinical and quality of life outcome measures To evaluate the utility of coagulation, ﬁbrinolytic, and inﬂammatory biomarkers in diagnosing DVT and providing prognostic information regarding type and duration of therapy Creation of a specimen bank (vein, skin, blood) with clinical data to facilitate CVD research To identify markers predicting susceptibility and disease progression To standardized acute and chronic venous disease testing To develop uniform testing protocols To deﬁne normal ranges and signiﬁcant variations To identify a standard for quality of life and hemodynamic outcomes To identify patterns of reﬂux that correlate with CEAP categories To identify patterns of reﬂux predicting progression to CEAP 4 to 6 To identify patterns of reﬂux predicting success after intervention To develop a severity score for valvular incompetence To compare strategies of permanent ﬁlters, removable ﬁlters, and surveillance in patients with trauma and intracerebral hemorrhage To develop a non-thrombogenic, non-immunogenic, ﬂexible, and adaptable prosthetic venous valve To develop minimally invasive techniques to restore valve function To assess the role of the endothelium and identify mechanisms of ambulatory venous hypertension, inﬂammatory skin changes, and ulceration in animal and clinical models To develop a compression device to treat advanced CVD ● Portable and easy to use ● Responds to patient position and movement ● Provides physician feedback To create a dedicated venous stent with greater radial strength and low thrombogenicity To characterize the vein wall reaction to stents To identify mechanisms of re-stenosis To identify the role of periprocedural pharmacotherapy To develop wireless, functional venous tests enabling real-time study during exercise

CEAP: C, clinical; E, etiology; A, anatomy; P, pathophysiology. CVD, chronic venous disease; DVT, deep vein thrombosis.

References 703

IMUA: THE FUTURE OF VENOUS DISEASE The goals of the Fifth Paciﬁc Vascular Symposium were to establish the current state of knowledge in acute and chronic venous disease and develop a 10 year plan for advancement of the ﬁeld. The current state of knowledge in the ﬁeld was detailed in the December 2007 supplement of the Journal of Vascular Surgery.4–7 Additionally, several organizational and investigative priorities were established, initial protocols developed, and experts recruited to participate in the individual projects. Perhaps most importantly, deﬁnitive plans were made to guide overall progress and identify priorities for AVF support through establishment of an imua (Hawaiian for moving forward in a positive direction) committee. The committee has distilled the initiatives generated by the four working groups into two organizational (Table 64.1) and 13 investigative projects (Table 64.2). Some validation of the importance of the research initiatives is provided by the observation that many similar projects were ranked as a high priority by an independent multidisciplinary consensus panel organized by the SIR.11,51 As discussed above, the ability to accomplish these projects will require innovative approaches to funding including partnerships with the NIH and other governmental agencies, industry, the AVF, and other interested societies. Further information, including contact information for interested investigators, is available on the AVF website (http://www.venousinfo.com/). Despite the progress made during the ﬁfth Paciﬁc Vascular Symposium and the importance of these individual initiatives, the broader goal of deﬁning a 10 year plan for the advancement of venous disease was only partially accomplished and should continue to be addressed in future meetings.

●5.

●6.

●7.

●8.

●9.

10.

●11.

12.

13.

14.

15.

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20. Porter J, Moneta G. Reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635–45. ◆21. Porter J, Rutherford R, Clagett G, et al. Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–81. ●22. van Bemmelen PS, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reﬂux with duplex ultrasound scanning. J Vasc Surg 1989; 10: 425–31. 23. Birdwell B, Raskob G, Whitsett T, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998; 128: 1–7. 24. Cogo A, Lensing AWA, Koopman MMW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 617–20. 25. Anderson DR, Wells PS, Stiell I, et al. Management of patients with suspected deep vein thrombosis in the emergency department: combining use of a clinical diagnosis model with D-dimer testing. J Emerg Med 2000; 19: 225–30. 26. Dryjski M, O’Brien-Irr MS, Harris LM, et al. Evaluation of a screening protocol to exclude the diagnosis of deep venous thrombosis among emergency department patients. J Vasc Surg 2001; 34: 1010–15. ◆27. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995; 345: 1326–30. ●28. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795–8. 29. Elias A, Mallard L, Elias M, et al. A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected ﬁrst episode of deep venous thrombosis of the lower limbs. Thromb Haemost 2003; 89: 221–7. 30. Schellong SM, Schwarz T, Halbritter K, et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003; 89: 228–34. 31. Kistner RL. Primary venous valve incompetence of the leg. Am J Surg 1980; 140: 218–24. 32. Masuda EM, Kistner RL. Long-term results of venous valve reconstruction: a four- to twenty-one-year follow-up. J Vasc Surg 1994; 19: 391–403. 33. Perrin M. Reconstructive surgery for deep venous reﬂux: a report on 144 cases. Cardiovasc Surg 2000; 8: 246–55. 34. Raju S. New approaches to the diagnosis and treatment of venous obstruction. J Vasc Surg 1986; 4: 42–54. 35. Johnson BF, Manzo RA, Bergelin RO, Strandness DE. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six- year follow-up. J Vasc Surg 1995; 21: 307–13.

36. Johnson BF, Manzo RA, Bergelin RO, Strandness DE. The site of residual abnormalities in the leg veins in longterm follow-up after deep venous thrombosis and their relationship to the development of the post-thrombotic syndrome. Int Angiol 1996; 15: 14–19. 37. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary ﬁbrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. BMJ (Clin Res Ed) 1982; 285: 1071–2. 38. Herrick SE, Sloan P, McGurk M, et al. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 1992; 141: 1085–95. 39. Higley HR, Ksander GA, Gerhardt CO, Falanga V. Extravasation of macromolecules and possible trapping of transforming growth factor-beta in venous ulceration. Br J Dermatol 1995; 132: 79–85. 40. Leu H. Morphology of chronic venous insufﬁciency: light and electron microscopic examinations. Vasa 1991; 20: 330–42. 41. Thomas PRS, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. BMJ 1988; 296: 1693–5. 42. Weckroth M, Vaheri A, Lauharanta J, et al. Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996; 106: 1119–24. 43. Sullivan GW, Carper HT, Novick WJ Jr, Mandell GL. Inhibition of the inﬂammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 1988; 56: 1722–9. 44. Tripathi R, Sieunarine K, Abbas M, Durrani N. Deep venous valve reconstruction for non-healing leg ulcers: techniques and results. ANZ J Surg 2004; 74: 34–9. 45. Nehler MR, Moneta GL, Woodard DM, et al. Perimalleolar subcutaneous tissue pressure effects of elastic compression stockings. J Vasc Surg 1993; 18: 783–8. 46. Nehler MR, Porter JM. The lower extremity venous system. Part II. The pathophysiology of chronic venous insufﬁciency. Perspect Vasc Surg 1992; 5: 81. 47. Mayrovitz HN, Sims N. Effects of ankle-to-knee external pressures on skin blood perfusion under and distal to compression. Adv Skin Wound Care 2003; 16: 198–202. 48. Murphy MA, Joyce WP, Condron C, Bouchier-Hayes D. A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy. Eur J Vasc Endovasc Surg 2002; 23: 349–52. 49. Hartung O, Otero A, Bouﬁ M, et al. Mid-term results of endovascular treatment for symptomatic chronic nonmalignant iliocaval venous occlusive disease. J Vasc Surg 2005; 42: 1138–44; discussion 44. 50. Neglen P. Endovascular treatment of chronic iliofemoral venous obstruction: a review. Phlebolymphology 2003; 43: 204–11.

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Vedantham S, Rundback JH, Khilnani NM, et al. Development of a research agenda for endovenous treatment of lower-extremity venous reﬂux: proceedings from a multidisciplinary consensus panel. J Vasc Interv Radiol 2005; 16: 1575–9. 52. Partsch H, Rabe E, Stemmer R. Compression Therapy of the Extremities. Paris: Editions Phlebologiques Francaise, 1999.

53. Partsch H, Clark M, Bassez S, et al. Measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness – consensus statement. Dermatol Surg 2006; 32: 224–32; discussion 33.

65 Summary of Guidelines of the American Venous Forum PETER GLOVICZKI, MICHAEL C. DALSING, BO EKLÖF, GREGORY L. MONETA, THOMAS W. WAKEFIELD, JOANN M. LOHR, MONIKA L. GLOVICZKI AND MARK M. MEISSNER

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.0.0

Part 1: Basic considerations of venous disorders

1.1.0

Development and anatomy of the venous system, Chapter 2, p. 12

1.1.1

The main deep vein of the thigh between the popliteal and the common femoral vein is the femoral vein. The old term “superﬁcial femoral vein” should be abandoned

1

1.1.2

The main superﬁcial veins of the lower limb are the great saphenous vein and the small saphenous vein

1

1.1.3

The old terms “Cockett” and “Giacomini” veins should be replaced by the new terms “posterior tibial perforating vein” and “intersaphenous vein,” respectively. The use of eponyms is discouraged

1

1.2.0

The physiology and hemodynamics of the normal venous circulation, Chapter 3, p. 25

1.2.1

Venous return follows a continued dynamic pressure gradient. The majority of the energy imparted by the pumping action of the heart is dissipated in the arterial distribution

A

1.2.2

The hydrostatic pressure in the venous system is directly related to the height of the column of blood in relation to the zero-point of the right atrium

A

1.2.3

Venous return against gravity is accomplished by the combined action of active extremity muscular pumps and the function of one-way venous valves

A

1.2.4

The plantar venous pump acts to prime the calf muscular pump

C

1.2.5

The thigh muscular pump contributes little to venous return.

B

1.2.6

The anatomic structure of the vein allows for great variation in its diameter and thus the capacity of the venous system. This facilitates the venous system in responding to acute volume changes and to adjusting temperature

A

1.2.7

External pressure on collapsible proximal veins increases distal venous pressure

B

Summary of Guidelines of the American Venous Forum 707

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

1.3.0

Classiﬁcation and etiology of chronic venous disease, Chapter 4, p. 37

1.3.1

The CEAP (clinical class, etiology, anatomy, pathophysiology) classiﬁcation is recommended to describe chronic venous disorders. The system has been validated.

1

1.3.2

The full CEAP classiﬁcation system is recommended for clinical research

1

1.3.3

Primary venous insufﬁciency is a slowly progressive degenerative disorder that results in vein wall weakness producing valvular reﬂux, usually beginning in superﬁcial veins

B

1.3.4

Secondary post-thrombotic venous insufﬁciency is progressive inﬂammatory disease that results in vein valve and wall distortion producing combinations of obstruction and reﬂux; it usually begins in deep veins

B

1.3.5

We recommend that primary venous insufﬁciency is differentiated from secondary post-thrombotic venous insufﬁciency, because the two conditions differ in pathophysiology and management

1.4.0

The physiology and hemodynamics of chronic venous insufﬁciency of the lower limb, Chapter 5, p. 47

1.4.1

Persistent ambulatory venous hypertension is the main cause of chronic venous insufﬁciency

1.5.0

Pathogenesis of varicose veins and cellular pathophysiology of chronic venous insufﬁciency, Chapter 6, p. 56

1.5.1

Genetics and deep venous thrombosis are predisposing factors for varicose veins

A

1.5.2

Age, female gender, pregnancy, weight, height, race, diet, bowel habits, occupation and posture are predisposing factors for varicose veins

C

1.5.3

Vein wall remodeling and ﬁbrosis, affected by hemodynamic factors, matrix metalloproteinases and plasminogen activators, lead to varicose vein formation

C

1.5.4

In chronic venous insufﬁciency the transmission of high venous pressures to the dermal microcirculation causes extravasation of macromolecules and red blood cells that serve as the underlying stimulus for inﬂammatory injury

A

1.5.4

TGF-β1 and matrix metalloproteinases play key roles in the inﬂammatory injury in chronic venous insufﬁciency that leads to chronic inﬂammation, lipodermatosclerosis and skin changes

B

1.6.0

Venous ulcer formation and healing at cellular levels, Chapter 7, p. 70

1.6.1

Leukocyte activity and interaction with endothelial cells initiates a cascade of inﬂammatory events that lead to venous ulcer formation

A

1.6.2

Macrophages have a major role in ulcer formation

B

1.6.3

Dysfunctional leukocytes and senescent ﬁbroblasts contribute to delayed ulcer healing

B

1.6.4

Altered regulatory cell cycle proteins (p21, pRb) affect ﬁbroblast proliferation and delay ulcer healing

B

1.6.5

Venous ulcer ﬂuid has elevated inhibitory cytokines and matrix metalloproteinases

A

1.6.6

Matrix metalloproteinases have an integral role in the pathogenesis of venous ulcers

A

1.6.7

Factor XIII, plasminogen, and extracellular matrix metalloproteinase inducer (EMMPRIN) modulate matrix metalloproteinase activity and contribute to venous ulcers

B

1

B

B

A

708

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

1.7.0

Acute venous thrombosis: pathogenesis and evolution, Chapter 8, p. 83

1.7.1

Acute venous thrombosis causes an acute to chronic inﬂammatory response in both the vein wall and the thrombus. This leads to thrombus ampliﬁcation, organization, and recanalization, and damage to the vein wall and the valves

A

1.7.2

D-dimer, endothelial-, and platelet-derived microparticles and soluble P-selectin are markers of thrombosis and they are increased in patients with acute venous thromboembolism

A

1.7.3

Resolution of acute thrombus is modulated by natural anticoagulants such as antithrombin III, proteins C and S, and thrombin

B

1.7.4

Polymorphonuclear cells promote both ﬁbrinolysis and collagenolysis and they play a key role in early thrombus resolution. Monocytes are essential in the late phase of thrombus resolution

A

1.8.0

The epidemiology of and risk factors for acute deep venous thrombosis, Chapter 9, p. 94

1.8.1

In the USA each year 275 000 new cases of venous thromboembolism are observed. The incidence of a ﬁrst episode of venous thromboembolism is 50.4 per 100 000 person years

A

1.8.2

The most important risk factors for acute venous thromboembolism include age, major surgery, trauma, hypercoagulable states, malignancy, hospital/ nursing home care, history or family history of venous thromboembolism, immobilization, central venous catheters, pregnancy, estrogen replacement, oral contraceptives, hormonal treatment and long distance travels

A

1.8.3

Heterozygous factor V Leiden mutation increases the risk of venous thromboembolism three- to eightfold, whereas the risk with homozygous mutation is increased by 50- to 80-fold

A

1.8.4

The highest risk group for postoperative venous thromboembolism includes patients with multiple risk factors, those after hip or knee arthroplasty or operations for hip fracture, and patients with major trauma or spinal cord injury

A

1.9.0

Epidemiology of chronic venous disorders, Chapter 10, p. 105

1.9.1

The prevalence of varicose veins in the adult Western population is more than 20% (21.8–29.4%)

A

1.9.2

About 5% (3.6–8.6%) of the adult Western population have skin changes or ulcers due to chronic venous insufﬁciency

B

1.9.3

Active venous ulcers are present in 0–0.5% of the adult Western population, and 0.6–1.4% have healed ulcer

B

1.9.4

Advanced age is a risk factor for varicose veins and chronic venous insufﬁciency

A

1.9.5

Positive family history, female gender and multiparity are risk factors for varicose veins

B

1.9.6

Positive family history and obesity are risk factors for chronic venous insufﬁciency

B

2.0.0

Part 2: Diagnostic evaluations and venous imaging studies

2.1.0

Evaluation of hypercoagulable states and molecular markers of acute venous thrombosis, Chapter 11, p. 113

2.1.1

We recommend evaluation for thrombophilia for patients with the following conditions: 1 unexplained or “idiopathic” thromboembolism (ﬁrst event)

Grade of recommendation (1, we recommend; 2, we suggest)

1

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

C

Summary of Guidelines of the American Venous Forum 709

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

2 secondary, non-cancer-related ﬁrst event and age < 50 (includes thrombosis on oral contraceptives and hormone replacement therapy) 3 recurrent “idiopathic,” or secondary non-cancer-related events 4 thrombosis at unusual sites (portal vein, sinus veins, etc.) 5 extensive thrombosis 6 strong family history of venous thromboembolism 2.1.2

We recommend testing for thrombophilia for most patients 2–4 weeks after completing the typical course (usually 6 months) of anticoagulant therapy

1

C

2.1.3

We suggest against long-term, primary pharmacologic thromboprophylaxis of asymptomatic thrombophilic patients

2

B

2.1.4

We recommend that patients with thrombophilia receive thromboprophylaxis at times of high thrombotic risk such as surgery, trauma, prolonged immobility, pregnancy, or acute illness

1

A

2.1.5

We recommend prolonged anticoagulation following acute deep vein thrombosis in patients with thrombophilia

1

B

2.2.0

Duplex ultrasound scanning for acute venous disease, Chapter 12, p. 129

2.2.1

We recommend duplex ultrasound scanning as the standard of care to diagnose acute deep vein thrombosis of the limbs

1

A

2.2.2

We recommend that duplex examination for deep vein thrombosis includes three phases in each vein segment studied: thrombus visualization, venous coaptability or compressibility, and detection of venous ﬂow

1

A

2.2.3

Duplex scanning has an accuracy of ≥ 90% for detection of femoropopliteal thrombosis and a range of 50–90% for calf vein thrombosis

A

2.2.4

Duplex scanning for upper extremity deep vein thrombosis has a sensitivity between 78 and 100% and speciﬁcity between 82 and 100%

A

2.3.0

Duplex ultrasound scanning for chronic venous obstruction and valvular incompetence, Chapter 13, p. 142

2.3.1

We recommend duplex scanning as the ﬁrst diagnostic test to all patients with suspected chronic venous obstruction or valvular incompetence. The test is safe, non-invasive, cost-effective, and reliable

1

A

2.3.2

We recommend four components of duplex scanning examinations for chronic venous disease: visualization, compressibility, venous ﬂow and augmentation

1

A

2.3.3

Duplex scanning is suggested to distinguish acute from chronic venous occlusion

2

B

2.3.4

We recommend that reﬂux is elicited in two ways: increased intra-abdominal pressure using a Valsalva maneuver or manual or cuff compression and release of the limb distal to the point of examination

2

B

2.3.5

We recommend that the cut-off value for abnormally reversed venous ﬂow (reﬂux) is 500 ms

1

B

2.4.0

Evaluation of venous function by indirect noninvasive testing (plethysmography), Chapter 14, p. 156

2.4.1

Plethysmography is recommended for noninvasive physiologic evaluation of the venous system of an extremity. Clinical correlations with abnormal ﬁndings need to be established

2.5.0

Direct contrast venography, Chapter 15, p. 160

2.5.1 2.5.2

1

C

Contrast venography is recommended before performing endovenous reconstructions for acute or chronic venous obstructions

1

B

Contrast venography is suggested for patients with high clinical suspicion for deep venous thrombosis if other diagnostic modalities are inconclusive

2

B

710

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

2.6.0

Computed tomography and magnetic resonance imaging in venous disease, Chapter 16, p. 169

2.6.1

Computed tomography with intravenous contrast is recommended for evaluation of obstruction of large veins in the chest, abdomen and pelvis. Computed tomography accurately depicts the underlying pathology, conﬁrms extrinsic compression, tumor invasion, traumatic disruption, anatomic variations, extent of thrombus and position of a caval ﬁlter

1

B

2.6.2

Computed tomography with intravenous contrast is recommended to diagnose pulmonary embolism. Sensitivity and speciﬁcity approaches 100% for central emboli while for small, subsegmental pulmonary emboli sensitivity and speciﬁcity are 83% and 96%, respectively

1

A

2.6.3

Magnetic resonance venography is recommended for diagnosis of acute iliofemoral and caval deep vein thrombosis. A sensitivity of 100% and speciﬁcity 96% was reported. The study is also recommended to diagnose portal, splenic or mesenteric venous thrombosis

1

A

2.6.4

Magnetic resonance imaging and magnetic resonance venography are recommended to image inferior vena cava thrombus associated with renal, adrenal, retroperitoneal, primary caval or metastatic malignancies. Magnetic resonance venography reveals the presence or absence of bland thrombus or tumor thrombus in the renal veins and the inferior vena cava

1

A

3.0.0

Part 3: Management of acute thrombosis

3.1.0

The clinical presentation and natural history of acute deep venous thrombosis, Chapter 17, p. 195

3.1.1

The term venous thromboembolism should include both deep venous thrombosis and pulmonary embolism

1

A

3.1.2

We recommend that clinical examination alone is inaccurate for diagnosis, since presentation of deep vein thrombosis is non-speciﬁc

1

A

3.1.3

Early ambulation, combined with compression, is recommended for patients with deep vein thrombosis. Pain and swelling resolve faster and the risk of pulmonary embolism is not increased

1

A

3.1.4

Early ambulation is recommended to patients with deep vein thrombosis to decrease the risk of post-thrombotic syndrome

1

C

3.1.5

Compression is recommended to patients with deep vein thrombosis to decrease the risk of post-thrombotic syndrome

1

A

3.1.6

Early anticoagulation with heparin and adequate duration and intensity of oral anticoagulation is recommended to decrease the risk of recurrent venous thromboembolism

1

A

3.1.7

Thrombolytic therapy is suggested for selected patients with deep vein thrombosis to promote recanalization

2

B

3.1.8

Low molecular weight heparin is recommended for deep vein thrombosis in cancer patients with early or limited disease, to improve survival.

1

B

3.2.0

Diagnostic algorithms for acute deep venous thrombosis and pulmonary embolism, Chapter 18, p. 208

3.2.1

In symptomatic outpatients with suspected acute deep vein thrombosis, we recommend that a clinical score and D-dimer level should be obtained ﬁrst to select patients for further diagnostic studies

1

B

3.2.2

D-dimer

1

B

levels are inaccurate to diagnose deep vein thrombosis in several clinical conditions including recent surgery, pregnancy, malignancy, infection, elevated bilirubin, trauma, and heparin use. In these situations we recommend alternate diagnostic modalities

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

Summary of Guidelines of the American Venous Forum 711

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

3.2.3

In patients with high clinical suspicion of deep vein thrombosis and negative duplex studies we recommend repeat duplex scan or alternate imaging modality

1

B

3.2.4

Magnetic resonance venography (MRV) has excellent sensitivity and speciﬁcity to diagnose above-the-knee acute deep vein thrombosis. We suggest MRV instead of contrast venography

2

B

3.2.5

We suggest Gadolinium is used judiciously in patients with renal insufﬁciency because of the risk of nephrogenic systemic ﬁbrosis

2

C

3.3.0

Medical treatment of acute deep vein thrombosis and pulmonary embolism. Based on recommendations of The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy, Buller et al.6 Chapter 19, p. 221

3.3.1

For patients with objectively conﬁrmed deep vein thrombosis we recommend, short-term treatment with subcutaneous low-molecular weight heparin or, alternatively, intravenous unfractionated heparin followed by vitamin K antagonists

1

A

3.3.2

For patients with a high clinical suspicion of deep vein thrombosis we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests

1

C

3.3.3

In acute deep vein thrombosis we recommend initial treatment with lowmolecular-weight heparin or unfractionated heparin for at least 5 days followed by vitamin K antagonists

1

C

3.3.4

In acute deep vein thrombosis we recommend initiation of vitamin K antagonist together with low-molecular-weight heparin or unfractionated heparin on the ﬁrst treatment day, and discontinuation of heparin when the international normalized ratio is stable and > 2.0 (consider for 2 consecutive days)

1

A

3.3.5

For patients with a ﬁrst episode of deep vein thrombosis secondary to a transient (reversible) risk factor, we recommend long-term treatment with a vitamin K antagonist for at least 3 months over treatment for shorter periods

1

A

3.3.6

For patients with a ﬁrst episode of idiopathic deep vein thrombosis, we recommend treatment with a vitamin K antagonist for at least 6 to 12 months

1

A

3.3.7

We recommend that the dose of vitamin K antagonist be adjusted to maintain a target international normalized ratio of 2.5 (range 2.0–3.0) for all treatment durations

1

A

3.3.8

We recommend against high-intensity vitamin K antagonist therapy (international normalized ratio range 3.1–4.0) and against low-intensity therapy (international normalized ratio range 1.5–1.9) compared with international normalized ratio range of 2.0–3.0

1

A

3.3.9

For patients with objectively conﬁrmed non-massive pulmonary embolism, we recommend acute treatment with subcutaneous low-molecular weight heparin or, alternatively, iv unfractionated heparin

1

A

3.3.10

For most patients with pulmonary embolism, we recommend clinicians not use systemic thrombolytic therapy

1

A

3.3.11

For the duration and intensity of treatment for pulmonary embolism, the recommendations are similar to those for deep vein thrombosis

1

A

3.4.0

Catheter-directed thrombolysis for treatment of acute deep venous thrombosis, Chapter 20, p. 239

3.4.1

In patients with symptomatic deep vein thrombosis and large thrombus burden, particularly in iliofemoral deep vein thrombosis, we suggest a treatment strategy that includes thrombus removal

2

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

B

712

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.4.2

In selected patients with iliofemoral deep vein thrombosis and symptoms < 14 days’ duration we suggest catheter-directed thrombolysis, if appropriate expertise and resources are available, to reduce acute symptoms and post-thrombotic morbidity

2

B

3.4.3

We suggest pharmacomechanical thrombolysis, with thrombus fragmentation and aspiration, over catheter-directed thrombolysis alone in the treatment of iliofemoral deep vein thrombosis, to shorten treatment time, if appropriate expertise and resources are available

2

B

3.4.4

In selected patients with iliofemoral deep vein thrombosis with symptoms < 14 days duration we suggest systemic thrombolysis as an alternative to catheter-directed thrombolysis, if appropriate expertise and resources are available, to reduce acute symptoms and post-thrombotic morbidity

2

B

3.5.0

Surgical thrombectomy and percutaneous mechanical thrombectomy for treatment of acute iliofemoral deep venous thrombosis, Chapter 21, p. 255

3.5.1

We suggest catheter-directed thrombolysis for proximal DVT, especially in iliofemoral thrombosis, in active patients at low risk for bleeding. Systemic thrombolysis is not suggested

2

C

3.5.2

For patients with symptomatic iliofemoral deep vein thrombosis who are not candidates for catheter-directed thrombolysis we suggest surgical thrombectomy

2

C

3.5.3

For patients with massive iliofemoral deep vein thrombosis at risk of limb gangrene secondary to venous occlusion we recommend surgical thrombectomy

1

C

3.5.4

To shorten time for thrombolysis and rapidly decrease thrombus load, we suggest adding catheter-based mechanical thrombectomy to catheterbased thrombolysis for patients with iliofemoral deep vein thrombosis

2

C

3.6.0

Treatment algorithm for acute deep venous thrombosis, Chapter 22, p. 265

3.6.1

Low-molecular-weight heparin is now preferred over standard unfractionated heparin for the initial treatment of deep vein thrombosis

1

A

3.6.2

We recommend that criteria for discontinuation of oral anticoagulation include thrombosis risk, residual thrombus burden, and coagulation system activation (as suggested by D-dimer measurements)

1

A

3.6.3

Heparin-induced thrombocytopenia remains a problem with all heparin preparations, but is more frequent with unfractionated heparin than lowmolecular-weight heparin. We recommend using alternative agents including hirudin, argatroban and fondaparinux

1

C

3.6.4

We recommend strong compression and early ambulation after deep vein thrombosis treatment to signiﬁcantly reduce the long term morbidity of pain and swelling resulting from the deep vein thrombosis

1

A

3.7.0

Current recommendations for prevention of deep venous thrombosis, Chapter 23, p. 277

3.7.1

When the risk of bleeding from pharmacologic agents is high, we recommend using non-pharmacologic methods of venous thromboembolism prophylaxis including elastic compressive stockings, intermittent pneumatic compression devices, leg elevation and early ambulation. Each of these reduces venous thrombotic events by approximately 20%

1

C

3.7.2

For patients at very high risk for venous thromboembolism we suggest non-pharmacologic methods of venous thromboembolism prophylaxis in combination with pharmacologic agents

2

A

Summary of Guidelines of the American Venous Forum 713

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.7.3

For patients with acute venous thromboembolism within 1 month, who undergo urgent/ emergent surgery or if other circumstances prohibit anticoagulation we recommend placement of an inferior vena cava ﬁlter

1

C

3.7.4

We suggest an inferior vena cava ﬁlter for prophylaxis for the multiple trauma patient with bleeding risk precluding pharmacologic prophylaxis

2

C

3.7.5

We recommend that the indications for temporary, retrievable, or optional inferior vena cava ﬁlters are the same as those for permanent inferior vena cava ﬁlters

1

C

3.7.6

Aspirin is either ineffective or inferior to other forms of venous thromboembolism prophylaxis. Its use provides modest beneﬁt at best and we do not recommend it alone for prophylaxis

1

A

3.7.7

We recommend that for moderate-risk patients, venous thromboembolism prophylactic low-dose unfractionated heparin or prophylactic dose lowmolecular weight heparin (< 3400 IU/day) is used

1

A

3.7.8

For high-risk general surgery patients we recommend elastic compression stockings combined with either low-dose heparin (5000 units tid) or lowmolecular-weight heparin (> 3400 units/day)

1

A

3.7.9

In very-high-risk general surgical patients with multiple concomitant risk factors, the use of either unfractionated heparin (5000 units tid), lowmolecular-weight heparin (>3400 units/day) or fondaparinux is appropriate and we recommend it combined with mechanical prophylaxis

1

A

3.7.10

Following total joint replacement or hip fracture surgery we recommend appropriate venous thromboembolism prophylaxis for at least 10 days

1

A

3.7.11

For patients undergoing total hip arthroplasty or hip fracture surgery, we recommend that prophylaxis is continued for 4 weeks particularly in patients with continuing venous thromboembolism risk factors (e.g., a previous history of venous thromboembolism, obesity, continued immobilization, bilateral simultaneous total knee replacement)

1

A

3.7.12

We suggest low-dose unfractionated heparin or low-molecular-weight heparin as prophylactic agents for high-risk patients in neurosurgery

2

B

3.7.13

Low-dose unfractionated heparin is safe and effective prophylaxis for hospitalized patients with other general medical conditions

1

A

3.8.0

The management of axillo-subclavian venous thrombosis in the setting of thoracic outlet syndrome, Chapter 24, p. 292

3.8.1

For axillary–subclavian venous thrombosis in patients with thoracic outlet syndrome we recommend venous thrombolysis followed by thoracic outlet decompression. This combination is safe and effective

1

B

3.8.2

We do not recommend subclavian vein stenting in the immediate postoperative period following thrombolysis and surgical decompression for subclavian vein thrombosis in the setting of thoracic outlet syndrome

1

B

3.8.3

For patients with residual stenosis following thrombolysis for subclavian vein thrombosis in the setting of thoracic outlet syndrome we suggest early surgical decompression and direct open surgical repair or alternatively stent placement

2

C

714

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

3.9.0

Indications, techniques, and results of inferior vena cava ﬁlters, Chapter 25, p. 299

3.9.1

We recommend placement of inferior vena cava ﬁlters in patients with deep vein thrombosis and/or pulmonary embolism and a baseline contraindication to anticoagulation; in patients who suffer a complication from anticoagulation; in patients that develop recurrent deep vein thrombosis or pulmonary embolism despite adequate anticoagulation; and in patients who previously have had a massive pulmonary embolism and cannot tolerate further cardiopulmonary insult that would be associated with an additional pulmonary embolism

1

A

3.9.2

We recommend placement of an inferior vena cava ﬁlter in patients with a free ﬂoating thrombus greater than 5 cm in length within an iliac vein or the inferior vena cava

1

B

3.9.3

We recommend prophylactic ﬁlters to patients if their associated medical conditions (malignancy or traumatic injuries) predispose to deep vein thrombosis or pulmonary embolism

1

B

3.9.4

We suggest caution in special situations prior to ﬁlter placement for patients with untreated or uncontrolled bacteremia, and pediatric patients and pregnant women because of the uncertain long-term effects and durability of the ﬁlters

2

C

3.9.5

We suggest bedside placement of inferior vena cava ﬁlters by using either transabdominal duplex or intravascular ultrasound guidance. Both have been shown to be safe and effective

2

B

3.9.6

We suggest performing additional studies to document the safety and efﬁcacy of the placement of retrievable ﬁlters in patients with time-limited contraindications to anticoagulation

2

B

3.9.7

We suggest follow-up examination annually to patients with vena caval ﬁlters to evaluate the mechanical stability of the ﬁlter. In addition, the condition of the lower extremities is evaluated to monitor the on-going risk for recurrent thrombosis

2

B

3.10.0

Superﬁcial venous thrombophlebitis, Chapter 26, p. 314

3.10.1

For saphenous vein thrombophlebitis within 1 cm of the saphenofemoral or saphenopopliteal junction, we suggest high saphenous vein ligation with or without saphenous vein stripping to avoid extension into the deep system and embolization. Anticoagulation is an acceptable alternative therapy

2

B

3.10.2

For thrombophlebitis localized in the distal segment or in tributaries of the great saphenous vein we suggest ambulation, warm soaks and nonsteroidal anti-inﬂammatory agents. We suggest surgical excision only in rare cases of recurrent bouts of thrombophlebitis in spite of maximal medical management

2

B

3.11.0

Mesenteric vein thrombosis, Chapter 27, p. 320

3.11.1

We recommend computed tomography angiography and magnetic resonance angiography for the diagnosis of mesenteric venous thrombosis

1

B

3.11.2

We recommend immediate anticoagulation for treatment of mesenteric venous thrombosis to improve outcome

1

B

3.11.3

We recommend surgery to patients with mesenteric venous thrombosis if they have evidence of peritonitis or perforation

1

B

3.11.4

In patients with high risk inherited thrombotic disorders or other permanent risk for thrombosis, we recommend lifelong anticoagulation

1

B

Summary of Guidelines of the American Venous Forum 715

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.0.0

Part 4: Management of chronic venous disorders

4.1.0

Clinical presentation and assessment of patients with venous disease, Chapter 28, p. 331

4.1.1

For clinical examination of the upper limb we recommend inspection with comparison with the contralateral limb, palpation, auscultation, and examination of the axilla for adenopathy. In patients with adenopathy or swollen arm we recommend examination of the breast to exclude malignancy

1

B

4.1.2

For clinical examination of the lower limbs in patients with suspected acute deep vein thrombosis we recommend inspection (edema, cyanosis, varicosity), palpation (tenderness, pitting edema), auscultation (arterial bruit, heart and lung exam) and examination of the deep and superﬁcial veins and calf muscles for tenderness or palpation of a cord

1

B

4.1.3

We suggest the use of the clinical scoring system of Wells to predict the pretest probability of deep vein thrombosis

2

B

4.1.4

For clinical examination of the lower limbs for varicosity and chronic venous insufﬁciency we recommend inspection (varicosity, edema, skin discoloration, corona phlebectatica, ulcer, lipodermatosclerosis); palpation (cord, varicosity, tenderness, induration, reﬂux, pulses, thrill); auscultation (bruit); examination of the groins and abdomen (masses, collateral veins or lymphadenopathy); and ankle mobility

1

B

4.1.5

Clinical presentation of patients with varicose veins may include symptoms like aching, heaviness and tension, sensation of swelling, tiredness, restless legs, nocturnal cramps and itching. We suggest that there is little or no relationship between these symptoms and the presence and severity of varicose veins or the pattern and severity of reﬂux

2

B

4.2.0

Diagnostic algorithm for telangiectasias, varicose veins, and venous ulcers, Chapter 29, p. 342

4.2.1

We recommend that in patients with telangiectasias, varicose veins and chronic venous insufﬁciency a complete history and detailed physical examination is complemented by duplex scanning of the deep, superﬁcial, and, selectively, the perforating veins, to evaluate valvular incompetence

1

B

4.2.2

We recommend that in patients with telangiectasias, varicose veins and chronic venous insufﬁciency laboratory examination is needed selectively for those with a personal or family history of thrombophilia (screening for hypercoagulability), in patients with long-standing venous stasis ulcers (blood count and metabolic panel) and in a case of general anesthesia for the treatment of chronic venous disease

1

B

4.2.3

We recommend in patients with telangiectasias, varicose veins and chronic venous insufﬁciency selective use of plethysmography, computed tomography, magnetic resonance imaging, ascending and descending venography and intravascular ultrasound

1

B

4.3.0

Compression treatment of chronic venous disorders, Chapter 30, p. 348

4.3.1

Compression therapy is the primary treatment for venous ulceration

1

B

4.3.2

No one form of compression therapy is clearly superior to another. Compression devices should be individualized to the individual patient

1

B

4.3.3

Compliance is integral to initial success with compression therapy and long-term compression is likely beneﬁcial in reducing recurrence of ulceration

1

B

4.3.4

We suggest superﬁcial venous surgery in addition to compression therapy to reduce ulcer recurrence in certain classes of patients with venous ulceration

1

A

716

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.4.0

Drug treatment of varicose veins, venous edema, and ulcers, Chapter 31, p. 359

4.4.1

We suggest phlebotonic drugs to improve symptoms and edema associated with chronic venous disease. These could be used in association with compression for the management of troublesome symptoms

2

B

4.4.2

We recommend for long-standing or large venous ulcers treatment with either pentoxifylline or micronized puriﬁed ﬂavonoid fraction used in combination with compression

1

B

4.4.3

We suggest diosmine and hesperidine in trophic disorders as well as cramps and swelling. We suggest rutosides in patients with venous edema

2

B

4.5.0

Sclerotherapy in the management of varicose veins of the extremities, Chapter 32, p. 366

4.5.1

Sclerotherapy, either liquid or foam, is a well-accepted therapeutic method for all sizes of varicose veins. We recommend sclerotherapy for treatment of telangiectasias

1

B

4.5.2

As a single form of treatment for varicose veins, sclerotherapy has a high incidence of recurrences. We recommend combining it with either conventional surgery or endovenous saphenous ablation

1

C

4.5.3

To reduce post-sclerotherapy hyperpigmentation, we suggest microthrombectomy in the ﬁrst 2–3 weeks after treatment

2

C

4.5.4

We recommend compression after sclerotherapy of telangiectasias and varicose veins

1

B

4.6.0

Foam sclerotherapy, Chapter 33, p. 380

4.6.1

We suggest the use of foam sclerosant generated by the Monfreux, Tessari, and the double-syringe system techniques for the treatment of symptomatic reﬂux of the great saphenous vein, C2–C6 patients with varicose veins, and recurrent varicose veins

2

B

4.6.2

We suggest the use of foam sclerotherapy to treat saphenous vein, tributary varicose vein, and perforating vein incompetence in patients with venous ulcers, lipodermatosclerosis, and venous malformations when compared with conservative therapy (e.g., compression)

2

B

4.7.0

Percutaneous laser therapy of telangiectasias and varicose veins, Chapter 34, p. 390

4.7.1

For telangiectasias with vein diameters below 0.5 mm and for telangiectatic matting we recommend the ﬂashlamp pumped dye lasers at 595 nm wavelength

1

C

4.7.2

For telangiectasias with diameters below 0.7 mm we recommend the potassium-titanyl-phosphate (KTP) laser at 532 nm wavelength

1

C

4.7.3

For large telangiectasias up to 3 mm vein diameter we suggest treatment with long-pulse Nd:YAG (neodymium-doped yttrium aluminum garnet) lasers at 1064 nm wavelength

2

C

4.7.4

During laser treatment we recommend cooling to avoid thermal skin damage using dynamic spray cooling, contact cooling, or cooled air

1

C

4.7.5

We do not recommend cosmetic laser treatment of leg telangiectasias in a tanned skin with increased melanin content after sun exposure

1

A

4.8.0

Surgical treatment of the incompetent saphenous vein, Chapter 35, p. 400

4.8.1

For treatment of the incompetent great saphenous vein we recommend high ligation and inversion stripping of the saphenous vein to the level of the knee

1

B

Summary of Guidelines of the American Venous Forum 717

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.8.2

To decrease recurrence we suggest ligation and division of the saphenous vein tributaries beyond their secondary branches

2

C

4.8.3

To reduce hematoma formation we recommend postoperative compression bandage

1

C

4.9.0

Radiofrequency treatment of the incompetent saphenous vein, Chapter 36, p. 409

4.9.1

Radiofrequency ablation of the great saphenous vein is safe and effective and we recommend it for treatment for saphenous incompetence

1

A

4.9.2

Clinical outcome after radiofrequency ablation of the great saphenous vein up to 5 years is comparable to traditional stripping and ligation

4.9.3

Because of reduced convalescence, complications, and morbidity, we suggest radiofrequency ablation of the great saphenous vein in highrisk patients such as the obese, those takings anticoagulants, and those with signiﬁcant medical problems

4.10.0

Laser treatment of the incompetent saphenous vein, Chapter 37, p. 418

4.10.1

B 2

C

Endovenous laser therapy of the great saphenous vein is safe and effective and we recommend it for treatment of saphenous incompetence

1

A

4.10.2

Clinical outcome after endovenous laser therapy up to 3 years is comparable to traditional stripping and ligation and we recommend it for treatment of the incompetent great saphenous vein

1

C

4.11.0

Phlebectomy, Chapter 38, p. 429

4.11.1

We recommend ambulatory phlebectomy, an outpatient procedure performed under local anesthesia, as an effective and deﬁnitive treatment for varicose veins. The procedure is performed after saphenous ablation, either during the same procedure or, as recommended by most experts, at a later stage

1

B

4.11.2

Powered phlebectomy (TriVex) has been effective in multiple studies for the treatment of varicose veins. We suggest it as an option to treat varicose veins

2

C

4.11.3

We suggest phlebectomy over sclerotherapy for treatment of varicose veins

2

B

4.12.0

Treatment algorithms for telangiectasias and varicose veins: current guidelines, Chapter 39, p. 439

4.12.1

For patients with class 1 chronic venous disease we recommend treatment of symptomatic patients, but treatment can be considered in asymptomatic patients as well. We recommend sclerotherapy or laser for spider telangiectasias, and liquid or foam sclerotherapy for reticular veins

1

A

4.12.2

For treatment of the incompetent saphenous vein, we recommend either surgical stripping or thermal ablation (laser, radiofrequency)

1

B

4.12.3

For treatment of the incompetent saphenous vein, we suggest chemical ablation (catheter, syringe; liquid, foam)

2

C

4.12.4

For treatment of the incompetent perforating veins we recommend ultrasound-guided sclerotherapy, thermal ablation, or subfascial endoscopic perforating vein surgery

1

B

4.12.5

For treatment of bulging varicose veins we suggest phlebectomy and sclerotherapy (liquid, foam) and transilluminated powered phlebectomy (TriVex)

2

B

718

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.13.0

Recurrent varicose veins: etiology and management, Chapter 40, p. 446

4.13.1

For clinical description of recurrent varicose veins, we recommend using the REVAS (Recurrent Varicose Veins After Surgery) classiﬁcation

1

B

4.13.2

For evaluation of recurrent varicose veins we recommend duplex scanning for venous mapping, for assessment of the source and duration of reﬂux, and to help establish the etiology of recurrence

1

B

4.13.3

For treatment of recurrent varicose veins, treatment with sclerotherapy, surgery, or endovenous thermal ablation or coil embolization is suggested, depending on the etiology and extent of varicosity

2

C

4.14.0

Local treatment of venous ulcers, Chapter 41, p. 457

4.14.1

For local wound cleansing of venous ulcers we recommend tap water and the surrounding skin should be washed with a mild soap

1

B

4.14.2

We recommend sharp debridement of venous ulcers if tolerated by the patient

1

A

4.14.3

As an alternative to debridement we recommend a hydrogel or an enzymatic dressing to reduce the necrotic material and bioburden, which impede wound healing

1

B

4.14.4

Routine use of antibiotics for venous ulcers is not recommended. We recommend systemic antibiotics for treatment of obvious infections as manifested by systemic signs, periwound cellulitis, or gross purulence

1

B

4.14.5

For localized infections we recommend topical antimicrobials, such as silver-based wound dressings

1

A

4.14.6

For uncomplicated venous ulcers we recommend compression treatment with occlusive dressings, such as Tegasorb, while Viscopaste provides the concomitant advantages of mild rigid compression and a decreased frequency of dressing changes

1

A

4.14.7

For non-infected wounds with some degree of granulation tissue we recommend the xenograft Oasis®, while for hard to heal and large ulcers without infection but with supportive granulation tissue we recommend Apligraf®

1

A

4.14.8

For large ulcers, which will require an extended period of time to heal by secondary intention, we suggest skin grafting. Pinch grafts have the advantage over split thickness skin grafts because they can be performed in an ambulatory setting and avoid hospitalization

2

B

4.15.0

Surgical repair of deep vein valve incompetence, Chapter 42, p. 472

4.15.1

We recommend valve reconstruction in primary valvular incompetence after less invasive therapies have failed

1

A

4.15.2

We suggest valve reconstruction or valve transfer procedures may be considered in post-thrombotic cases after other available forms of therapy have failed

2

B

4.16.0

Artiﬁcial venous valves, Chapter 43, p. 483

4.16.1

For patients with venous ulcer and isolated deep vein valvular incompetence, who fail standard treatment modalities, we suggest the procedure of venous valve leaﬂet construction from autologous vein

2

C

4.16.2

We recommend that non-autologous venous valve substitutes currently NOT be used in the treatment of patients with symptomatic chronic deep venous insufﬁciency

1

C

Summary of Guidelines of the American Venous Forum 719

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

4.17.0

Endovascular reconstruction for chronic iliofemoral venous obstruction, Chapter 44, p. 491

4.17.1

For chronic iliac vein obstruction we recommend endovenous stenting to improve symptoms and the quality of life of the patients

4.18.0

Endovascular reconstruction of complex iliocaval venous occlusions, Chapter 45, p. 503

4.18.1

We suggest endovascular stents for reconstruction of complex iliocaval venous occlusions

4.19.0

Open surgical reconstructions for non-malignant occlusion of the inferior vena cava or iliofemoral veins, Chapter 46, p. 514

4.19.1

For symptomatic patients with unilateral iliofemoral venous occlusions who fail attempts at endovascular reconstruction we recommend open surgical bypass using saphenous vein as a crosspubic bypass (Palma procedure)

1

B

4.19.2

For symptomatic patients with iliac vein or inferior vena cava obstruction we recommend open surgical bypass using an externally supported polytetraﬂuoroethylene prosthesis, if endovascular options fail or they are not possible

2

B

4.20.0

The management of incompetent perforating veins with open and endoscopic surgery, Chapter 47, p. 523

4.20.1

For open surgical treatment we no longer recommend the modiﬁed open Linton procedure owing to associated morbidities

1

A

4.20.2

We recommend treatment of perforating vein incompetence in patients with advanced venous disease to improve venous hemodyanamics and clinical outcomes

2

B

4.20.3

We recommend perforating vein interruption preferentially in patients with primary valvular incompetence and less so in those with post-thrombotic syndrome

2

B

4.21.0

Percutaneous ablation of perforating veins, Chapter 48, p. 536

4.21.1

We suggest percutaneous ablation of perforating veins (PAPs) using ultrasound-guided sclerotherapy or thermal ablation as an outpatient procedure, performed under local anesthesia. It is repeatable with minimal morbidity

2

C

4.22.0

A treatment algorithm for venous ulcer: current guidelines, Chapter 49, p. 545

4.22.1

We recommend ablation of superﬁcial axial reﬂux and treatment of perforating vein incompetence to improve venous hemodynamics and to promote ulcer healing

1

B

4.22.2

We recommend superﬁcial venous surgery to decrease ulcer recurrence in patients with superﬁcial venous incompetence

1

A

4.22.3

We suggest superﬁcial venous surgery with subfascial endoscopic perforator surgery for treatment of venous ulcers

2

C

5.0.0

Part 5: Special venous problems

5.1.0

Surgical and endovenous treatment of superior vena cava syndrome, Chapter 50, p. 553

5.1.1

In patients with malignant superior vena cava obstruction we recommend stenting as the primary therapy

1

A

5.1.2

In patients with superior vena cava syndrome due to non-malignant etiology we recommend endovascular treatment as the initial therapy

1

B

5.1.3

We recommend surgical reconstruction of the superior vena cava with autogenous vein or ePTFE bypass as effective and durable alternative in patients who fail or who are unsuitable for endovascular intervention

1

B

1

2

A

B

720

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

5.2.0

The management of extremity venous trauma, Chapter 51, p. 568

5.2.1

For patients with multisystem injury who are unstable, we recommend ligation of the injured veins including the common femoral or popliteal veins

1

B

5.2.2

For hemodynamically stable trauma patients with single-system injuries we recommend repair of major venous injuries, speciﬁcally, the axillary, subclavian, common iliac, external iliac, common femoral, or popliteal veins

1

B

5.2.3

For patients with massive extremity swelling following traumatic venous injuries or ligation of major veins, we recommend leg elevation and fourcompartment fasciotomies

1

B

5.3.0

Primary and secondary tumors of the inferior vena cava and iliac veins, Chapter 52, p. 574

5.3.1

For patients with invasion of the wall of the inferior vena cava by primary or secondary tumor we recommend caval replacement if the vein was patent before surgery, if the collateral circulation appears inadequate following caval resection and in those in whom important collateral veins had to be ligated or resected during tumor removal. Repair with externally supported polytetraﬂuoroethylene graft is safe, effective and durable

1

B

5.3.2

For inferior vena cava tumor thrombus, usually a renal cell carcinoma, that extends into the right heart we recommend removal with cardiopulmonary bypass, with or without hypothermic circulatory arrest

1

B

5.4.0

Arteriovenous malformations: evaluation and treatment, Chapter 53, p. 583

5.4.1

For symptomatic arteriovenous malformations we suggest endovascular treatment with embolization or sclerotherapy. We suggest it for both deﬁnitive treatment of surgically “inaccessible” lesions and for initial therapy of surgically “accessible” lesions

2

C

5.5.0

The management of venous malformations, Chapter 54, p. 594

5.5.1

For symptomatic venous malformations, not responding to compression treatment, we suggest sclerotherapy with alcohol or foam

2

C

5.5.2

For surgically accessible and localized symptomatic venous malformations we suggest surgical excision as an alternative to sclerotherapy

2

C

5.6.0

The management of venous aneurysms, Chapter 55, p. 604

5.6.1

We recommend surgical repair of even asymptomatic lower extremity venous aneurysms because of the risk of thromboembolic complications

1

B

5.6.2

For aneurysms of superﬁcial veins of the arm or leg or of deep veins of the arm we suggest observation unless cosmetic reasons or complications warrant repair

2

C

5.6.3

For jugular vein aneurysms we suggest observation unless cosmetic reasons or psychological reasons warrant surgical repair

2

B

5.6.4

For abdominal venous aneurysms we suggest repair because of the risk of rupture and thromboembolism

2

B

5.6.5

Thoracic venous aneurysms are infrequently associated with rupture or thromboembolic complications and we suggest observation in most cases

2

B

5.7.0

Management of pelvic venous congestion and perineal varicosities, Chapter 56, p. 617

5.7.1

We recommend duplex scanning for initial evaluation of patients with suspected pelvic varicose veins. Ultrasound will conﬁrm pelvic varicose veins and usually determines their etiology

1

B

Summary of Guidelines of the American Venous Forum 721

No. of guideline

Guideline

5.7.2

We recommend selective contrast pelvic venography to conﬁrm the diagnosis and exact etiology of pelvic and perineal varicose veins and delineate the anatomy for planning endovenous treatment

1

B

5.7.3

We recommend endovenous ablation of the ovarian vein reﬂux, but longterm results and degree of recanalization after coil embolization are not known

1

B

5.7.4

We suggest surgical ligation and excision of ovarian veins to treat reﬂux

2

B

6.0.0

Part 6: Lymphedema

6.1.0

Lymphedema: pathophysiology, classiﬁcation, and clinical evaluation, Chapter 57, p. 629

6.1.1

Lymphedema is divided into two major categories: primary and secondary. Primary lymphedema may be further subdivided into three categories: ●

●

●

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

B

Congenital lymphedema (10%) develops within 2 years of birth. Some of the congenital forms are hereditary Lymphedema praecox (80%) occurs between the ages of 2 and 25 years. Although sporadic cases are most common, a few forms are hereditary Lymphedema tarda (10%) has its onset in those over 35 years of age

Secondary lymphedema is caused by inﬂammation or obstruction of the lymph vessels. Some of the most common causes include ﬁlariasis, cancer, trauma (mostly iatrogenic), infection/inﬂammation 6.1.2

Lymphatic abnormalities can be divided into four anatomical categories: aplasia, hypoplasia, numerical hyperplasia, and hyperplasia

B

6.1.3

There are three major categories of lymphatic pathophysiological abnormalities: obstruction, reﬂux, and overproduction of lymph ﬂuid

B

6.2.0

Lymphoscintigraphy and lymphangiography, Chapter 58, p. 635

6.2.1

We recommend lymphoscintigraphy for the initial evaluation of patients with lymphedema

1

B

6.2.2

We suggest lymphoscintigraphy, using visual interpretation of the images with a semiquantitative scoring index, to document response to treatment of lymphedema

2

B

6.3.0

Lymphedema: medical and physical therapy, Chapter 59, p. 649

6.3.1

To reduce lymphedema we recommend multimodal complex decongestive therapy that includes manual lymphatic drainage; multilayer short-stretch bandaging; remedial exercise; skin care; and instruction in long-term management

1

B

6.3.2

To reduce lymphedema, we recommend short-stretch bandages that remain in place for longer than 22 hours per day

1

B

6.3.3

To reduce lymphedema we recommend treatment daily, a minimum of 5 days per week, and continue until normal anatomy or a volumetric plateau is established

1

B

6.3.4

To reduce lymphedema we suggest compression pumps in some patients

2

C

6.3.5

For maintenance of lymphedema we recommend an appropriately ﬁtting compression garment

1

A

6.3.6

For maintenance of lymphedema in patients with advanced (stages II or III) disease we recommend using short-stretch bandages during the night. Alternatively, compression devices may substitute for short-stretch bandages

1

B

722

Summary of Guidelines of the American Venous Forum

No. of guideline

Guideline

Grade of recommendation (1, we recommend; 2, we suggest)

Grade of evidence (A, high quality; B, moderate quality; C, low or very low quality)

6.3.7

For remedial exercises we recommend wearing compression garments or bandages

1

C

6.3.8

For cellulitis or lymphangitis we recommend antibiotics with superior coverage of Gram-positive cocci, particularly streptococci. Examples include cephalexin, penicillin, clindamycin, cefadroxil

1

A

6.3.9

For prophylaxis of cellulitis in patients with more than three episodes of infection we recommend antibiotics with superior coverage of Grampositive cocci , particularly streptococci, at full strength for 1 week per month, Examples include cephalexin, penicillin, clindamycin, cefadroxil

1

C

6.4.0

Principles of surgical treatment of chronic lymphedema, Chapter 60, p. 658

6.4.1

All interventions for chronic lymphedema should be preceded by at least 6 months of non-operative compression treatment

1

C

6.4.2

We suggest excisional operations or liposuction only to patients with late stage non-pitting lymphedema, who fail conservative measures

2

C

6.4.3

We suggest microsurgical lymphatic reconstructions in centers of excellence for selected patients with secondary lymphedema, if performed early in the course of the disease

2

C

6.5.0

The management of chylous disorders, Chapter 61, p. 665

6.5.1

For primary treatment of chylous effusions and ﬁstulas due to reﬂux we recommend ﬁrst a low-fat or medium-chain triglyceride diet, followed by drug therapy that may include somatostatin and its analogs, diuretics, and sympathomimetic drugs to enhance thoracic duct contractions. This is followed by percutaneous aspirations of chylous ﬂuid by thoracentesis or paracentesis

1

B

6.5.2

In patients with primary lymphangiectasia and chylous ﬁstulas or lymphedema who fail conservative treatment, we suggest the selective use of ligation of lymphatic ﬁstulas, excision of dilated lymphatics, sclerotherapy, lymphatic reconstruction, or placement of a peritoneovenous shunt

2

C

Index Figures and tables are comprehensively referred to from the text. Therefore, signiﬁcant material in ﬁgures and tables have only been given a page reference in the absence of their concomitant mention in the text referring to that ﬁgure. Abbreviations: AVM, arteriovenous malformations; DVT, deep vein thrombosis; IVC, inferior vena cava; PE, pulmonary embolism; QoL, quality of life; SVC, superior vena cava; VTE, venous thromboembolism.

A component of CEAP classiﬁcation see anatomy abdomen aneurysms 609–10 AVMs, CT 173 radiographs of mesenteric vein thrombosis 324 veins anatomy 20 aneurysms 609–10 Aberdeen questionnaire 690 accessory great saphenous vein 16 activated partial thromboplastin time (aPTT) and heparin dose 224, 225 activated protein C resistance see factor V Leiden acute venous disease future directions 696–7 outcome assessment 675–83 see also thrombosis adhesion molecules, leukocyte 53, 63, 65, 71 adhesive embolization see glue/adhesive embolization adrenal carcinoma 186 adrenergic innervation 28 adventitia (tunica adventitia) 22 aescin see horse chestnut seed/root extract age and DVT risk 94, 95–6 “air-block” technique in sclerotherapy 380 criticism 381 telangiectasias 373 air plethysmography 156–7, 344, 691 ulcers and compression therapy 349 air travel see travel alexandrite laser, long-pulse 395 alginates 460, 463, 464 allergic/hypersensitivity reactions dye or contrast media in lymphangiography 645 laser treatment 396–7 sclerosants 371 Allevyn 460, 463 allograft valves 483–4

ambulatory phlebectomy see phlebectomy ambulatory venous pressure 691 elevated (hypertension) 441 compression therapy effects on 348 pathologic consequences 240 perforator incompetence and 524 perforator ablation and reduction in 531–2 in saphenous incompetence, measurement 403 American College of Chest Physicians guidelines (ACCP) on thrombus treatment 239, 261–2 American Venous Forum 695, 703, 706–22 on aneurysms (venous), management 610 on chronic venous disease/insufﬁciency (in general) classiﬁcation and etiology 37, 45 clinical presentation and assessment 340 diagnostic algorithm 346 duplex ultrasound 153 epidemiology 109 pathophysiology and hemodynamics 53, 66 Clinical Severity Score 677–8 on congenital malformations AVMs, evaluation and treatment 589 management 601 on CT and MRI 190 on deep vein thrombosis (DVT) of axillo-subclavian vein in thoracic outlet syndrome 297 catheter-directed thrombolysis 251 clinical presentation and natural history 203 diagnostic algorithm 216 duplex ultrasound 143 epidemiology and risk factors 101 medical treatment 234 molecular markers 126 pathogenesis and evolution 90

prophylaxis 287, 311 surgical thrombectomy and percutaneous mechanical thrombectomy 262 treatment algorithm 274 on deep vein valve incompetence, surgical repair 480 on development and anatomy 22 on hypercoagulable state evaluation 126 on iliocaval venous obstruction, endovascular recanalization 512 on iliofemoral venous obstruction endovascular reconstruction 500 open reconstruction 521 on injured veins, management 571 on IVC ﬁlters 311 on IVC and iliac vein tumors 580 on IVC obstruction, open reconstruction 521 on lymphangiography 647 on lymphedema medical and physical therapy 655 pathophysiology/classiﬁcation/clini cal evaluation 633 surgery 663 on lymphoscintigraphy 647 on mesenteric vein thrombosis 325 on PE diagnostic algorithms 216 medical treatment 234 on pelvic venous congestion, management 625 on perforator incompetence open and endoscopic surgery 533 percutaneous surgery 542 on perineal varicosities 625 on phlebography/venography 167 on physiology and hemodynamics 34 of chronic venous insufﬁciency 53, 66 on plethysmography in venous functional assessment 157 on superﬁcial thrombophlebitis 318 on SVC obstruction, surgical and endovenous treatment 566

724

Index

American Venous Forum – (contd) on telangiectasia treatment algorithm 444 laser therapy 397 on ulcers (venous) compression therapy 356 drug therapy 30 formation and healing at cellular levels 80 local treatment 469 treatment algorithm 548 on valve incompetence artiﬁcial valves 489 deep veins, surgical repair 480 on varicose and incompetent veins algorithm 444 drug therapy 364 endovenous laser therapy 426 foam sclerotherapy 388 liquid sclerotherapy 378 pathogenesis 66 percutaneous laser therapy 397 phlebectomy 437 radiofrequency treatment of saphenous incompetence 415 recurrence management 455 surgery for saphenous incompetence 406 on venous edema drug therapy 364 anastomoses (surgical), lymphovenous see lymphovenous anastomoses Anatomic Score (Venous Segmental Disease Score) 685, 687–8 anatomy in CEAP classiﬁcation (=A) in lymphedema 633 in CEAP classiﬁcation (=A) in venous disease 37, 38–9 in severity scoring 686, 687–8 historical perspectives 3 variant see congenital anatomical anomalies anesthesia local/regional see local and regional anesthesia phlebectomy 432 radiofrequency treatment of saphenous incompetence 410 aneurysms, venous 604–16 abdominal 609–10 cervicofacial 607 etiopathogenesis 604–5 lower extremity 605–6 thoracic 608–9 angiography see computed tomography; lymphangiography; magnetic resonance imaging; phlebography; pulmonary angiography Angiojet 259–60

angioplasty (percutaneous transluminal dilatation) deep veins (lower limb/in general) 259 subclavian vein 295 SVC 557, 558 results 562–3 angioscopic valvuloplasty 475 ankle ﬂare see corona phlebectatica ankle tourniquet, phlebography 163 antecubital vein, median, cannulation 292 antibiotics in endovascular recanalization of iliocaval venous occlusions, prophylactic 508 septic thrombophlebitis 267 venous ulcers 362, 467, 468 antibodies to phospholipds see antiphospholipid syndrome anticardiolipin antibody 120 anticoagulants (drugs) antiphospholipid syndrome 120 antithrombin deﬁciency 115 bleeding risk see hemorrhage DVT prophylaxis 125, 281–8 postoperative see surgery recommendations 283–8 DVT therapy 83, 125, 221–38, 255, 267–9, 696–7 adjuncts to 222, 235 complications as indication for IVC ﬁlter 301 contraindicated, as indication for IVC ﬁlter 300–1 duration/length 126, 268, 696–7 failure as indication for IVC ﬁlter 301 following radiofrequency treatment of saphenous incompetence 411 indeﬁnite 223 long-term 222–3, 228–9, 230–3 thrombolytics compared with 241, 270 in heparin-induced thrombocytopenia 121–2, 269 intravenous see heparin mesenteric vein thrombosis 324 oral see oral anticoagulants PE prevention see subentries below protein C deﬁciency 116 protein S deﬁciency 116 sclerotherapy contraindications 371 superﬁcial thrombophlebitis 316, 317–18 SVC obstruction, postoperative 561 antiphospholipid syndrome 100, 119–20 tests 120, 123

antiplatelet drugs, venous ulcers 363 antithrombin (antithrombin III) deﬁciency 99, 114–15 superﬁcial thrombophlebitis and 315 tests 114, 123 heparin binding to 221 antithrombotic agents conventional see anticoagulants; antiplatelet drugs; thrombolysis new 228, 269 Antwerp clinical score 214 Apligraf 361, 461, 463, 464 argatroban 269, 283 prophylactic 282, 283 arm phlebography see phlebography arterial disease, peripheral, outcome assessment 684 arterial injection of sclerosant, accidental 376 arterial insufﬁciency (lower limbs) co-existing with venous ulcers, assessment 350 sclerotherapy contraindications 370–1 arterial thromboembolism activated protein C resistance 117 antiphospholipid syndrome 120 antithrombin deﬁciency 115 coagulation factor elevations 118 in heparin-induced thrombocytopenia 121 hyperhomocysteinemia 118 protein C deﬁciency 115 protein S deﬁciency 116 prothrombin gene 20210A mutation 117 arterial ulcers vs venous ulcers 338 arteriography, pulmonary see pulmonary angiography arteriovenous ﬁstulas and shunts 52, 587 adjuvant/deliberately manufactured 516–17 in IVC and iliofemoral reconstruction non-malignant occlusion 516–17 in IVC malignant involvement 578 in thrombectomy 257, 258 pathologic effects (ulcers etc.) 52, 59 traumatic 368 treatment 587 varicose veins and 368 arteriovenous malformations (AVMs) 583–93 classiﬁcation 583–4 evaluation 584 CT 173 extratruncular vs truncular 584

Index 725

treatment 585–9 indications 585 modalities 585–7 strategies 585, 587 upper limb 333 arthroplasty see joint replacement arthroscopy, knee, thromboprophylaxis 285 artifacts, CT venography 170 ascites, chylous 668–9 aspirin thromboprophylactic 283 with venous ulcers 363 asthma patients, sclerotherapy contraindications 371 atrium, left, oblique vein of 13 atrophie blanche 40 auscultation, chronic venous disease 343 upper limb 334 autoantibodies to phospholipids see antiphospholipid syndrome autoimmune disease, telangiectasias 391 autologous artiﬁcial venous valves 485–6 autolytic debridement 466, 467 axillary vein anatomy 21 thrombosis see axillosubclavian vein thrombosis transfer 477 trauma, treatment 569–70 axillosubclavian vein 292–8 operative reconstruction 295–7 thrombosis 292–8, 333 diagnosis/investigations 142, 267 management 292–8 presentation and assessment 333 primary 333 secondary 333 in thoracic outlet syndrome 292–8 azygos vein anatomy 21 aneurysms 608–9 CT venography 170 development 13, 14 thoracic duct and, surgical anastomoses 670 B-mode imaging, venous thrombi 142 balloon catheter in thrombectomy 257, 260–1 balloon dilatation see angioplasty balloon dissection in SEPS 526 balloon-expanding stent, iliocaval venous recanalization 510 bandages, compression see compression bandages basilic vein 14

anatomy 20 Bean’s syndrome 599 benzopyrones in lymphedema 655 phlebotonic 360 biologic dressings 460–1 bird’s nest ﬁlter 303, 303–4 performance 309, 310 birthmarks, vascular, characteristics 596 bivalrudin 269, 283 prophylactic 282, 283 black blood MR venography 180–1 bleeding see hemorrhage blood ﬂow, venous in duplex ultrasound in acute vs chronic obstruction, characteristics 143, 144 of DVT 131, 136–7 thrombogenesis and 197 blood tests, mesenteric vein thrombosis 324 see also laboratory tests blood volume, venous depletion, compensatory responses 32–3 pressure and, relationships between 27 calf pump and 30, 31 blue dye in lymphangiography 641, 643 reactions to 645 blue leg, painful see phlegmasia cerulea dolens blue rubber-bleb nevus syndrome 599 Bonn Vein Study, Germany 107 brachial vein, anatomy 20 brachiocephalic (innominate) vein anatomy 21 aneurysms 609 CT 169–70 development 12 breast cancer, lymphedema 655 post-mastectomy 661 breath-hold imaging (MR venography) 183 bright blood MR venography 181 broad ligament varices 618, 619, 620 management 622, 623 Brodie, Sir Benjamin 6 Brugia malayi and Brugia timori 631 bulging vein treatments 443 N-butylcyanoacrylate see cyanoacrylate bypass, venovenous, in hepatectomy and suprarenal IVC replacement with malignancy 578–80 bypass grafts, iliofemoral and IVC 517–19, 547 C component of CEAP classiﬁcation see “clinical” component

calf, symptoms in DVT 196 calf muscle, venous sinus anatomy 19 calf muscle pump 29–30 function (physiology) 29–30, 33, 48–9 SEPS effects on 532 functional assessment, plethysmography 158 outﬂow see outﬂow tract calf veins perforators 49–50 incompetence 50 thrombosis clinical presentation 335, 336 recurrence 199–200 cancer see malignant tumors cannulation see catheterization capacitance–pressure relationships 27–8 capacitance vessels, venoconstriction 25 capillary malformations 598–9 carcinomas adrenal 186 renal cell (involving IVC) 183, 186, 575 tumor thrombus removal 577–8 cardinal veins anterior, development 12 posterior, development 13 cardiolipin autoantibodies 120 cardiopulmonary monitoring in embolo/sclerotherapy of AVMs 586 of ﬁstulous type 587 cardiovascular death risk in DVT 197 catheter-directed thrombosis treatment (CDT) axillo-subclavian venous thrombosis 292–5 lower limb DVT 239–54, 257, 262, 270–1 mechanical methods see mechanical methods patient evaluation 246–7 pharmacologic methods 241–51 mesenteric vein thrombosis 324–5 catheterization/cannulation median antecubital vein 292 for phlebography 164 for radiofrequency treatment of saphenous incompetence 410 caval veins see vena cava CC chemokine receptor-2 88, 89 CD147 (EMMPRIN) 78, 79 CEAP classiﬁcation/evaluation lymphedema (=CEAP-L) 629, 632–4 venous disease 37, 37–41, 45, 142, 156, 439 basic 40 clinical application 41 development 37–8

726

Index

CEAP classiﬁcation/evaluation – (contd) venous disease – (contd) disability in 688–9 epidemiologic studies based on 105–8 full 40, 45 in outcome assessment 685, 686–8 revised 38–9, 44 terminology and new deﬁnitions 39–40 ulcers 546–7 varicose veins 367 writing 40–1 see also individual components cellular pathophysiology (of chronic venous insufﬁciency) 52–3, 56–69, 70–82 ulcer formation 70–82 cellulitis in lymphedema 629, 631 chronic recurrent 656 lymphedema susceptibility in, and its prevention 650 Celsus, Aulus Cornelius 6 phlebectomy 429 central venous return 26 cephalic vein anatomy 20 development 14 cervicofacial aneurysms 607 Charing Cross Venous Ulcer questionnaire 690 Charles procedure 659–60 chemical ablation see sclerotherapy chemokine receptors 88, 89 chest radiography, PE 216 children, jugular aneurysms 607 chronic venous disease/insufﬁciency (of lower limb) 42–4, 56–69, 142–55, 329–552, 334–40, 684–93, 698–701 classiﬁcation and etiology 37–46 clinical presentation and assessment 334–40 deﬁnition 47 diagnosis (incl. investigations) 342–7, 691–2 algorithms 342–7 levels of investigation 40, 41 duplex ultrasound 142–55 epidemiology 105–10 hemodynamics see hemodynamics historical aspects 6–7, 58–9 management 329–52 etiologic knowledge inﬂuencing 44 surgical see surgery outcome assessment 684–93 pathophysiology see pathophysiology phlebography 161–2, 345 primary 42–3

future of 698–9 progression, ultrasound studies 151–2 risk factors 108–9 secondary 43–4, 547 future of 699–701 superﬁcial see superﬁcial veins chronic venous disease/insufﬁciency (of upper limb), clinical presentation and assessment 331–4 chylothorax 669–70 chylous disorders 665–72 etiology and clinical presentation 665–72 evaluation 666 management 666–71 clinical practice guidelines 670–1 non-surgical 666–7 cip1 (p21) 74 Circ-aid 355 CIVIQ and CIVIQ2 679–80, 690 post-thrombotic syndrome 678 clamps, phlebectomy 433 cleansing, ulcer wound 467, 468 “clinical” component (C) of CEAP classiﬁcation lymphedema 632–3 venous disease 37, 38 C1 disease see telangiectases C2 disease see varicose veins in severity scoring 686–7 clinical examination see examination clinical initiatives 695 clinical probability scoring DVT 208–9, 335 PE 214 Clinical Severity Score, Venous 677–8, 685, 686–7 Closure procedure (VNUS) 409–16, 442 clotting see coagulation coagulation factors, elevated levels 118 tests 118, 123 coagulation system changes in thrombosis etiology 98–9, 197–8 in cancer 98 coaptability (compressibility) maneuver, duplex ultrasound of DVT 130, 131, 134–5 Coban2 layer kit 353 Cockett operation 400, 525 Cockett syndrome see May–Thurner syndrome Cockett veins/perforators 19, 49, 524, 526, 527 coil embolotherapy AVMs 586 of ﬁstulous type 587 ovarian vein 622–3

results 624 collagen synthesis and venous ulcers 73 collagenases and venous ulcers 76–7 collateral circulation in obstruction duplex ultrasound in acute vs chronic obstruction 144 iliofemoral veins 494 SVC 554 color, telangiectasia 391 colorectal surgery, thromboprophylaxis 283–4 communicating (incl. perforating) vein(s) 49–50, 523–44 anatomy 15, 16, 17, 18, 19, 523–4 diagnostic examination 344 hemodynamic and clinical signiﬁcance 524 valves dysfunction see communicating vein incompetence function 29 communicating (incl. perforating) vein incompetence/reﬂux 49–50, 443–4 calf 50 duplex ultrasound 149, 151 natural history 542 percutaneous ablation 536–44 history 536–7 results 540–2 technique 537–40 theoretic advantages and disadvantages 537 recurrence 542, 548 surgery (ablation) 524–33, 536–44, 547 indications and contraindications 524–5 Linton’s subfascial ligation 523, 525, 536 open 525, 528 preoperative evaluation 525 results 528–32 subfascial endoscopic see subfascial endoscopic perforator surgery treatment 443–4 percutaneous see subheading above sclerotherapy 370 surgical see subheading above ulceration and 548 complex decongestive therapy 652–3 compressibility (coaptability), maneuver, duplex ultrasound of DVT 130, 131, 134–5 compression (pathologic) deep vein, left common iliac vein by right iliac artery see May–Thurner syndrome pelvic veins 618 subclavian vein 332

Index 727

thoracic outlet 292–8 compression (technique) for embolo/sclerotherapy of AVMs 586 for radiofrequency treatment of saphenous incompetence 410 compression bandages future innovations 701 lymphedema 653 for ulcers 352–5, 467 compression–release (technique), reﬂux evaluation by duplex ultrasound 148 compression stockings/hosiery/garments 204, 255, 270, 350–1 deep venous thrombosis and PE 234–5 future for 700, 701 lymphedema 654 saphenous incompetence 403 ulcers 350–1 varicose veins, post-sclerotherapy 374 compression therapy (in general) 348–58 forms 350–6 future directions 700, 701 historical aspects 6, 7 lymphedema 653–4 mechanism 348–50 post-sclerotherapy 374 pneumatic see pneumatic compression varicose veins 371 recurrent 452 venous ulcers 348–58 patient evaluation 350 surgery vs 356 computed tomography 169–73 chylous disorders 666 lymphedema, preoperative 658 pulmonary arteries (incl. embolism) 171–2, 215–16 renal transplant living donors 187 spiral see spiral CT veins (CT venography) 169–73 catheter-directed thrombolysis employing 246 congenital malformations 586 DVT 170, 186 iliofemoral chronic obstruction 494 iliofemoral obstruction before endovenous reconstruction 494 IVC and iliofemoral obstruction before open surgery 516 IVC tumors 576 mesenteric vein thrombosis 321–2 MR venography compared with 174–80, 188

saphenous incompetence 402 SVC obstruction 554–7 thoracic aneurysms 608 congenital anatomical anomalies/variations lymph vessels 632, 649 veins 13, 14, 16, 17 congenital lymphedema 630–1 congenital reﬂux vs primary and secondary reﬂux 146–8 congenital thrombophilias (hereditary thrombophilias) 95, 114–19, 278 congenital vascular malformations/anomalies 583–602 arteriovenous, see also arteriovenous malformations classiﬁcation 583, 594–5 lymphatic system 632 of venous predominance 594–602 clinical presentation 595 diagnosis 599 etiology 595 evaluation 596 treatment 370, 372, 599–600 consent, informed saphenous surgery 403 thrombophilia testing 125 constriction and lymphedema risk 651 continuous wave Doppler, DVT 137 contrast-enhanced CT iliocaval venous occlusions 505 mesenteric vein thrombosis 321–2 venous malformations 596 contrast-enhanced MR venography 182, 184–5 contrast lymphangiography see lymphangiography contrast media lymphangiography see Ethiodol MR venography new agents 188–90 safety aspects 184–5, 212 phlebography 163, 164 adverse reactions 163, 166, 212 in pregnancy 212 contrast phlebography see phlebography/venography (standard) cooling systems, laser treatment 396 copper bromide laser, 578nm 395 corona phlebectatica (ankle ﬂare) 337 deﬁnition 39 presentation 337 corrosive sclerosants 371 coumarins 229–30 side-effects 233 see also oral anticoagulants; warfarin counseling, thrombophilia testing 125 crossover bypass grafts, iliofemoral and IVC 517, 547

crosspubic prosthetic femoral bypass 517 cryopreserved allograft valves 484 cubital vein, median 20 CuBr (copper bromide) laser, 578nm 395 cyanoacrylate (incl. N-butylcyanoacrylate/NBCA) glue embolization AVMs 586 of ﬁstulous type 587 venous malformations 599, 600 cystic hygromas and venous aneurysms 605 cytokines and chronic venous insufﬁciency 63–5 D-dimer

assay 113–14 for DVT 113–14, 212, 266 combined with duplex ultrasound 211 for PE 215 dalteparin 228 in endovenous reconstruction for chronic iliofemoral vein obstruction 496 death (mortality) acute DVT-associated 197, 675–6 malignant involvement of IVC, postoperative 580–1 debridement, ulcer wound 462–3, 466–7, 468 decompression, thoracic outlet syndrome 294, 295, 296, 297 deep veins (in general) 51–2 in anatomic component of CEAP classiﬁcation 39 anatomy lower limb 18 upper limb 20–1 aneurysms 605–6 incompetence (and reﬂux) 51–2, 472–82 coexisting/association with superﬁcial vein reﬂux 151 post-thrombotic syndrome associated with 677 recurrent varicosities and 455 superﬁcial reﬂux combined with 547 surgical pathology 473 surgical repair see reconstructive surgery obstruction (thrombotic) 256 thrombosis see thrombosis; thrombus valves 472–82 incompetence see subheading above see also speciﬁc veins dehydration, responses 32–3

728

Index

demographic risk factors for DVT 95–7 Dermagraf 461 dermal (skin) equivalents, human, venous ulcers 361, 460–1, 463 dermatan sulfate 362 dermatitis, stasis 63 dermis (in chronic venous insufﬁciency) 65–6 ﬁbroblast function 65–6 ﬁbrosis 63 detergent sclerosants 371 foam sclerotherapy 372, 382 development 12–13 anomalies/variations see congenital anatomical anomalies; congenital vascular malformations diagnostics, future directions 697–8 diet/nutrition chylous disorders and 667 lymphedema and 651 diffusion block 52, 59 dilatation intradermal venules see telangiectases physiological see venodilation surgical see angioplasty vein aneurysmal see aneurysm terminology 604 diode lasers (810–980m) 395–6 diosmin–hisperidin 363 disability in lymphedema 632 Venous Disability Score 688–9 disease see medical illness diuretics chylous disorders 667 lymphedema 654 Doppler ultrasound see ultrasound double veins (reduplications) IVC 14, 306 SVC 13 double-port SEPS 525–6 dressings for ulcers 458–66, 468 evidence-based rationale for selection 462–5 frequency of changes 462 randomized controlled trials 461–2, 463 systematic reviews 462–5 implications 465–6 types 458–61, 462, 463 selection 466 drug(s) chylous disorders 667 edema therapy 359–60, 363–4 lymphedema 654–5 mesenteric vein thrombosis 324–5 catheter-directed 324–5 superﬁcial thrombophlebitis 316–18

varicose veins 359–60, 363–4 VTE prophylaxis 281–3 recommendations 283–8 VTE/PE treatment 221–38, 267–9 axillo-subclavian 292–5 catheter-directed see catheterdirected thrombosis treatment new agents 228, 267 see also speciﬁc (types of) drugs drug users, intravenous, DVT diagnosis 213 DUMSAD study 699 Duoderm 459, 460, 463 duplex ultrasound see ultrasound duplications see double veins DURAC trial 199 Dutch SEPS trial 530–1 DVT risk and, gender 96 dye see blue dye dye laser 395 dynamic pressure 26–7 E component of CEAP classiﬁcation see “etiology” component E-selectin 84 E2F transcription factor 74 ecchymosis sclerotherapy-related 376–7 echogenicity in duplex ultrasound in acute vs chronic obstruction 144 thrombus 135–6 eczema (dermatitis), stasis 63 edema (and swelling) causes 133–4 deﬁnition 40, 105 drug therapy 359–60, 363–4 recurrent 452 lymphatic see lymphedema in Venous Clinical Severity Score 678, 687 effort thrombosis (Paget–von Schrötter syndrome) 267 historical aspects 8 Eisman–Malette valve 485 EKOS LysUS Infusion Catheter System 248, 250, 259, 261 elastic compression bandages for ulcers 353–5 elastic compression stockings 701 deep venous thrombosis and PE 234–5 historical aspects 7 ulcers 350–1 elderly, sclerotherapy contraindications 270 “elephantiasis” 629 elevation, limb, varicose veins 371 embolectomy, evidence-based guidelines 223

embolism, pulmonary see pulmonary embolism embolization AVMs, and sclerotherapy 585–7 clinical experiences 589 incompetent and varicose veins in extremities, recurrent 454 ovarian 622 venous malformations ± sclerotherapy 599–600 EMMPRIN 78, 79 endoscopic perforator surgery see subfascial endoscopic perforator surgery endothelium/endothelial cell in chronic venous insufﬁciency 61 in thrombosis etiology, injury 197 endovascular/endovenous/intravascular techniques AVMs 585–7 clinical experience 589 of ﬁstulous type 587 dilatation and stenting see angioplasty; stenting imaging-guided 152–3 IVC ﬁlter placement 307 ovarian reﬂux/incompetence 622–3 results 624 SVC obstruction 557–8, 585–7 results 561–3 thrombolysis see catheter-directed thrombosis treatment ultrasound in chronic venous disease 345 iliocaval venous occlusion 508 iliofemoral venous obstruction 494–5 valve repair 699 varicose veins 409–16, 418–28 laser therapy see laser therapy radiofrequency treatment see radiofrequency treatment recurrent varicosities 452–3, 453 venous malformations 600 energy delivery in radiofrequency treatment perforator incompetence 539 saphenous incompetence 410 enoxaparin 228, 229 prophylactic use in colorectal surgery 283–4 superﬁcial thrombophlebitis 317–18 environmental risk factors for DVT 95 enzymatic debridement 466 epidural anesthesia, thromboprophylaxis 287, 288 epithelialization, venous ulcer 74–5 ePTFE see PTFE erect stance and venous ulcers 523–4

Index 729

ERK 1/2 74, 76, 78 ESCHAR study 524 escin see horse chestnut seed/root extract Estienne, Charles 3 estrogen see hormonal contraceptives and therapy ethanol, arteriovenous malformation sclerotherapy with 586 ﬁstulous 587 Ethiodol in lymphangiography 644 complications 645 ethnicity and DVT 96–7 etilefrine 667 “etiology” (E) component of CEAP classiﬁcation lymphedema 633 venous disease 37, 38 in severity scoring 686 European Agency for the Evaluation of Medicinal Products (EMEA) criteria for major bleeding 676 examination, clinical/physical chronic venous disease 343 lower limb 337–40 upper limb 333–4 in IVC and iliofemoral vein occlusion, preoperative 515 saphenous incompetence 401 varicose veins 367–9 recurrent 451–2 exercise excess, lymphedema risk 651 foot vein pressure during 47, 48 limb volume reduction (in lymphedema) with 650–1 lymphoscintigraphy and 636 see also effort thrombosis expanded PTFE see PTFE extracellular matrix 62–3 metalloproteinases see metalloproteinases proteins 65–6 so-called “pericapillary ﬁbrin cuffs” (as barrier) 52, 53, 59, 63 ulcers and 76–8 extravasation of contrast media into skin 166 extremities see limbs Fabricius, Hieronymous 3 facial aneurysms 607 factor III see thromboplastin factor V, elevated levels 118 factor V Leiden (activated protein C resistance) 97, 99, 116–17, 268 tests 117, 123 factor VII, elevated levels 118 factor VIII, elevated levels 118

tests 118, 123 factor IX, elevated levels 118 tests 118, 123 factor X, elevated levels 118 factor Xa inhibitors 269 factor XI, elevated levels 118 tests 118, 123 factor XIII and venous ulcer wound healing 77 family history of varicose veins 108 recurrent veins and 451 fascia (lower limb), pressures relating to 32 see also subfascial endoscopic perforator surgery; subfascial ligation femoral veins (generally/unspeciﬁed) anatomy 18 grafts, in SVC obstruction 560 phlebography 160, 164 pressure measurement see pressure thrombosis clinical presentation 336 imaging 144, 160 trauma, treatment 569–70 valve incompetence, reconstructive surgery see reconstructive surgery see also iliofemoral vein thrombosis; saphenofemoral junction femoral veins, common anatomy 18 right, as access site for IVC ﬁlter placement 306 stenting 506–7 femorofemoral saphenous vein transposition 517 femoroiliocaval bypass 518–20 femoropopliteal vein grafts, in SVC obstruction 560 ﬁbrin, D-dimer degradation product, assay 113–14 ﬁbrin cuffs, pericapillary (as barrier) 52, 53, 59, 63 ﬁbrinogen, I-125–labelled 5 ﬁbrinolytic drugs see thrombolysis ﬁbrinolytic system defects in thrombotic disease etiology 119 ﬁbroblasts (in chronic venous insufﬁciency) 65–6, 72–4 ulcers and 72–4, 79 ﬁbrosis (tissue) in chronic venous insufﬁciency 63–5 dermal 63 vein wall 58 ﬁlariasis 631, 650 lymphovenous reconstructions 661 ﬁlm dressings 460 ﬁlters IVC 223, 271, 281, 299–313, 696

complications 308–9 contraindications 301–2 CT of position/orientation 171 follow-up 308 historical background 6, 299–300 ideal characteristics 302 indications 223, 271, 281, 300–1 performance comparisons of various types 309–10 placement technique 306–8 prophylactic (before DVT/PE occurrence) 301 research initiatives 696 suprarenal 310 temporary/optionally-retrievable 304–5 types 302–4 SVC 310 ﬁrst rib resection, axillo-subclavian vein decompression 292, 293, 294, 295 ﬁstula, arteriovenous see arteriovenous ﬁstulas ﬂashlamp-pumped pulsed dye laser 395 ﬂavonoids/ﬂavenoids lymphedema 655 venoactive 360 ulcers 363, 364 ﬂow see blood ﬂow ﬂuid, venous ulcer wound 76, 79 ﬂying see travel foam dressings 460 foam injection for assessing endovenous laser ablation 425 foam sclerotherapy 372, 380–9 clinical practice guidelines 387–8 contraindications and adverse effects 385–7 history 380–2 preparation of foam 382–3 results 383–5 technique 383 fondaparinux 227, 228, 269 prophylactic 282 foot pump 30, 47 foot veins anatomy deep veins 18 superﬁcial veins 15 pressure measurements during exercise 47, 48 fractures, hip, surgical thromboprophylaxis 285 French chronic venous disease study 107 function (physiology) of veins 25–36 compensatory mechanisms 32–5 investigations/tests 156–9 plethysmography 156–9 see also pathophysiology

730

Index

G2 (Generation 2) ﬁlter 305, 305–6 gadolinium-based MR venography 182, 184–5 safety aspects 184–5, 212 Galen 3, 7–8 gangrene, venous, DVT-related 266 Gay, John 7 gelatinases and venous ulcers 76 gender DVT risk and 96 varicose veins and 108 general anesthesia, radiofrequency treatment of saphenous incompetence 410 Generation 2 ﬁlter 305, 305–6 genetic factors chronic venous disease (in general) 699, 700 DVT 95 varicose veins 56–7, 391 venous malformations 595, 600 geographic risk factors for DVT 96–7 Germany, Bonn Vein Study 107 Gianturco stent iliocaval venous recanalization 510 SVC obstruction 558 results 562–3 Ginsberg scale 677 glide wire, endovenous recanalization of iliocaval venous occlusions 505 glomovenous malformations 595, 600 glue/adhesive embolization AVMs 586, 586–7 of ﬁstulous type 587 venous malformations 599–600 glutaraldehyde preservation allograft valves 483 xenograft valves 484, 487 gluteal veins, anatomy 20 gold-198 (198Au) in lymphoscintigraphy 635 gonadal vein embolization 454 grafts, lymphatic 661–2 grafts, skin, with ulcers 468, 468–9 artiﬁcial 466 grafts, veins, and transfers for incompetent valves axillary 477 segment 476–7 for injury repair 570 for IVC and iliofemoral nonmalignant occlusion 517–21, 547 adjuncts improving patency 516–17 surveillance 521 prosthetic see prosthetic grafts for SVC obstruction 560–1 results 563–5 selection 559–60

“gravity” score, lymphedema 633 grayscale median (GSM), thrombi 142 Greece (ancient) 6 Greenﬁeld ﬁlter 6, 300, 302 stainless steel over-the-wire 302, 303, 310 titanium 302, 303, 310 growth factors chronic venous insufﬁciency and 63–5 venous ulcer therapy 361, 461, 463 Günther Tulip ﬁlter 305 performance 310 Hamburg classiﬁcation, congenital vascular malformations 583 Harvey, William 3 health-related quality of life following varicose vein surgery 405 heat body, regulation of/responses to loss 29, 33–4 in laser treatment see thermal effects helical CT see spiral CT hemangiomas (strawberry marks) 597–8 congenital malformations vs 594, 596 diagnosis and management 597–8 hematologic diseases, prothrombotic 265 hemiazygos vein, anatomy 21 hemodynamics (of veins) 25–36 chronic venous disease (in general) 47–55 compression therapy effects on 348–9 future directions incl. research 697–8 iliofemoral vein obstruction see iliofemoral vein obstruction perforator incompetence 524 effects of surgery 531–2 recurrent varicose vein treatment and 454–5 hemoglobin-speciﬁc laser wavelengths 442 hemolymphatic malformation see Parkes Weber syndrome hemorrhage/bleeding anticoagulant-induced 676 intravenous (heparin) 226 as IVC ﬁlter indication 301 oral 232–3 compensatory responses 32–3 in stenting of iliocaval venous occlusions 512 from varicose vein, sclerotherapy 370 heparin 221–32 complications 226, 268–9 as IVC ﬁlter indication 301

thrombocytopenia see thrombocytopenia effects/activities 221–4 evidence-based guidelines 222 low molecular weight see lowmolecular-weight heparin superﬁcial thrombophlebitis treatment 317 thrombosis prevention 123, 125 antiphospholipid syndrome 120 duration of treatment 126 in endovenous reconstruction for iliocaval venous occlusion 509 in endovenous valve reconstruction surgery 478 protein C deﬁciency 116 protein S deﬁciency 116 recommendations 283–8 unfractionated 203, 204 thrombosis treatment 125, 221–32, 255, 267–9 combined with warfarin 224 following radiofrequency treatment of saphenous incompetence 411 long-term 222, 228–9 protocol 224 heparin cofactor II and its deﬁciency 119 hepatectomy and suprarenal IVC replacement with malignancy 578–80 hepatic segment of IVC, development 14 heredity factors see genetic factors hip surgery fractures, thromboprophylaxis 285 joint replacement, thromboprophylaxis 284 Hippocrates 3, 8, 70 phlebectomy conceptualized by 429 hirudin, recombinant see lepirudin hisperidin–diosmin 363 histology 21–2 post-thrombotic veins 201 history (of patient) in chronic venous insufﬁciency 337, 342 in IVC and iliofemoral vein occlusion, preoperative 515 with varicose veins 342, 367 family history as risk factor 108 recurrent veins 451 saphenous incompetence 401 history (of venous medicine) 3–11 chronic venous insufﬁciency (in general) 6–7, 58–9 IVC ﬁlters 6, 299–300 lymphangiography 9, 641 lymphoscintigraphy 9, 635

Index 731

perforator incompetence treatment 536–7 varicose veins see varicose veins Homans, John 4–5, 6 operation for lymphedema 9 modiﬁed 660 homocysteinemia 118–19 hooks, phlebectomy 432–3 HOPE trial 119 hormonal (estrogen-containing) contraceptives and therapy (HRT) DVT risk 99–100, 279 varicose veins risk 108 horse chestnut seed/root extract (aescin) lymphedema 655 varicose veins 359–60 hospital admission for venous ulcers 548 thrombosis risk in 278–9 hydrocolloids 459, 466 hydrogels debridement using 466–7 dressings 459 hydrostatic pressure 26–7 hygiene, extremity, with varicose veins 371 hygromas, cystic, and venous aneurysms 605 hypercoagulable states see thrombophilias hyperhomocysteinemia 118–19 hyperpigmentation see pigmentation hypersensitivity see allergic reactions hypertension, venous ambulatory see ambulatory venous pressure pathologic consequences 27, 63, 240 portal, with aneurysms 609 hyphen webs see telangiectases hypoplasia, saphenous, duplex ultrasound 149–50 hypoxia and chronic venous insufﬁciency 59 ICAM-1 and chronic venous insufﬁciency 63 idraparinux 269 ifetroban 363 iliac anastomosis 13 iliac veins common anatomy 20 left, compression by right common iliac artery see May–Thurner syndrome development 13 malignancy see malignant tumors non-thrombotic obstruction (NIVL) 492

stenting 480 reﬂux, treatment 623 stents see stenting thrombotic obstruction MR phlebography 185 standard phlebography 160 see also iliocaval venous occlusions; iliofemoral vein obstruction; iliofemoral vein thrombosis; May–Thurner syndrome iliocaval venous occlusions, complex, endovascular reconstruction (incl. stenting) 503–13, 547 clinical practice guidelines 512 outcome incl. complications 510–12 patient evaluation 503–5 stent selection 509–10 technique 505–9 iliofemoral vein obstruction, chronic 491–502, 514–22 endovenous reconstruction (with stents) 491–502 clinical outcome 498–9 clinical practice guidelines 500 complications 496–7 in-stent recurrent stenosis 498 stent outcome 497–8 technique 495–6 etiology 491–2 hemodynamic results 499 hemodynamically signiﬁcant 493 morphological, imaging 493–5 open surgery 514–22 patient selection 514 preoperative evaluation 515–16 symptoms 492–3 iliofemoral vein thrombosis 255–64 clinical presentation 336 diagnosis/investigations 266 phlebography 160 management 255–64 catheter-directed thrombolysis 246 obstruction following 491, 499 imaging lymphatic system 635–48 development 8–9 preoperative, in lymphedema 658–9 venous 129–55, 160–85 in chronic venous disease 344–5 IVC ﬁlter placement 306–8 see also speciﬁc modalities and conditions immobilization, DVT risk 98 in air travel 280 immunogold labelling of leukocytes, chronic venous insufﬁciency 64 immunohistochemistry, chronic venous insufﬁciency 64

impedance plethysmography chronic venous disease 344 DVT 210–11 IMUA committee 703 incompetence (venous/venous valve) 29 communicating veins see communicating vein incompetence deep veins (in general) see deep veins duplex ultrasound 142–55 American Venous Forum on 153 perforators, preoperative 525 saphenous veins 402 ovarian vein see ovarian vein saphenous vein see saphenofemoral junction; saphenous vein thrombosis-related 256 see also reﬂux indanediones 229, 230, 233 induration in Venous Clinical Severity Score 678, 687 infection antibiotics and see antibiotics lymphedema due to 631, 650 avoidance 650 inﬂammation DVT and inﬂammation in pathogenesis 83–5, 87–90 inﬂammatory response 256–7 lymphedema due to 631 vein wall 83–4, 87–90 inﬂammatory bowel disease, DVT risk 280 informed consent see consent inguinal veins, superﬁcial 16 conﬂuence see saphenofemoral junction inherited factors see genetic factors injection sclerotherapy see sclerotherapy injury, traumatic arteriovenous ﬁstula following, varicose veins as sequelae 268 lymphedema due to 631 major/multiple, DVT in 97 prevention 286 spinal cord, thromboprophylaxis 285–6 to veins (predominantly in extremities) 568–73 diagnosis 569 distribution 568–9 etiology 568–9 IVC traumatic disruption, CT 171 outcome 570–1 superﬁcial thrombophlebitis following 315 treatment 569–70 see also fractures

732

Index

innominate vein see brachiocephalic vein inspection, chronic venous disease 343 lower limb 337–8 upper limb 333–4 insufﬁciency arterial, co-existing with venous ulcers, assessment 350 chronic venous see chronic venous disease/insufﬁciency integrated care pathway and varicose vein surgery 405 intense pulsed light treatment of telangectasias 396 confounders of 392 future directions 397–8 side-effects/complications 397 intercostal vein, superior 21 intermittent pneumatic compression see pneumatic compression international normalized ratio (INR) 230, 231, 233 interposition grafts and patches injury repair 570 recurrent varicosities 453 intima, anatomy/histology 21 intra-arterial injection of sclerosant, accidental 376 intracellular adhesion molecules-1 in chronic venous insufﬁciency 63 intravascular techniques see endovascular techniques intravenous drug users, DVT diagnosis 213 INVEST project 697–8 investigations and tests in CEAP, level of 40 iodinated contrast media in lymphangiography see Ethiodol iodine-125–labelled ﬁbrinogen 5 iodine-131 (131I) in lymphoscintigraphy 635 iron overload and ulceration 77, 79 ISR-VDS 699 Italian 24–Cities Cohort Study 107 Italian (Maleti–Lugli) neovalve 476, 486 JNK 74, 78 joint replacement (arthroplasty), thromboprophylaxis hip 284 knee 285 Joint Venous Council 695, 702 jugular vein aneurysms 607 phlebectasia 607 right, as access for IVC ﬁlter placement 306

Kabnick phlebectomy instrument 433 Kasabach–Merritt syndrome 598 keratinocytes cultured, in venous ulcer dressings 460–1 in venous ulcers 74–5, 79 ketorolac, endovenous reconstruction for chronic iliofemoral vein obstruction 496 kidney carcinoma see carcinomas impairment, low-molecular-weight heparin in 228 Kistner’s valvuloplasty 474 Kistner’s vein segment transfer 476–7 Klippel–Trenaunay syndrome 598–9 aneurysms in 604 Parkes Weber syndrome as extended form of 584 Parkes Weber syndrome vs 598 sclerotherapy 370 foam, contraindicated 385 knee (joint) arthroscopy, thromboprophylaxis 285 replacement surgery, thromboprophylaxis 284–5 KTP laser, 532nm 394–5 laboratory tests chronic venous disease 343 future directions 699 thrombophilias see thrombophilias varicose veins 369 see also blood tests laparoscopy, pelvic congestion syndrome and varices 620 laser therapy endovenous, for varicosities/saphenous incompetence 418–28 clinical practice guidelines 426–7 follow-up 422 outcomes incl. complications 422–4 pathophysiologic effects of laser energy 418–19 patient selection 419 scientiﬁc background 418–19 technique 420–2 percutaneous, for perforator incompetence results 541–2 technique 539–40 percutaneous, for telangiectasias and varicosities 392–9 alternatives to 397 cooling systems 396

future directions 397 patient selection 392 pretreatment diagnostics and requirements 392 for recurrent veins 453 side-effects/complications 396–7 successful, confounders of 392 types of lasers 394–6 leg see lower limb legging orthosis 355 leiomyosarcoma 574 Leonardo’s vein 16, 524 lepirudin (recombinant hirudin) 269, 283 prophylactic use 282, 283 leukocytes (white blood cells) in chronic venous insufﬁciency 52–3, 59–62, 71–2, 79 activation 52–3, 59–62, 71 distribution/location 61–2, 71 signalling markers and 71 types 61–2 in venous ulceration, as therapeutic target 362–3 see also speciﬁc types LGM (VenaTech) ﬁlter 303 lidocaine, lymphangiography 643 ligation (of vessels) caval, historical aspects 5–6 congenital malformations 599 injured veins 569–70 lymphatics in chylous disorders 667 ovarian vein 621–2 perforators open 525, 529 subfascial (Linton’s operation) 523, 525, 536 light reﬂection rheography 157 light–tissue interactions, laser and intense pulsed light therapy 392 limb(s)/extremities elevation 371 injury to veins see injury lower see lower limb lymphoscintigraphy in normal vs swollen limbs 638–40 limb veins anatomy 14–19, 20–1 development 14 lower see lower limb upper see upper limb veins Linton RR 7 Linton’s operation 523, 525, 536 lipodermatosclerosis 77 deﬁnition 40 healing process 77 presentation 337 liposuction in lymphedema 660

Index 733

liver lymphoscintigraphic visualization 637 resection (with malignancy), and suprarenal IVC replacement 578–80 local and regional anesthesia lymphangiography 643 neuraxial, thromboprophylaxis 286–8 phlebectomy 432 radiofrequency treatment of saphenous incompetence 410 long-pulse alexandrite laser, 755nm 395 low-molecular-weight heparin (LMWH) 123, 125, 203, 204, 222, 226–7, 255, 267–9, 281–2 complications 226, 227 duration of treatment 126 following radiofrequency treatment of saphenous incompetence 411 long-term 222, 228–9 prophylactic use 123 antiphospholipid syndrome 120 in endovenous iliofemoral venous recanalization 509 in endovenous valve reconstruction surgery 478 protein C deﬁciency 116 protein S deﬁciency 116 recommendations 283–8 special features 269 special patient groups 227–8 superﬁcial thrombophlebitis 317–18 see also speciﬁc drugs low-proﬁle VenaTech see VenaTech Low-proﬁle ﬁlter lower limb anesthesia see tumescent anesthesia arterial insufﬁciency see arterial insufﬁciency edema see edema elevation with varicose veins 371 lymphatic grafting 661–2 pain, causes 133–4 paralysis, thromboprophylaxis in spinal cord injury with 285–6 pressure relationships 32 vein, aneurysms 605–6 veins anatomy 14–19 chronic disease see chronic venous disease/insufﬁciency development 14 thrombosis see superﬁcial thrombophlebitis; thrombosis, deep venous

lumen characteristics in duplex ultrasound in acute vs chronic obstruction 144 lung Ethiodol-associated complications 645 scintigraphy see radioisotope scans lupus anticoagulant 120 lymph, overproduction 632 lymph node metastases, lymphoscintigraphy 636–7 lymphangiography 641–5, 645, 647 contraindications 645 development 9, 631 indications 645 preoperative 658–9 interpretation 644–5 technique 641–4 lymphangitis 632 lymphedema and 629, 631 lymphatic drainage massage (manual lymph drainage) 651–2 lymphatic system anatomy 631–2 historical aspects of disease affecting 8 imaging see imaging lymphedema 627–72 acute vs chronic 629 clinical presentation 629 comorbidities 656–7 deﬁnitions 649 differential diagnosis 651 mimicking conditions 630 DVT vs 266 as endovenous laser therapy complication 423 etiology 630–1, 649 cancer see malignant tumors risk factors and risk reduction 650–1 lymphedema risk 650 lymphoscintigraphy 639–40 pathophysiology 632 primary 630–1, 649 secondary 631, 649, 650 stages 649 treatment 649–64 non-surgical 649–57, 666 surgical 658–64 lymphedema praecox 631 lymphedema tarda 631 lymphocytes in chronic venous insufﬁciency 60–1 lymphoscintigraphy 635–41, 645, 647 chylous disorders 666 history/development 9, 635 interpretation 637–8 in neoplastic disease 636–7

normal vs swollen limbs 638–40 preoperative, in chronic lymphedema 658 technique 635–6 lymphovenous anastomoses chylous disorders 667 chylothorax 670 lymphedema 660–1 LysUS Infusion Catheter System (EKOS) 248, 250, 259, 261 macrophages (in chronic venous insufﬁciency) 61–2 ulcers and 71, 74, 79 magnetic resonance imaging chylous disorders 666 IVC ﬁlter compatibility with 302, 303 lymphedema, preoperative 658 pulmonary artery (for PE) 216 of veins (MR phlebography/venography) 173–90 chronic venous disease 344–5 clinical applications 185–7 congenital malformations 596 CT compared with 174–80, 188 future prospects 188–90 iliocaval venous occlusions 505 iliofemoral and IVC venous obstruction before open surgery 516 iliofemoral venous obstruction before endovenous surgery 494 IVC tumors 576 mesenteric veins (incl. thrombosis) 187, 322 outﬂow obstruction 698 pelvic congestion syndrome 619 saphenous incompetence 402 SVC obstruction 557 techniques 180–5 thoracic aneurysms 608 thrombosis 185–6, 190, 211–12 Maleti–Lugli (Italian) neovalve 476, 486 malformations, congenital vascular see congenital vascular malformations malignant tumors IVC and iliac vein invasion/obstruction 574–82 clinical presentation 575 evaluation 575–6 imaging 183, 186, 576 outcome and survival 580–1 treatment 576–80 types 574–5 lymphedema in 631 in breast cancer see breast cancer lymphoscintigraphy 636–7 renal vein invasion/obstruction 183, 186

734

Index

malignant tumors – (contd) secondary see metastases SVC-obstructing 553 treatment 557, 562 thromboembolism risk 98, 122, 280 IVC ﬁlter indicated with 300–1 postoperative 283–4 thrombus see tumor thrombus see also speciﬁc histologic types manual lymph drainage 651–2 MAPK 74, 78, 79 Marshall, vein of 13 massage, lymphatic drainage (=manual lymphatic drainage) 651–2 mast cells in chronic venous insufﬁciency 61–2 mastectomy, lymphedema following 661 matrix see extracellular matrix; metalloproteinases matting, sclerotherapy causing 376 May–Thurner syndrome (Cockett’s/iliac vein compression syndrome) 172–3, 344, 345, 492, 514 foam sclerotherapy contraindicated 385 Mayer–Brücke device 381 mechanical methods of thromboprophylaxis 280–1 of thrombus removal (percutaneous mechanical thrombectomy) 247, 259–61, 270 evidence-based guidelines 223 mesenteric vein 325 wound debridement 466 media 21–2 medical illness (incl. systemic disease) lymphedema caused by 631 lymphedema comorbid with other conditions 655–6 in sclerotherapy as adverse event 375–6 as contraindication 370 thrombosis in 97–8, 265 Medical Outcomes Study Short Form (SF-36) 690 mesenteric veins aneurysms 609 MRI 187, 322 thrombosis 320–7 clinical presentation 321 diagnostic methods 321–4 etiology 320–1 management 324–5 outcomes/recurrence 325 metalloproteinases, matrix (MMPs) 66 tissue inhibitors of see tissue inhibitors of metalloproteinases varicose veins and 58, 66

venous ulcers and 73, 76–8, 79 metastases (secondary tumors) IVC and iliac vein 574–5 lymph node, lymphoscintigraphy 636–7 SVC-obstructing 553 treatment 557 methylene-tetrahydrofolate reductase (MTHFR) mutations 118 microcirculation, lower limb in chronic venous insufﬁciency 61 cutaneous 15 microfoam 381, 382 micronized puriﬁed ﬂavonoid fraction (MPFF) 363, 364 microparticles, platelet-derived 85–7 microphlebectomy see phlebectomy, ambulatory microthrombectomy, post-sclerotherapy 374–5 migratory thrombophlebitis 315 military ﬁelds (and war), venous injury diagnosis 569 distribution 569 etiology 568 outcome 570 treatment 569, 570 Miller’s staged subcutaneous excision 660 mitogen-activated protein kinases (MAPKs) 74, 78, 79 Mobin-Uddin umbrella 6, 300 Mondor’s disease 315 monocytes in chronic venous insufﬁciency 60–1 DVT and 88 mortality see death MT1–MMP 78 Muller phlebectomy 429, 429–30 multilayered compression bandages lymphedema 653 ulcers 352–5 muscle pump see calf muscle pump; pump musculoskeletal activity 33 musculoskeletal disorders, sclerotherapy contraindications 370 myoﬁbroblast differentiation 73 nadroparin 228, 229 NASEPS registry 529, 531 National Venous Registry, evaluation of catheter-directed thrombolysis 243, 245 Nd:YAG laser 532nm 395 1064nm 396 intense pulsed light compared with 396

neck, aneurysms 607 necrosis, cutaneous sclerosant-induced 377 warfarin/coumarin-induced 115–16, 268, 301 neodymium:YAG laser see Nd:YAG laser neoplasms see tumors neovalves and artiﬁcial venous valves 476, 483–90 autologous 485–6 non-autologous 483–5 percutaneously-implantable 486–8, 701 neovascularization complicating endovascular varicose vein obliteration, in endovenous laser therapy 424, 447 nephrotic syndrome, DVT risk 280 nerve injury, radiofrequency treatmentrelated 411 Netherlands (Dutch) SEPS trial 530–1 neuraxial anesthesia, thromboprophylaxis 286–8 neurosurgery, thromboprophylaxis 285 neutrophils, polymorphonuclear chronic venous insufﬁciency and 71–2 DVT and 87–8 nevus blue rubber-bleb 599 strawberry see hemangiomas nevus ﬂammeus (port-wine stain), varicose veins 368 Nitinol ﬁlters Recovery 305, 305–6 Simon 303, 309, 310 Nitinol stent, iliocaval 510 non-invasive tests in chronic venous disease 344 varicose veins 369 non-occlusive dressings 458, 459, 460, 462 non-steroidal anti-inﬂammatory drugs (NSAIDs) superﬁcial thrombophlebitis therapy 317–18 VTE/PE therapy 222 North American SEPS (NASEPS) registry 529, 531 NORVIT trial 119 nutrition see diet Oasis 464, 465, 466, 468 obesity low-molecular-weight heparin in 227 lymphedema in 650 thrombosis and 101 varicose veins and 109

Index 735

sclerotherapy contraindications 371 oblique vein of left atrium 13 obstruction/occlusion/stenosis lymphatic 632 thoracic duct, surgery 669, 670 venous acute, duplex ultrasound, compared to chronic 144 chronic, duplex ultrasound 143–4 iliocaval, complex see iliocaval venous occlusions iliofemoral, chronic see iliofemoral vein obstruction plethysmography 157, 157–8 standardization of non-invasive tests 691 subclavian vein, intermittent, presentation 331–2 see also restenosis occlusion, pathologic see obstruction occlusion plethysmography, venous 691 occlusive dressings 458, 459–60, 463, 466 Opsite 460 OptEase ﬁlter 304, 305 oral anticoagulants (vitamin K antagonists) 229–35 adverse effects 232–3 commencing 222 discontinuation criteria 273 long-term 222, 223, 230–3 monitoring and therapeutic range 230 see also coumarins; phenindione; warfarin oral contraceptives see hormonal contraceptives orthopedic surgery, thromboprophylaxis 284–5 orthosis, legging 355 osmotic sclerosants 371 osteoporosis, heparin-induced 226 outcome assessment in venous disease 675–93 acute disease 675–83 chronic disease 684–93 see also quality of life outﬂow tract (of calf pump, obstruction 50 magnetic resonance venography 698 ovarian vein incompetence and reﬂux 620 management 621–3 over-the-wire stainless steel Greenﬁeld ﬁlter 302, 303, 310 P component of CEAP classiﬁcation see pathophysiology

P-selectin inhibitors 269 in thrombosis/DVT etiology 84–7 p21 74 p38 74, 78 Paciﬁc Vascular Symposium, 5th 694, 696, 701, 702 Paget–von Schrötter syndrome see effort thrombosis pain DVT 196 lower limb (in general), causes 133–4 ulcers, management 467 in Venous Clinical Severity Score 678, 687 Palma operation 517 palpation, chronic venous disease lower limb 338 upper limb 334 panel grafts, injured veins 570 paralysis of lower limb/leg, thromboprophylaxis in spinal cord injury with 285–6 paresthesia (sensory abnormalities), radiofrequency treatment-related 411, 412 Parkes Weber syndrome (hemolymphatic malformation) 584 Klippel–Trenaunay syndrome vs 598 paste (Unna) boot 7, 351–2 pathophysiology (of venous disease primarily chronic) 47–55, 56–69 in CEAP classiﬁcation (=P) in lymphedema 633–4 in CEAP classiﬁcation (=P) in venous disease 37, 39 in severity scoring 687 cellular aspects 52–3, 56–69 duplex ultrasound studies 149–52 historical aspects 3 see also speciﬁc disorders patient-based assessments of QoL in chronic venous disease 690–1 Pavcnik valve 488 PDGF see platelet-derived growth factor pediatric jugular aneurysms 607 pelvic veins anatomy 20 congestion 617–26 clinical practice guidelines 625 diagnosis and investigations 619–20 etiology 618–19 treatment 620–5 embolization 454 segmental reﬂux 623 varicose 617–26 clinical practice guidelines 625 etiology 618–19

pelvis, AVMs, CT 173 pentoxifylline 362, 363 percussion, chronic venous disease, upper limb 334 percutaneous (transcutaneous) approach/access angioplasty and stenting see angioplasty; stenting artiﬁcial valve implantation 486–8, 701 laser therapy see laser therapy perforator ablation see communicating vein incompetence thrombectomy see mechanical methods perforating veins see communicating (incl. perforating) veins perfusion scans (lung), arteriovenous shunts 584 see also ventilation–perfusion scans perfusion scintigraphy, transarterial lung, arteriovenous shunts 584 perineal varicosities 617–18 management/treatment 623, 625 peripheral arteries see entries under arterial peroneal veins, anatomy 18 Pﬂug’s staged subcutaneous operation 660 pharmacomechanical thrombolysis 247–8, 259–61 pharmacotherapy see drugs phase contrast pulse sequences in MR venography 181–2 phenindione 229 see also oral anticoagulants phlebectasia 604 genuine diffuse 604 jugular vein 607 phlebectomy 429–38, 443 ambulatory (stab avulsion; microphlebectomy) 430–7, 443 anesthesia 432 beneﬁts 431 clinical practice guidelines 437 complications 434–5 concurrent truncal reﬂux abolishment 431 contraindications 431 deﬁnition 430 discharge recommendations 433–4 equipment 432–3 indications 430 powered device 435–7, 443 preoperative evaluation 431 procedure 433 surgical plan 431–2 history 529–30

736

Index

phlebitis, radiofrequency treatmentrelated 411–12 see also superﬁcial thrombophlebitis phlebography/venography CT see computed tomography lower limb see phlebography/venography, lower limb MR see magnetic resonance imaging pelvic veins 620 upper limb axillary/subclavian vein thrombosis 267 SVC syndrome 557 phlebography/venography, lower limb and in general (standard/X-ray contrast) ascending (basic aspects) 162, 163, 164, 167, 345 chronic venous disease 161–2, 345 complications 166 congenital malformations 596 descending (basic aspects) 162, 164–6, 345 DVT 160, 210, 257 axillo-subclavian vein 267 in pregnancy, risks 212 historical development 5 iliocaval venous occlusions 504–5 iliofemoral venous obstruction (chronic), preoperative before endovenous surgery 493–4 before open surgery 515–16 indications 160–2 IVC (venacavography) for ﬁlter placement 306–7 for IVC malignancy 576 for open surgery for IVC occlusion 515–16 mesenteric vein thrombosis 323–4 saphenous incompetence 402–3 SVC syndrome, upper limb 557 techniques 162–4 varicose veins 402–3 phlebotonic drugs 359–60, 363–4 for recurrent varicosities 452 phlegmasia alba dolens (white leg) 208, 266 phlegmasia cerulea dolens lower limb (painful blue leg) 195, 266, 309, 336 interventions 248, 255, 257, 258 upper limb 333 phospholipids, autoantibodies see antiphospholipid syndrome photography, varicose vein sclerotherapy 373 photoplethysmography 157, 691

photothermolysis, selective, concept of 391, 395 physical examination see examination physical therapy, lymphedema 651–4, 655, 666–7 physiology and physiologic tests see function; pathophysiology pigmentation/hyperpigmentation 40 causes laser therapy 397 sclerotherapy 374, 376 in Venous Clinical Severity Score 678, 687 pinch grafts 469 PIOPED study 214, 215 PISA-PED study 215 plant medicines lymphedema 655 phlebotonic 359–60 plantar veins/venous plexus 18 pumping of blood (=foot pump) 30–1, 47 plasminogen, venous ulcers and 77, 79 plasminogen activators in catheterdirected thrombolysis 241, 243, 244 dose and volume 246 see also tissue plasminogen activator; urokinase platelet(s) in thrombosis, in etiology 85–7 in venous ulcers, inhibitors 363 see also thrombocytopenia platelet-derived growth factor/PDGF (and chronic venous insufﬁciency) 64–5 ulcers and 72, 73 therapeutic use of PDGF 461 plethysmography 142, 156–9, 344, 691 air see air plethysmography compression therapy and 349 historical development 5 impedance see impedance plethysmography saphenous incompetence 403 strain-gauge see strain-gauge plethysmography technical principles 156–7 thrombosis 210–11 ulcers and compression therapy 349 pneumatic compression, intermittent (compression pumps) 701 future directions 700, 701 lymphedema 654 thromboprophylaxis in multiple trauma 286 ulcers 355–6 polidocanol perforator incompetence 541 varicose veins 372, 381, 382

adverse events 385–7 Polish chronic venous disease study 107 polymorphonuclear neutrophils see neutrophils polytetraﬂuoroethyelene prostheses/grafts see PTFE popliteal veins anatomy 18 aneurysms 605–6 phlebography 164 trauma, treatment 569–70 valve incompetence, reconstructive surgery see reconstructive surgery port-wine stain, varicose veins 368 portal vein aneurysms 609 Portland valve 487–8 position (patient), examining chronic venous insufﬁciency of lower limb 337 postoperative monitoring and care, venous ulcers 547 post-thrombotic disease/damage see thrombosis post-thrombotic obstruction of iliofemoral vein, chronic 491, 499 post-thrombotic syndrome 143, 197, 200–2, 676–9 determinants 201–2 evidence-based guidelines for management 223 medical management 234–5 outcome/natural history 200–2, 203 assessment 676–9 pathophysiology 200–1 presentation and assessment, upper limb 333 ulcer see ulcers (venous) varicose veins 368 posture and varicose veins 159 potassium titanylphosphate laser, 532nm 394–5 Power-Pulse Angiojet 259–60 powered phlebectomy 435–7, 443 pregnancy thromboembolism/DVT diagnosis 212 risk 100, 279–80 varicose veins in risk 108 sclerotherapy contraindications 270 vulval 618, 624 PREPIC study 304–5 prerenal segment of IVC, development 14 pressure lower limb 32 under compression bandages 352–3 pressure, venous 26–8, 32

Index 737

ambulatory see ambulatory venous pressure gradients 26, 691 high see hypertension measurement 684 in femoral veins in endovenous iliofemoral venous obstruction 493 in femoral veins in open surgery for iliofemoral and IVC obstruction 516 in saphenous incompetence 403 Profore multilayered bandage system 353 Proguide 354 prostacyclin analogs, ulcers 363 prostaglandin E1, ulcer therapy 362, 364 prosthetic grafts injured veins 570 IVC and iliofemoral non-malignant obstruction 516, 517, 519 IVC malignant involvement 578 SVC 560, 561, 564, 566 prosthetic sleeve valvuloplasty 476 protein C activated, resistance see factor V Leiden deﬁciency 99, 115 superﬁcial thrombophlebitis and 315 tests 115, 123 protein S deﬁciency 99, 116 superﬁcial thrombophlebitis and 315 tests 116, 123 prothrombin gene 20210A mutation 99, 117, 268 tests 117, 123 prothrombotic states see thrombophilias PSGL-1 84, 85 receptor antagonist (rPSGL-Ig), effects 84, 85 PTFE (ePTFE) graft femoral vein 517 IVC malignant involvement 578 SVC obstruction 560 results 564 pudendal varicose veins 618 pulmonary angiography/arteriography 215 CT 171–2 MR 216 pulmonary AVMs 173 pulmonary embolism (thrombotic) 5–6, 171–2, 196, 221–38, 675–6 acute 172 aneurysms of extremities and 606 popliteal 605 chronic 172

clinical features (signs/symptoms) 196, 213–14 ultrasound of DTV in patients with 130 diagnosis 213–17 algorithm 213, 216, 217 historical aspects 5–6 investigations, imaging 171–2, 214–15, 215–16 medical management 221–38 alternative/future 269 outcome assessment 675–6 surgery (embolectomy), evidencebased guidelines 223, 235 pulmonary thromboembolism see pulmonary embolism pulse repetition frequency (duplex ultrasound) 142 pulse sequences in MR venography phase contrast 181–2 steady-state free precession 181 pulse-spray technique (thrombolysis) 243, 247, 260 pulsed dye laser, ﬂashlamp-pumped 395 pump (device), compression see pneumatic compression pump (muscle), peripheral 29–32 see also calf muscle pump; foot pump; thigh pump Pütter bandage 353 quality of life in chronic iliofemoral venous obstruction following endovenous reconstruction 499 in chronic venous disease, patientbased assessments 690–1 in post-thrombotic syndrome 678–9 with varicose veins, postoperative 405 in recurrent disease 452 race and DVT 96–7 radiofrequency (RF) treatment for perforator incompetence results 541 technique 538–9 for saphenous incompetence, endovenous 409–16, 442 clinical practice guidelines 416 complications, management 412 diode laser combined with 396 future aspects 414 long-term results 412–14 technique 410–11 radiography abdominal, mesenteric vein thrombosis 324

PE 216 veins see phlebography radioisotope scans/scintigraphy lung for arteriovenous shunts 584 for PE 214–15 lymphatic system, development 9 radiology see imaging and speciﬁc modalities raloxifene and DVT 279 Rb (retinoblastoma protein) 74 recanalization in radiofrequency occlusion, rate 413 with stents see stenting in thrombosis 198, 200 rate related to ultimate valve function 202, 203–4 ultrasound visualization 136 receptor tyrosine kinase and venous malformations 595 reconstructive surgery axillosubclavian vein 295–7 chylous disorders 667, 670 deep vein valve incompetence (incl. femoral/popliteal/tibial veins) 472–82, 547–8 anticoagulants 478 controversies 478–9 identiﬁcation of valve attachment lines 473–4 indications and patient selection 472 morbidity 478 new developments 480 outcome 478 preoperative assessment 472–3 techniques 473, 474–7 endovenous see endovascular techniques; stenting lymphatic 660–1 lymphoscintigraphy in evaluation for 639–40 open, IVC and iliofemoral vein nonmalignant obstruction 514–22 open, SVC obstruction 557, 559–60 results 563–5 technique 560–1 Recovery Nitinol ﬁlter 305, 305–6 reduplication see double veins reﬂexes 28–9 reﬂux, chylous 665 surgery 667–8 reﬂux, venous 142, 144–9, 547, 698 communicating veins see communicating vein incompetence/reﬂux congenital, deﬁnition 146–8 deep veins see deep veins

738

Index

reﬂux, venous – (contd) duplex ultrasound 144–9, 149–50 progression of reﬂux 151–2 technique 148–9 future directions in assessment of 698 groin/truncal abolishment, phlebectomy performed concurrently with 431 following radiofrequency treatment of saphenous incompetence 413 lymphedema in 632 ovarian vein see ovarian vein phlebography, reﬂux grading 166 plethysmography 157, 158 severity assessment 158 post-thrombotic 202 primary 473 deﬁnition 146–8 superﬁcial see superﬁcial veins with recurrent varicose veins combined deep vein 455 degree 450–1 sources 450, 454–5 saphenous see saphenofemoral junction; saphenous vein secondary 146–8 standardization of non-invasive tests 691 see also incompetence regional anesthesia see local and regional anesthesia Regranex 461 renal problems/investigations see kidney and entries below renal segment of IVC, development 14 renal vein anomalies 14 IVC ﬁlter placement and 307 IVC stents placed across 507 MR venography 186–7 thrombosis in nephrotic syndrome 280 tumor thrombus 183 Reno Vein Clinic, Closure procedure 410, 412 research initiatives chronic venous disease primary 699 secondary 700–1 diagnostics and hemodynamics 697–8 organizational issues 695 thromboembolic disease treatment 696–7 restenosis of stents iliofemoral vein 498 SVC 563

reticular veins/varices 336 deﬁnition 39, 105 treatment 440–1 retinoblastoma protein 74 retroperitoneal lymphatics, ligation 667 retroperitoneal sarcoma 575 return, venous 25–9 central 26 peripheral 26 physiologic components 26–9 REVAS classiﬁcation 449, 450–1 reviparin 228, 229 rib resection, ﬁrst, axillo-subclavian vein decompression 292, 293, 294, 295 “Rokitansky” stenosis 491 Rome (ancient) 6 round ligament varices 623, 624 sacral vein, median anatomy 20 development 13 saline wet-to-dry dressings 459 San Diego Population Study 105–7 saphenofemoral junction (conﬂuence of superﬁcial inguinal veins) 16 anatomic variants 17 duplex ultrasound 146 incompetence/reﬂux Closure procedure in elimination of 409–16 recurrent 152 interposition patch for varicosity recurrence at 453 saphenous surgery and the great 403 small 404 superﬁcial thrombophlebitis treatment 316–17 saphenous vein (in general) grafts for occlusion iliofemoral and IVC 517 SVC 559 hypoplasia, duplex ultrasound 149–50 phlebography 164 reﬂux, treatment 441–2 varicose and incompetent 400–8 clinical presentation and assessment 401–2 investigation 402–3 laser therapy see laser therapy non-surgical options 403 outcome and quality of life following surgery 405 radiofrequency treatment see radiofrequency treatment recurrent, surgery 404–5 surgery 403–6

saphenous vein, long/great (GSV) anatomy 15–16 variations 16, 149, 150 incompetence 441–4 laser therapy see laser therapy radiofrequency treatment see radiofrequency treatment surgery 403–4, 404 treatment options and algorithm 441–4 reﬂux, duplex ultrasound 149, 150 thrombus, duplex ultrasound 145 saphenous vein, short/small (SSV) anatomy 16–17 duplex ultrasound 147 reﬂux 149, 150 incompetence, surgery 404 thrombosis/thrombophlebitis 315 SAPK (JNK) 74, 78 saponins 360 sarcoma, retroperitoneal 575 see also leiomyosarcoma scintigraphy see radioisotope scans sclerotherapy (chemical ablation) 369–70, 369–77, 442 adverse events 375–6, 385–7 agents (sclerosants) in concentration related to vein sizes 372 selection 371–2 types 371 congenital arteriovenous malformations, embolization and see embolization congenital venous malformations 370, 372 embolization and 600 foam see foam sclerotherapy historical accounts 6 materials 372–3 ovarian vein 622–3 perforator incompetence results 541 technique 540 telangiectases 372, 373–4, 440–1 varicose veins, extremities 369–89, 442 contraindications 370–1, 385–7 historical review 6, 366–7, 380–2 indications 369–70 recurrent 452–3, 453 varicose veins, perineal 623 screening for hypercoagulable states/thrombophilias 99, 265–6 sdi1 (p21) 74 sedentary patients, sclerotherapy contraindications 270 segment transfers in valve incompetence 476–7

Index 739

Segmental Disease Score, Venous 685, 687–8 Seldinger technique, IVC ﬁlters 300 selectins 84–7 P- see P-selectin selective estrogen receptor modulator, DVT risk 279 self-expanding stent in autologous vein and valve transplantation 487 iliocaval venous recanalization 509–10, 510 iliofemoral venous recanalization 495–6 in SVC obstruction 558 semi-occlusive dressings 458, 459–60, 463 senescent ﬁbroblasts and venous ulcers 72–3, 74 sensory abnormalities (paresthesia), radiofrequency treatment-related 411, 412 sentinel lymph nodes, lymphoscintigraphy 637 SEPS see subfascial endoscopic perforator surgery septic thrombophlebitis, treatment 267 Servelle’s excisional operation 660 severity scoring systems 685–8 clinical 677–8, 685, 686–7 sex see gender SF-36 690 shunts (intravascular) arteriovenous see arteriovenous ﬁstulas and shunts temporary, use in venous trauma 570 Simon Nitinol ﬁlter 303 single-port SEPS 525–6 sinus(es), venous, calf, anatomy 19 SIS valve 487–8 skin 52–3 in chronic venous disease, pathophysiology 52–3, 60, 63 compression therapy mechanisms and 349–50 cooling in laser treatment 396 extravasation of contrast media into 166 grafts see grafts lower limb, and subcutaneous pressures 32 in lymphedema care 650 morphology 632 microcirculation in lower limb 15 necrosis see necrosis pigmentation see pigmentation

sclerotherapy-related lesions 376–7, 377 telangiectases see telangiectases ulceration see ulcers see also percutaneous approach skin (dermal) equivalents, human, venous ulcers 361, 460–1, 463 smooth muscle cells, varicose veins 57–8 socioeconomic consequences, recurrent varicose veins 447 sodium tetradecyl sulfate (sclerosant) perforator incompetence 541 varicose veins 382, 383, 384 sole, deep veins 18 somatostatin and analogs, chylous disorders 667 Sorbsan 460 spider veins/webs see telangiectases spinal anesthesia, thromboprophylaxis 286–8 spinal cord injury, thromboprophylaxis 285–6 spiral (helical) CT chronic iliofemoral venous obstruction 494 PE 215–16 spiral vein grafts injured veins 570 IVC and iliofemoral occlusion 519, 521 SVC occlusion 559, 560, 561, 564, 566 splanchnic circulation 28 splenic vein aneurysms 609 split-thickness skin grafts 468, 468–9 spoiled gradient echo images 184 stab avulsion see phlebectomy, ambulatory stainless steel over-the-wire Greenﬁeld ﬁlter 302, 303, 310 standing (patient), chronic venous insufﬁciency of lower limb examination 337 stanozolol, venous ulcers 361 stasis, pathologic consequences due to 52, 59, 60, 63 thrombosis 197 static (dynamic) pressure 26–7 steady-state free precession pulse sequence 181 stenosis see obstruction; restenosis stenting (endovascular) 479 in autologous vein and valve transplantation 486–7 future for 701 iliac vein 507, 508 non-thrombotic obstructive lesion 480

thrombotic obstruction 259 iliocaval venous segment (complex occlusions) see iliocaval venous occlusions iliofemoral venous segment (in chronic obstruction) see iliofemoral vein obstruction superior vena cava 558 results 562, 562–3 stocking, compression see compression stockings strain-gauge plethysmography 156–7, 344 in chronic venous disease 344 Straub Clinic, Closure procedure 412 strawberry marks see hemangiomas strip test for deep vein incompetence postoperative 474–5 preoperative 474 stripping great saphenous vein 403, 404 short saphenous vein 404 stroke volume and calf pump output 31 Sturge–Weber syndrome 598 subcardinal veins 13 subclavian vein anatomy 21, 332 aneurysms 609 intermittent obstruction, presentation 331–2 thrombosis see axillosubclavian vein subcutaneous heparin 227 low-molecular weight 227 unfractionated, ﬁxed-dose weightadjusted 225–6 subcutaneous pressures 32 subfascial endoscopic perforator surgery (SEPS) 400, 453, 523, 525–7, 536–7 advantages of percutaneous ablation over 542–3 results 528–31, 532 technique 525–7 subfascial ligation of perforators (Linton’s operation) 523, 525, 536 sulodexide 362 superﬁcial thrombophlebitis 267, 314–19 clinical presentation and assessment 314, 334 upper limb see upper limb diagnosis 267, 316 etiology 314–15 sclerotherapy 377 pathology 315 treatment 233–4, 272–3, 316–18 superﬁcial veins (in general) in anatomic component of CEAP classiﬁcation 39

740

Index

superﬁcial veins (in general) – (contd) anatomy lower limb 15–18 upper limb 20 incompetence/insufﬁciency/reﬂux 48–9 coexisting/association with deep vein reﬂux 151 duplex ultrasound 149 primary, deep reﬂux combined with 547 superior vena cava syndrome see vena cava, superior supine position, chronic venous disease examined in 343 suppurative superﬁcial thrombophlebitis 267, 315 supracardinal veins 13 suprarenal IVC absence 14 ﬁlter placement 310 reconstruction 520–1 replacement in malignant involvement 578–80 surgery, DVT/thromboembolism after or as risk factor in 97, 123–4, 279, 283–5 prevention 283–5 risk stratiﬁcation 283 surgery, vascular and in venous disease adjunctive procedures impacting on outcomes assessment 689 aneurysms abdominal 609–10, 610 extremities/deep veins 605–6, 606 jugular 607 thoracic 608, 608–9 axillo-subclavian vein 295–7 chronic venous disease/insufﬁciency (in general) 405 etiologic knowledge inﬂuencing 44 future directions 700 historical aspects 7–8 chylous disorders 667–70 congenital malformations of arteriovenous type 585 of ﬁstulous type 589 congenital malformations of venous predominance 599 duplex ultrasound before/during/after 152–3 incompetent veins and reﬂux endovascular see endovascular techniques ovarian 621–2, 624 perforator see communicating veins superﬁcial veins 151 valve see valve lymphedema 9, 658–64

PE, historical aspects 5–6 reconstructive (for incompetent or occluded veins) see endovascular techniques; reconstructive surgery superﬁcial thrombophlebitis 316, 317 SVC obstruction 557, 559–60 results 563–5 technique 560–1 of thrombosis historical aspects 5 mesenteric vein 325 thrombus removal see thrombectomy thrombosis after, and its prevention 284 in endovenous reconstruction for iliocaval venous occlusion 509 in endovenous reconstruction for iliofemoral vein obstruction 496, 496–7 in open surgery for IVC and iliofemoral vein reconstruction (for non-malignant occlusion) 517 in valve reconstruction surgery 478 tumors of IVC and iliac veins 576–80 outcome and survival following 580–1 ulcers, compared with compression therapy 356 varicose vein 403–8, 429–38 clinical practice guidelines 406 complications and their prevention 404 history and development 6, 366–7, 400–1 outcomes and quality of life 405 recurrence following see varicose veins for recurrent varicosities 404–5 redo (surgery for recurrence) 404–5, 452–3, 453 saphenous 403–8 see also speciﬁc techniques systemic disease see medical illness tamoxifen and DVT 279 technetium-99m in lymphoscintigraphy 635, 636 Tegagel 459, 460 Tegapore 460, 463, 464 Tegasorb 463, 464, 466, 468 telangiectases, cutaneous (C1 disease; dilated intradermal venules; hyphen webs; spider veins; thread veins) 390–9, 439–41 deﬁnition 39, 105 diagnosis 342–7

etiology/pathogenesis 390 presentation and classiﬁcation 336, 391 primary 391 secondary 391 symptomatic vs asymptomatic 440 treatment 390–9, 439–41 algorithm 440–1 intense pulsed light treatment see intense pulsed light treatment laser therapy see laser therapy sclerotherapy 372, 373–4, 440–1 temperature body, regulation 29, 33–4 environmental, and lymphedema risk 651 tenoxicam, superﬁcial thrombophlebitis 317–18 Tessari technique 382, 383 tests see investigations and speciﬁc tests TGF-β see transforming growth factor-β therapy, advancing the art and science of 695 thermal ablation see laser therapy; radiofrequency treatment thermal effects (heat damage) with lasers in endovenous laser treatment 418, 419 in percutaneous laser treatment 393, 394 as side-effect, minimizing 396 thermal relaxation time 393 thermoregulation 29, 33–4 thigh pump 30, 47 thoracic aneurysms 607–8 thoracic central veins, MR venography 187 thoracic duct obstruction, surgery 669, 670 thoracic outlet syndrome, axillosubclavian vein thrombosis in 292–8 thoracoepigastric vein, thrombophlebitis 315 three-dimensional MR venography 182, 183–4 thrombectomy (TE)/thrombus removal 44, 257–9, 270 complications 258–9 evidence-based guidelines 223 mesenteric vein 325 new developments 259 percutaneous mechanical see mechanical methods post-sclerotherapy microthrombectomy 374–5 in radiofrequency treatment-related DVT 411 results 258–9

Index 741

thrombin inhibitors, direct (DTIs) 269 in heparin-induced thrombocytopenia 121, 269 prophylactic use 282–3 thrombocytopenia, heparin-induced 120–1, 226, 268–9, 273 low-molecular-weight 227, 268, 282 thromboembolism arterial see arterial thromboembolism pulmonary see pulmonary embolism thrombolysis/ﬁbrinolysis (drugs) 83, 204, 239–54, 270 as adjunct to heparin 222 axillo-subclavian vein thrombosis 292–5 catheter-directed see catheter-directed thrombosis treatment evidence-based guidelines 222 mechanical see mechanical methods mesenteric vein 324–5 pharmacomechanical 247–8, 259–61 rationale 240 recanalization rate related to ultimate valve function 202, 204 SVC syndrome of benign etiology 562 systemic 241 venous ulcer therapy 361–2 thrombolysis/ﬁbrinolysis (natural), simultaneous thrombosis and 136 thrombophilias (and hypercoagulable/prothrombotic states) 95, 98–9, 265, 278 acquired (incl. situational) and secondary 95, 119–20, 278 clinical practice guidelines 124–5 DVT and 95, 98–9, 113–28 DVT treatment 125, 223 general recommendations 125–6 hereditary/congenital/primary 95, 114–19, 278 mesenteric vein thrombosis 321 mixed/combined types 95, 122 patient care considerations 122 superﬁcial thrombophlebitis and 267, 314–15 tests for 114–21 pros and cons 124 screening 99, 265–6 who/when/what of 125 thrombophlebitis, superﬁcial see superﬁcial thrombophlebitis thromboplastin, tissue (tissue factor) activated partial thromboplastin time (aPTT) and heparin dose 224, 225 in thrombosis/DVT etiology 84, 85, 86 thromboprophylaxis see thrombosis, deep venous

thrombosis deep venous lower extremity and in general see thrombosis, deep venous, lower limb upper extremity see axillary vein; effort thrombosis; subclavian vein; upper limb veins mesenteric vein see mesenteric veins superﬁcial venous see superﬁcial thrombophlebitis of telangiectasias 397 thrombosis, deep venous, lower limb and generally 4–5, 43–4, 195–313, 334–5, 696–7 categories 265–6 clinical probability scale 208–9, 335 complications 196–7 death 197, 675–6 non-fatal events 676 damaging/destructive/ pathophysiologic effects (postthrombotic damage) 42–4, 51–2, 256–7 primary 42–3, 45 secondary 43–4, 45, 547 valvular see valves see also post-thrombotic syndrome diagnosis 129–41, 208–13, 257, 266 algorithm 209, 216, 217 delayed 196 differential 266 imaging see subheading below epidemiology 94–5, 101, 277 etiology/pathogenesis 83–93, 95–101, 197–8 endovenous laser therapy 423 post-radiofrequency treatment 411 postoperative see surgery risk factors 95–101, 265–6, 278–80 sclerotherapy 377 varicose veins 56–7, 101, 315 future directions 696–7 historical aspects 4–5 idiopathic 268 imaging 210–11, 211–12 contrast phlebography 160, 210, 257 CT phlebography 170, 186 MR venography 185–6, 190, 211–12 ultrasound see ultrasound incidence 265 limb outcome after, identifying and grading risk factors affecting 692 management 44, 83, 202, 221–313, 696–7 aggressive therapies 269–71, 273–4 algorithms 272 guidelines 222–3, 235, 272–4

indications for intervention 257 non-pharmacologic non-surgical 266 preventive see prophylaxis (subheading below) standard/medical 221–54, 267–9 with thrombophilias 125, 223 molecular markers 113–14 natural history 197–202 clinical relevance 202–4 obstruction by 256 duplex ultrasound in acute vs subacute obstruction, characteristic 143–4, 144 postoperative see surgery previous, as risk factor for recurrence 98 prognostic biomarkers 696–7 prophylaxis 277–8, 280–8 pharmacologic see drugs postoperative see surgery with thrombophilias 125 recurrence (rethrombosis) 199–200, 203, 231–2 anticoagulants in prevention of 125 incidence and risk of 231 oral anticoagulant therapy 231–2 previous thrombosis as risk factor for 98 saphenofemoral junction thrombophlebitis and, concurrent 317 signs 195–6, 208 symptoms 195–6, 208 see also speciﬁc veins thrombus deep vein see thrombus, deep vein post-sclerotherapy 374–5 tumor see tumor thrombus thrombus, deep vein duplex ultrasound visualization 130, 131 attachment to wall 142 echogenicity 135–6 formation/development 197–8, 334–5 imaging see thrombosis, deep venous outcome related to characteristics 698 recanalization see recanalization removal 696 mechanical methods, evidencebased guidelines 223 pharmacologic see thrombolysis rationale for early removal 240, 255–6 research initiatives 696 surgical see thrombectomy resolution 87–90

742

Index

tibial veins anterior, anatomy 18 posterior anatomy 18 phlebography 164 valve incompetence, reconstructive surgery see reconstructive surgery time gain compensation (duplex ultrasound) 142 time of ﬂight techniques (MR venography) 181 tinzaparin 228 tissue factor see thromboplastin tissue ﬁbrosis see ﬁbrosis tissue inhibitors of metalloproteinases (TIMPs) varicose veins and 58, 66 venous ulcers and 76, 77 tissue plasminogen activator (tPA/rtPA) in catheter-directed thrombolysis 243, 244 in venous ulcer therapy 361–2 titanium Greenﬁeld ﬁlter 302, 303, 310 Tourbillon (Tessari) technique 382, 383 tourniquet phlebography 163 plethysmography 157, 158 transabdominal duplex ultrasound, IVC ﬁlter placement 307–8 transarterial embolo/sclerotherapy of AVMs 586 transarterial lung perfusion scintigraphy, arteriovenous shunts 584 transcommissural valvuloplasty (valve repair) 475–6 transcutaneous approach see percutaneous approach transfers, vein see grafts transforming growth factor-β chronic venous insufﬁciency (in general) and 63–4 DVT and 89 venous ulcers and 73 transplants, renal, MR and CT venography of living donors 187 see also grafts transport index, lymphatic 638 preoperative determination 658 transposition, femorofemoral saphenous vein 517 TrapEase ﬁlter 303 performance 310 traumatic injury see injury travel (air) DVT risk 280 lymphedema risk 651 treatment, advancing the art and science of 695

Trellis-8 peripheral infusion system 247, 260–1 Trendelenburg F 7 Trendelenburg test 338–9 TriVex System 435–7, 443 trunk AVMs 584 reﬂux see reﬂux varices 336 vein development 12–13 tumescent anesthesia phlebectomy 432 radiofrequency treatment of saphenous incompetence 410 tumor(s) (neoplasms) 574–82 malignant see malignant tumors; metastases see also speciﬁc histologic types tumor thrombus in IVC CT 171 inadequate removal 580 MRI 183, 186 removal 577–8 secondary tumors with 575 in renal vein, MRI 183, 186 tunica adventitia 22 tunica intima, histology 21 tunica media 21–2 24–Cities Cohort Study, Italy 107 two-port SEPS 525–6 tyrosine kinase receptors and venous malformations 595 ulcers (arterial), differential diagnosis 338 ulcers (venous) 70–82, 348–58, 360–4, 457–71, 545–52 CEAP classiﬁcation and diagnosis 41 deﬁnition 40 diagnosis 342–7 differential 338 etiology/pathogenesis 52–3, 65, 70–82, 524 historical aspects 58–9 perforator incompetence 524 examination/assessment 337–8, 340 healing 70–82 agents encouraging 361–3 perforator ablation and effects on 528, 529, 530, 531 post-thrombotic 677 examination 340 QoL questionnaire 690 recurrence perforator ablation and effects on 528, 529, 530, 531 wound dressing trials and rates of 465

treatment 348–58, 360–4, 457–71, 545–52 algorithm and guidelines 545–52 compression see compression therapy drug 360–4, 364 local 457–71 with varicose veins modalities 461–2 sclerotherapy 372 Venous Clinical Severity Score 678, 687 wound see wound ultrasound (Doppler – primarily duplex) 129–55, 691 in chronic venous disease 344, 699 endovascular see endovascular techniques obstruction see subheading below congenital malformations 596 DVT 129–41, 143, 143–4, 211, 213, 257, 266, 698 accuracy 142 future directions 699 indications 130–1 pregnancy 212 quality assurance 137 research 142 upper limb (axillo-subclavian vein) 142, 267 endoscopic perforator vein ablation guided with 528, 542 endovascular techniques guided with 152–3 IVC ﬁlter placement 307–8 laser therapy in saphenous incompetence 421 historical aspects 5 incompetence see incompetence interpretation of image 131–4 abnormal ﬁndings and differential diagnosis 133–4 normal veins 131–3 lymphedema, preoperative 658 mesenteric vein thrombosis 323 obstruction, chronic 142–55 iliocaval venous 503–4 iliofemoral 494–5, 499, 508 percutaneous ablation of perforators guided by 537 pre-/peri-/postoperative use 152–3 in radiofrequency treatment of saphenous incompetence perioperative 410–11 postoperative 411 technical aspects 142–3 varicose veins extremities 369 pelvic 617, 619–20

Index 743

ultrasound transducer in catheterdirected thrombolysis 247–8 umbilical veins 12 Unna boot 7, 351–2 upper limb lymphedema in breast cancer 655 upper limb veins anatomy 20–1 development 14 phlebography see phlebography superﬁcial venous thrombosis/thrombophlebitis 316 presentation and assessment 333 thrombosis 292–8, 333 diagnosis 142, 267 management 233, 292–8 presentation and assessment 333 in thoracic outlet syndrome 292–8 see also axillary vein; effort thrombosis; subclavian vein ureteric vein reﬂux, treatment 623 urokinase (uPA) in catheter-directed thrombolysis 243, 244 venous ulcers pathophysiology and 77 vacuum-assisted closure therapy (with ulcers) 467–8, 548 Valsalva manoeuvre phlebography ascending 163 descending 164, 165 reﬂux elicited by 148 valves, venous 472–82 anatomy deep veins of lower limb 18–19 superﬁcial veins of lower limb 17–18 artiﬁcial see neovalves deep veins see deep veins histology 21 incompetence see incompetence surgery 472–82, 547 future directions 699 reconstructive (in deep vein incompetence) see reconstructive surgery; valvuloplasty replacement see neovalves thrombosis-related damage/effects 256, 270 recanalization rate related to ultimate valve function 202, 203–4 surgical pathology and valve reconstruction in 473, 479 valvuloplasty 474–6 angioscopic 475 external 475 internal 474–5

prosthetic sleeve 476 transcommissural 475–6 varicocele (male) 618 varicorrhage, sclerotherapy 370 varicose veins (varices; varicosities; C2 disease) 6, 56–69, 336–7, 369–99, 429–38 deﬁnition 39, 105 diagnosis 342–7, 430 epidemiology 107, 107–8, 336 etiology/pathogenesis 52–3, 56–69, 367, 390 risk factors 108–9 historical perspectives 6, 58–9, 366–7 treatment 6, 366–7, 380–2, 400–1, 429 pelvic see pelvic veins presentation (incl. symptoms) and complications 336–7, 342–3, 391 primary 367 recurrence (after treatment; REVAS) 446–56 classiﬁcations 448–51 clinical presentation 451 deﬁnitions 446 epidemiology 446–7 investigations 452 mechanisms and physiopathology 447–8 medical history 451 pathology 448 physical examination 451–2 quality of life questionnaires 452 socioeconomic consequences 447 symptomatic vs asymptomatic 454 treatment 404–5, 452–5 ultrasound studies 152 residual, deﬁnition 446 saphenous see saphenous vein saphenous hypoplasia occurring in 149–50 secondary 367 thrombophlebitis involving 315–16 thrombosis and 56–7, 101, 315 varicose veins as post-thrombotic episode 368 treatment 359–60, 363–4, 369–408 of bulging veins 443 general measures 371 historical review 6, 366–7, 380–2, 400–1, 429 laser see laser therapy options 430–1 phlebectomy see phlebectomy sclerosant see sclerotherapy surgical see surgery ulcers and see ulcers Venous Clinical Severity Score 678, 687

vascular endothelial growth factor and chronic venous insufﬁciency 64–5 vascular laboratory, diagnostic 343–4 vascular malformations/anomalies, congenital see arteriovenous malformations; congenital vascular malformations vasoconstriction, local venoarteriolar 53 Vassaeus, Ludovicus 3 VEDICO trial 385 VEGF and chronic venous insufﬁciency 64–5 VEINES QoL/sym questionnaire 690–1 post-thrombotic syndrome 678–9 vena cava, inferior anatomic variants 170, 306 aneurysms 610 development 13–14 developmental anomalies 13, 14 double 14, 306 iliofemoral vein stent extending into 497 imaging CT phlebography 170–1 MR venography 186–7 standard phlebography see phlebography (standard/X-ray contrast) malignancy see malignant tumors occlusion/obstruction, deliberate ﬁlters for see ﬁlters historical accounts 5–6 occlusion/obstruction, pathologic 186–7, 514–22 investigations incl. imaging 186–7 malignant, presentation 575 treatment see subheading below see also iliocaval venous occlusions replacement with malignant involvement 578 treatment of occlusion/obstruction 547 open surgery for malignant occlusion 577 open surgery for non-malignant occlusion 514–22 see also iliocaval venous occlusions vena cava, superior anatomy 21 aneurysms 608 development 12–13 anomalies 13 ﬁlters 310 obstruction (and SVC syndrome) 553–67 clinical presentation 553–4 diagnostic evaluation 554–7 etiology 553 phlebography 169–70

744

Index

vena cava, superior – (contd) treatment 557–65 indications 557 results 561–5 venacavography see phlebography VenaTech ﬁlter 303 performance 309, 310 VenaTech low-proﬁle ﬁlter 303 performance 310 venipuncture, phlebography 163, 164 venoconstriction 28, 29, 34 capacitance vessels 25 venodilation 34–5 venography see phlebography venotonic drugs see phlebotonic drugs Venous Clinical Severity Score 677–8, 685, 686–7 Venous Disability Score 688–9 Venous Segmental Disease Score 685, 687–8 venovenous bypass in hepatectomy and suprarenal IVC replacement with malignancy 578–80 ventilation–perfusion scans, PE 214–15 see also perfusion scans venules, dilated intradermal see telangiectases see also capillary malformations Vesalius, Andreas 3 videotaping, phlebography 163, 165 Villalta scale 677 Virchow’s triad 95, 97, 113, 197 superﬁcial thrombophlebitis 314 Viscopaste 464, 466, 468 VISP trial 119 vitamin K antagonists see oral anticoagulants vitamin therapy hyperhomocysteinemia 118 venous ulcers 361 vitelline veins 12 VNUS Closure procedure 409–16, 442

vulval varicose veins in pregnancy 618, 624 waf1 (p21) 74 wall, venous 21–2, 27–8, 57–8 capacity and pressure and 27–8 in duplex ultrasound in acute vs chronic obstruction, characteristics 143, 144 histopathology and functional alterations in chronic venous insufﬁciency 57–8 inﬂammation, DVT and 83–4, 87–90 structure 21–2, 57–8 thrombus attachment, ultrasound imaging 143 thrombus formation and 197 see also adventitia; intima; media Wallstent in autologous vein and valve transplantation 487 in iliocaval venous obstruction 510 in iliofemoral venous obstruction 495–6 SVC obstruction 558 results 562–3 war see military ﬁelds warfarin 123, 125, 230, 268 antidote 233 complications cutaneous necrosis 115–16, 268, 301 as IVC ﬁlter indication 301 duration of treatment 126 heparin combined with 224 heparin-induced thrombocytopenia and 122, 269 long-term 231, 232, 233 monitoring and therapeutic range 230 prophylactic use 123, 282 antiphospholipid syndrome 120 antithrombin deﬁciency 115

protein C deﬁciency 116 protein S deﬁciency 116 saphenofemoral junction thrombophlebitis 317 see also oral anticoagulants Wells score DVT 208–10, 266, 335 combined with D-dimer assay 212 PE 214 white atrophy 40 white blood cells see leukocytes white swollen leg (phlegmasia alba dolens) 208, 266 Wireless functional venous diagnostic tests 699 Wisemann, Richard 7 wounds ulcer 457–71 bed, preparation 466 cleansing 467, 468 debridement 462–3, 466–7, 468 ﬂuid environment 76, 79 local care 457–71 ulcer, healing 70–82 agents encouraging 361–3 biology 458 rates with various types of dressing 464–5 Wuchereria bancrofti 631, 650 X-ray see radiography xenograft valves 484–5, 487 ximelagatran 269 Z-stent in autologous vein and valve transplantation 486–7 in SVC obstruction 557 zinc oxide-impregnated stockinette 463, 464 zinc oxide paste dressings 463, 464 zinc supplements 361